Immediate-release Formulation Research Articles

In vivo screening of oral formulations using rats: Effects of ingested water volume on oral absorption of BCS class I and III drugs from immediate-release formulations

This study investigated the effects of ingested water volume on drug absorption to confirm the applicability of rats for oral formulation screening and to optimize the experimental conditions. Mini-sized capsules (ϕ2.6 × 7.2 mm) or tablets (ϕ2.5 × 2.2 mm) as immediate-release formulations containing acetaminophen (ACE), metoprolol tartrate (MET), and atenolol (ATE) were administered to the fasted rats with 0.5 or 1 mL of water with pre-dissolved deuterium-labeled ACE (ACE-d4). Mean absorption times (MATs) of ACE, ATE, and MET from capsule form when ingested with 0.5 mL of water were significantly longer than those with 1 mL of water. Similar effects were detected for ACE and MET from tablet form. The ingested water volume significantly influenced the mean dissolution time of ACE from capsule form calculated from MATs of ACE and ACE-d4. One milliliter of ingested water rather than 0.5 mL revealed that absorption rate constants of drugs strongly depended on the membrane permeability of drugs. Furthermore, the rate-limiting step of oral absorption of all drugs administered with 1 mL of water corresponded well with that in humans, irrespective of formulations. This study demonstrated that 1 mL of water can sufficiently dissolve and empty the drugs from the stomach, suggesting that rats can be used to evaluate oral drug absorption from immediate-release formulations.

In vitro evaluation of a novel immediate-release formulation of oxy-codone (RoxyBond™) for the potential for abuse via injection.

Immediate-release (IR) oxycodone formulations may be manipulated for nonoral routes of administration. Oxycodone abuse-resistant immediate-release (ARIR) is a novel abuse-deterrent formulation (ADF) of IR oxycodone. This study aimed to assess the intravenous (IV) abuse potential of oxycodone ARIR relative to commercially available IR oxycodone tablets using in vitro laboratory studies. Intact or manipulated tablets were incubated in 5 or 10 mL of room temperature water for increasing amounts of time. For each timepoint, syringeability, defined as the ability to draw up water-immersed intact or manipulated tablets into a syringe, was assessed on a scale of 1 (very easy) to 10 (impossible). If the prepared sample could be drawn into a syringe, the proportion of syringeable oxycodone was measured analytically. In all conditions, it was nearly impossible to draw any liquid into a syringe from samples containing manipulated oxycodone ARIR tablets (N = 5/group), and most samples released very low concentrations (<10 percent) of their total oxycodone content, regardless of sample volume. In contrast, samples containing crushed IR oxycodone (N = 5/group) in small volumes of fluid were easily drawn into a syringe through the smallest needle, and more than 90 percent of the oxycodone content was released from relatively small sample volumes (5 mL). The difficulty required to prepare an injectable solution from oxycodone ARIR when manipulated suggests that oxycodone ARIR has abuse-deterrent properties that may deter IV abuse.

Safe, swallowable and palatable paediatric mini-tablet formulations for a WHO model list of essential medicines for children compound – A promising starting point for future PUMA applications

More than 10 years after the Paediatric Regulation came into place there is still a strong need for paediatric medicines for off-patent drug substances. Numerous compounds for which a paediatric formulation does not exist can be found on the WHO Model List of Essential Medicines for Children and in the EMA Inventory of the Needs for Paediatric Medicines. Many of these compounds are off patent, which offers the opportunity for obtaining marketing authorisations for paediatric use.The present study focused on the development of paediatric immediate-release mini-tablet formulations for furosemide. Essential formulation criteria included the use of excipients that are regarded as safe for children, the ease of manufacturing, a high dose flexibility, fast disintegration, a robust drug release and a good acceptability.Only excipients regarded as safe for use in children were used in formulation screening. Compressibility, tablet hardness, disintegration and palatability were the main screening parameters. Formulations with a hardness of > 20 N, a disintegration time < 3 min (fast disintegration) and a good palatability were selected for mini-tablet production. Based on this pre-assessment two mini-tablet formulations with a furosemide drug load of 2.5 mg were developed. Both were easy to manufacture, had an appropriate hardness, a short disintegration time and met pharmacopoeial requirements with regard to content uniformity and physical testing. Biorelevant in vitro dissolution experiments mimicking different modes (with water or dosing vehicles) of administering age-appropriate furosemide doses to children of different age groups indicated a fast and robust drug release. Overall, the novel mini-tablet formulations present with an increased dose flexibility, excipient safety, swallowability and palatability and are thus a promising starting point for the development of solid oral dosage forms for drugs with paediatric therapeutic needs.

