Extended-release Characteristics Research Articles

Efficacy, safety, and pharmacokinetics of CPL-01, an investigational long-acting ropivacaine, in bunionectomy: Results of a phase 2b study

CPL-01 (ropivacaine extended-release injection) is formulated to safely provide postoperative analgesia and reduce opioid use. Participants undergoing unilateral distal first metatarsal bunionectomy with osteotomy were randomized to receive either CPL-01 (200 mg in Cohort 1, 300 mg in Cohort 2), ropivacaine HCl (50 mg in Cohort 1, 75 mg in Cohort 2), or volume-matched placebo into the surgical site prior to closure. Participants remained in an inpatient setting for 72 h to assess efficacy (Numeric Rating Scale [NRS] scores for pain with activity adjusted for opioid usage, and rescue medication usage), safety and pharmacokinetics. Seventy-three participants were randomized and treated, and 71 participants completed the study. Participants who received 300 mg CPL-01 had a mean (SD) area under the curve from 0 to 72 h (AUC0–72) of the NRS score with activity of 356.9 (132.82), which was lower than placebo, indicating less pain. Participants who received CPL-01 300 mg also had numerically lower mean total opioid consumption. CPL-01 was safe and well-tolerated, with no evidence of increased AEs in one group versus another. Infiltration of CPL-01 had no impact on wound or bone healing. CPL-01 showed predictable and consistent extended-release pharmacokinetics, with no indication of “dose-dumping.” Ropivacaine HCl delivered 94.3–99.7 % of its ropivacaine dose in the first 24 h; the 300 mg CPL-01 dose delivered 38.5 %. While this Phase 2b study was small, results demonstrated the safety, efficacy, and extended-release characteristics of this long-acting ropivacaine formulation in this surgical model, supporting further development of CPL-01 in Phase 3 clinical studies. Level of Clinical Evidence1

Development, optimization and in vitro-in vivo evaluation of solid lipid microparticles for improved pharmacokinetic profile of bisoprolol

The current research aimed at designing and optimizing controlled release solid lipid microparticles (SLMs) of Bisoprolol (BPL) from biocompatible waxes by using Box-Bhenken design (BBD) for improving the drug pharmacokinetics, enhancing compliance in hypertensive patients as well as eliminating inefficiencies of traditional methods of drug delivery. Seventeen formulations (F1 to F17) of controlled release BPL loaded SLMs were made by melt emulsification technique where Carnauba wax (CW) and Ceresin wax (CSW) were used as carriers and Tween 80 was used as stabilizer. The SLMs were characterized using fourier transforms infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). Results revealed that micromeritics properties of all SLMs were satisfactory and showed good percentage yield (PY) and entrapment efficiency (EE). The minimum EE was observed by formulation-1 (F1) as 21.66% whereas F3 has showed maximum EE as 88%. Results of in vitro release study revealed that all formulations showed a well-controlled release in simulated intestinal medium at pH 7.4. The formulation F3 with high wax concentration revealed best extended release characteristics (29%) in 12 h. The pharmacokinetics studies of SLMs demonstrated an expressively lower Cmax (maximum plasma concentration) of BPL (53.61 ± 2:52) with a satisfactorily higher time to achieve maximum plasma concentration (Tmax) of 10.24 h as compared to Cmax (79.63 ± 5.75) and Tmax (2.45 ± 3.83) of BPL released from commercial brands. Moreover the attainment of greater bioavailability of BPL was most probably due to the increase in half-life (20.44 ± 2.82), mean residence time (24.81 ± 4.22) and area under the plasma concentration level curve (AUC0–24) of 9688.6 ± 4.18 for BPL released from SLMs. Convincingly, the inventive technique could not only sustain the drug release in the in vitro and in vivo environment but also maintain the plasma drug concentration level constant for a longer time without elevating Cmax.

