Extended-release Products Research Articles

Justification of Widened Dissolution Specifications of an Extended Release Product Using Physiologically Based Biopharmaceutics Modeling

Drug product meeting the dissolution specifications is crucial in order to ensure consistent clinical performance. However, in certain cases wider dissolution specifications may be required based on product behavior. While justification of such wider specifications may be challenging from a regulatory context, approaches such as physiological based biopharmaceutics modeling (PBBM) can be utilized for this purpose. Product DRL is a fixed dose combination product consisting of an immediate (IR) and extended release (ER) portions. For the ER portion, the dissolution specifications consisted of four time points and a proposal was made to relax the specification at the 2h time point (from 50-70% to 45-67%) to reduce the batch failures at commercial scale. To support wider specification, a PBBM was developed and extensively validated with literature & in-house studies. Virtual bioequivalence was performed using the pivotal clinical study data. Virtual dissolution profiles for proposed wider specifications were generated using three different approaches. Incorporation of lower and upper dissolution profiles into the model indicated absence of impact on in vivo performance thereby justifying the specifications. Regulatory acceptance of proposed specifications with PBBM indicated the significance of using modeling approaches to reduce repeated testing thereby facilitating faster approvals.

Effect of patients in-use and accelerated stability conditions on quality attributes and pharmacokinetic profile of four FDA approved extended-release anti-epileptic-drug products

Divalproex (DVS) is a popular drug widely used in various neurological and psychiatric disorders. Commercially, it is a multisource-drug available in different generic equivalents. Incidents of (class II)-recalls have been repeated over the last years due to failure to consistently meet dissolution specifications. Class II recalls are known to be associated with temporary or medically reversible adverse health consequences. This study aimed to evaluate the dissolution profiles, among other quality attributes, of select FDA-approved extended-release DVS products before and after exposure to conditions usually seen as short-lived and insignificant on product stability, such as pharmacy dispensing and patients’ in-use conditions to assess their possible role in the failures observed. Products were stored for 6 weeks in pharmacy vials at 30 °C/75 % RH to simulate patient in-use conditions, for 12 weeks in unsealed HPDE bottles at 25 °C/65 % RH to simulate the pharmacy storage conditions, and for 3 days in open containers at 40 °C/75 % RH for accelerated stability studies. Physicochemical changes were detected by near infrared imaging, Fourier transformed infrared, X-ray powder diffraction and differential scanning calorimetry. All samples were analyzed for in vitro dissolution. Two products were further selected for in vivo study on Beagle dogs before and after storage. The physicochemical characterization tests revealed changes in tablets’ composition and drug crystallinity over time. An improved discriminatory dissolution test was developed and used in this study. The in vitro release testing revealed that short-lived environmental changes at 30 or 25 °C could fail some unit doses and significantly lower the drug release (average reduction among all products was 12.97 ± 11.3 % and 27.48 ± 10.26 %, respectively). Some extended-release products showed a significant increase in the amount of drug dissolved in the first 6 h (early burst) owing to changes in tablet surface morphology and enhanced drug dissolution. In vivo studies showed a decrease in the AUC0-t by overall average of 21.1 % using the non-transformed data, a decrease that mirrored the dissolution results. The study shows that significant changes can occur during routine drug dispensing and patients’ use that might variably impact the stability and quality of commercial bioequivalent unit doses. It is possible that these changes may also contribute to the adverse effects reported on DVS or upon drug switches that were previously attributed to the intersubject variability. The study findings are encouraging to further investigate the effect of such minor excursions on the drug effectiveness during products’ shelf lives especially for narrow therapeutic index drugs.