Population Pharmacokinetic Models of Tacrolimus in Adult Transplant Recipients: A Systematic Review

Numerous population pharmacokinetic (PK) models of tacrolimus in adult transplant recipients have been published to characterize tacrolimus PK and facilitate dose individualization. This study aimed to (1) investigate clinical determinants influencing tacrolimus PK, and (2) identify areas requiring additional research to facilitate the use of population PK models to guide tacrolimus dosing decisions. The MEDLINE and EMBASE databases, as well as the reference lists of all articles, were searched to identify population PK models of tacrolimus developed from adult transplant recipients published from the inception of the databases to 29 February 2020. Of the 69 studies identified, 55% were developed from kidney transplant recipients and 30% from liver transplant recipients. Most studies (91%) investigated the oral immediate-release formulation of tacrolimus. Few studies (17%) explained the effect of drug-drug interactions on tacrolimus PK. Only 35% of the studies performed an external evaluation to assess the generalizability of the models. Studies related variability in tacrolimus whole blood clearance among transplant recipients to either cytochrome P450 (CYP)3A5 genotype (41%), days post-transplant (30%), or hematocrit (29%). Variability in the central volume of distribution was mainly explained by body weight (20% of studies). The effect of clinically significant drug-drug interactions and different formulations and brands of tacrolimus should be considered for any future tacrolimus population PK model development. Further work is required to assess the generalizability of existing models and identify key factors that influence both initial and maintenance doses of tacrolimus, particularly in heart and lung transplant recipients.

An enteric polymer mitigates the effects of gastric pH on oral absorption of poorly soluble weak acid drugs from supersaturable formulations: A case study with dantrolene

This study demonstrated that an enteric polymer can mitigate the effects of gastric pH on the oral absorption of a poorly water-soluble weak acid drug, dantrolene (DNT). An amorphous solid dispersion (ASD) of DNT with hydroxypropyl methylcellulose (HPMC) acetate succinate (ASD-HPMCAS) was prepared as the enteric released ASD (ER-SF). ASD with HPMC (ASD-HPMC) and DNT sodium salt were also used as immediate-release supersaturable formulations (IR-SFs) with and without water-soluble polymer, respectively. In vivo study with rats and in vitro study with a dissolution/permeation (D/P) system were performed to evaluate oral DNT absorption from each formulation under normal and high gastric pH conditions in rats and humans, respectively. The oral absorption of DNT from both IR-SFs in rats with a high gastric pH was significantly higher than that in rats with a normal gastric pH. In contrast, ASD-HPMCAS attenuated the difference in oral absorption between normal and high gastric pH conditions with significant improvement of DNT absorption. In vivo results implied that an enteric polymer delayed the onset of dissolution until after gastric emptying. ASD-HPMCAS generated supersaturation in the small intestine irrespective of gastric conditions, which was supported bythe in vitrostudy using the D/P system. This study suggested that an enteric polymer is useful to mitigate the inter- and intra-individual differences in oral absorption of poorly water-soluble weak acid drugs.

Morphine for the symptomatic reduction of chronic breathlessness: the case for controlled release.

Clinicians who seek to reduce the symptomatic burden of chronic breathlessness by initiating regular low-dose morphine has the choice of immediate or sustained-release formulations - which will be better for this often frail population, and which has the more robust evidence to inform its prescription? Both formulations can be used. For chronic breathlessness, three factors consistently favour the use of regular, low-dose, sustained-release morphine over immediate-release formulations: SUMMARY: As the evidence base expands for the symptomatic reduction of chronic breathlessness, pharmacological interventions will play a part. Using the best available evidence underpins patient-centred approaches that seek to predictably maximize the net effect.As such, the weight of evidence in patient-centred clinical care favours the use of regular, low-dose sustained-release morphine for the symptomatic reduction of chronic breathlessness.