Comparative Quality Analysis of Three Marketed Melatonin Containing Products in Spain for the Improvement of Sleep

Background: Exogenous melatonin may effectively improve the sleep-wake cycle and sleep quality in subjects with age or disease related decrease in endogenous melatonin production or response. A controlled release melatonin-based medication, Circadin® has been developed and licensed for insomnia; in addition to several food supplements available on the market. However, the quality and release profile of these melatonin containing products may vary.
 Aims: The current study aimed to compare three melatonin containing products, all of them marketed in Spain: a licensed medicine prolonged release tablet, Circadin® 2 mg, and two food supplements, Aquilea® 1,95mg and Oniria® 1,98 mg.
 Materials and Methods: Three batches of each product were analyzed for melatonin content, inter-batch variability and dissolution profile.
 Results: Our results confirm a large gap in quality control of the two melatonin containing food supplements, where Aquilea® and Oniria® showed poorer quality control as demonstrated by high variability between batches in melatonin content compared to Circadin®. Moreover, the extended release characteristics of Circadin® were evident in its profile, which exhibited an initial release of 70% at the 4-hour mark, followed by a consistent and sustained release lasting up to 8 hours.
 Conclusion: In terms of the dissolution profile, only Circadin® provides the prolonged release profile as indicated in the specifications, with proven efficacy and safety for the improvement of sleep-onset, sleep maintenance and quality throughout the whole night.

FA-HA-Amygdalin@Fe2O3 and/or γ-Rays Affecting SIRT1 Regulation of YAP/TAZ-p53 Signaling and Modulates Tumorigenicity of MDA-MB231 or MCF-7 Cancer Cells.

Breast cancer (BC) has a complex and heterogeneous etiology, and the emergence of resistance to conventional chemo-and radiotherapy results in unsatisfactory outcomes during BC treatment. Targeted nanomedicines have tremendous therapeutic potential in BC treatment over their free drug counterparts. Hence, this study aimed to evaluate the newly fabricated pH-sensitive multifunctional FAHA- Amygdalin@Fe2O3 nano-core-shell composite (AF nanocomposite) and/or γ-radiation for effective localized BC therapy. The physicochemical properties of nanoparticles were examined, including stability, selectivity, responsive release to pH, cellular uptake, and anticancer efficacy. MCF-7 and MDA-MB-231 cells were treated with AF at the determined IC50 doses and/or exposed to γ-irradiation (RT) or were kept untreated as controls. The antitumor efficacy of AF was proposed via assessing anti-proliferative effects, cell cycle distribution, apoptosis, and determination of the oncogenic effectors. In a bio-relevant medium, AF nanoparticles demonstrated extended-release characteristics that were amenable to acidic pH and showed apparent selectivity towards BC cells. The bioassays revealed that the HA and FA-functionalized AF markedly hindered cancer cell growth and enhanced radiotherapy (RT) through inducing cell cycle arrest (pre-G1 and G2/M) and increasing apoptosis, as well as reducing the tumorigenicity of BCs by inhibiting Silent information regulation factor 1 (SIRT1) and restoring p53 expression, deactivating the Yes-associated protein (YAP)/ Transcriptional coactivator with PDZ-binding motif (TAZ) signaling axis, and interfering with the tumor growth factor- β(TGF- β)/SMAD3 and HIF-1α/VEGF signaling hub while up-regulating SMAD7 protein expression. Collectively, the novel AF alone or prior RT abrogated BC tumorigenicity.

3D Printed Punctal Plugs for Controlled Ocular Drug Delivery.

