Sustained-release Pellets Research Articles

Preparation and Evaluation of Glaucocalyxin A SustainedRelease Pellets Based on Phospholipid Complex System with Enhanced Bioavailability

Preparation and Evaluation of Glaucocalyxin A SustainedRelease Pellets Based on Phospholipid Complex System with Enhanced Bioavailability

Development of arsenic trioxide sustained-release pellets for reducing toxicity and improving compliance

Arsenic trioxide (ATO) is first-line drug for acute promyelocytic leukemia. Clinically, the continuously slow intravenous infusion is adopted to maintain effective blood concentration and reduce toxic effects, but it causes poor patient' compliance for a considerable infusion period. To overcome these disadvantages, we developed an oral ATO sustained-release preparation which was constructed via the ATO core pellets prepared by extrusion spheronization and followed by a coating membrane by fluid-bed technology. The prepared coated pellets displayed a round surface and uniform particle size. All in vitro release profiles of ATO pellets in different pH media and rotation speeds had no statistical difference. Importantly, the coated pellets can release completely in 12 h without obvious burst release. There was no distinct change in appearance and release behaviors in stability experiments. In vivo pharmacokinetics was studied by one-time intragastric administration of rats. Compared with free drug, the AUC0–∞ of the ATO coated pellets was 2.3-fold higher, indicating the oral bioavailability was significantly increased. Cmax decreased by about a half and Tmax extended about 15 h. In particularly, the ATO level at 96 h only decreased about 20% of Cmax , suggesting that the ATO sustained-release preparation could not only decrease the peak concentration, but also maintain a relatively constant blood concentration for a long period. Further, the in vivo absorption could be well predicted by in vitro release experiments. Therefore, the ATO sustained-release preparation formulated by the mature preparation technology, possessing satisfactory stability and improving bioavailability, had great application potentials for industrialization.

LC-MS/MS analysis of pharmacokinetics of 3, 29-dibenzoyl karounitriol in rats following administration of Trichosanthes sustained-release pellets

To study the plasma concentration and pharmacokinetics of 3, 29-Dibenzoyl Karounitriol (3, 29-DK) from sustained- release pellets and extracts of Trichosanthes at different time points in rats using high-performance liquid chromatography- tandem mass spectrometry (LC-MS/MS). Healthy male SD rats were given a single gavage of Trichosanthes sustained-release pellets or Trichosanthes extract, and orbital blood samples were taken at different time points within 48 h after drug administration in the pellet group and within 5 h in Trichosanthes extract group for determination of the plasma concentrations of 3, 29-DK using LC-MS/MS. The standard curve of 3, 29-DK content was established, and the specificity, minimum detection limit, precision and accuracy, extraction recovery, stability and matrix effect of LC-MS/MS analysis were assessed. The mean plasms levels of 3, 29-DK at different time points after the drug administration were determined and its pharmacokinetic parameters were calculated using Das 2.0 software. LC-MS/MS analysis showed a good linearity of 3, 29-DK concentration within the range of 0.5-32 ng/mL, and the results of methodological validation confirmed the validity of this method for biological sample determination. Trichosanthes sustained-release pellets and Trichosanthes extract showed significant differences in their AUC(0-t), AUC(0-∞), MRT(0-t), MRT(0-∞), t1/2z and Tmax of 3, 29-DK after administration in rats (P < 0.05). Trichosanthes sustained-release pellets are capable of sustained-release of 3, 29-DK in rats, and thus provides a basis for the study of new dosage forms of Trichosanthes.