C-L Psychiatry Vital in Assessing Patients Before, After Bariatric Surgery

C-L Psychiatry Vital in Assessing Patients Before, After Bariatric Surgery

Application of the Gastrointestinal Simulator (GIS) Coupled with In Silico Modeling to Measure the Impact of Coca-Cola® on the Luminal and Systemic Behavior of Loratadine (BCS Class 2b).

In the present work, we explored if Coca-Cola® had a beneficial impact on the systemic outcome of the weakly basic drug loratadine (Wal-itin®, immediate-release formulation, 10 mg, generic drug product). To map the contribution of underlying physiological variables that may positively impact the intestinal absorption of loratadine, a multi-compartmental and dynamic dissolution device was built, namely the Gastrointestinal Simulator (GIS). The luminal behavior of one immediate-release (IR) tablet of 10 mg of loratadine was tested under four different fasted state test conditions in the GIS: (i) with 250 mL of water and applying a predetermined gastric half-life (t1/2,G) of 15 min; (ii) with 250 mL of water and applying a t1/2,G of 30 min; (iii) with 250 mL of Coca-Cola® and a t1/2,G of 15 min; (iv) with 250 mL of Coca-Cola® and a t1/2,G of 30 min. After initiating the experiments, solution concentrations and solubility were measured in the withdrawn samples, and pH was monitored. To address the impact of the present CO2 in Coca-Cola® on the disintegration time of the tablet, additional disintegration experiments were performed in a single-vessel applying tap water and sparkling water as dissolution media. These experiments demonstrated the faster disintegration of the tablet in the presence of sparkling water, as the present CO2 facilitates the release of the drug. The buffer capacity of Coca-Cola® in the presence of FaSSGF was 4-fold higher than the buffer capacity of tap water in the presence of FaSSGF. After performing the in vitro experiments, the obtained results were used as input for a two-compartmental pharmacokinetic (PK) modeling approach to predict the systemic concentrations. These simulations pointed out that (i) the present CO2 in Coca-Cola® is responsible for the enhancement in drug release and dissolution and that (ii) a delay in gastric emptying rate will sustain the supersaturated concentrations of loratadine in the intestinal regions of the GI tract, resulting in an enhanced driving force for intestinal absorption. Therefore, co-administration of loratadine with Coca-Cola® will highly likely result in an increased systemic exposure compared to co-administration of loratadine with tap water. The mechanistic insights that were obtained from this work will serve as a scientific basis to evaluate the impact of Coca-Cola® on the systemic exposure of weakly basic drugs for patients on acid-reducing agents in future work.

Oxycodone prescribing in the emergency department during the opioid crisis.

Misuse of prescription opioids is a significant public health issue in Australia. There has been a rapid rise in prescription opioid use, with an associated increase in overdose and death. The over-prescribing of oral opioids, especially oxycodone, in the ED has been identified as a contributor to this problem overseas. It is unclear if similar practice occurs in the Australian ED. The primary aim of our study was to identify the incidence of oral oxycodone administration to patients within the ED. The secondary outcome was to identify the incidence of oxycodone prescribed to patients on discharge from the ED into the community. Our study was designed as an observational, retrospective data analysis of the incidence of oxycodone prescribed within the three EDs of a large Australian public health service. All immediate-release (IR) and slow-release (SR) oral oxycodone prescribed over a 4-year period (2015-2018) was included. There were 890 557 presentations to the three EDs during the period, which resulted in 288 242 episodes of oxycodone administration within department, equivalent to 324 administrations per 1000 presentations. There were 39 381 prescriptions for oxycodone provided on discharge, resulting in an incidence of 44 prescriptions per 1000 discharged. The most frequently prescribed opioid medication in the ED was oxycodone IR 5 mg, 78.6% of discharge prescriptions generated provided a maximum quantity (20 for IR formulation or 28 for SR) of tablets allowable under the pharmaceutical benefits scheme. There is a higher incidence of oxycodone prescribing in the Australian ED than previously recognised. An overuse of oxycodone may be contributing to adverse patient outcomes and a public health crisis. Hospitals should consider appropriate steps to reduce the incidence of opioid prescribing and the supply of these medications into the community.

