Delayed-release Tablets Research Articles

Therapeutic drug monitoring of posaconazole delayed-release tablets and injections in pediatric patients.

This study aimed to investigate the dose and trough concentration (Cmin) of posaconazole delayed-release tablets and injections, and their correlation with efficacy and safety in pediatric patients. Patients younger than 18 years old received posaconazole delayed-release tablets or injections for prophylaxis or treatment of invasive fungal disease (IFD). Blood samples were collected to determine the plasma Cmins, and dose regimen adjustments were made if necessary. Clinical data were collected. A total of 210 Cmins of 113 pediatric patients were detected. The median Cmins were 1.0 and 1.3 mg/L for tablets and injections, respectively (P < 0.05). The median doses required to achieve the target Cmin were about 6.0 mg/kg of body weight/day, and no statistical difference was observed between different age groups, formulations, or indications (P > 0.05). Concomitant treatment of tacrolimus and diarrhea were found to affect Cmins of tablets, while age, gender, and BMI were found to be correlated with Cmins of injections. IFD breakthrough occurred in 9.2% of patients with a median Cmins of 0.74 mg/L for prophylaxis, and infection progression occurred in 43.2% of patients with a median Cmins of 0.97 mg/L for treatment, respectively. Transaminitis was the most common adverse event. Posaconazole delayed-release tablets and injections are safe for prophylaxis and treatment of IFD in pediatric patients. An empirical initial dose of 6.0 mg/kg of body weight/day is appropriate for prophylaxis, while a higher dose should be required for the treatment of IFD. It is necessary to adjust the dose regimen according to the results of therapeutic drug monitoring.This study is registered with chictr.gov.cn under identifier ChiCTR2300070008.

Evaluation of Crushed Posaconazole Delayed Release Tablets in Lung Transplant Recipients.

Invasive fungal infections can cause serious complications after lung transplant; therefore, prophylaxis with posaconazole is common. The posaconazole delayed-release (DR) tablet is preferred. Although the package insert states DR tablets cannot be crushed, recent data suggest it is reasonable. We hypothesized that crushed posaconazole DR tablets could reach therapeutic levels in lung transplant recipients. A retrospective study of lung transplant recipients between January 2018 and July 2023, who received crushed posaconazole DR for at least 5 days was completed. Posaconazole troughs were evaluated, and differences were compared between subjects who were therapeutic to those who were subtherapeutic. A cost analysis was also performed. Thirty subjects received crushed posaconazole DR and 50% were therapeutic. The median trough was 1mg/L for those who were therapeutic and 0.4mg/L for those who were not (p < 0.001). The median cumulative dose was 2000mg, and there were no significant differences in the incidence of diarrhea or tube feeds. More subjects in the therapeutic group were loaded (33%vs. 13%), although this was not statistically significant (p = 0.39). No subjects had breakthrough aspergillus one month after starting crushed therapy. Crushed posaconazole DR tablets are a viable and cost savings option, but loading doses and higher maintenance doses may be required to reach therapeutic levels. Those who received loading doses (intravenously or crushed) followed by a daily crushed dose of 400mg were more likely to be therapeutic. Limitations of our study include that it is single-center, small in sample size, and retrospective.

Crushed posaconazole delayed-release tablets for antifungal prophylaxis and treatment in children.

Therapeutic drug monitoring (TDM) is recommended for posaconazole to achieve target concentrations of ≥0.7 mg/L and ≥1.0 mg/L for prophylaxis and treatment of invasive fungal infection (IFI), respectively. However, target attainment is challenging with the oral suspension, particularly in children. Here, we describe our experience using crushed delayed-release tablet (DRT) in a paediatric cohort, with a focus on TDM. We undertook a retrospective audit of crushed posaconazole DRT administration via enteral feeding tubes (EFTs) for patients aged ≤18 years over 18 months at The Royal Children's Hospital Melbourne who had at least one trough concentration measured at steady state. Details of patient demographics, posaconazole dosing, monitoring and adverse effects were recorded. Twelve patients with a median age of 9 years (range 2 to 14) received posaconazole DRT via EFT for prophylaxis (n = 8) or treatment (n = 4). All children achieved target concentration, with a median dose of 7 mg/kg/day (range 5 to 11) for prophylaxis and 13 mg/kg/day (range 9 to 20) for treatment. The median time to reach therapeutic levels was 7 days (range 5 to 14) for prophylaxis and 20 days (range 15 to 35) for treatment. One child had blockage of their EFT, which was attributed to posaconazole. No other adverse effects were observed. Crushed posaconazole DRT administered via EFT may be used as a method of attaining therapeutic posaconazole concentrations in children for antifungal prophylaxis and treatment.

