Modified-release Formulation Research Articles

Bazedoxifene for HRT?

Duavive (Pfizer) is a modified-release formulation of conjugated oestrogens plus bazedoxifene acetate (a selective oestrogen receptor modulator). It is licensed for treatment of oestrogen deficiency symptoms in postmenopausal women with...

Mechanistic investigation of the negative food effect of modified release zolpidem

AimsWhen administered orally as either an immediate or modified release dosage form, zolpidem demonstrates a negative food effect, i.e. decrease in Cmax and AUC. The aim of the study was to arrive at a better understanding of the absorption of this BCS class I compound in vivo and to simulate the observed plasma profiles using in vitro and in silico methods. MethodsPharmacokinetic profiles of zolpidem are presented from a bioavailability (8mg intravenous; 10mg immediate release Stilnox®; 10mg and 12.5mg modified release Ambien® CR) and from a food effect study (12.5mg modified release Ambien® CR). The dissolution behavior of the 12.5mg strength was investigated using compendial methods in the USP apparatus II and using biorelevant methods in the USP apparatus III and IV. The mean plasma profiles as well as selected individual plasma profiles were simulated with Simcyp® and GastroPlus™. The absorption behavior was additionally investigated using the Qgut model, which entails algebraic deconvolution of all individual profiles, incorporating both first pass gut and liver extraction. ResultsIt was possible to simulate the mean plasma profiles using a “middle-out” approach, based on in vitro data combined with pharmacokinetic parameters obtained after intravenous administration, using PBPK software (Simcyp® and GastroPlus™), resulting in average fold error (AFE) values <1.5. Deconvolution verified that the in vivo absorption rate from the modified release formulation is controlled by the formulation in the fasted state, whereas in the fed state, the absorption rate is mainly controlled by gastric emptying. One-stage in vitro tests suggested that interactions with meal components, resulting in incomplete release, may be the source of the negative food effect for both the immediate and modified release formulations. ConclusionsThe present study demonstrated that a combination of biorelevant dissolution testing with modeling approaches enables a mechanistic understanding of the absorption of zolpidem from various formulations and can serve as a useful biopharmaceutical approach for the development of modified release solid oral dosage forms.

Pluronic F127 as a suitable carrier for preparing the imatinib base solid dispersions and its potential in development of a modified release dosage forms

In recent years, considerable attention focuses on making sustained release dosage forms also containing solid dispersions. The objective of this study is evaluation of imatinib base (IMA) solid dispersion physicochemical properties which can be useful to controlled release solid dosage formation. The solid dispersions were obtained by kneading method, containing of 10–90% w/w Pluronic F127 (PLU). Drug dissolution test was determined by rotating-disc system method in 0.1 M hydrochloric acid (pH 1.2) and phosphate buffer (pH 6.8). XRD, DSC, FTIR, and SEM observations were performed to evaluate the physical characteristics of solid dispersions. These studies showed that there was no chemical interaction of the IMA with PLU in the solid state and revealed that IMA and PLU form a simple eutectic phase diagram. Our research has shown that the dynamics of the release of imatinib base from solid dispersions with Pluronic F127 depends on the pH of dissolution medium. At pH 1.2, the presence of polymer in solid dispersion causes delaying of drug release due to formation a viscous gel layer, whereas at pH 6.8 significant enhancement of the drug dissolution rate from solid dispersions has been observed compared to pure IMA. The highest improvement was observed in solid dispersions containing 20 and 30% w/w polymer. The present investigation confirmed that the hydrophilic polymer Pluronic F127 could be applied as a suitable matrix to design modified release formulations of imatinib base.