0545 Bi-Layer Melatonin Tablet Provides Immediate and Extended Absorption to Address Primary Sleep Issues

Abstract Introduction Melatonin is a naturally-occurring hormone that functions in the regulation of the sleep-wake cycle. Exogenous melatonin has demonstrated utility for the induction and maintenance of sleep. Modulation of tablet dissolution rates can be achieved by strategically using binding agents in two layers to rapidly raise melatonin levels and sustain elevated levels over time to better emulate normal nocturnal melatonin secretion. Methods A randomized, double-blind, controlled cross-over study was conducted in healthy adults (n=18) to investigate the pharmacokinetics of a 4.5 mg melatonin bi-layer tablet with either prolonged-release (PR) or immediate-release (IR) characteristics. Blood samples were collected at 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8 and 10 h post-ingestion and melatonin concentrations were quantified. Results The PR formulation had a lower maximum concentration (Cmax, p&amp;lt;0.002), but a longer time to reach maximum concentration (Tmax, p&amp;lt;0.001). Absorption rate constant (Ka) and terminal disposition rate constant (λ) were both lower in PR melatonin than the IR formulation (p&amp;lt;0.001), indicating slower absorption and elimination rates. These measures were consistent with significantly greater absorption (ta1/2, p&amp;lt;0.002) and elimination half-lives (t1/2, p&amp;lt;0.001) in the IR formulation compared to the PR formulation. Additionally, plasma melatonin concentrations reached pre-ingestion values by 8 h post-administration of the PR formulation, indicating that individuals sleeping for a recommended 7-9 hours will wake with normal melatonin levels, when taken an hour before bedtime. Conclusion Prolonged-release bi-layer melatonin tablet safely and effectively extends the absorption of exogenous melatonin compared to an immediate-release formulation. Support Pharmavite, LLC

Physiologically based pharmacokinetic model outputs depend on dissolution data and their input: Case examples glibenclamide and dipyridamole

A plethora of dissolution tests exists for oral dosage forms, with variations in selection of the dissolution medium, the hydrodynamics and the dissolution equipment. This work aimed at determining the influence of media composition, the type of dissolution test and the method for entering the data into a PBPK model on the ability to simulate the in vivo plasma profile of an immediate release formulation.Using two rDCS IIa substances, glibenclamide and dipyridamole, housed in immediate-release formulations as model dosage forms, dissolution tests were performed in USP apparatus II with the biorelevant media FaSSGF, FaSSIF V1, V2 and V3 using both single-stage and two-stage test designs. The results were then integrated into the PBPK software SimcypⓇ either as the observed release profile (dissolution rate model, DRM) or using a semi-mechanistic model (diffusion layer model, DLM) and compared with in vivo plasma profiles.The selection of the FaSSIF version did not appear to have any relevant influence on the dissolution of the weakly basic dipyridamole, while the weakly acidic glibenclamide was sensitive to the difference in pH between FaSSIF V1, V2 and FaSSIF V3. Since both compounds have pKa values close to the pH of biorelevant media representing conditions in the small intestine, these results may be specific to compounds with similar ionization behavior. Single-stage and two-stage testing led to equivalent simulations for glibenclamide. Only results from the single-stage test in FaSSGF led to a close simulation of the pharmacokinetic profile of dipyridamole when data were inputted using the DRM, while simulations from two-stage testing were most similar to the observed pharmacokinetic profile when DLM with selection of a dynamic pH profile in the small intestine was selected as the data input method. These results emphasize the importance of data input to the simulation results.

Pharmacokinetics of Ambroxol Sustained Release (Mucosolvan® Retard) Compared with Other Formulations in Healthy Volunteers.