Novel long-acting treatment for schizophrenia based on paliperidone dissolving and implantable microarray patches

Schizophrenia is a severe mental disorder that affects millions of people worldwide. Several atypical antipsychotic medications, including paliperidone (PPD), has been developed and proven effective in treating it. To date, four PPD extended-release products have been launched commercially, providing up to six months of therapeutic effect with a single administration. However, the need for hospital injections by professional healthcare workers not only lead to poor patients’ adherence, but also put additional pressure on the healthcare system. Therefore, three PPD microarray patch (PPD MAP) systems based on dissolving microneedle technology and implantable microneedle technology were developed in this work. The two dissolving microarray patch systems contained either PPD crude drug (PPD DMAP-CD) or PPD nanocrystal (PPD DMAP-NC) and the implantable MAP contained PPD crude drug (PPD IMAP). All three types of PPD MAPs showed excellent mechanical and insertion properties as they achieved over 256 µm insertion depth in skin model. In vitro release study showed that PPD released from IMAP in a much more sustained manner (up to 14 days) than PPD did from DMAPs (7 days), with only 20 % initial burst release from IMAP compared with 43–71 % from DMAPs. The MAP dissolution study showed that both DMAPs can be immediately dissolved within less than 3 min once inserted into the skin, indicating a faster action potential compared with IMAP. Ex vivo delivery study showed that 1.68 ± 0.23 mg, 1.39 ± 0.07 mg, and 1.18 ± 0.12 mg were delivered from DMAP-CD, DMAP-NC and IMAP, respectively, demonstrating that over 50 % and up to 70 % of PPD in the MAPs can be delivered into the skin. The IMAP offers most sustained release of PPD whereas DMAP-NC exhibits fastest PPD release (11.19 % vs 20.01 % into Franz cell receiver compartment over 24 h). This work presents a promising alternative for the sustained delivery of antipsychotic drugs, allowing for patient self-administration and extended release concurrently. Patients may potentially use both DMAP and IMAP to achieve a sustained release of PPD while also avoid having an initial therapeutic lag.

Two Sustained Release Membranes Used in Formulating Low Strength Testosterone Reservoir Transdermal Patches.

Several Testosterone Replacement Therapies exist for hypogonadism, but an in-depth analysis of these products reveals a high dosing frequency and a high drug loading, up to 120 mg for a potent drug like Testosterone. This may lead to patient non-compliance and toxicity problems if used improperly. Androderm® is the only 24-hour marketed transdermal patch. Testopel pellets are another extended-release product given subcutaneously every 3-6 months. But it requires surgical implantation and is associated with severe adverse effects. For this reason, the development of other extended- release testosterone products is needed. The study aims at using different excipients for the exploration of sustained-release patches. Reservoir formulations were prepared using Carbomer 941 and HPMC K100M as the sustained- release polymers plus CoTran™ 9702 and CoTran™ 9712 as the release membranes. The formulated patches were subjected to in vitro dissolution for 24 h. The amount of drug release at each time point was determined using the developed HPLC assay. FDA Similarity Factor, f2, t-test, and ANOVA were applied to all nine-point collected samples. CoTran™ 9712 membrane was found to be a better candidate than CoTran™ 9702. The in vitro release profiles of the four formulations were compared (Carbomer vs. HPMC, and CoTran™ 9702 vs. CoTran™ 9712). CoTran™ 9702 releases testosterone significantly lower. Carbomer and CoTran™ 9712 were the best formulation among all with the highest drug release of 2.16 ± 0.36 mg.

Patient In-Use Stability Testing of FDA-Approved Metformin Combination Products for N-Nitrosamine Impurity.

Between February 2020 and January 2022, the Food and Drug Administration (FDA) recalled 281 metformin extended-release products due to the presence of N-nitrosodimethylamine (NDMA) above the acceptable daily intake (ADI, 96ng/day). Our previous studies indicated presence of NDMA levels above ADI in both metformin immediate and extended-release products. When metformin products have NDMA impurities, it is indispensable to check for the same impurities in metformin combination products. Therefore, the objective of the present study was to evaluate in-use stability of commercial metformin combination products for NDMA. For this purpose, metformin products in combination with glyburide (GB1-GB12), glipizide (GP1-GP8), pioglitazone (P1-P3), alogliptin (A1, A2), and linagliptin (L1, L2) were repacked in pharmacy vials, stored at 30°C/75% RH for 3months, and monitored for NDMA impurity. The NDMA level varied from 0 to 156.8 ± 32.8ng/tablet initially and increased to 25.4 ± 5.1 to 455.0 ± 28.4ng/tablet after 3months of exposure to in-use condition. Initially, 18 products have NDMA level below ADI limit before exposure which decreased to 7 products (GB5, GP3, GP5, A1, A2, L1, and L2) meeting specification. In conclusion, in-use stability study provides quality and safety risk assessment of drug products where nitroso impurities are detected in the probable condition of use.