Reply: Crushed Posaconazole Delayed-Release Tablets Via Enteral Feeding Tubes: A Cautionary Tale.

Reply: Crushed Posaconazole Delayed-Release Tablets Via Enteral Feeding Tubes: A Cautionary Tale.

Effect of postprandial gastric conditions on in vitro drug release from modified release mesalamine formulations

The effect of gastric prandial conditions on in vitro drug release from oral, locally acting, colon-targeted, mesalamine formulations has not been previously evaluated. In vitro dissolution of four mesalamine formulations were investigated using a USP II paddle apparatus. Fed gastric conditions were simulated under three consecutive phases of milk/buffer at different ratios to simulate changes in physicochemical, gastric composition during food digestion. Drug release was not observed from enteric coated preparations in the fasted state. Under simulative postprandial gastric conditions, however, drug release from Apriso® extended release (ER) capsules was 19 ± 4.7 %. As for Lialda® delayed release (DR) tablets, following two hours of exposure to simulative ileo-colonic media comprising bicarbonate buffer, drug release in the fed and fasted states was 55.7 ± 22.4 % and 12.4 ± 6.4 %, respectively. Significant differences in in vitro dissolution profiles were not observed between fasted and fed conditions for Pentasa® ER capsules and Asacol® HD DR tablets. Published pharmacokinetic data for Apriso and Lialda show higher systemic absorption of mesalamine in fed compared to fasted individuals. Our in vitro data is consistent with these pharmacokinetic findings since fed conditions may give rise to a higher extent of proximal drug release and therefore greater systemic absorption. Furthermore, extent of systemic exposure to mesalamine from Pentasa and Asacol was found not to be affected by food intake. In vitro dissolution studies simulating the gastric prandial state can possibly predict the impact of food on drug release from delayed and sustained release, locally acting formulations.

Evaluation of Posaconazole Serum Concentrations Achieved With Delayed-release Tablets and Oral Suspension in Patients Undergoing Intensive Chemotherapy for Acute Myeloid Leukemia and Myelodysplastic Syndrome.

Data on posaconazole serum levels of patients on prophylaxis with delayed-release tablets or oral suspension during intensive chemotherapy for acute myeloid leukemia and myelodysplastic syndrome are scarce. In this analysis, the proportion of patients with acute myeloid leukemia/myelodysplastic syndrome achieving posaconazole target concentrations with delayed-release tablets was higher than with oral suspension.

Posaconazole in paediatric malignancy and haematopoietic stem cell transplant: dosing to achieve therapeutic concentration.

Posaconazole is increasingly used for the treatment and prophylaxis of invasive fungal infections in immunocompromised children. We aimed to review evidence for paediatric posaconazole dosing regimens focusing on attainment of target concentrations and frequency of adverse effects. In May 2023, the Cochrane, Embase, MEDLINE and PubMed databases were searched for articles reporting posaconazole dosing in children with malignancy or post-haematopoietic stem cell transplantation. Studies reporting the attainment of target serum concentrations were included. Overall, 24 studies were included. Eighteen studies of the oral suspension consistently reported poor attainment of target concentrations for prophylaxis (≥0.7 µg/mL, 12%-78%) despite high daily doses of 14-23 mg/kg/day (max. 1200 mg/day). Target attainment was significantly affected by gastric pH and food intake. Six studies of the delayed-release tablet (DRT) reported 58%-94% achieved concentrations ≥0.7 µg/mL, with the majority using lower doses of 4-12 mg/kg/day (max. 300 mg/day). Similarly, one study of powder for oral suspension found 67%-100% achieved target concentrations with a dose of 6 mg/kg/day (max. 300 mg/day). As expected, the IV formulation had high attainment of prophylaxis targets (81%-90%) with 6-10 mg/kg/day (max. 400 mg/day). All formulations were well tolerated, and no relationship between adverse effects and posaconazole concentrations was identified. The required posaconazole dose in immunocompromised children varies depending on the formulation. The IV infusion had the highest attainment of therapeutic concentration followed by the DRT and powder for suspension. By contrast, the oral suspension had low attainment of target concentrations despite higher daily doses.

