Sustained-release Pellet Formulation Research Articles

Bioavailability of a novel sustained-release pellet formulation of 5-flucytosine in healthy-fed participants for use in patients with cryptococcal meningitis.

Cryptococcal meningoencephalitis (CM) is an opportunistic fungal infection and a major cause of death among people living with human immunodeficiency virus in sub-Saharan Africa. 5-flucytosine (5-FC) is a unique, brain-permeable antifungal agent used to reduce mortality from CM and to prevent disease in individuals carrying cryptococcal antigen. 5-FC has a short plasma half-life, requiring 6-hourly oral dosing with an immediate-release (IR) formulation, a significant challenge in hospital and outpatient settings, risking a lack of compliance. We recently reported the relative bioavailability in fasting conditions of a sustained release (SR) oral pellet formulation of 5-FC. In this phase I study, we assessed the safety and pharmacokinetic profiles of the new 5-FC SR formulation in a single dose (2 × 3000 mg), relative to 5-FC IR tablets (Ancotil®; 1500 mg b.i.d.) in healthy participants in fed conditions. This randomized, two-period crossover study was conducted in South Africa to confirm the dose of the identified 5-FC SR formulation for a twice-daily 5-FC regimen in patients. Thirty-six healthy participants were included. All treatments were well tolerated and no serious adverse event was reported. Cmax and AUC(0-t) for the SR formulation (49.2 ± 10.49 μg/mL and 640.4 ± 126.4 h.μg/mL, respectively) were significantly higher than for the IR formulation (36.8 ± 7.61 μg/mL and 456.6 ± 72.8 h.μg/mL, respectively). A physiological based pharmacokinetic model (PBPK) predicted that under fasting conditions, 6000 mg SR pellets would show a good overlap with the IR product (3000 mg b.i.d), thus 6000 mg SR 5-FC b.i.d. in fasting conditions is recommended.

Optimization and evaluation of Lisinopril mucoadhesive sustained release matrix pellets: In-vitro and ex-vivo studies

Lisinopril (LIS) is antihypertensive drug, classified as a class III drug with high water solubility and low permeability. To overcome the low permeability, 32 factorial designs aimed to formulate LIS as a sustained-release (LIS-SR) matrix pellet by extrusion/spheronization. Matrix pellets were composed of wet mass containing Avicel® and polymeric matrix polymers (sodium alginate (SA) and chitosan (CS)). Evaluation of the effect of two independent variables, matrix-forming units (SA and CS) on mean line torque, on pellet size, dissolution rate after 6 h, and mucoadhesion strength of the pellets were assessed using Statgraphics software. The tested formulations (F1-F9) showed that mean line torque ranged from 1.583 to 0.461 Nm, with LIS content in the LIS-SR pellets ranged from 87.9 to 103%, sizes varied from 1906 to 1404 µm and high percentages of drug released from pellets formulations (68.48 to 74.18 %), while the mean zeta potential value of mucoadhesive range from −17.5 to –22.9 mV.The selection of optimized formulation must have the following desirability: maximum peak torque, maximum pellets’ particle size, and minimum % LIS release after 6hr. LIS optimized sustained release pellet formula composed of 2,159 % SA and 0.357 % CS was chosen as optimized formula. It’s showed a 1.055 Nm mean line torque was responsible for the increased pellet size to 1830.8 μm with decreased release rate 56.2 % after 6 hr, and −20.33 mV average mucin zeta potential.Ex-vivo mucoadhesion studies revealed that that the optimize formulation, exhibited excellent mucoadhesive properties, after 1 h, about 73% of the pellets were still attached to the mucus membrane. Additionally, ex-vivo permeation determination of LIS from the optimized LIS-SR formulation was found to be significantly higher (1.7-folds) as compared to free LIS.In conclusion: LIS-SR matrix pellets, prepared with an extrusion/spheronization have desirable excellent characteristics in-vitro and ex-vivo sustained-release pellet formulation of LIS-SR was able to sustain the release of LIS for up to 8 h.

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.