Biopharmaceutics Risk Assessment-Connecting Critical Bioavailability Attributes with In Vitro, In Vivo Properties and Physiologically Based Biopharmaceutics Modeling to Enable Generic Regulatory Submissions.

Quality risk assessment following ICH Q9 principles is an important activity to ensure optimal clinical efficacy and safety of a drug product. Typically, risk assessment is focused on product performance wherein critical material attributes, formulation variables, and process parameters are evaluated from a manufacturing perspective. Extending ICH Q9 principles to biopharmaceutics risk assessment to identify factors that can impact in vivo performance is an upcoming area. This is evident by recent regulatory trends wherein a new term critical bioavailability attributes (CBA) has been coined to identify such factors. Although significant work has been performed for biopharmaceutics risk assessment for new molecules, there is a need for harmonized biopharmaceutics risk assessment workflow for generic submissions. In this manuscript, we attempted to provide a framework for performing biopharmaceutics risk assessment for generic regulatory submissions. A detailed workflow for performing biopharmaceutics risk assessment includes identification of initial CBA (iCBA), their confirmatory evaluation followed by definition of the control strategy. Tools for biopharmaceutics risk assessment, i.e., bio-discriminatory dissolution method and physiologically based biopharmaceutics modeling (PBBM) were discussed from a practical perspective. Furthermore, a case study for CBA evaluation using PBBM modeling for an extended-release product for regulatory submission has been described using the proposed workflow. Finally, future directions of integrating CBA evaluation, biopharmaceutics risk assessment to the FDA Knowledge Aided Structured Assessment (KASA) initiative, the necessity of risk assessment templates, and knowledge sharing between industry and academia are discussed. Overall, the work described in this manuscript can facilitate and provide guidance for biopharmaceutics risk assessment for generic submissions.

Dispersant-First Dispersive Liquid-Liquid Microextraction (DF-DLLME), a Novel Sample Preparation Procedure for NDMA Determination in Metformin Products

Since December 2019, global batch recalls of metformin pharmaceutical products have highlighted an urgent need to control N-nitrosodimethylamine (NDMA) contamination to demonstrate patient safety and maintain supply of this essential medicine. Due to their formulation, the metformin extended-release products present difficult analytical challenges for conventional sample preparation procedures, such as artefactual (in-situ) NDMA formation, gelling, and precipitation. To overcome these challenges, a new version of dispersive liquid-liquid microextraction (DLLME) termed dispersant-first DLLME (DF-DLLME) was developed and optimized for the analysis of NDMA in metformin extended-release products using a detailed Design of Experiments (DoE) to optimize sample preparation. Gas chromatography-high resolution accurate mass-mass spectrometry (GC-HRAM-MS) combined with automated DF-DLLME were successfully applied to monitor the NDMA levels of two different metformin extended-release AstraZeneca products to ultra-trace levels (parts per billion). The additional benefits associated with DF-DLLME, which include automation, time/costs saving, and greener sample preparation, make this novel technique easier to transfer from a development to Quality Control (QC) environment. In addition, this also offers an attractive candidate for the wider platform analysis of N-nitrosamines in pharmaceutical drug products.