Optimized flurbiprofen sustained-release matrix pellets prepared by extrusion/spheronization

Flurbiprofen (FBP) is an ibuprofen derivative with less gastric side effects and short biological half-life (4.7–5.7 h). The study aimed to formulate FBP as a sustained-release pellets by extrusion/spheronization to overcome its short half-life and to decrease dose frequency. The wet mass of the pellets containing Avicel® and a polymeric matrix polymer was determined by measuring the mean line torque. The impacts of different types and concentrations of matrix-forming units (HPMC, Carbopol, and PVP) (independent variables) on pellet size, mean line torque, and dissolution rate after 8 h were assessed using the Box-Behnken design. The results showed that the formulation containing higher concentrations of HPMC and Carbopol, such as F14, had high mean line torque value. This high mean line torque was responsible for the increased pellet size (>1100 μm) and decreased release rate (68 ± 2.8%) after 8 h of F14, compared with those of F5, which did not contain HPMC or Carbopol and had the lowest mean line torque, smallest pellet size (875.9 ± 27.5 μm), and highest dissolution rate after 8 h (100 ± 5.9%). In conclusion, sustained-release pellet formulation of FBP was able to sustain the release of FBP for up to 8 h.

Losartan potassium sustained release pellets with improved in vitro and in vivo performance

The aim of this study was to formulate and evaluate SR matrix pellets containing losartan potassium (LP) solid dispersion using extrusion–spheronization technique to minimize the fluctuation of its plasma concentration. LP solid dispersions were prepared by using different hydrophobic polymers at different weight ratios (0.5, 1, 2, and 5%). LP-Eudragit RS solid dispersion at 1:5 ratio resulted in slower drug release (only 20% of LP was released in about 8 h). Different concentrations of hydrophilic polymer, PEG 6000, were mixed with Avicel® PH 101 to prepare the LP SR matrix pellets containing solid dispersion using 32 full factorial design to evaluate the effects of formulation parameters on the pellets attributes. The magnitude of torque for the pellet wet masses and binder ratio were decreased significantly with increasing PEG 6000 concentration. LP sustained release pellet formula composed of 9.24% PEG 6000 and 8 × 10−9% PVP K30 solution was chosen as optimized formula. Pharmacokinetic studies revealed that calculated t max was 9.72 ± 2.22 h from the optimized sustained release pellets compared to 2.11 ± 0.49 h in case of Cozaar® immediate release tablet, indicating a slower release of the LP from pellets.

MO061PLASMINOGEN DEFIENCY DOES NOT PROTECT MICE FROM SODIUM RETENTION IN EXPERIMENTAL NEPHROTIC SYNDROME

Abstract Background and Aims Sodium retention and edema formation are the hallmarks of nephrotic syndrome and thought to be mediated by proteolytic activation of the epithelial sodium channel (ENaC) by aberrantly filtered serine proteases. Plasmin is highly abundant in nephrotic urine and has been proposed to be the principal serine protease responsible for ENaC activation in nephrotic syndrome. However, there is not enough evidence to demonstrate the essential role of plasmin in mediating sodium retention in an experimental nephrotic model. Method We investigated sodium retention and edema formation in a mouse model of nephrotic syndrome based on an inducible podocyte-specific podocin knockout (Bl6-Nphs2tm3.1Antc or Δipod * Tg(Nphs1-rtTA*3G8Jhm)* Tg(tetO-cre) 1Jaw). To generate an inducible podocin knockout with plasminogen deficient model (Nphs2Δipod * Plg-/-, hereafter referred to as Plg-/-), plasminogen deficient mice (Bl6-Plgtm1Jld or -/-) were intercrossed with Nphs2Δipod mice. Nephrotic syndrome was induced after oral doxycycline treatment for 14 days. Body weight, urinary protein, urinary sodium excretion, as well as urinary plasmin activity were daily determined 14 days after end of induction. To determine if sodium retention can be prevented by serine protease inhibitor aprotinin in Plg+/+ and Plg-/- mice after induction of nephrotic syndrome, sustained-release pellets containing aprotinin (2 mg per day) or placebo pellets were implanted to either Plg+/+ or Plg-/- mice (n=4 per group). Results Uninduced Plg+/+ (n=6-13) and Plg-/- mice (n=6-14) had normal kidney function and sodium handling. After end of doxycycline induction, there was no significant differencein proteinuria increase between Plg+/+ (from 2 ± 0 to 161 ± 16 mg/mg creatinine, p<0.05) and Plg-/- mice (from 9 ± 8 to 146 ± 44 mg/mg creatinine, p<0.05) leading to similar hypoalbuminemia. In urine samples from Plg+/+ mice, Western blot revealed urinary excretion of plasminogen/plasmin which was completely absent in Plg-/- mice. Accordingly, urinary plasmin activity was only detectable in Plg+/+ mice using a chromogenic substrate. After onset of proteinuria, amiloride-sensitive natriuresis was increased compared to uninduced mice indicating ENaC activation. While urinary sodium excretion dropped in both genotypes indicating sodium retention (from 193 ± 16 to 16 ± 6 µmol/24h in Plg+/+ mice, p<0.05; from 229 ± 11 to 26 ± 7 µmol/24h in Plg-/-mice, p<0.05). As a consequence, body weight maximum increased in both genotypes 21 ± 1% in Plg+/+ and 17 ± 2% in Plg-/- mice (p=0.616) and was paralleled by development of ascites. Urinary amidolytic activity were completely prevented by the presence of aprotinin, as well as sodium retention and ascites in both Plg+/+and Plg-/- mice. Conclusion This study shows for the first time that mice lacking urinary plasmin are not protected from ENaC-mediated sodium retention in experimental nephrotic syndrome, however it can be prevented by aprotinin. These findings point to an essential role of other hitherto unknown serine proteases excreted in nephrotic urine.