Increased bioavailability of tylosin phosphate as in-feed medication formulated for long-action pellets in broiler chickens

Circadian variation of serum concentrations of tylosin in broiler chickens after in-feed medication prompted a comparison study of the serum profiles of this drug after in-feed medication with standard tylosin phosphate (Tprf reference formulation group), and after in-feed medication with a sustained-release pellet formulation (Tpsr group), based on Patent No.MX/a/2012/013222 and PCT/MX2013/000137, in broiler chickens. Six hundred 4-week-old Ross broiler chickens were in-feed medicated with tylosin phosphate at an approximate dose of 25.2 mg/kg/d, based on daily feed consumption values and a final concentration of tylosin in feed of 200 mg/kg of feed. Approximately 2 to 3 mL of blood were obtained per 5 chickens every 2 h, avoiding the sampling of a bird more than once and during 72 h after making medicated feed available for the first time. Serum concentrations of tylosin were determined by HPLC. Gaussian multi-peak regressions were then fitted to serum concentration vs. time profiles. Day by d areas under the serum concentration vs. time profiles (AUC0–24), as well as overall AUC0–72, were statistically higher for the Tpsr group (P < 0.001). Also, maximum serum concentrations obtained and relative bioavailability for the Tpsr formulation were statistically higher (382.8%) as compared to the Tprf group (P < 0.01). Considering the referred improved values of AUC observed in the Tpsr formulation, as well as the fact that tylosin is a time-dependent antibacterial drug, better clinical responses are postulated with this pharmaceutical preparation intended for chickens. Tissue deposition studies for this new formulation of tylosin are required.

Preparation and evaluation of ziprasidone-phospholipid complex from sustained-release pellet formulation with enhanced bioavailability and no food effect.

The purpose of this work was to develop ziprasidone-phospholipid complex (ZIP-PLC) in sustained-release pellets to enhance the oral bioavailability and overcome the food effect of ziprasidone. Ziprasidone-phospholipid complex was formulated by solvent-evaporation method. The complexes were characterized by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and solubility testing. The optimized ZIP-PLC was used to prepare ZIP-PLC sustained-release pellets via extrusion-spheronization method. The pellets were characterized by in vitro drug-release studies and administered to fasted and fed beagle dogs, and their pharmacokinetics were compared with commercial formulation Zeldox capsule as a control. The results of FTIR, SEM, DSC and PXRD studies confirmed the formation of phospholipid complex. Solubility studies showed there was a higher solubility in water for ZIP-PLC than monohydrate ziprasidoe. The in vitro release rate of ziprasidone from the ZIP-PLC sustained-release pellet exhibited controlled-release characteristics with over 95% total release in 12 h. Pharmacokinetic studies in beagle dogs showed ziprasidone with prolong actions, and no food effect was achieved simultaneously in ZIP-PLC sustained-release pellet compared with Zeldox capsule. The results indicated a sustained release with prolonged actions of schizophrenia and bipolar disorder treatment.

Characterization and evaluation of self-nanoemulsifying sustained-release pellet formulation of ziprasidone with enhanced bioavailability and no food effect

The purpose of this work was to develop self-nanomulsifying drug delivery systems (SNEDDS) in sustained-release pellets of ziprasidone to enhance the oral bioavailability and overcome the food effect of ziprasidone. Preformulation studies including screening of excipients for solubility and pseudo-ternary phase diagrams suggested the suitability of Capmul MCM as oil phase, Labrasol as surfactant, and PEG 400 as co-surfactant for preparation of self-nanoemulsifying formulations. Preliminary composition of the SNEDDS formulations were selected from the pseudo-ternary phase diagrams. The prepared ziprasidone-SNEDDS formulations were characterized for self-emulsification time, effect of pH and robustness to dilution, droplet size analysis and zeta potential. The optimized ziprasidone-SNEDDS were used to prepare ziprasidone-SNEDDS sustained-release pellets via extrusion-spheronization method. The pellets were characterized for SEM, particle size, droplet size distribution and zeta potential. In vitro drug release studies indicated the ziprsidone-SNEDDS sustained-release pellets showed sustained release profiles with 90% released within 10 h. The ziprsidone-SNEDDS sustained-release pellets were administered to fasted and fed beagle dogs and their pharmacokinetics were compared to commercial formulation of Zeldox as a control. Pharmacokinetic studies in beagle dogs showed ziprasidone with prolonged actions and enhanced bioavailability with no food effect was achieved simultaneously in ziprsidone-SNEDDS sustained-release pellets compared with Zeldox in fed state. The results indicated a sustained release with prolonged actions of schizophrenia and bipolar disorder treatment.