Accuracy of the paracetamol-aminotransferase multiplication product to predict hepatotoxicity in modified-release paracetamol overdose

Context: The paracetamol-aminotransferase multiplication product (APAP × ALT) is a risk predictor of hepatotoxicity that is somewhat independent of time and type of ingestion. However, its accuracy following ingestion of modified-release formulations is not known, as the product has been derived and validated after immediate-release paracetamol overdoses.Objective: The aim of this retrospective cohort study was to evaluate the accuracy of the multiplication product to predict hepatotoxicity in a cohort of patients with modified-release paracetamol overdose.Methods: We assessed all patients with modified-release paracetamol overdose presenting to our hospital network from October 2009 to July 2016. Ingestion of a modified-release formulation was identified by patient self-report or retrieval of the original container. Hepatotoxicity was defined as peak alanine aminotransferase ≥1000 IU/L, and acute liver injury (ALI) as a doubling of baseline ALT to more than 50 IU/L.Results: Of 1989 paracetamol overdose presentations, we identified 73 modified-release paracetamol exposures treated with acetylcysteine. Five patients developed hepatotoxicity, including one who received acetylcysteine within eight hours of an acute ingestion. No patient with an initial multiplication product <10,000 mg/L × IU/L developed hepatotoxicity (sensitivity 100% [95%CI 48%, 100%], specificity 97% [90%, 100%]). Specificity fell to 54% (95%CI: 34, 59%) at a product cut-off point <1500 mg/L × IU/L. When calculated within eight hours of ingestion, mild elevations of the multiplication product fell quickly on repeat testing in patients without ALI or hepatotoxicity.Conclusions: In modified-release paracetamol overdose treated with acetylcysteine, the paracetamol-aminotransferase multiplication product demonstrated similar accuracy and temporal profile to previous reports involving mostly immediate-release formulations. Above a cut-point of 10,000 mg/L × IU/L, it was very strongly associated with the development of acute liver injury and hepatotoxicity, especially when calculated more than eight hours post-ingestion. When below 1500 mg/L × IU/L the likelihood of developing hepatotoxicity was very low. Persistently high serial multiplication product calculations were associated with the greatest risk of hepatotoxicity.

Neurologic complications in kidney transplant recipients.

<i>Transplantology experiences continuous growth and kidney transplantation is the most frequently transplanted solid organ. Metabolic, cardiovascular, infectious or kidney function-related aspects are widely recognised and are of key interest for transplant doctors. Neurological complications seen in these patients, although known, are less covered in the literature. According to some reports, neurologic symptoms are experienced by almost 9 per 10 transplant recipients. The intensity, severity and type of abnormalities may vary, and most frequently the complications seem to be associated with a direct or indirect effect of immunosuppressive medications, including their direct effect on cells, on blood vessels, and susceptibility to infections. Increasing age of transplant recipients and relaxation of transplantation eligibility criteria enriches the population with patients already compromised, with a higher present risk of stroke, neuropathy, malignancy etc. Research on and introduction to clinical practice of new agents like belatacept, proteasome inhibitors, or modified release formulations of tacrolimus, changes the picture and type of abnormalities within the nervous or neuromuscular system but does not eliminate them. Thus, it seems justified to remind the society of the whole array of neurologic complications they can see in their practice despite advances in the field.</i>.

Microphase separation in solid lipid dosage forms as the cause of drug release instability

Although lipid excipients are of increasing interest for development of taste-masked and modified release formulations, the drug release instability and the lack of mechanistic understanding in that regard still prevent their larger-scale application. In this work, we investigated the physical stability of a binary (tripalmitin/polysorbate 65) lipid coating formulation with a known stable polymorphism. The coating composition was characterized using DSC to construct the phase diagram of binary system and polarized light microscopy to display the microstructure organization. The water uptake and the erosion of slabs cast from the coating formulations were investigated post-production and after storage. Subsequently, N-acetylcysteine particles were coated with the selected formulations and the drug release stability was investigated. Additionally, microstructure characterization was performed via SEM and X-ray diffraction. The drug release instability was explained by polysorbate 65 and tripalmitin phase growth during storage, especially at 40°C, suggesting that polysorbate 65 can leak out of tripalmitin spherulitic structures, creating lipophilic and impermeable tripalmitin regions. The growth of polysorbate 65 phase leads to larger hydrophilic channels with reduced tortuosity. This work indicates that for obtaining stable drug release profiles from advanced lipid formulations, microphase separation should be prevented during storage.