Dry eye disease is a common ocular disorder that is characterised by tear deficiency or excessive tear evaporation. Current treatment involves the use of eye drops; however, therapeutic efficacy is limited because of poor ocular bioavailability of topically applied formulations. In this study, digital light processing (DLP) 3D printing was employed to develop dexamethasone-loaded punctal plugs. Punctal plugs with different drug loadings were fabricated using polyethylene glycol diacrylate (PEGDA) and polyethylene glycol 400 (PEG 400) to create a semi-interpenetrating network (semi-IPN). Drug-loaded punctal plugs were characterised in terms of physical characteristics (XRD and DSC), potential drug-photopolymer interactions (FTIR), drug release profile, and cytocompatibility. In vitro release kinetics of the punctal plugs were evaluated using an in-house flow rig model that mimics the subconjunctival space. The results showed sustained release of dexamethasone for up to 7 days from punctal plugs made with 20% w/w PEG 400 and 80% w/w PEGDA, while punctal plugs made with 100% PEGDA exhibited prolonged releases for more than 21 days. Herein, our study demonstrates that DLP 3D printing represents a potential manufacturing platform for fabricating personalised drug-loaded punctal plugs with extended release characteristics for ocular administration.

Galactosylated nanoconstructs of Berberine with enhanced Biopharmaceutical and cognitive potential: A preclinical evidence in Alzheimer ‘s disease

Numerous oral treatment options have been reported for neurological diseases, particularly Alzheimer's disease (AD). Berberine (BRB), a promising phytoactive drug, has been successfully explored for effective therapeutic management of AD and other neurodegenerative disorders. However, it poses formidable challenges of exceedingly poor oral bioavailability of 0.68%, primarily owing to its poor intestinal permeation, extremely low aqueous solubility, and extensive P-glycoprotein efflux transport. The present studies, accordingly, were undertaken to develop the galactose-tethered nanostructured lipidic carriers of BRB for efficient brain uptake. NLCs were systematically developed and optimized using QbD paradigms, and thoroughly characterized for particle size, zeta potential, morphology, entrapment efficiency and in vitro drug release. U-87 cell lines studies indicated augmentation in cellular permeability and uptake of the galactosylated NLCs. Oral bioavailability was found to be highly significantly enhanced with over 8.21-folds and 3.56-folds (p < 0.001 each) improvement in the values of AUC48h and Cmax, respectively, along with substantial elevation in brain drug levels too (p < 0.05 to p < 0.001). Also, tmax was found to be notably increased by 1.41-folds (p < 0.05), indicating extended release characteristics of the galactosylated NLCs. Studies on brain homogenates exhibiting distinctly superior biochemical parameters, and behavioural studies demonstrating marked cognitive potential in β-amyloid treated rats further substantiated their promising utility in the management of AD. High degree of Level A linear correlations were established between fractions of drug dissolved (in vitro) and of drug absorbed (in vivo) BRB and its NLC formulations. Stability studies at 5 °C indicated robustness of galactosylated NLCs for 6 months. The current preclinical findings, accordingly, offer distinctive potential of the developed NLCs in enhanced drug efficacy, extended duration of action and effective therapeutic management of AD.

NEW DOSAGE FORMS FOR THE DELAYED RELEASE OF MESALAZINE TO THE COLON

Objective: The aim of the present work was to develop new solid pharmaceutical delivery systems of mesalazine (5-aminosalicylic acid, 5-ASA) for its colon targeted release.&#x0D; Methods: Four different types of tablets of the same consistency (matrix and three-layered, with 5-ASA and dextran or pectin as excipients) were placed in a hard gelatin capsule. The 5-ASA release behavior from these formulations was compared to the release of the commercially available Asalazin® in three pH aqueous media in the presence of enzymes.&#x0D; Results: The produced tablet formulations conformed to the Pharmacopoeia standards. The results showed delayed-release (&lt;10%) during the first two hours, in acidic media (pH 1.5), and modified-release thereafter (pH 6 and 7.4). When dextran was used, the drug release showed more extended-release characteristics, in comparison to pectin formulations, due to the formation of a thicker hydrogel.&#x0D; Conclusion: The new dosage forms could serve as a per os administration alternative dosage form for the delayed release of mesalazine to the colon