FORMULATION AND EVALUATION OF FLOATING PELLETS OF OMEPRAZOLE BY EXTRUSION SPHERONIZATION METHOD

Objective: The aim of the present study was design, develop and to evaluate a model of floating sustained release pellets formulations for Omeprazole by extrusion and spheronization technique.
 Methods: Omeprazole at different drug to polymer ratios were prepared by extrusion and spheronization technique and the release rate of the drug from the pellets was studied. Further, the in-vitro release studies of pellets were carried out in 0.1N HCL for 12 hours. Prepared pellets were subjected to characterization by different techniques such as loose bulk density, tapped bulk density, compressibility index and angle of repose. To optimize the formulation on the basis of acceptable pellet properties friability, drug content, moisture content, and loss on drying and in-vitro drug release tests were done. In addition, the compatibility studies were performed by using FTIR and DSC.
 Results: These above studies indicated that the drug release can be modulated by varying the concentration of the polymer. The resulting formulation produced robust pellets with acceptable drug content and low friability. Further, release data was fitted to various mathematical models such as, Higuchi, Korsmeyer-Peppas, First-order, and Zero-order to evaluate the kinetics and mechanism of the drug release. Kinetic modeling of in-vitro dissolution profiles revealed the release mechanism ranges from Quasi-Fickian transport to Anomalous (non-Fickian transport), which was only dependent on the type and amount of polymer used. The drug release of the optimized formulation (F5) follows Zero order kinetics and the mechanism was found to be diffusion controlled. The FTIR and DSC studies reveal that there is no interaction between the drug and the polymer/excipients mixture.
 Keywords: Floating, Ethyl cellulose, HPMC, Pellets, Omeprazole.

Colon targeted bioadhesive pellets of curcumin and cyclosporine for improved management of inflammatory bowel disease.