State of the art: systemic rosacea management.

Based on numerous trials, oral tetracyclines and most commonly their second-generation derivative doxycycline have become the main pillar in systemic rosacea treatment. However, the only preparation that has been approved so far in this setting is 40mg doxycycline in an anti-inflammatory dosage and with a modified release formulation. With the introduction of this once-daily, non-antibiotic dosing of doxycycline, oral therapy is more commonly prescribed as first-line treatment in moderate to severe papulopustular rosacea. In addition, topical and oral strategies are often used in combination due to the more substantial improvements compared to monotherapy. Although several other non-approved oral agents like macrolides, isotretinoin, and carvedilol have been evaluated for systemic treatment and showed promising results, yet the experience with these drugs in rosacea is limited, and thus they should be reserved for special situations.

Pharmacokinetic analysis of modified-release metoprolol formulations: An interspecies comparison

In the current study, we investigated the metoprolol absorption kinetics of an in-house produced oral sustained-release formulation, matrices manufactured via prilling, and two commercially available formulations, ZOK-ZID® (reservoir) and Slow-Lopresor® (matrix) in both New Zealand White rabbits and Beagle dogs, using a population pharmacokinetic analysis approach.The aim of this study was to compare the in vivo pharmacokinetic (PK) profiles of different formulations based on metoprolol, a selective adrenergic β1-receptor antagonist, in dogs and rabbits and to contrast the observed differences. To that end, metoprolol (50 to 200mg) was administered to 6 Beagle dogs and 6 New Zealand White rabbits as a single intravenous (IV) bolus injection and to 8 dogs and 6 rabbits as an oral modified release formulation. To derive pharmacokinetic parameters from the data, a non-linear mixed-effects model was developed using NONMEM® where the contribution of observations below the limit of detection (BDL, below detection limit) to the parameter estimates was taken into account in the parameter estimation procedure.In both species and for the three modified release formulations, different absorption models were tested to describe the PK of metoprolol following oral dosing. In Beagle dogs, plasma concentration-time profiles were best described using a sequential zero- and first-order absorption model. In rabbits though, the absorption phase was best described using a first-order process only.In both species, the reservoir formulation ZOK-ZID® was behaving quite similarly. In contrast, the absorption properties of both matrix formulations were rather different between species. This study indicates that the PK of the reservoir formulation is similar in both species, even after accounting for the almost completely missed absorption phase in rabbits. The insights gained further illustrate that rabbits are not very well suited to study the PK of the current matrix formulations in view of their less optimal prolonged release characteristics and the resulting fast decline in metoprolol plasma levels.

Novel Gastroretentive Controlled Release Formulations for Once-Daily Administration: Assessment of Clinical Feasibility and Formulation Concept for Raltegravir.

Raltegravir is an integrase strand transfer inhibitor indicated in combination with other anti-retroviral medicinal products for the treatment of HIV-1 infection, given twice daily. Although a BCS class II compound, raltegravir exhibits low colonic absorption, thus making development of modified release formulations challenging. It was hypothesized that a gastroretentive (GR) formulation would increase trough (C24 h) concentrations of raltegravir, hence being amenable to a once-daily (QD) regimen. Iterative prototype GR formulations were developed in monolithic, bilayer, and trilayer tablet designs. Four phase I studies in healthy subjects were conducted to provide proof of formulation concept. Raltegravir C24 h was increased by a GR formulation with scintigraphy data supporting gastric retention. Single-dose exposures from a trilayer tablet administered in the morning with a high-fat meal resulted in acceptable C24 h values. However, C24 h values for evening dosing with a high-fat meal did not meet the success criteria for QD administration. Raltegravir C24 h and area under the curve (AUC) values after AM dosing with a low-fat meal were significantly lower than after dosing with a moderate-fat meal. Skipping, delaying, or giving a low-fat, low-calorie lunch after dosing with a high-calorie breakfast also resulted in an unacceptable decline in C24 h values. The requirements for consistent product performance under varying conditions of diet, timing of dosing, and dose were not favorable when given as GR tablets. The findings from these studies offer valuable insights into modifying the absorption of candidate drugs with limiting colonic permeability and solubility characteristics and the interplay between meal, dose timing, and GR formulation performance.