The availability of drug by liposomal drug delivery

SummaryLately, the usefulness of liposomal drug delivery systems has been debated. To better understand the underlying pharmacokinetics of the targeted drug delivery by liposomes, individual encapsulated and non-encapsulated drug concentrations in blood, tumor, liver, spleen and kidneys were quantified after i.v. administration of liposomal prednisolone phosphate in mice. Kinetic analysis shows that the tumor influx of encapsulated drug is not dominant compared to the uptake by the other tissues. Further, from a quantitative point of view, the availability of non-encapsulated drug in the tumor tissue after liposomal delivery is not pronounced as compared to the other tissues studied. However, drug release in the tumor seems more extended than in the other tissues and the non-encapsulated drug concentration decreases more slowly in the tumor than in the liver and spleen. The spleen shows a high affinity for the uptake of encapsulated drug as well as the release of drug from the liposomes. Subsequently, released drug in the spleen, and possibly also in other tissues, is probably quickly redistributed towards the blood and other tissues. This also impairs the drug delivery effect of the liposomes. In contrast to the released drug in the central circulation, liver and spleen, the released drug concentration in the tumor remains at a fairly constant level likely due to the extended release kinetics from the liposomes. These extended release characteristics in the tumor most probably contribute to the beneficial effect. Nevertheless, it should be noted that larger released drug concentrations are formed in healthy tissues.

Development and evaluation of injectable nanosized drug delivery systems for apigenin

The purpose of this study was to develop different injectable nanosized drug delivery systems (NDDSs) i.e. liposome, lipid nanocapsule (LNC) and polymeric nanocapsule (PNC) encapsulating apigenin (AG) and compare their characteristics to identify the nanovector(s) that can deliver the largest quantity of AG while being biocompatible. Two liposomes with different surface characteristics (cationic and anionic), a LNC and a PNC were prepared. A novel tocopherol modified poly(ethylene glycol)-b-polyphosphate block-copolymer was used for the first time for the PNC preparation. The NDDSs were compared by their physicochemical characteristics, AG release, storage stability, stability in serum, complement consumption and toxicity against a human macrovascular endothelial cell line (EAhy926). The diameter and surface charge of the NDDSs were comparable with previously reported injectable nanocarriers. The NDDSs showed good encapsulation efficiency and drug loading. Moreover, the NDDSs were stable during storage and in fetal bovine serum for extended periods, showed low complement consumption and were non-toxic to EAhy926 cells up to high concentrations. Therefore, they can be considered as potential injectable nanocarriers of AG. Due to less pronounced burst effect and extended release characteristics, the nanocapsules could be favorable approaches for achieving prolonged pharmacological activity of AG using injectable NDDS.

The Pharmacokinetics of Potassium in Humans Is Unusual.

Potassium is critical for maintaining cellular tonicity, propagation of nerve impulses, contraction of cardiac, skeletal, and smooth muscles, and normal renal function. The focus of this review is on the pharmacokinetics of potassium, K(+) , after administration of liquid and solid formulations of potassium chloride, KCl, to healthy subjects. Potassium can be considered an endogenous and exogenous compound. The amounts of endogenous K(+) are kept constant by balancing intake and loss of exogenous K(+) . Food and ingestion of KCl-containing medicines are sources for exogenous K(+) . In the pharmacokinetic context exogenous K(+) from KCl-containing medicines, K(+) exo,dose , is of primary interest. The distinction between the different K(+) entities is critical for obtaining unbiased estimates of the kinetic parameters for K(+) exo,dose . A literature search using prespecified acceptance criteria was performed. Publications were selected that reported plasma and urine data of K(+) exo,dose directly or provided information allowing their determination. Additional criteria applied included that the studies used a randomized design and controlled for the important covariates. Most of the selected publications reported urinary excretion data. Only 2 publications also reported plasma concentrations. The excursions of the plasma concentrations of K(+) exo,dose were considered too small to be of use by most investigators. The aggregate results indicate that urinary recovery data have the potential for providing reliable estimates for bioavailability and bioequivalence of K(+) exo,dose with KCl-containing formulations. Absorption efficiency, peak rates, and corresponding times of K(+) exo,dose with liquid formulations are fairly consistent among studies. The mean absorption efficiency of K(+) exo,dose with solid and liquid formulations of KCl ranges between 70% and 90%. The absorption rate of liquid formulations is rapid, whereas the solid formulations show extended release characteristics. The time-averaged renal clearance of K(+) exo,dose is about 200 mL/min during daytime and significantly smaller around midnight. Circadian rhythm and delayed homeostatic control of potassium make the pharmacokinetics of K(+) exo,dose time dependent. The impact of these endogenous controls makes the pharmacokinetics of K(+) exo,dose unusual.