Predicting Food Effects on Oral Extended-Release Drug Products: A Retrospective Evaluation

Theoretically, the risk of food effects for extended-release (ER) products compared to IR products may be less because: (1) postprandial physiological changes are usually transient and last for 2-3h only; and (2) the percentage of drug release from an ER product within the first 2-3h post dose is usually small under both fasted and fed states. The major postprandial physiological changes that can affect oral absorption of ER drugs are delayed gastric emptying and prolonged intestinal transit. Oral absorption of ER drugs under fasted state mainly occurs in large intestine (colon and rectum) while the absorption of ER drugs under fed state occurs in both small and large intestines. We hypothesized that food effects for ER products are mainly caused by intestinal region-dependent absorption and food intake is more likely to increase rather than decrease the exposure of ER products due to a longer transit time and improved absorption in small intestine. For drugs with good absorption from large intestine, food effects on the area under the curve (AUC) of ER products are usually not expected. Our survey of oral drugs approved by the US FDA between 1998-2021 identified 136 oral ER drug products. Among the 136 ER drug products, 31, 6 and 99 products exhibited increased, decreased, and unchanged AUC under fed conditions, respectively. In general, when an ER product exhibits a fasted bioavailability (BA) relative to its corresponding immediate-release (IR) product between 80-125%, regardless the solubility or permeability of drug substances, substantial food effects on the AUC of ER product are generally not expected. If the fasted relative BA data are not available, a high in vitro permeability (i.e., Caco-2 or MDCK cell permeability comparable or higher than that of metoprolol) may inform no food effect on the AUC of an ER product of high-solubility (BCS class I and III) drug.

Patient-specific in vitro drug release testing coupled with in silico PBPK modeling to forecast the in vivo performance of oral extended-release levodopa formulations in Parkinson’s disease patients

Biorelevant in vitro release models are valuable analytical tools for oral drug development but often tailored to gastrointestinal conditions in ‘average’ healthy adults. However, predicting in vivo performance in individual patients whose gastrointestinal conditions do not match those of healthy adults would be of great value for optimizing oral drug therapy for such patients. This study focused on establishing patient-specific in vitro and in silico models to predict the in vivo performance of levodopa extended-release products in Parkinson’s disease patients. Current knowledge on gastrointestinal conditions in these patients was incorporated into model development. Relevant in vivo pharmacokinetic data and patient-specific in vitro release data from a novel in vitro test setup were integrated into patient-specific physiologically-based pharmacokinetic models. AUC, cmax and tmax of the computed plasma profiles were calculated using PK-Sim®. For the products studied, levodopa plasma concentration–time profiles modeled using this novel approach compared far better with published average plasma profiles in Parkinson’s disease patients than those derived from in vitro release data obtained from the ‘average’ healthy adult setup. Although further work is needed, results of this study highlight the importance of addressing patient-specific gastrointestinal conditions when aiming to predict drug release in such specific patient groups.

Efficacy of 3 Buprenorphine Formulations for the Attenuation of Hypersensitivity after Plantar Incision in Immunodeficient NSG Mice.

Buprenorphine is perhaps the most prescribed analgesic for management of postoperative pain in mice. Although various buprenorphine formulations are effective in commonly used immunocompetent mouse strains, a knowledge gap exists regarding its efficacy in immunodeficient mice. Here we used a plantar incision to evaluate the efficacy of 3 buprenorphine formulations for attenuating postoperative mechanical and thermal hypersensitivity in the immunodeficient NSG mouse strain. We also characterized the pharmacokinetics of these formulations over a 72-h period. We hypothesized that all 3 buprenorphine formulations evaluated-the standard preparation and 2 extended-release products (Bup-HCl, Bup-ER, and Bup-XR, respectively)-would attenuate postoperative mechanical and thermal hypersensitivity resulting from a plantar incision in NSG mice. Male and female NSG mice (n = 48) were allocated to 4 treatment groups: saline (0.9% NaCl, 5 mL/kg SC once); Bup-HCl (0.1 mg/kg SC, BID for 2 d); Bup-ER (1.0 mg/kg SC once); and Bup-XR (3.25 mg/kg SC once). Mechani- cal and thermal hypersensitivity assessments were conducted 24 h before surgery and at 4, 8, 24, 48, and 72 h afterward. All groups of mice showed mechanical and thermal hypersensitivity within the first 24 h after surgery. Behavioral pain indicators (guarding, toe-touching [intermittent partial weight bearing], licking the incision, vocalizations) were observed in some mice from each group at every postoperative time point. Plasma buprenorphine was measured in a separate group of mice and concentrations surpassed the suggested therapeutic level (1.0 ng/mL) for less than 4 h for Bup-HCl, for at least 24 h for Bup-ER, and for 72 h for Bup-XR. Our results indicate that at the dosages studied, these buprenorphine formulations do not adequately attenuate postoperative mechanical and thermal hypersensitivity in the plantar incisional model in NSG mice. These findings support the need for strain-specific analgesic protocols for mice used in research.