Investigation of the Dissolution Profile of Gliclazide Modified-Release Tablets Using Different Apparatuses and Dissolution Conditions.

In the absence of an official dissolution method for modified-release tablets of gliclazide, dissolution parameters, such as apparatuses (1, 2, and 3), rotation speeds, pH, and composition of the dissolution medium were investigated. The results show that although the drug presents a pH-mediated solubility (pH 7.0 > 6.8 > 6.4 > 6.0 > 5.5 > 4.5), the in vitro release of the studied tablets was not dependent on this parameter, despite of the apparatus tested. On the other hand, the rotation speed demonstrated a greater influence (100rpm >50rpm). Using similar hydrodynamic conditions, the three different apparatuses were compared in pH 6.8 and provided the following trend: apparatus 1 at 100rpm >2 at 50rpm ≈3 at 10dpm. As a complete, but slow release is expected from modified-release formulations, apparatus 2, in phosphate buffer pH 6.8 and 100rpm, were selected as the optimized dissolution method. In comparison to apparatus 1 under the same conditions, the paddle avoids the stickiness of formulation excipients at the mesh of the basket, which could prejudice the release of gliclazide. Results obtained with biorelevant medium through the developed dissolution method were similar to the buffer solution pH 6.8. The application of the optimized method as a quality control test between two different brands of gliclazide modified-release tablets showed that both dissolution profiles were considered similar by the similarity factor (f2 = 51.8). The investigation of these dissolution profiles indicated a dissolution kinetic following first-order model.

In vitro and in silico characterisation of Tacrolimus released under biorelevant conditions

This work aims to better understand the in vivo behaviour of modified release (MR) formulations (Envarsus® tablets and Advagraf® capsules) using in vitro properties of tacrolimus and in silico simulations. The in silico concentration profiles of tacrolimus released from the MR formulations were predicted after building a three compartments PK model with GastroPlus™, and using the experimentally determined in vitro physico-chemical properties as input parameters. In vitro-in vivo correlations (IVIVC) were obtained after deconvolution of in vivo data from a clinical trial. The IVIVC showed that the in vitro dissolution was faster than the in vivo deconvoluted dissolution for Advagraf®, while the in vitro dissolution was slightly slower than the in vivo deconvoluted dissolution for Envarsus®. Population PK simulation showed that variability in the simulation was lower for Envarsus® compared to Advagraf®. The in silico predicted preferential absorption sites were the proximal and distal tract for Advagraf® and Envarsus®, respectively. The integration of experimental in vitro solubility, permeability and biorelevant dissolution data allowed to generate in silico tacrolimus concentrations for two different MR formulations. This permitted to compare the two formulations in a single PK profile, in a simulated population PK study and with respect to their absorption sites.

"Dark Victory" (prognosis negative): The beginnings of neurology on screen.

Editors' Note: In WriteClick this week, Dr. Gilbert clarifies a naming error in “‘Dark Victory’ (prognosis negative): The beginnings of neurology on screen” and provides several interesting details, historical and neurologic, about the lives of Susan Hayward and Rita Hayworth. In reference to “The place of generic modified-release formulations for epilepsy: Slow and steady,” Dr. Baumann questions whether there are any proven benefits in efficacy or adherence …

The place of generic modified-release formulations for epilepsy: Slow and steady

Editors' Note: In WriteClick this week, Dr. Gilbert clarifies a naming error in “‘Dark Victory’ (prognosis negative): The beginnings of neurology on screen” and provides several interesting details, historical and neurologic, about the lives of Susan Hayward and Rita Hayworth. In reference to “The place of generic modified-release formulations for epilepsy: Slow and steady,” Dr. Baumann questions whether there are any proven benefits in efficacy or adherence with extended-release formulations. Author French responds. —Megan …