The objective of the present work was to develop and optimize multiparticulate pH-dependent bioadhesive pellets of curcumin and cyclosporine for the management of intestinal bowel disease (IBD). The bioadhesive sustained release pellets were intended for targeting the affected site for an improved therapeutic effect. Bioadhesive pellet cores of curcumin and cyclosporine were formulated using Carbopol 940 (CP940) and hydroxypropyl cellulose (HPC-H) by the extrusion/spheronization method, and drug delivery to the colon was controlled by the pH-sensitive polymer Eudragit® S100. Microcrystalline cellulose (Avicel PH101) was found to be the best forming agent for pellet core. The ratio of CP940 to HPC-H was kept at 1:1 to achieve 100% bioadhesion. The in vitro dissolution profiles of coated pellets depicted that 12.327 ± 0.342% of curcumin and 14.751 ± 0.112% of cyclosporine were released at the end of 6h (at pH6.8), whereas 71.278 ± 0.100% of curcumin and 76.76 ± 0.195% of cyclosporine were released at the end of 24h (at pH7.4). The drug release profile was found to follow zero-order kinetics for both drugs. The selected formulation was evaluated on an acetic acid-induced ulcerative colitis in the rat model to evaluate the efficiency of drug-loaded pellets coated with Eudragit®S100. The pharmacodynamic study revealed the therapeutic efficacy of Eudragit®S100-coated pellets of curcumin and cyclosporine in alleviating the conditions of the acetic acid-induced colitis model as reflected by weight gain as well as improvement of clinical, macroscopic and microscopic parameters of induced colitis, as compared with free curcumin and cyclosporine. The combination of curcumin and cyclosporine has been proven to have a synergistic effect for the successful management of IBD when used in a low dose as compared with individual drugs with high doses. Hence, curcumin- and cyclosporine-loaded bioadhesive pellets may act as a promising targeted drug delivery system in the management of IBD. Graphical abstract.

Piperine fast disintegrating tablets comprising sustained-release matrix pellets with enhanced bioavailability: formulation, in vitro and in vivo evaluation

Piperine (Pip) has been widely studied for its multiple activities such as antidepressant, anti-epileptic, and so forth. However, the poor water solubility coupled with low bioavailability may inevitably hinder the application of Pip in the clinical setting. In this study, a formulation strategy was proposed to spontaneously resolve the low bioavailability and dose dividing issue of Pip. The matrix pellets (Pip-SR-pellets) consisting of Pip solid dispersion (Pip-SD) and hydroxypropylmethyl cellulose-K100 were developed to achieve an increased and sustained release profile in vitro. The Pip-SR-pellets were compacted into fast disintegrating tablets (FDTs) with a blend of excipients comprising lactose, MCC, LS-HPC, and CMS-Na. The Pip-SD was characterized by solubility study and XRD. The evaluation of the cross-sectional morphology of the Pip-FDTs via scanning electron microscope proved that Pip-SR-pellets maintained its structural integrity during compression and were uniformly distributed in the Pip-FDTs. The release profile of Pip-SR-pellets was highly consistent with the Pip-FDTs. In vivo pharmacokinetics study demonstrated that the relative bioavailability of Pip-SR-pellets was approximately 2.70-fold higher than that of the pure drug, and 1.62-fold compared with that of Pip-SD. This work therefore showed a potential industrialized method could be applied to formulate poorly water-soluble drug that has dose-dividing requirement.

Formulation and Development of Sustained Release Pellets of Nifedipine by Fluidized Bed Processor

Recently, extended release pharmaceutical products became a very useful tool in medical practice, offering a wide range of actual and perceived advantages to the patients. Oral drug delivery is the most preferred route for the various drug molecules among all other routes of drug delivery, because ease of administration which lead to better patient compliance. So, oral extended release drug delivery system becomes a very promising approach for those drugs that are given orally but having the shorter half-life and high dosing frequency. Extended release is also providing promising way to decrease the side effect of drug by preventing the fluctuation of the therapeutic concentration of the drug in the body. Recent trends indicate that multiparticulates drug delivery systems are especially suitable for achieving extended release oral formulations with low risk of dose dumping, flexibility of blending to attain different release patterns as well as reproducible and short gastric residence time. Development of Nifedipine Sustained Release pellets by Fluidized Bed Processing technology. The different trials were formulated and evaluated for its percent Cumulative drug release, percent Swelling index and scanning electron microscopy. The release of drug from pellets depends on a variety of factors including the carrier used to form pellets and the amount of drug contained in them. In these, trial 2 is Shows better results Such as, percent Cumulative Drug Release is 84.34%, and Scanning Electron Microscopy study shows Pellets uniformities and Spherical shape particle's also less Agglomeration.