Dosage unit uniformity and dissolution testing of extended-release pharmaceutical products marketed in the U.S.

An international sampling study yielded 69 samples of extended-release prescription pharmaceuticals for legal sale in the U.S. Samples included 29 lots of innovator and 40 lots of generic solid oral extended-release drugs manufactured at 16 different facilities and containing 6 different active ingredients. Dosage unit uniformity and dissolution were tested for each lot. All samples met the relevant testing criteria for dosage unit uniformity and dissolution. There were no indications that manufacturer or region impacted a product’s acceptability for use by patients. The variability of attributes was used to calculate a process performance index (Ppk) for each facility. Higher Ppk values suggest less variability relative to specification limits. Only two manufacturers fell below a 4-sigma manufacturing benchmark Ppk of 1.33 for dosage unit uniformity: a European manufacturer of a brand drug and an Asian manufacturer of a generic drug. Conversely, all but four manufacturers fell below a 4-sigma benchmark for the minimum Ppk across their product’s dissolution timepoints: generic drug manufacturers in India (two), the U.S., and Canada. Compared to the immediate-release products of a previous study, Ppks were generally lower for extended-release products. A retrospective analysis found that manufacturers performing below median Ppks submitted more Field Alert Reports after the end of the sampling period.

Convolution- and Deconvolution-Based Approaches for Prediction of Pharmacokinetic Parameters of Diltiazem Extended-Release Products in Flow-Through Cell Dissolution Tester

The present study evaluated the effect of different configuration setups of the Flow-Through Cell (USP IV) dissolution tester in developing in vitro–in vivo correlation (IVIVC). A Biopharmaceutics Classification System (BCS) Class I Diltiazem (DTZ), formulated in extended-release (ER) gel-matrix system, was employed for this purpose. The study also assessed the validity and predictability of IVIVC employing both deconvolution- and convolution-based approaches. In vitro release was conducted in USP IV as open- or closed-loop setups, while the pharmacokinetic (PK) data were obtained from a previous fasted-state cross-over study conducted on 8 healthy male volunteers, after oral administration of ER matrix tablets against market product (Tildiem Retard® 90 mg). PK parameters (Cmax, AUC0-t and AUC0-∞) were predicted, and compared with actual data to establish the strength of correlation models. Results showed that DTZ release from ER products was influenced by operating the FTC in different configuration-setups, where ≥ 75% of labeled DTZ was released after 6 h and 12 h using the open- and closed-loop settings, respectively. Correlation between fraction-dissolved versus fraction-absorbed for both ER products displayed linear relation upon employing FTC open-loop setup. Convolution-based approach was more discriminative in predicting DTZ in vivo PK parameters with a minimal prediction error, compared to deconvolution-based approach. A successful trial to predict DTZ PKs from individual in vitro data performed in USP IV dissolution model was established, employing convolution technique. Basic principle of the convolution approach provides a simple and practical method for developing IVIVC, hence could be utilized for other BCS Class I extended-release drug products.Graphical abstract