Factors Influencing Serum Posaconazole Concentrations in Patients With Hematologic Malignancies Receiving Delayed-Release Tablets.

Posaconazole (PCZ) plays a crucial role in the prophylaxis and treatment of invasive fungal infections in hematologic malignancies. PCZ concentrations reportedly vary among patients receiving delayed-release tablets (DRT). However, the factors influencing these concentrations remain insufficiently elucidated. Therefore, this study aimed to evaluate the factors influencing PCZ concentrations and their effect on the probability of target attainment (PTA) using a population pharmacokinetic (PPK) approach. We also explored the relationship between PCZ exposure and hepatotoxicity. This retrospective study included adult patients with hematologic malignancies who received PCZ DRT. A PPK model was developed based on observational data for 130 concentrations in 28 patients. Simulation analyses were performed to assess the PTA at standard doses of 0.7 and 1.0 mg/L for prophylaxis and treatment, respectively. Estimated concentrations were used to evaluate the correlation between PCZ exposure and hepatotoxicity. Significant factors influencing PCZ concentrations included body weight, serum total protein levels, and diarrhea. Diarrhea correlated with decreased PCZ concentrations resulting in up to 26% lower PTA compared with that without diarrhea. Moreover, PTA declined markedly as the total protein levels decreased from 6.6 g/dL to 4.4 g/dL. The incidence of hepatotoxicity was 17.4% (4/23); no significant relationship could be established between the PCZ concentrations and hepatotoxicity ( P = 0.188). We identified the factors affecting PCZ exposure, which could not be detected by PPK analysis using data from clinical trials. Our results suggest that the generally recommended dose of PCZ causes underexposure in patients with hematologic malignancies characterized by high body weight, hypoproteinemia, or concurrent diarrhea. Therapeutic drug monitoring for DRT may be recommended, especially in patients with these risk factors.

Real-world Experience of Posaconazole Therapeutic Drug Monitoring in Oncology Patients: Clinical Implications of Hypoalbuminemia as a Predictor of Subtherapeutic Posaconazole Levels.

Posaconazole maintains broad antifungal activity and is employed for prevention and treatment of invasive fungal infections in oncology patients. Older formulations required therapeutic drug monitoring, and specific plasma drug levels have been recommended. This study evaluated factors associated with subtherapeutic concentrations with the newer delayed-release tablet formulation. In this retrospective, single-center cohort study at a national comprehensive cancer center, all oncology patients receiving delayed-release posaconazole at standard dosing of 300 mg orally per day from 06/2021 to 07/2023 with plasma drug concentration evaluation were identified. Demographic, clinical, and laboratory data were evaluated to identify risk factors associated with subtherapeutic drug levels at targets of ≥1.25 µg/mL and ≥1.8 µg/mL. Of 110 patients identified, 98 met criteria for inclusion in the study. The median time from initiation of posaconazole to drug level assessment was 13 days, and the median concentration was 1.29 µg/mL. Of the 22 patients receiving posaconazole for prophylaxis, 5 (22.7%) failed to achieve concentrations ≥0.7 µg/mL, and of 76 patients receiving posaconazole for treatment, 38 (50%) failed to achieve concentrations of ≥1.25 µg/mL. In multivariable analysis, albumin of ≤3 g/dL and ideal body weight ≥60 kg were found to be associated with subtherapeutic levels. For a higher target of ≥1.8 µg/mL, only albumin ≤3 g/dL was associated with subtherapeutic levels for the variables evaluated. A higher initial dosing strategy and therapeutic drug monitoring for oncology patients with albumin ≤3 g/dL receiving posaconazole, particularly for the treatment of invasive fungal infection, could be considered.

Comparison of In vitro Dissolution Tests of five brands of Diclofenac Sodium delayed release tablets in Moroccan market

This study aims to evaluate the similarity of in-vitro dissolution profiles, of commercially available generics of diclofenac sodium delayed-release tablets, of 25mg strength, with the innovator brand in Moroccan Market. Dissolution profiles for five brands were determined using the paddle method from the United States Pharmacopoeia. For the aptitude verification of the method, in our experimental conditions, linearity and accuracy tests were performed. The rate of dissolution was determined by Ultra-Violet Spectroscopy at 276nm. The assessment between the generics and the brand medicine was carried out under the similarity factor approach. We also presented an overview of the dissolution principles of tablet dosage form, and the pharmacopoeia dissolution test recommendations in our case. To compliance with US pharmacopoeia specifications, the rate of dissolution should be not more than 10% after 2hours in the acid stage, and not less than 75% at 45 minutes in the buffer stage. Furthermore, two dissolution profiles are considered similar when the f2 value is ≥50. According to routine quality control, evaluating the rate dissolution at the final point, all the generic medicines marketed in Morocco, meet the specification of the dissolution testing. However, using the comparison of dissolution profiles, only generic-2 is interchangeable with the innovator brand.