Sustained-release pellets of nifedipine using microcrystals combined with MCC-based matrix

The purpose of this study was to prepare sustained-release pellets of nifedipine (NSPs) based on MCC matrix. Wet-milling and extrusion-spheronization techniques were employed to prepare the microcrystals and pellets, respectively. The drug release mechanism and the influencing factors were investigated. After milled with HPMC (E5), the mean particle size of nifedipine in co-grinding mixture (CGM) was 5 μm, which is 15-fold smaller than that of raw material. DSC, X-ray powder diffraction and microscopic observation confirmed the microcrystals of drug were maintained in the CGM. With increased milling time and the content of HPMC, the dissolution rate was greatly enhanced compared with the raw material. The NSPs prepared by MCC and the CGM, which was obtained by cogrinding nifedipine with 5% HPMC solution for 210 min, exhibited sustained release pattern within 8 h. Nifedipine release from MCC-based NSPs followed the Korsmeyer model and closely related to the microstructure of pellet. High stability of NSPs was confirmed after 6 months of accelerated stability test. Using commercially available sustained product as reference, bioequivalence study in beagle dogs was executed and two formulations were bioequivalent. This sustained release pellet formulation of nifedipine was advantageous with convenient and easy scaled-up preparation process.

Characterization and evaluation of self-microemulsifying sustained-release pellet formulation of puerarin for oral delivery

The present study aims to develop self-microemulsifying drug delivery systems (SMEDDS) in sustained-release pellets of puerarin to enhance the oral bioavailability of puerarin. The performances of puerarin–SMEDDS including oils, emulsifiers, and co-emulsifiers were evaluated. Pseudo-ternary phase diagrams shows that the optimized formulation consisted of castor oil as the oil phase, Cremophor® EL as the emulsifier, and 1,2-propanediol as the co-emulsifier. SMEDDS sustained-release pellets were prepared via extrusion–spheronization. The particle size distributions of the formulations were determined using transmission electron microscopy and scanning electronic microscopy. The mean particle size was 50±8nm. The pharmacokinetics and bioavailability of the puerarin–SMEDDS sustained-release pellets and puerarin tablets were evaluated and compared in beagle dogs. The absolute bioavailability of the puerarin–SMEDDS sustained-release pellets was enhanced by approximately 2.6-fold compared with that of the puerarin tablet. The relative bioavailability (Frel) of the SMEDDS pellets was 259.7% compared with the tablet group. The results demonstrated that the puerarin–SMEDDS sustained-release pellets had a sustained-release effect, and could remarkably improve the oral bioavailability of puerarin.

Sustained-Release Pellets Prepared by Combination of Wax Matrices and Double-Layer Coatings for Extremely Water-Soluble Drugs

This study was performed in order to develop a sustained-release pellet formulation containing venlafaxine hydrochloride (VEN), an extremely water-soluble drug, prepared by combination of wax matrices and double-layer coatings. The influence of both double-layer polymeric coats and wax matrices on the release of VEN from sustained-release pellets was investigated. The pellets were prepared by wet mass extrusion spheronization methods and then coated with a fluidized bed coater. For the pellets coated with Eudragit® NE30D alone, a coating level of nearly 40% was required to pass the dissolution test compared with commercial product, and it was accompanied by an unacceptable lag time. The application of an alcohol-soluble polymeric subcoat, Opadry® I, was added before the Eudragit® NE30D coating process, which resulted in a marked delay in drug release. However, a faster release was observed for the formulation coated with a high subcoat level (10%) at the end of the dissolution test. A further delay in drug release was observed when a wax matrix, octadecanol, was added to the core pellet formulation. The kinetics of drug release changed from the Higuchi model to a zero order model and the predominant mechanism controlling drug release changed from diffusion to dissolution upon increasing the amount of octadecanol within the matrix pellets. In addition, the drug release was markedly influenced by the drug to matrix ratio. In conclusion, the 40% drug-loaded core pellets with double-layer coatings (8% Opadry® I and 12% Eudragit® NE30D) and 20% octadecanol matrix produced the desired profile for once-daily sustained release compared with the commercial product, and these pellets remained stable during storage.