In-use stability assessment of FDA approved metformin immediate release and extended release products for N-Nitrosodimethylamine and dissolution quality attributes

Metformin is a widely used first-line oral antidiabetic agent. TheFood and Drug Administration (FDA) confirmed the presence of the ofN-nitrosodimethylamine (NDMA) impurity, a carcinogenic, above the acceptable daily intake (ADI, 96 ng/day) in certain metformin products. The objective of the present study was to assess in-use stability of commercial metformin products for NDMA and dissolution quality attributes. Four immediate-release (M1-M4) and six extended-rerelease (M5-M10) metformin products were evaluated in the stability testing. All products were repacked in pharmacy vials and stored at 30 °C/75% RH for 12 weeks. Five products (M2, M3, M5, M7 and M10) had NDMA level above ADI limit (96 ng/day) before in-use stability exposure. NDMA in M2 (1164 ± 52.9 ng/tablet) and M3 (3776 ± 351.9 ng/tablet) products were 12 and 39 folds of ADI, respectively. Similarly, ER products, M5 (191 ± 94.1 ng/tablet), M7 (1473 ± 47.3 ng/tablet) and M10 (423 ± 55.8 ng/tablet) exhibited NDMA of 1.9, 15.3 and 4.4 folds of ADI, respectively. The impurity level significantly (p < 0.05) increased after 12-week stability exposure to 2.72, 2.47, 2.23 and 2.78 folds of initial values in M2, M3, M7 and M10. In summary, these findings suggested that carcinogenic impurity generation was affected by in-use stability condition exposure and it is expected that several more products currently in the market may also be recalled soon.

A phase 3, single arm, open-label study evaluating ovarian suppression following 3-month leuprolide acetate for injectable suspension in combination with endocrine therapy in premenopausal subjects with HR+, HER2-negative breast cancer (OVELIA).

TPS608 Background: In US clinical practice, GnRH agonists are widely used to suppress ovarian function in pre/perimenopausal patients with breast cancer that is moderate-to high-risk for recurrence. Despite extensive use of leuprolide acetate (LA) for ovarian suppression, regulatory approval for this indication has not been established in the US. Additionally, existing three month formulations may not reliably provide ovarian suppression, as demonstrated by escapes in estradiol (E2). An extended-release LA product with a 3-month dosing period specifically developed for ovarian suppression in patients with breast cancer could fill this unmet need. TOL2506 is a 3-month, extended-release formulation of 30 mg of LA. This combination of active drug and in situ polymeric extended release technology is expected to deliver higher exposure to drug than the currently available 3-month (22.5 mg) formulations of LA marketed for advanced prostate cancer and potentially reduce escapes in E2 over the dosing period. Methods: TOL2506A (OVELIA) is a phase 3, single arm, open-label study evaluating the effectiveness of TOL2506 to suppress ovarian function in premenopausal women with HR+, HER2-negative breast cancer. Approximately 250 subjects will be enrolled, with 30% aged 40 years or younger. Subjects must be premenopausal women, age 18-49, with a diagnosis of Stage I, II, or III HR+, HER2-negative breast cancer (ER &gt; 1% and/or, PR &gt; 1%, HER2-negative per ASCO CAP guidelines), who are candidates for ovarian suppression with endocrine therapy. For subjects receiving chemotherapy, premenopausal status will be determined, and confirmed by central lab hormone testing, prior to initiating chemotherapy. Male subjects with HR+, HER2-negative breast cancer may also be eligible, but will be evaluated for safety analyses only. Eligible subjects will enter the 48 week treatment period in 2 groups: those receiving tamoxifen concurrently with TOL2506 or those who initiate therapy with an aromatase inhibitor (AI; letrozole, anastrozole, or exemestane) beginning 6 weeks after the first administration of TOL2506, if E2 &lt; 20 pg/mL has been achieved. After Week 12, subjects will be allowed to switch from receiving an AI to receiving tamoxifen or from tamoxifen to AI at the Investigator’s discretion. Subjects will receive 4 doses of TOL2506 every 12 weeks over the 48 week study duration. Achievement of ovarian suppression will be defined as ≥ 90% of subjects with luteinizing hormone (LH) levels &lt; 4 IU/L at Week 6. Secondary endpoints include suppression of LH, E2 (&lt; 20 pg/mL for tamoxifen cohort and &lt; 2.72 pg/mL for AI cohort) and absence of menses at weeks 6, 12, 24, 36, and 48. Clinical trial information: NCT04906395.