Effects of orally administered crofelemer on the incidence and severity of neratinib-induced diarrhea in female dogs.

Targeted therapies have increased cancer therapy-related diarrhea (CTD) burden, with high incidence and/or severity of diarrhea for some agents that inhibit epidermal growth factor receptor and receptor tyrosine kinases. Neratinib is a pan-HER tyrosine kinase inhibitor approved for breast cancer treatment and causes severe diarrhea in >95% of patients. Crofelemer, a novel intestinal chloride ion channel modulator, is an approved antidiarrheal drug for symptomatic relief of noninfectious diarrhea in patients with HIV/AIDS receiving antiretroviral therapy. The objective of this study was to evaluate the effectiveness of crofelemer prophylaxis in reducing the incidence /severity of neratinib-induced diarrhea without concomitant administration of loperamide in female beagle dogs. A pilot study using 3 dogs determined a maximum daily tolerated dose of neratinib was between 40 and 80 mg; this dose would induce a consistent incidence/severity of diarrhea without risking severe dehydration. In the definitive study, 24 female beagle dogs (8/group) received neratinib once daily and placebo capsules (CTR) four times/day, or neratinib once daily and crofelemer 125 mg delayed-release tablets given two times (BID), or neratinib once daily and crofelemer 125 mg delayed-release tablets given four times per day (QID). Fecal scores were collected twice daily using an established canine stool scoring scale called the Purina Fecal Scoring (PFS) System. After 28 days, using analysis of covariance (ANCOVA), dogs in the CTR group had a significantly higher average number of weekly loose/watery stools (PFS of 6 or 7) when compared to either crofelemer BID (8.71±2.2 vs. 5.96±2.2, p = 0.028) or crofelemer QID (8.70±2.2 vs. 5.74±2.2, p = 0.022) treatment groups. The average number of weekly loose/watery stools were not different between the crofelemer BID and QID treatment groups (p = 0.84). This study showed that crofelemer prophylaxis reduced the incidence/severity of neratinib-associated diarrhea in female beagle dogs without the need for any loperamide administration.

Clinical Implications of Proton Pump Inhibitors and Vonoprazan Micro/Nano Drug Delivery Systems for Gastric Acid-Related Disorders and Imaging.

Excessive stomach acid or bacterial infection are the root causes of gastric acid-related disorders, such as peptic ulcer disease and gastroesophageal reflux disease. Proton pump inhibitors including lansoprazole, omeprazole, esomeprazole, rabeprazole, etc. are medications used to treat gastric acid-related diseases. One of the most effective drugs for treating gastroesophageal reflux disease is vonoprazan, owing to its ability to strongly inhibit gastric acid. Proton pump inhibitors and vonoprazan work in distinct ways to prevent the production of stomach acid. Vonoprazan inhibits acid secretion by blocking the potassium-competitive acid blocker receptor, whereas proton pump inhibitors function by irreversibly blocking the proton pump in the parietal cells of the stomach. Delayed release tablets, delayed release capsules, minitablets, pellets, bilayer, floating, mucoadhesive tablets and nanoparticles, are some of the methods used in the development of micro/nano formulations with proton pump inhibitors and vonoprazan. Diagnosis and therapy of gastric acid-related illnesses, particularly those treated with drugs such as vonoprazan and proton pump inhibitors, rely heavily on imaging modalities such as CT scans, X-rays, endoscopy, fluorescence and HRM imaging. This review provides a comprehensive update on various micro/nanoformulations of proton pump inhibitors and vonoprazan. Moreover, we provide an outlook on clinical imaging of proton pump inhibitors and vonoprazan formulation for gastric acid related diseases. We have limited our discussion to case studies and clinical trials on proton pump inhibitors and vonoprazan for gastric acid related disease.