The influence of polymer content on early gel-layer formation in HPMC matrices: The use of CLSM visualisation to identify the percolation threshold

Percolation theory has been used for several years in the design of HPMC hydrophilic matrices. This theory predicts that a minimum threshold content of polymer is required to provide extended release of drug, and that matrices with a lower polymer content will exhibit more rapid drug release as a result of percolation pathways facilitating the faster penetration of the aqueous medium. At present, percolation thresholds in HPMC matrices have been estimated solely through the mathematical modelling of dissolution data. This paper examines whether they can be also identified in a novel way: through the use of confocal laser scanning fluorescence microscopy (CLSM) to observe the morphology of the emerging gel layer during the initial period of polymer hydration and early gel formation at the matrix surface.In this study, matrices have been prepared with a polymer content of 5–30% w/w HPMC 2208 (Methocel K4M), with a mix of other excipients (a soluble drug (caffeine), lactose, microcrystalline cellulose and magnesium stearate) to provide a typical industrially realistic formulation. Dissolution studies, undertaken in water using USP apparatus 2 (paddle) at 50rpm, provided data for the calculation of the percolation threshold through relating dissolution kinetic parameters to the excipient volumetric fraction of the dry matrix. The HPMC percolation threshold estimated this way was found to be 12.8% v/v, which was equivalent to a matrix polymer content of 11.5% w/w.The pattern of polymer hydration and gel layer growth during early gel layer formation was examined by confocal laser scanning fluorescence microscopy (CLSM). Clear differences in gel layer formation were observed. At polymer contents above the estimated threshold a continuous gel layer was formed within 15min, whereas matrices with polymer contents below the threshold were characterised by irregular gel layer formation with little evidence of HPMC particle coalescence. According to percolation theory, this implies that a continuous cluster of HPMC particles was not formed.The images provide the first direct evidence of how the percolation threshold may be related to the success or failure of early gel layer development in HPMC matrices. It also shows how extended release characteristics are founded on the successful coalescence of hydrated polymer particles to form a continuous coherent diffusion barrier, which can then inhibit further percolation of the hydration medium. The correlation between percolation thresholds estimated from dissolution and imaging techniques suggests that confocal imaging may provide a more rapid method for estimating the percolation thresholds, facilitating the rational design of HPMC extended release matrices at lower polymer contents with minimal risk of dose dumping.

Chondroitin-based nanoplexes as peptide delivery systems – Investigations into the self-assembly process, solid-state and extended release characteristics