Formulation and Evaluation of sustained release pellets of Zidovudine by using Extrusion and Spheronization Technique

Formulation and Evaluation of sustained release pellets of Zidovudine by using Extrusion and Spheronization Technique

IMPLEMENTATION OF QUALITY BY DESIGN (QBD) APPROACH IN FORMULATION AND DEVELOPMENT OF RITONAVIR PELLETS USING EXTRUSION SPHERONIZATION METHOD

Objective: Ritonavir is an antiretroviral drug used for HIV-AIDS treatment. The purpose of this research work was to implement the quality by design (QbD) approach in formulation of ritonavir sustained-release pellets by industrially applied extrusion spheronization technique.
 Methods: Pellets were prepared by extrusion spheronization method and evaluated for their physicochemical properties. Initially, on the basis of prior knowledge Quality Target Product Profile (QTTP) element was identified and further Critical Quality Attributes (CQA) elements were defined. Risk assessment (RA) was done by two tools as failure mode and effect analysis (FMEA) and fishbone diagram (Ishikawa plot). Placket Burman design was implemented as a screening design using seven high-risk factors (spheronization speed, spheronization time, extrusion speed, drying method, PVP K 30, cross povidone, and solvent). Optimization study was done by 23 full factorial design with three critical factors as (spheronization speed, extrusion speed and PVP K 30). The in vitro drug release was studied in both gastric and intestinal fluids for 12 h using USP Ι apparatus. Control space was established for the sustained release pellets.
 Results: Among all batches obtained in 23 full factorial design, batch R7 was found to be effective with carr’s index value of 5.281, percentage yield of 69.6%, time required to release 50% drug was 8 h and percent drug release after 12 h was found 83.132 %, R7 batch was selected as optimized batch. Statistical analysis showed model terms were significant.
 Conclusion: We can conclude that; sustained-release pellets of ritonavir were successfully designed using QbD approach.

Optimization and characterization of novel sustained release supermicro-pellet based dry suspensions that load dexibuprofen

Traditional dosage forms of dexibuprofen extremely limit their clinical applications because of the bitter taste and the frequent drug administration caused by the relatively short half-life of the drug. This study aims to design novel sustained release (SR) supermicro-pellet based dry suspensions that load dexibuprofen, and also optimize the formulations in terms of morphology, release rate, flowability, and physicochemical stability of dosage forms. Drug-loaded pellets were prepared by using a bottom spray fluid bed coating technique using microcrystalline cellulose supermicro-pellets as the core and PVP K30 or Poloxamer 188 as the binder. The drug-loaded pellets were further coated with Kollicoat SR 30D to form SR pellets. The optimal SR dry suspensions are composed of SR pellets, diluent granules, and suspending agents. PVP K30- and Poloxamer 188-based SR pellets release the drug molecules in a SR manner over 8 h and show a high release profile for Poloxamer 188-based pellets. The drug release profile is not affected by the rotation speed of the paddle but shows a distinct pH-responsive behavior. The physical property of dexibuprofen has been changed during the preparation process. The SR dry suspensions (F5, with high amount of xanthan gum in suspending agents and low amount of poloxamer 188 in diluent granules) show high physical stability with the sedimentation rate of 0.8 (Hu/H) within 5 min and good flowability with the angle of repose (θ) at 27°. Low content variations were observed with a value of A+1.80SD ≤ 15, and no significant change was found in the drug content under high humidity and strong light. In conclusion, novel SR supermicro-pellet based dry suspensions have been successfully prepared, and the optimal formulation shows excellent SR, good flowability, content uniformity, and physicochemical stability.

Role of Differential Estrogen Receptor Activation in Airway Hyperreactivity and Remodeling in a Murine Model of Asthma.