Intercalation of salicylic acid into ZnAl and MgAl layered double hydroxides for a controlled release formulation

Salicylic acid was intercalated into an inorganic host consisting of ZnAl/MgAl-layered double hydroxides lamella by reconstruction method. Powder X-ray diffractograms showed that the basal spacing of the layered double hydroxide bearing salicylate as the intergallery anion expanded from 7.6 and 7.8 A in the precursors to 14.49 A and 14.85 in ZnAl and MgAl layered double hydroxide, respectively. These values suggest that the organic molecules form bilayers in the interlayer space. Fourier transform infrared study further confirmed intercalation of salicylate into the interlayer’s of the layered double hydroxides. The thermal stability of the intercalated salicylic acid is significantly enhanced compared with the pure form before intercalation. Using the XRD results combined with a molecular simulation model, a possible representation of the salicylate anion positioning between the lamellar layers has been proposed. The in vitro drug release from intercalated material was remarkably lower than that from the corresponding physical mixture at pH 7.5. The kinetic analysis showed the importance of the diffusion through the particle in controlling the drug release rate. The obtained results show that hydrotalcite may be used to prepare modified release formulations.

Proposing the Use of Partial AUC as an Adjunctive Measure in Establishing Bioequivalence Between Deltoid and Gluteal Administration of Long-Acting Injectable Antipsychotics.

The maximum plasma concentration (C max) and the area under the plasma concentration-time curve (AUC) are commonly used to establish bioequivalence between two formulations of the same oral medication. Similarly, these pharmacokinetic parameters have also been used to establish bioequivalence between two sites of administration for the same injectable formulation. However, these conventional methods of establishing bioequivalence are of limited use when comparing modified-release formulations of a drug, particularly those with rates of absorption that are amenable to change with the site of injection. Inherent differences in the rate of absorption can result in clinically significant differences in early exposure and drug response. Here, we propose the use of the partial AUC (pAUC) as a measure of early exposure to aid in the assessment of bioequivalence between the gluteal and the deltoid site of administration for long-acting injectable antipsychotics.

Mo1319 Syn-010, a Proprietary Modified-Release Formulation of Lovastatin Lactone, May Improve Constipation by Inhibiting Enzymes in the Archaeal Methanogenesis Pathway: Results of Computational M. Smithii Enzyme-Ligand Docking Experiments

Mo1319 Syn-010, a Proprietary Modified-Release Formulation of Lovastatin Lactone, May Improve Constipation by Inhibiting Enzymes in the Archaeal Methanogenesis Pathway: Results of Computational M. Smithii Enzyme-Ligand Docking Experiments

Su1210 SYN-010, a Proprietary Modified-Release Formulation of Lovastatin Lactone, Lowered Breath Methane and Improved Stool Frequency in Patients With IBS-C: Results of a Multi-Center Randomized Double-Blind Placebo-Controlled Phase 2a Trial

Su1210 SYN-010, a Proprietary Modified-Release Formulation of Lovastatin Lactone, Lowered Breath Methane and Improved Stool Frequency in Patients With IBS-C: Results of a Multi-Center Randomized Double-Blind Placebo-Controlled Phase 2a Trial

Interchangeability, Safety and Efficacy of Modified-Release Drug Formulations in the USA: The Case of Opioid and Other Nervous System Drugs.