A SIMPLE RP-HPLC METHOD DEVELOPMENT AND VERIFICATION OF THE DISSOLUTION OF BROMELAIN-A COMPLEX MIXTURE OF PROTEOLYTIC ENZYMES, IN DELAYED-RELEASE TABLETS

Objective: To develop a simple, accurate, precise and linear Reverse Phase High-Performance Liquid Chromatographic (RP-HPLC) method and verify for the quantitative estimation (Dissolution) of Bromelain in delayed-release tablets. Methods: The optimized RP-HPLC method for both acid and buffer stage dissolutions of delayed-release tablets uses Zorbax 300 SB-C8 column (150 mm X 4.6 mm; 3.5μ), a mobile phase-A of 0.1% trifluoroacetic acid in water and a mobile phase-B of 0.1% Trifluoroacetic acid in Acetonitrile in the gradient proportion, flow rate of 1.0 ml/min, injection volume of 25 µl, detection wavelength of 280 nm using a UV/PDA detector, column temperature of 40 °C, sample tray/compartment temperature of 5 °C and a run time of 20 min. Results: The developed method gave Bromelain eluting at about 6 min. Bromelain exhibited linearity in the range 53.4-800.6 μg/ml (r2=0.99992). The precision is exemplified by relative standard deviation of 1.3 and 2.3% for acid and buffer stages, respectively. Percentage recovery of the drug was found to be between 90.0 and 110.0 during accuracy studies. Conclusion: A simple, accurate, precise, and linear RP-HPLC method was developed and verified for the quantitative estimation (Dissolution) of Bromelain in tablets and hence this method can be explored for the analysis of Bromelain in tablets in various pharmaceutical industries.

Formulation and Validation of An Analytical Method for the Estimation of Rabeprazole Sodium Delayed-Release Tablets

Background Rabeprazole sodium is a proton pump inhibitor used for the treatment of peptic ulcer and gastroesophageal reflux disease by inhibiting the enzyme HKATPase the acidic pump. In addition erosive esophagitis and Zollinger-Ellison syndrome are treated with it.In this study the objective was to develop a pharmaceutically stable and cost-effective and quality-improved formulation and UV spectrophotometry method have been developed to estimate Rabeprazole sodium delayed-release tablets. To achieve these goals various prototype formulation trails will be taken and evaluated.Methods Rabeprazole sodium prolonged release tablets were prepared by direct compression technique used to the different excipients as well as varying concentrations of polymer proportion using HPMC phthalate 55 which is an enteric coating material.Results The results indicated that the final product formulation 12 met all the specifications of the physical properties and invitation release and is comparable to the innovator product.Conclusions In the present study Rabeprazole enteric-coated tablets were prepared using HPMC phthalate 55 enteric polymer. Formulation 12 was found to be the best of all formulations showing drug release that matches the innovator product so all quality control tests were performed for conformation for the formulation. The tablets were tested for acid release during the stability period and the results confirmed that the results were within the limits.

Design, Optimization and In vitro Evaluation of Mesalazine 400 mg Delayed Release Tablet for Colon Specific Delivery

Ulcerative colitis is a chronic inflammatory disease, and patients would get benefit more if the drug is given directly to the colon. Mesalazine is intended to deliver to the colon for treating ulcerative colitis. Here, we aimed to design and optimize mesalazine 400 mg delayed release tablet for colon-specific delivery using a quality by design (QbD) approach. The tablet was first formulated as an optimized core tablet and then coated with Eudragit S 12.5 for ensuring colonic delivery. The experimental design for the core tablet was constructed using a 32 full factorial design, where the percentages of sodium starch glycolate (SSG) and polyvinylpyrrolidone (PVP K-30) were independent variables and the tablet hardness (kg/cm2) and cumulative percentage of drug release at pH 7.2 phosphate buffer after 1.5 hours were treated as responses. Responses obtained from the initial exploratory formulations were evaluated to develop an optimized formulation to have a hardness value of 7-8 kg/cm2 and the maximum amount of drug release at pH 7.2 buffer. The optimized formulation involved the use of SSG and PVP K-30 at 3.05% and 1.69%, respectively. Hardness and cumulative percent of drug release obtained for the optimized core tablet were 7.8 kg/cm2 and 91.76%, respectively. The compatibility of drug and excipients was studied utilizing XRD, FTIR and TGA. The optimized core tablet was then coated with Eudragit S 12.5 to deliver the drug selectively to the colon and further assessed for its in vitro dissolution. Dissolution studies indicated that coated tablets with a weight gain of 7.4% exhibited the maximum cumulative percent of drug release (91.19 ± 0.11%), with a zero-order drug release profile (R2 = 0.943). A stability study performed according to ICH Q1A (R2) guidelines at accelerated storage conditions identified that there was no significant change in drug content over the storage period, indicating the stability of the formulated tablet batches. Together, these data suggest that the mesalazine tablet developed through the QbD approach offers excellent physical properties and drug release profile and, therefore, could be recommended for commercial manufacturing. Dhaka Univ. J. Pharm. Sci. 22(2): 189-201, 2023 (December)