Evidence suggests that airway hyperresponsiveness (AHR) is a characteristic feature of asthma. Epidemiological studies have confirmed that the severity of asthma is greater in women, suggesting a critical role of female sex steroid hormones (especially estrogen). Very few in vivo studies have examined the role of sex steroid hormones in asthma, and the sequence of events that occur through differential activation of estrogen receptors (ERs) remains to be determined in asthmatic airways. Our recent in vitro findings indicated that ERβ had increased expression in asthmatic airway smooth muscle (ASM), and that its activation by an ERβ-specific agonist downregulated airway remodeling. In this study, we translated the in vitro findings to a murine asthma model and examined the differential role of ER activation in modulating lung mechanics. C57BL/6J male, female, and ovariectomized mice were exposed to mixed allergen (MA) and subcutaneously implanted with sustained-release pellets of placebo, an ERα agonist (4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol [PPT]), and/or an ERβ agonist (WAY-200070). We then evaluated the effects of these treatments on airway mechanics, biochemical, molecular, and histological parameters. Mice exposed to MA showed a significant increase in airway resistance, elastance, and tissue damping, and a decrease in compliance; pronounced effects were observed in females. Compared with PPT, WAY treatment significantly reversed the MA-induced changes. The increased mRNA/protein expression of ERα, ERβ, and remodeling genes observed in MA-treated mice was significantly reversed in WAY-treated mice. This novel study indicates that activation of ERβ signaling downregulates AHR and airway remodeling, and is a promising target in the development of treatments for asthma.

Self-Micro-Emulsifying Controlled Release of Eugenol Pellets: Preparation, In vitro/In vivo Investigation in Beagle Dogs.

This report aimed to formulate self-micro-emulsifying (SMEDDS) controlled-release pellets delivery system to improve aqueous solubility and in vivo availability of eugenol, a main constituent of clove oil with multiple pharmacological activities. The optimal formulation of eugenol-SMEDDS was eugenol: ethyl oleate: cremophor EL: 1, 2-propylene glycol at the ratio of 5:5:12:8. The SMEDDS were observed under transmission electron microscopy (TEM), and the size distribution was measured with dynamic laser light scatting (DLS). The particle size, index of dispersity (PDI), and zeta potential (Z-potential) were 68.8 ± 0.1nm, 0.285 ± 0.031, and - 11.62 ± 0.63mV, respectively. Eugenol-SMEDDS exhibited substantial increased in vitro dissolution compared with the free eugenol. The eugenol-SMEDDS sustained-release pellets (eugenol-SMEDDS-SR pellets) comprising of eugenol-SMEDDS, hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose (MCC), and ethyl cellulose (EC) coats were obtained via extrusion spheronization technique. Consequently, the obtained pellets observed under scanning electron microscopy (SEM) showed spherical shape with smooth surface, desirable drug loading capacity (7.18 ± 0.17%), greater stability, and controlled release. Meanwhile, the oral test showed that bioavailability of eugenol in pellets was highly improved 23.6-fold to the free eugenol. Overall, these results suggested that the improvement of the oral bioavailability of eugenol-SMEDDS-SR could be due to the successful incorporation of the drug into SMEDDS.

Development and In Vitro-In Vivo Evaluation of a Novel Sustained-Release Loxoprofen Pellet with Double Coating Layer.

This study aimed to develop a novel sustained release pellet of loxoprofen sodium (LXP) by coating a dissolution-rate controlling sub-layer containing hydroxypropyl methyl cellulose (HPMC) and citric acid, and a second diffusion-rate controlling layer containing aqueous dispersion of ethyl cellulose (ADEC) on the surface of a LXP conventional pellet, and to compare its performance in vivo with an immediate release tablet (Loxinon®). A three-level, three-factor Box-Behnken design and the response surface model (RSM) were used to investigate and optimize the effects of the citric acid content in the sub-layer, the sub-layer coating level, and the outer ADEC coating level on the in vitro release profiles of LXP sustained release pellets. The pharmacokinetic studies of the optimal sustained release pellets were performed in fasted beagle dogs using an immediate release tablet as a reference. The results illustrated that both the citric acid (CA) and ADEC as the dissolution- and diffusion-rate controlling materials significantly decreased the drug release rate. The optimal formulation showed a pH-independent drug release in media at pH above 4.5 and a slightly slow release in acid medium. The pharmacokinetic studies revealed that a more stable and prolonged plasma drug concentration profile of the optimal pellets was achieved, with a relative bioavaibility of 87.16% compared with the conventional tablets. This article provided a novel concept of two-step control of the release rate of LXP, which showed a sustained release both in vitro and in vivo.