IntroductionAmbroxol is used in the treatment of acute and chronic respiratory conditions characterized by abnormal mucus secretion and impaired mucus transport and is available in a variety of formulations. This study aimed to compare the steady-state (SS) pharmacokinetic characteristics of extended-release (ER) 75-mg retard capsules with two immediate-release (IR) formulations (60-mg effervescent tablets and 30-mg tablets) over a 24-h period.MethodsAn open-label, randomized, three-period, six-sequence crossover study was conducted in healthy volunteers aged 18–45 years who had a normal body mass index. The test (ER 75-mg retard capsule once daily) and reference treatments (half of IR 60-mg effervescent tablet twice daily or 30-mg IR tablet twice daily) were administered on days 1–5 of each treatment period. Meals were standardized and concomitant therapy was prohibited. Blood samples for pharmacokinetic assessment were collected on day 5 (SS) of each treatment period. The co-primary endpoints were exposure (AUCSS 0–24) and maximum plasma level (Cmax SS).ResultsTwenty-four participants received ambroxol (male n = 13, 54.2%; mean ± standard deviation [SD] age 25.0 ± 6.4 years) and 23 completed the study. ER retard capsules provided similar AUCSS 0–24 compared to IR tablets (geometric means ratio [GMR] 110.7%; 90% confidence interval [CI] 99.8%, 122.7%) and effervescent tablets (GMR 106.9%; 90% CI 100.3%, 114.0%). ER retard capsules provided similar Cmax SS compared to IR tablets (GMR 84.7%, 90% CI 77.0%, 93.3%), and lower Cmax SS compared to effervescent tablets (GMR 80.9%, 90% CI 73.9%, 88.6%). Time to Cmax SS (tmax SS) was longer with ER retard capsules (6.0 h) than with IR tablets (2.0 h) or effervescent tablets (1.0 h).ConclusionsER ambroxol 75-mg retard capsules given once daily showed a similar pharmacokinetic profile to IR ambroxol formulations and therefore can be used instead of these in the treatment of respiratory conditions.ClinicalTrials.gov identifierNCT02036775.Electronic supplementary materialThe online version of this article (10.1007/s41030-020-00116-7) contains supplementary material, which is available to authorized users.

A tunable extruded 3D printing platform using thermo-sensitive pastes.

Extruded 3D printing is emerging as an attractive fabrication technology in the field of personalized oral medicines. The objective of this study was to develop a tunable extruded 3D printing platform based on thermo-sensitive gelatin pastes to meet the needs of achieving different drug release characteristics with flexible dosing and design. The printability and mechanisms of extrusion and deposition of the gelatin pastes were systematically studied. Ibuprofen and diclofenac sodium were used as model drugs for immediate- and sustained-release formulations, respectively. Following the optimization of formulation and process parameters, ibuprofen immediate-release formulations with different designs, and reservoir-type diclofenac sodium sustained-release formulations were printed. Target drug release patterns were successfully obtained for both model drugs. Rheological studies revealed that additives such as microcrystalline cellulose and hydroxypropyl methylcellulose can act as both thickeners and proppants of gelatin matrix. Furthermore, computational fluid dynamics simulation was used to visualize the printing process, and quantitatively analyze the influence of material viscosity, inlet velocity and nozzle diameter on the pressure and velocity of extrusion flow field. The present study demonstrated the great potential of extruded 3D printing technology using the thermo-sensitive gelatin paste platform for personalized oral medicines.

Relative bioavailability, pharmacokinetic and food effect assessment of two immediate-release formulations of the NaV1.6-selective sodium channel blocker XEN901: Pediatric Granules and Adult Tablets (4840)

Relative bioavailability, pharmacokinetic and food effect assessment of two immediate-release formulations of the NaV1.6-selective sodium channel blocker XEN901: Pediatric Granules and Adult Tablets (4840)

Safety, tolerability, and pharmacokinetics of the selective prostacyclin receptor agonist ralinepag in single and multiple dosing studies of an immediate-release oral formulation in healthy volunteers.

Ralinepag (APD811), an oral, potent, and selective prostacyclin receptor (IP) agonist is being developed for treatment of pulmonary arterial hypertension. Two, single-center, randomized, double-blind, placebo-controlled, Phase 1 studies (single ascending dose and multiple ascending dose) evaluated an oral immediate-release capsule formulation of ralinepag in healthy subjects. Blood samples assessed plasma pharmacokinetics and safety and tolerability data monitored adverse events, vital signs, laboratory findings, physical examination, and electrocardiograms. Eighty-two healthy subjects (single ascending dose (n = 32) and multiple ascending dose (n = 50)) completed the studies. No clinically significant safety issues were observed, except one serious adverse event of atrial fibrillation considered moderate in intensity. In the single ascending dose study, ralinepag was tolerated up to 100 µg (single dose), but not 200 µg due to nausea and vomiting. Dose proportional mean ralinepag plasma exposure measures were observed. Maximum plasma concentrations were reached within 1.0–1.5 h post-dose and mean terminal elimination half-life values from 20.5–26.4 h. In the multiple ascending dose study, ralinepag tolerability decreased with increasing QD or BID dose. Dose proportional steady-state plasma exposure measures were observed where evaluable, with mean steady-state peak-to-trough ratios ranging from 3.34–4.49 (QD dosing) and 1.95–2.36 (BID dosing). Mean effective half-life values ranged from 17.5–18.4 h, reflecting ∼1.7-fold (QD dosing) and ∼2.6-fold (BID dosing) accumulation in plasma exposure. Safety and tolerability of oral immediate-release ralinepag was generally consistent with expectations for this drug class, but more individualized dose escalation appears warranted. Ralinepag exhibited favorable pharmacokinetic properties, with BID dosing producing desired minimal steady-state peak-to-trough fluctuation. Overall, results supported further clinical investigation of ralinepag and guided development of an extended-release formulation to facilitate QD dosing.