A new type of self-assembled polyelectrolyte complex nanocarrier composed of chondroitin (CHON) and protamine (PROT) was designed and the ability of the carriers to bind salmon calcitonin (sCT) was examined. The response of sCT-loaded CHON/PROT NPs to a change in the properties of the liquid medium, e.g. its pH, composition or ionic strength was studied and in vitro peptide release was assessed. The biocompatibility of the NPs was evaluated in Caco-2 cells.CHON/PROT NPs were successfully obtained with properties that were dependent on the concentration of the polyelectrolytes and their mixing ratio. X-ray diffraction determined the amorphous nature of the negatively charged NPs, while those with the positive surface potential were semi-crystalline. sCT was efficiently associated with the nanocarriers (98–100%) and a notably high drug loading (13–38%) was achieved. The particles had negative zeta potential values and were homogenously dispersed with sizes between 60 and 250nm. CHON/PROT NPs released less than 10% of the total loaded peptide in the first hour of the in vitro release studies. The enthalpy of the decomposition exotherm correlated with the amount of sCT remaining in NPs after the release experiments. The composition of medium and its ionic strength was found to have a considerable influence on the release of sCT from CHON/PROT NPs. Complexation to CHON markedly reduced the toxic effects exerted by PROT and the NPs were compatible and well tolerated by Caco-2 cells.

Gastrointestinal release behaviour of modified-release drug products: Dynamic dissolution testing of mesalazine formulations

The aminosalicylate mesalazine (mesalamine) forms the mainstay of treatment in ulcerative colitis (UC), a disease for which many commercial modified-release products have been developed with the aim of providing targeted gastrointestinal release. The release profiles of five of these commercial formulations were evaluated in bicarbonate buffer using a novel dissolution model that mimics the dynamic conditions of the gastrointestinal tract. Monolithic and multi-particulate mesalazine formulations with pH-dependent and/or independent release mechanisms were evaluated (Asacol® 800, Octasa®, Mezavant® XL, Salofalk®, Pentasa®), and each of the products displayed a distinctive dissolution profile. The dissolution results for Mezavant® XL (Lialda®) (lag time 290min) demonstrated good correlation with previously reported in vivo disintegration times assessed by gamma-scintigraphy in humans. Octasa® showed a similar lag time to Mezavant® XL. Drug release from Asacol® 800 (Asacol® HD) showed a wide standard deviation, reflecting the great variability in vivo. Salofalk® displayed both delayed release and extended release characteristics. Pentasa® released more than 50% of its drug load in the stomach compartment of the model, which is attributed to the absence of a gastro-resistant coating in this product. The new dissolution method provided a realistic and discriminative in vitro assessment of mesalazine release from different formulations. These results demonstrate that this strategy can be used to predict intestinal release behaviour, and potentially aid the rational design of products developed to target different sites of the gut.

Formulation Development and In vitro Evaluation of Oral Extended release Capsules Containing Biodegradable Microspheres

Oral extended-release delivery of Biopharmaceutics Classification System (BCS) class II and III compounds is desirable in order to decrease dosing frequency and potential adverse effects. Maintaining an extended-release profile of the drug is ideal to minimize fluctuations in plasma concentrations. The main objective of this research was to formulate a polymeric microsphere drug delivery system that will effectively provide extended-release characteristics via an orally administered capsule. Using acetaminophen and ibuprofen as model drugs, this drug delivery system was shown to provide extended-release characteristics of the drug for enhanced efficacy. The biodegradable polymeric matrix was formulated using bovine serum albumin (BSA) with glutaraldehyde as the crosslinker. The drug of interest was then encapsulated into the polymeric matrix and spray-dried into microspheres. Once prepared, the drug-loaded microsphere powder was placed into hard gelatin capsules. The physicochemical properties of the microsphere formulations were characterized. Additionally, differential scanning calorimetry was utilized to examine the thermal stability of the encapsulated drug. Release studies were conducted in vitro to examine the release profile of the drug. Cell uptake studies were carried out to examine the internalization capability of microsphere formulations. Drugloaded microspheres were found to be approximately 2 microns in size and exhibited a uniform size distribution. Zeta potential measurements were shown to be approximately -30 mV, which indicated that the microspheres are stable in dispersions. Release data showed a constant release of the drug from the microsphere and capsule formulations for at least 16 hours. Formulated microspheres were able to be internalized into human intestinal Caco-2 cells. These data provided evidence for the role of the microsphere delivery system in the extended-release delivery of BCS Class II and III drug substances.