Switching from batch to continuous granulation: A case study of metoprolol succinate ER tablets

Continuous manufacturing (CM) has been used to produce several immediate release drug products. No extended-release (ER) product manufactured employing CM technology has been approved yet. This study investigated the critical aspects of switching from the batch mode of high shear granulation to the continuous operation of twin-screw granulation for extended-release tablets. Metoprolol succinate ER tablets was used as a model ER formulation for this purpose. A central composite design (CCD) was employed to determine the effects of high shear granulator (HSG) parameters, namely impeller speed, granulation time, and binder liquid feeding rate, on the critical granulation characteristics important for product performance. These critical granulation characteristics served as a guide for switching from the batch processing to the continuous operation for achieving the same breaking strength and dissolution for this ER metoprolol tablets.The granulation time was the most critical factor affecting the bulk properties of granules which contributed to tablet dissolution. The higher density and lower compressibility of granules were attained at the longest granulation time of 5.4 min with the fastest liquid feeding rate of 75 g/min. The granules’ density was the primary factor negatively affecting the dissolution of metoprolol tablets. However, the breaking strength of tablets confounded the effect of granules density on metoprolol dissolution. Switching the processing parameters of high shear granulation to twin-screw granulation achieved similar dissolution profiles (F2 greater than 50). The screw speed was not found to affect bulk properties of granules. The root cause of granulation failures in twin-screw granulation, such as premature consolidation, excessive swelling, poor cohesion, inconsistent shearing effects, and formation of deformed agglomerates, were identified. In conclusion, the use of critical granulation characteristics through a performance-based approach of ER tablets facilitated the switching of manufacturing of an ER formulation form batch to continuous operation.

Update on methylphenidate and dexmethylphenidate formulations for children with attention-deficit/hyperactivity disorder.

Current literature on the safety and efficacy of intermediate- and long-acting formulations of methylphenidate and dexmethylphenidate for attention-deficit/hyperactivity disorder (ADHD) is evaluated. Methylphenidate has been an established treatment for ADHD, but due to its relatively short half-life, numerous intermediate- and long-acting products have been developed. While these extended-release products provide efficacy similar to that of immediate-acting products, the pharmacokinetics and adverse effects can vary. Intermediate-acting methylphenidate products have effects that can last as long as 8 hours, but clinically patients have still required twice-daily dosing. Long-acting products have helped to address these challenges, with recently developed products including controlled-release and bimodal-delivery systems and a patch formulation. Many of these products can be opened and sprinkled on applesauce for ease of administration. Knowledge of the various formulations of methylphenidate and dexmethylphenidate is crucial for appropriate medication selection for control of ADHD symptoms. Knowledge of differences between release mechanisms and the pharmacokinetic properties are essential for appropriate use of these products.

Prediction of in vivo performance of oral extended release formulations prior to clinical evaluation: A case study for enteric coated polymeric beads formulation

To reduce cost and time for product development, an ideal strategy for the development of oral extended release (ER) product is to identify the desired formulation with minimum needsfor clinical evaluation. The aim of this work was to demonstrate the feasibility of adopting a “prediction-then-validation” strategy for the development of oral ER formulations. Instead of the traditional approach using multiple ER formulations for IVIVC development, an enteric-coated fast release formulation was successfully utilized for the development of a biopredictive tool to estimate the drug release from enteric coated polymeric ER formulations in the intestine. A TS1 (time scale factor between Tvitro and Tvivo equals to 1) system was designed and developed, based on which the in vivo pharmacokinetic (PK) performance of ER formulations in dog and in human were well predicted prior to in vivo evaluations. The model further passed a posteriori validation using the criteria for level A IVIVC and, as designed, provided a Tscale value of 1 for the IVIVC model.