Changing the Drug Delivery System: Does It Add to Non-Compliance Ramifications Control? A Simulation Study on the Pharmacokinetics and Pharmacodynamics of Atypical Antipsychotic Drug.

This study investigates the pharmacokinetic (PK) and pharmacodynamic (PD) consequences of shifting from Quetiapine fumarate immediate-release (IR) to extended-release (XR) formulation in non-adherent schizophrenia patients. Monte-Carlo simulations using population PK and PD models were implemented to predict the time course of plasma concentration and Brief Psychiatric Rating Scale (BPRS) scores following the oral administration of 200 mg Seroquel® every 12 h and 400 mg Seroquel XR® every 24 h in patients experiencing dose delay, omission or doubling. Parameters were computed and their distributions were compared using the Kolmogorov–Smirnov test. Dose irregularities with both formulations had different effects on plasma concentration and %reduction in BPRS scores from baseline. However, the odds ratio of getting a %reduction in BPRS below 14%, or plasma concentration exceeding 500 µg/L, were comparable for adherent and non-adherent patients. Plasma therapeutic concentration after treatment cessation was maintained for <24 h in 48% and 29.6% of patients, and a steady state recovery time of <48 h was achieved in 51% and 13.4% of patients on the IR and XR formulations, respectively. Monte-Carlo simulations predict that the risks associated with the IR dose irregularities are not worsened when the XR formulation is used instead. Non-adherence events involving a single dose of either formulation do not require rescue doses.

Economic Burden Associated With Extended-Release vs Immediate-Release Drug Formulations Among Medicare Part D and Medicaid Beneficiaries

The United States spends more money on medications than any other country. Most extended-release drugs have not consistently shown therapeutic or adherence superiority, and switching these medications to less expensive, generic, immediate-release formulations may offer an opportunity to reduce health care spending. To evaluate Medicare Part D and Medicaid spending on extended-release drug formulations and the potential savings associated with switching to generic immediate-release formulations. This cross-sectional study used the 2012 to 2017 Medicare Part D Drug Event and Medicaid Spending and Utilization data sets to analyze 20 extended-release drugs with 37 Medicare formulations and 36 Medicaid formulations. Only cardiovascular, diabetes, neurologic, and psychiatric extended-release drugs saving at most 1 additional daily dose compared with their immediate-release counterparts were included. Extended-release drugs with therapeutic superiority were excluded. Analyses were conducted from January to December 2019. Estimated Medicare Part D and Medicaid savings from switching extended-release to immediate-release drug formulations between 2012 and 2017. Of the 6252 drugs screened for eligibility from the 2017 Medicaid Drug Utilization database and the 2017 Medicare Part D database, 67 drugs with extended-release formulations that were identified in the Medicare data set (20 distinct drugs with 37 formulations [19 brand, 18 generic]) were included in the analysis. In 2017, Medicare Part D spent $2.2 billion and Medicaid spent $952 million (a combined $3.1 billion) on 20 extended-release drugs. Between 2012 and 2017, Medicare Part D and Medicaid spent $12 billion and $5.9 billion, respectively, on extended-release formulations. Switching from brand-name to generic extended-release formulations was estimated to be associated with a $247 million reduction in Medicare spending and $299 million reduction in Medicaid spending in 2017, whereas switching all brand-name and generic extended-release formulations to immediate-release formulations in both Medicare and Medicaid was estimated to reduce spending by $2.6 billion ($1.8 billion for Medicare and $836 million for Medicaid) in 2017. During the study period, the estimated spending reduction associated with switching all patients receiving extended-release formulations (brand name extended-release and generic extended-release) to generic immediate-release formulations was $13.7 billion ($8.5 billion from Medicare and $5.2 billion from Medicaid). The findings suggest that switching from extended-release drug formulations to therapeutically equivalent immediate-release formulations when available represents a potential option to reduce Medicare and Medicaid spending.