Selection of a hydrocodone bitartrate extended-release prototype with optimal tamper resistance and extended-release characteristics

Hydrocodone is available only in immediate-release (IR) combination products for treatment of pain in the United States. This randomized, open-label, crossover study intended to identify a prototype with the highest tamper resistance, which maintains optimal extended-release (ER) characteristics. Pharmacokinetic profiles were characterized for 3 ER hydrocodone prototypes designed to be resistant to rapid release of drug upon product tampering. After IRB approval and informed consent were obtained, healthy subjects were randomized.

Effects of Alcohol on the Pharmacokinetics of Morphine Sulfate and Naltrexone Hydrochloride Extended Release Capsules

Although contraindicated, coingestion of alcohol and opioids by patients or drug abusers is a major health concern because of dangerous additive and potentially life-threatening sedative and respiratory effects. In addition, alcohol has been shown to disrupt the extended-release characteristics of certain extended-release opioid formulations, releasing a hazardous amount of opioid over a short time period. Morphine sulfate and naltrexone hydrochloride extended release capsules (MS-sNT), which contain naltrexone sequestered in each pellet core, are indicated for management of chronic, moderate to severe pain. Sequestered naltrexone is designed for release upon product tampering (crushing) to potentially mitigate morphine-induced subjective effects. This open-label, single-dose, 4-way crossover, pharmacokinetic drug interaction study compared the relative bioavailability of morphine and naltrexone when MS-sNT is administered (under fasting conditions) with increasing doses of alcohol. Thirty-two healthy, opioid-naive adults were randomized to MS-sNT administered with 240 mL of 4%, 20%, or 40% alcohol or water. No drug interaction was found between morphine in MS-sNT and 4% or 20% alcohol. Administration with 40% alcohol did not affect overall morphine exposure but was associated with a 2-fold increase in C(max) and reduction of t(max) from 9 to 4 hours versus MS-sNT taken with water. Naltrexone sequestering was successful in all treatment arms and not affected by coadministration with alcohol over the dose range tested.

Drug-eluting Beads in the Treatment of Hepatocellular Carcinoma and Colorectal Cancer Metastases to the Liver

Drug-eluting beads (DEBs) may become a standard of care in the treatment of unresectable liver cancers. DEBs have a significant advantage by offering simultaneous embolisation, and sustained release of antineoplastic agents in a controlled manner, resulting in a localisation of the drug in the targeted tumour, while minimising its systemic exposure. This article reviews current treatment options for liver cancer and concentrates on the benefits of DEBs for patients with unresectable liver cancer. Preclinical and clinical studies suggest smaller microspheres and extended release characteristics as key properties that will enable DEB device technologies to become a standard of care for unresectable liver cancer. A new, tightly size-calibrated DEB ≤100 μm, Embozene TANDEM™, was designed to meet these requirements.

Pharmacokinetics of Betamethasone After Single-Dose Intramuscular Administration of Betamethasone Phosphate and Betamethasone Acetate to Healthy Subjects