Progesterone pretreatment reduces the incidence of drug-induced torsades de pointes in atrioventricular node-ablated isolated perfused rabbit hearts.

Higher progesterone concentrations are protective against drug-induced prolongation of ventricular repolarization. We tested the hypothesis that pretreatment with progesterone reduces the incidence of drug-induced torsades de pointes (TdP). Female New Zealand white rabbits (2.5-3.2 kg) underwent ovariectomy and were randomized to undergo implantation with subcutaneous 21-day sustained release pellets containing progesterone 50 mg (n = 22) or placebo (n = 23). After 20 days, hearts were excised, mounted, and perfused with modified Krebs-Henseleit solution. The atrioventricular (AV) node was destroyed manually. Following a 15-minute equilibration period, hearts were perfused with dofetilide 100 nM for 30 minutes, during which the electrocardiogram was recorded continuously. Incidences of spontaneous TdP, other ventricular arrhythmias and mean QTc intervals were compared. Median serum progesterone concentrations were higher in progesterone vs placebo-treated rabbits (3.8 [range, 2.8-5.1] vs 0.7 [0.4-1.7] ng/mL, P < 0.0001). Median serum estradiol concentrations were similar (58 [22-72] vs 53 [34-62] pg/mL), P = 0.79). The incidence of TdP was lower in hearts from progesterone-treated rabbits (27% vs 61%, P = 0.049). The incidences of bigeminy (36% vs 74%, P = 0.03) and trigeminy (18% vs 57%, P = 0.01) were also lower in hearts from progesterone-treated rabbits. There was no significant difference between groups in incidence of couplets (59% vs 74%, P = 0.54) or monomorphic ventricular tachycardia (14% vs 30%, P = 0.28). Maximum QT c interval and short-term beat-to-beat QT interval variability during dofetilide perfusion were significantly shorter in hearts from progesterone-treated rabbits. Pretreatment with progesterone reduces the incidence of drug-induced TdP, bigeminy, and trigeminy in isolated perfused AV node-ablated rabbit hearts.

FORMULATION AND INVESTIGATION OF POLYMERIC MULTIPLE UNIT PELLET SYSTEMS CONSISTING OF SUSTAINED RELEASE GLIMEPIRIDE AND IMMEDIATE RELEASE ATORVASTATIN CALCIUM

Objective: The objective of the present work was to develop novel fixed-dose combinations (FDCs) for improvement of glucose tolerance in type II diabetes mellitus patients associated with dyslipidemia.&#x0D; Methods: Multiple unit pellet systems (MUPSs) consisting of sustained release (SR) glimepiride and immediate release atorvastatin calcium pellets were formulated. The SR glimepiride pellets were prepared using a combination of locust bean gum and gum ghatti/guar gum. Similarly, the immediate release of atorvastatin calcium pellets was prepared using locust bean gum suspension as a binder.&#x0D; Results: The formulated pellets were characterized using Fourier transform infrared spectroscopy (FTIR) and Differential scanning calorimetry (DSC). Further, surface morphology of the formulated pellets was done by scanning electron microscopy (SEM). FT-IR and DSC studies suggested that there were no chemical interactions between the drug and natural polymers. SEM studies revealed that formulated pellets were in spherical shape. Based on in vitro evaluation, the SR glimepiride formulation developed using a combination of 2% locust bean gum and 2.5% gum ghatti polymers sustained the release of the drug up to 12 h. Similarly, the immediate release atorvastatin calcium formulation containing 1% w/w locust bean gum suspension as a binder and 7% croscarmellose sodium showed fast disintegration of pellets. The in vivo studies in albino Wistar rat revealed that there was an improvement in bioavailability of the drugs. Stability studies showed that there were no significant changes in the drug content and physical appearance of the prepared SR glimepiride and immediate release atorvastatin pellet formulations.&#x0D; Conclusion: Thus, the formulated FDC as MUPS can be used as an alternative approach for treating diabetes mellitus-induced dyslipidemia.