Incidence and Management of Fungal Infections in Oral and Maxillofacial Surgery

Mucormycosis are life-threatening fungal infections especially affecting immunocompromised or diabetic patients. This review provides an update on mucormycosis management. The latest recommendations strongly recommend as first-line therapy the use of liposomal amphotericin B (≥ 5mg/kg) combined with surgery whenever possible. Isavuconazole and intravenous or delayed-release tablet forms of posaconazole have remained second-line. Many molecules are currently in development to fight against invasive fungal diseases but few have demonstrated efficacy against Mucorales. Despite in vitro efficacy, combinations of treatment have failed to demonstrate superiority versus monotherapy. New approaches assessing relationships between host, fungi, and antifungal drugs, and new routes of administration such as aerosols could improve mucormycosis treatment.

2546. Administration of Crushed Posaconazole Delayed Release Tablets Failed to Achieve Therapeutic Levels

Abstract Background Posaconazole (POS) delayed release tablets (DRTs) are utilized for prophylaxis or treatment of invasive fungal infections. Other POS formulations are limited by impaired absorption, lack of indication for adult patients, and need for intravenous (IV) access. Small retrospective case series have demonstrated success with administration of crushed POS DRTs via enteral feeding tubes (EFTs). In October 2022, UNC Health permitted administration of POS DRTs via EFTs. This study aims to evaluate POS levels in patients that received crushed POS DRTs via EFTs. Methods This single-center, retrospective cohort study included patients that received crushed POS DRTs via EFTs with concurrent POS therapeutic drug monitoring (TDM). The primary outcome was achievement of serum POS level per indication of prophylaxis ( &amp;gt; 700 ng/mL) or treatment ( &amp;gt; 1000 ng/mL). The secondary outcome was the proportion of patients whose therapy was altered in response to POS level. Results A total of 10 patients were included (Table 1), with both prophylaxis (40%) and treatment (60%) indications. Most were initiated on oral or IV POS (80%). Crushed POS DRTs were administered via nasogastric (70%), post-pyloric (20%), and nasoduodenal (10%) routes. Therapeutic levels with crushed POS DRTs occurred in three patients (30%) and only two patients (20%) maintained therapeutic levels (Figure 1). Of the patients that transitioned from IV or oral POS to crushed POS DRT that maintained the same POS dose, 75% experienced a decrease in their serum POS level. Based on the initial crushed POS DRT level, three patients transitioned to IV or oral POS and 3 had their crushed POS DRT dose modified. Conclusion Crushed POS DRTs administered via EFTs failed to achieve therapeutic POS levels in 70% of patients. Caution should be used when implementing crushed POS DRTs and internal data should be reviewed if already implemented. Study limitations include small sample size, single-center design, and limited attempts to titrate crushed POS DRT regimens. Future studies should assess the clinical utility of crushed POS DRTs and explore the impact of standardized nursing administration, drug-drug interactions, and enteral feeding interactions/routes on crushed POS DRT pharmacokinetics. Disclosures All Authors: No reported disclosures

Successful enteral administration of crushed posaconazole delayed-release tablets in children.

Erratic absorption of posaconazole oral suspension necessitates frequent dosing and administration with meals or supplements. Alternative enteral formulations are desirable for patients intolerant to enteral nutrition. Crushed posaconazole delayed-release tablets (POS-DRT) show promise in adults; limited evidence exists in children. We used crushed POS-DRT in 10 encounters with nine pediatric patients, achieving target POS concentrations in 90% of encounters. This highlights crushed POS-DRT as a potential enteral option for pediatric antifungal prophylaxis and treatment.