Clinical and Forensic Aspects of Pharmacobezoars.

Pharmacobezoars are specific types of bezoars formed when medicines, such as tablets, suspensions, and/or drug delivery systems, aggregate and may cause death by occluding airways with tenacious material or by eluting drugs resulting in toxic or lethal blood concentrations. This work aims to fully review the state-of-the-art regarding pathophysiology, diagnosis, treatment, and other relevant clinical and forensic features of pharmacobezoars. Patients of a wide range of ages and of both sexes present with signs and symptoms of intoxications or more commonly gastrointestinal obstructions. The exact mechanisms of pharmacobezoar formation are unknown but are likely multifactorial. The diagnosis and treatment depend on the gastrointestinal segment affected and should be personalized to the medication and the underlying factor. A good and complete history, physical examination, image tests, upper endoscopy, and surgery through laparotomy of the lower tract are useful for diagnosis and treatment. Pharmacobezoars are rarely seen in clinical and forensic practice. They are related to controlled or immediate-release formulations, liquid, or non-digestible substances, in normal or altered digestive motility/anatomy tract, and in overdoses or therapeutic doses, and should be suspected in the presence of risk factors or patients taking drugs which may form pharmacobezoars.

Comparative pharmacokinetics of osmotic-controlled and immediate-release Eperisone tablet formulation in healthy human subjects using a sensitive plasma LC-ESI-MS/MS method

To evaluate and compare the pharmacokinetic (PK) characteristics of a newly developed oral osmotically controlled drug delivery system of Eperisone 150 mg tablets with Eperisone immediate release (IR) marketed tablet brand as a reference formulation. It was a single dose, two treatment, two sequence, randomized, crossover study, involving 12 healthy human subjects. A modified, sensitive LC-ESI-MS/MS method was developed and validated as per FDA guidelines for estimation of Eperisone in plasma using a simple extraction and quick protein precipitation method. Non-compartmental pharmacokinetic model was used for PK analysis. Results were statistically compared using logarithmically transformed data, where p > 0.05 was considered as non-significant with 90% CI limit of 0.8–1.25. The bio-analytical method used for estimating drug plasma concentration was found to be simple, selective, linear, accurate and precise with 0.01 ng/ml as limit of detection. The comparative PK analysis revealed an insignificant difference in AUC0-∞, AUC0-t, Vz/F, Cl/F and t1/2λz, whereas a significant difference in Cmax, Tmax and MTTs were found. The relative bioavailability of Eperisone osmotic tablet was 109.7%. The osmotic controlled release drug formulation was found to release Eperisone for an extended period with less inter individual fluctuation in pharmacokinetic variables.

One-step preparation of sustained-release ASDs using mesoporous spherical silica

Preparing amorphous solid dispersions (ASDs) is one of the most important approaches in formulation studies to improve the oral bioavailability of poorly water-soluble drugs. Although a large number of studies have reported the validity of ASDs, most are focused on immediate-release formulations. Therefore, the principal aim of the present study is to establish a practical approach for preparing a sustained-release ASD pellet using mesoporous spherical silica by a Wurster-type fluidized bed granulator. The mesoporous spherical silica used in the present study has a porous structure with silica of different pore sizes. As a model drug, indomethacin (IND) was layered onto the mesoporous spherical silica in an amorphous state, but a clear difference was found in the degree of amorphization and drug release rate of each kind of silica. Moreover, the dissolution profiles of IND after layering with a pH-independent sustained-release polymer on spherical silicate using a Wurster-type fluidized bed granulator were evaluated. Mesoporous silica, with small pore size, showed an ideal sustained-release profile with much smaller polymer amounts compared with larger-pore-size silica. In this approach, the pore size of mesoporous spherical silica was a very important factor to prepare sustained-release ASDs efficiently and stably.