Understanding the release performance of pellets with hydrophobic inclusions in sustained-release coating

The aim of this study was to evaluate how the addition of hydrophobic inclusions to sustained-release pellet film coat can affect drug release. Sustained-release formulations, in particular multiparticulate systems are gaining popularity because they are able to reduce the dosing frequency of drugs that require multiple dosing. In addition, the risk of dose dumping is low and local gastrointestinal irritation is minimised. Metformin-loaded pellets, prepared via extrusion-spheronisation, were coated with ethyl cellulose (EC)-based film coat, with and without hydrophobic inclusions to a series of coat thickness. Stearic acid 50 (SA) and hydrogenated castor oil (HCO) were the hydrophobic inclusions used. Drug release was investigated using the USP dissolution apparatus 2 and an ultraviolet imager. Release kinetics were analysed using the zero-order model. The physical properties of the pellets were characterised before and after dissolution. The addition of hydrophobic inclusions to EC-based film coat slowed down drug release, with SA slowing down drug release more than HCO. The influence of hydrophobic inclusions on drug release was clearly observable when the pellets were coated to 10% weight gain. It was postulated that the hydrophobic inclusions acted as physical barriers to increase the tortuosity of the diffusional path through the pellet film coat. The use of hydrophobic inclusions to control the rate of drug dissolution was shown to be promising. This could translate into potential cost and time savings with less materials and time used.

Development of sustained-release pellets to modulate the in vivo processes of the main active components of Danshen: A pharmacokinetic and pharmacodynamic evaluation

BackgroundDanshen is a first-line traditional Chinese medicine derived from Salvia miltiorrhiza Bunge consisting mainly of tanshinone IIA, tanshinol, protocatechuic aldehyde, and salvianolic acid B, it is widely used to treat cardiovascular diseases based on the synergistic effect of its multiple active components. Recent studies have indicated that the overall effect of traditional Chinese medicine is closely related to the in vivo coexistence of a variety of active components. HypothesisThe prolongation of the coexistence of the four active components in Danshen in vivo by regulating their pharmacokinetic processes may contribute to better efficiency. Methods/study designsIndividual sustained-release pellets of the four main active components in Danshen were respectively prepared according to the optimised formulations developed in our previous studies to modulate their in vivo processes, in which the desired release profiles of each kind of sustained-release pellets for formulation optimisation were calculated based on the point-area deconvolution and circadian rhythm of variant angina. The four kinds of sustained-release pellets were filled into capsules on the basis of the original weight ratio of the four active components in purified Salvia miltiorrhiza extract for further in vitro release and pharmacokinetic and pharmacodynamic investigations. ResultsThe release behaviours of the combined Danshen capsules composed of the four kinds of sustained-release pellets were evaluated in three media with different pH levels (pH 1.2, 6.8, and pure water). The release profiles of each kind of sustained-release pellets in pH 6.8 PBS and pH 1.2 HCl were similar to the release profile of those in pure water (similarity factors f2 > 50). Pharmacokinetic studies revealed that the four kinds of sustained-release pellets in the combined Danshen capsules possessed the same Tmax and similar and extended MRT. Moreover, pharmacodynamic studies indicated that the combined Danshen capsules had much better anti-angina effects than commercial Danshen capsules according to comprehensive evaluations via electrocardiogram, serum index (CK-MB, cTn-I, ET, and NO), myocardial oxidative damage, and myocardial pathologic biopsy. ConclusionSustained-release preparations can markedly prolong the in vivo coexistence of multiple components in Danshen to enhance their overall effects, which provides a potent strategy for developing the combination therapy of traditional Chinese medicine.