Retrospective analysis of the biopharmaceutics characteristics of solid oral Modified-Release drug products in approved US FDA NDAs designated as Extended-Release or Delayed-Release formulations

BackgroundModified Release (MR) orally administered drugs products [Extended-Release (ER) and Delayed-Release (DR)] differ from Immediate-Release (IR) drug products in their drug release site and/or rate to offer therapeutic advantages. It is important to understand the biopharmaceutics factors that determine how a drug works in the gastrointestinal tract and the various pharmacokinetic properties that determine a drug’s rate of absorption and release in the human body. To better understand the biopharmaceutics characteristics of ER and DR drug products, this study retrospectively analyzed submissions approved by the US Food and Drug Administration (FDA), from 2001 to 2021, and their corresponding review documents. This review work is expected to enhance the readers’ understanding regarding the biopharmaceutics properties that supported approval of these products’ ER claims, as per 21 CFR 320.25(f), and DR claims. MethodsA comprehensive search was conducted using the FDA’s internal New Drug Application (NDA) database for ER and DR oral drug products approved between 2001 and 2021. The search yielded 87 ER applications (23 ER capsules and 64 ER tablets) and 21 DR applications (10 DR capsules, 11 DR tablets) for which electronic records were accessible. These products were analyzed for overall drug product design, dosing frequency compared to the reference (if applicable), degree of fluctuation, dissolution method, and alcohol dose-dumping. ResultsOut of 87 total applications for ER drug products that were assessed, 62% of the ER tablets contained a polymer matrix formulation, and hypromellose (HPMC) was used in 50% of these products. 52% of the ER capsules consisted of polymer beads while about half of the DR drug products contained a non-bead formulation with a combination of polymers. The majority of ER drug products were found to have a reduction in dosing frequency and a decrease in the degree of fluctuation when compared to the IR reference product. The 13 ER drug products that exhibited an increase in degree of fluctuation exhibited general and pharmacodynamic benefits, such as reduced dosing frequency and reduced pill burden. The majority of DR formulations were developed to prevent drug degradation in the stomach, followed by to decrease potential stomach irritation, and lastly for localized release in the colon. The majority of ER drug products had 1:1 ratios of dissolution duration compared to dosing frequency (i.e., the majority of ER drug products had a dissolution duration of 24 h and were dosed every 24 h while those with a dissolution duration of 12 h were dosed every 12 h). The majority of ER applications had single-stage dissolution methods while most DR drug products used biphasic dissolution methods. All of the DR dissolution methods incorporated an acid stage of 2 h and a buffer stage with various timeframes. 53% the DR drug products had a ratio of dissolution duration to dosing frequency of 1:4 (e.g. a dissolution duration of 2 h to a dosing frequency of 8 h) or 1:8 (e.g. a dissolution duration of 2 h to a dosing frequency of 16 h). Of the ER tablets and DR drug products, 72% exhibited no alcohol dose-dumping under in vitro testing conditions. ER capsules, however, did not yield similar results—most of which exhibited alcohol induced dose-dumping. Alcohol dose dumping was mitigated by either in vivo studies or warnings on the drug product label. ConclusionThe results of this study help the reader understand the design, characteristics, and pharmacological advantages of the ER and DR drug products for patient benefit; as well as the regulations governing the FDA’s assessment of ER claims.

The Effect of Using Different Anticoagulant Types for Determination of Esomeprazole Levels in Human Plasma by High-Performance Liquid Chromatography

Esomeprazole is a Proton Pump Inhibitor (PPI) drug formulated in delayed-release tablets, that are included in the mandatory bioequivalence test. In vitro method validation used human plasma from the Indonesian Red Cross that used citrate as an anticoagulant. In the implementation of in vivo study, usually using human plasma used EDTA or heparin as an anticoagulant. This study aims to evaluate the effect of using anticoagulant types that may affect the analysis of esomeprazole in human plasma. Optimum chromatographic conditions used column C18 SunfireTM (5 μm, 250 mm x 4.6 mm); column temperature 40°C; mobile phase acetonitrile - phosphate buffer (40:60% v/v) pH 7.6; 1.0 mL/min flow rate with lansoprazole as an internal standard and wavelength 300 nm (PDA). The extraction was carried out by liquid-liquid extraction method using 500 μl plasma and 5 ml dichloromethane as extraction solvent. The result showed that the concentration range of calibration curve linearity in 5 – 1500 ng/mL. Recovery and broad peak response data of esomeprazole in plasma have significant differences between heparin-EDTA and citrate-EDTA anticoagulants (p&lt;0.05), but there is no significant difference for the stability test. In conclusion, heparin is better than EDTA as an anticoagulant for esomeprazole bioanalysis