BackgroundBetamethasone is used for its antiinflammatory and immunosuppressive effects in disorders of many organ systems. However, the pharmacokinetic properties of betamethasone in plasma after intramuscular injection of betamethasone sodium phosphate and betamethasone acetate dual-acting suspension need further investigation. ObjectivesThe main aim of this study was to determine the pharmacokinetic parameters of betamethasone, betamethasone acetate, and betamethasone phosphate after the administration of a single intramuscular dose of the dual-acting suspension to healthy human volunteers. MethodsTwo different studies were conducted in healthy males. Volunteers were judged healthy based on their medical history, physical examination, and laboratory test results. Before confinement, all volunteers were tested for freedom from alcohol and drugs of abuse. Following a 10-hour overnight fasting, a single dose of 1 mL of the dual-acting suspension containing 3 mg of betamethasone phosphate and 3 mg of betamethasone acetate was administered by intramuscular injection. Blood sampling covered 48 hours. The plasma samples obtained in the second study were stabilized to enable pharmacokinetic profiling of betamethasone esters. ResultsTwenty-four healthy males with mean (SD) age of 27 (6.62) years participated in each study. No incidences of serious adverse events were recorded during the studies. Six mild adverse events were reported in 2 subjects in the second study. One subject suffered from pain at the injection site and insomnia, and another subject complained of heartburn and drowsiness. Betamethasone phosphate appeared to be readily absorbed with a mean AUC0–t of 96.01 ng/h/mL and an AUC0–∞ of 97.96 (23.38) ng/h/mL. Betamethasone peak plasma concentration reached a mean t½ of 12.92 hours. Betamethasone acetate was not detected in the volunteers' plasma in either study (total of 2208 plasma samples). ConclusionThe observed pharmacokinetic parameters suggested that the acetate ester, and not the phosphate ester, of betamethasone acts as a prodrug or reservoir for betamethasone, conferring on it sustained- and extended-release characteristics.

The use of in situ near infrared spectroscopy to provide mechanistic insights into gel layer development in HPMC hydrophilic matrices

In this study, near infrared (NIR) spectroscopy has been used to track the spatial and temporal movement of a model drug (Compound A) while monitoring in situ the gel layer development in hydrophilic matrices based on hydroxypropyl methylcellulose (HPMC). To validate the NIR experimental set-up, Compound A was formulated in “slow” and “fast” drug releasing formulations with high (56% w/w) and low (18% w/w) levels of HPMC K100M, respectively. NIR microscopy was used to (i) define the extent of HPMC pseudo-gel swelling, (ii) elucidate the movement of the polymer swelling front and (iii) track movement of the drug through the gel layer. Dissolution testing (USP I) allowed correlation of mechanistic details ascertained using NIR with the rate and extent of drug release. Several critical differences were observable between “fast” and “slow” formulations. In the “fast” formulation, HPMC swelling front movement occurred at a slower rate and to a lesser extent compared to drug release, suggestive of inadequate gel layer formation and a partial loss of extended release characteristics. In contrast, the “slow” formulation exhibited a similar rate of HPMC swelling front movement compared to drug release, suggesting a release mechanism predominately controlled by polymer erosion, supported by an apparent zero order drug dissolution curve in USP I. In conclusion, the study suggests the potential future value of using NIR in situ to elucidate mechanistic insights in drug release rate from pharmaceutical formulations.

Mechanisms of drug release in citrate buffered HPMC matrices

Few studies report the effects of alkalizing buffers in HPMC matrices. These agents are incorporated to provide micro-environmental buffering, protection of acid-labile ingredients, or pH-independent release of weak acid drugs. In this study, the influence of sodium citrate on the release kinetics, gel layer formation, internal gel pH and drug release mechanism was investigated in HPMC 2910 and 2208 (Methocel E4M and K4M) matrices containing 10% felbinac 39% HPMC, dextrose and sodium citrate. Matrix dissolution at pH 1.2 and pH 7.5 resulted in complex release profiles. HPMC 2910 matrices exhibited biphasic release, with citrate increasing the immediate release phase (<60 min) and reducing the extended release. HPMC 2208 matrices were accelerated, but without the loss of extended release characteristics. Studies of early gel layer formation suggested gel barrier disruption and enhanced liquid penetration. pH modification of the gel layer was transitory (<2 h) and corresponded temporally with the immediate release phase. Results suggest that in HPMC 2910 matrices, high initial citrate concentrations within the gel layer suppress particle swelling, interfere with diffusion barrier integrity, but are lost rapidly whereupon drug solubility reduces and the diffusion barrier recovers. These Hofmeister or osmotic-mediated effects are better resisted by the less methoxylated HPMC 2208.