Exploring the use of extended release opioids at shortened dosing intervals in people with chronic pain and high risk medication or substance use.

Background Critical attention to rational opioid prescribing has emerged from the opioid epidemic in North America. Individuals with chronic pain are prescribed extended release opioids in an effort to maintain stable drug levels and for more convenient dosing, though evidence to support improvements in pain or function is lacking. It has been observed that extended release opioid products are used at intervals shorter than recommended by product monographs. The need for shortened intervals has been linked with potential inter-patient variability in pharmacokinetics, among other rationale. Implications of shortened dosing intervals for extended release opioids have not been systematically studied. Objective The aim of this study was to characterize the use of extended release opioid formulations at shortened dosing intervals in a population of patients with chronic pain and high risk for opioid-related harms. Setting This study took place in the Interprofessional Pain and Addiction Recovery Clinic, a specialty ambulatory clinic at the Centre for Addiction and Mental Health in Toronto, Canada for adults with chronic pain and a diagnosis or suspicion of substance use disorder. Method This was a retrospective cross-sectional study. Data were collected from records of patients with assessments completed in the years 2012-2017 (n = 210). Main outcome measure Proportion of patients using extended release opioids at shortened intervals. Results Sixty-one percent of individuals using extended release opioids (n = 78) were using them at shortened intervals. This use was associated with a higher daily morphine equivalent dose (533mg vs 236mg, p < 0.01), use of oxycodone extended release products (50% vs. 27%, p < 0.01), a longer duration of opioid therapy (8.9 vs. 6.8years, p = 0.03) and a diagnosis of chronic neuropathic pain (63% vs. 39%, p < 0.01), with no differences in reported pain intensities, compared with use at standard intervals. Conclusion The use of extended release opioids at shortened intervals was associated with increased daily morphine equivalent doses, thus an increased risk of opioid-related mortality. It is unlikely that of those using extended release opioids, the high proportion of use at shortened intervals is the result of inter-patient differences in metabolism alone. Further study is warranted to explore the underlying drivers and implications for people with chronic pain.

Nanosuspension Technology for Delivery of Poorly Soluble Drugs and Its Applications: A Review

Now a days, many drug candidates are water insoluble hence they show a limited drug release and poor bioavailability. It is difficult to formulate these drugs by conventional dosage form. Nanosuspension technology is a promising approach to solve the problems of poorly soluble and less bioavailable drugs. Nanosuspension is a very finely colloidal, biphasic, and uniformly dispersed solid drug particles in a suitable aqueous vehicle, having a particle size below 1 μm stabilized by suitable surface active agents and polymers. Nanosuspensions are prepared by various suitable techniques for drug delivery applications. Due to reduced particle size at the nano scale, surface area, saturation solubility, dissolution velocity and bioavailability of BCS class II and class IV drugs are increased sufficiently. Nanosuspension is suitable to administration via various routes such as oral, intravenous, topical, pulmonary and ocular delivery systems. Nanosuspension can be also used for targeting purpose in various diseases such as cancer, HIV and production of sustained and extended release products by choosing suitable polymers. Production and manufacturing are not complicated, easy to scale up. Top down and bottom technologies are used for the preparation of nanosuspensions. It includes methods such as high-pressure homogenization, by milling media method, precipitation method, probe sonication, dry-co-grinding, supercritical fluid method, and lipid emulsion method. Formulation consists of stabilizers, surfactant, and solvents. Nanosuspension can be stored in the form of dry powder using spray drying, freeze drying techniques. This review describes the advantages, various methods of preparation, formulation consideration and characterization of nanosuspension.

Metformin extended-release products recalled in USA

Metformin extended-release products recalled in USA