Modified-release drugs may provide clinical advantages compared to immediate-release forms and improve convenience to the patient and health outcomes. Concerns have been raised regarding interchangeability, efficacy, and safety of modified-release formulations. This study analyses all US Food and Drug Administration (FDA)-approved modified-release formulations and market trends, and illustrates how bioequivalence and safety of generic modified-release products compare to their respective brand name drugs and other generic drugs with different formulation design characteristics. This study also examines major concerns related to modified-release formulations: safety of opioids and bioequivalence of generic bupropion and methylphenidate. Study data were derived from the FDA electronic versions of the FDA's Orange Book (OB) and the FDA safety communications web page. Medicare Part D utilization and expenditures data were extracted from the Centers for Medicare and Medicaid. In May 2015, 276 (11.9%) of the 2325 active ingredients and fixed-dose combinations listed in the FDA's Orange Book had at least one modified-release form approved by the FDA. The number of approvals increased over time; 52.5% of modified releases were approved in the period 2000-May 2015. The FDA required a risk evaluation and mitigation strategy (REMS) to ensure that the benefits of extended-release opioids outweighed its risks of overdose and abuse. The REMS involved 16 new drug applications and 25 abbreviated new drug applications. The FDA addressed interchangeability problems with generic modified-release alternatives of bupropion and methylphenidate including lack of bioequivalence, reduced efficacy, and increased incidence of adverse events. Systematic post-marketing surveillance studies are needed to assess differences in safety, interchangeability, and efficacy of drugs with modified- and immediate-release formulations.

Physiologically Based Absorption Modeling to Impact Biopharmaceutics and Formulation Strategies in Drug Development—Industry Case Studies

In recent years, there has been a significant increase in use of physiologically based pharmacokinetic models in drug development and regulatory applications. Although most of the published examples have focused on aspects such as first-in-human (FIH) dose predictions or drug–drug interactions, several publications have highlighted the application of these models in the biopharmaceutics field and their use to inform formulation development. In this report, we present 5 case studies of use of such models in this biopharmaceutics/formulation space across different pharmaceutical companies. The case studies cover different aspects of biopharmaceutics or formulation questions including (1) prediction of absorption prior to FIH studies; (2) optimization of formulation and dissolution method post-FIH data; (3) early exploration of a modified-release formulation; (4) addressing bridging questions for late-stage formulation changes; and (5) prediction of pharmacokinetics in the fed state for a Biopharmaceutics Classification System class I drug with fasted state data. The discussion of the case studies focuses on how such models can facilitate decisions and biopharmaceutic understanding of drug candidates and the opportunities for increased use and acceptance of such models in drug development and regulatory interactions.

Slow drug delivery decreased total body clearance and altered bioavailability of immediate- and controlled-release oxycodone formulations.

Oxycodone is a commonly used analgesic with a large body of pharmacokinetic data from various immediate‐release or controlled‐release formulations, under different administration routes, and in diverse populations. Longer terminal half‐lives from extravascular administration as compared to IV administration have been attributed to flip‐flop pharmacokinetics with the rate constant of absorption slower than elimination. However, PK parameters from the extravascular studies showed faster absorption than elimination. Sustained release formulations guided by the flip‐flop concept produced mixed outcomes in formulation development and clinical studies. This research aims to develop a mechanistic knowledge of oxycodone ADME, and provide a consistent interpretation of diverging results and insight to guide further extended release development and optimize the clinical use of oxycodone. PK data of oxycodone in human studies were collected from literature and digitized. The PK data were analyzed using a new PK model with Weibull function to describe time‐varying drug releases/ oral absorption, and elimination dependent upon drug input to the portal vein. The new and traditional PK models were coded in NONMEM. Sensitivity analyses were conducted to address the relationship between rates of drug release/absorption and PK profiles plus terminal half‐lives. Traditional PK model could not be applied consistently to describe drug absorption and elimination of oxycodone. Errors were forced on absorption, elimination, or both parameters when IV and PO profiles were fitted separately. The new mechanistic PK model with Weibull function on absorption and slower total body clearance caused by slower absorption adequately describes the complex interplay between oxycodone absorption and elimination in vivo. Terminal phase of oxycodone PK profile was shown to reflect slower total body drug clearance due to slower drug release/absorption from oral formulations. Mechanistic PK models with Weibull absorption functions, and release rate‐dependent saturable total body clearance well described the diverging oxycodone absorption and elimination kinetics in the literature. It showed no actual drug absorption during the terminal phase, but slower drug clearance caused by slower release/absorption producing the appearance of flip‐flop and offered new insight for the development of modified release formulations and clinical use of oxycodone.