Comparative efficacy and tolerability of two sustained-release formulations of diclofenac: results of a double-blind, randomised study in patients with osteoarthritis and a reappraisal of diclofenac's use in this patient population

ABSTRACTObjective: To compare the analgesic efficacy and tolerability of a sustained-release pellet formulation of diclofenac (Olfen-100 SR Depocaps, SR-CAP, Mepha Ltd, Aesch, Switzerland) with the standard reference formulation (Voltaren retard 100, SR-TAB, Novartis Pharma AG, Basel, Switzerland), both containing 100 mg diclofenac sodium, in patients with osteoarthritis (OA) of the knee and/or hip. In addition, diclofenac's current place in the symptomatic therapy of OA is briefly reviewed.Methods: In this 2-week double-blind, active-controlled, non-inferiority trial, 210 OA patients were randomised to receive either SR-CAP once daily or SR-TAB once daily (n = 105 for both groups). The primary efficacy endpoint was the change in visual analogue scale (VAS) pain score (0–100 mm) at rest at Day 14 compared with baseline. Secondary variables included the change in VAS pain score on movement and global assessments of efficacy and tolerability using verbal rating scales (VRS).Results: Between baseline and Day 14, mean ± SD VAS pain score at rest decreased by 44.4 ± 18.5 mm in the SR-CAP group (n = 89) compared with 41.2 ± 19.8 mm in the SR-TAB group (n = 82) based on the per protocol population. Comparable changes were observed in the intention-to-treat population. The lower bound of the 1-sided 97.5% confidence interval was –2.7 mm and greater than the prespecified non-inferiority limit of –10 mm. There was a trend towards a better tolerability with SR-CAP compared with SR-TAB based on mean ± SD VRS scores (SR-CAP, 0.6 ± 0.68; SR-TAB, 0.9 ± 1.0 for assessment by patients; p = 0.063).Conclusion: SR-CAP is as effective as and possibly better tolerated than SR-TAB in patients suffering from painful OA.

Dose-Related Control of Allergic Rhinitis Symptoms by a H1-Receptor Antagonist

The aim of the study was to evaluate the efficacy and duration of two doses of dimethindene, in a sustained release pellet formulation, with a standardized grass pollen provocation model (Vienna Challenge Chamber, VCC). The study of 12 grass pollen-allergic volunteers (verified by case history, skin prick test and RAST) was carried out in a placebo-controlled, double-blind, cross-over design. 12 h before a 4-hour continuous challenge with permanent 1,000 Dactylis grass pollen/m3 of air in the VCC, 4 or 8 mg of dimethindene (Fenistil pellets) or an identically appearing placebo was administered in three sessions. Nasal flow and resistance, nasal secretion and subjective symptoms were recorded at 15-min intervals during this long-term challenge under reproducible conditions. In comparison to placebo, dimethindene leads to a statistically significant reduction (p < 0.05) in nasal response and clinical symptoms for at least 16 h after treatment. The efficacy of 8 mg dimethindene was superior to that of 4 mg dimethindene; however, the differences between both active treatments were not statistically significant. Therefore 4 mg dimethindene once a day is adequate for usual pollinotic disease conditions.

Pharmacokinetics of Nilvadipine

Nilvadipine is absorbed rapidly and completely and its absolute bioavailability is about 14-19% because of its high first-pass metabolism. Maximum plasma levels and the extent of bioavailability increase proportionally with the dose. Nilvadipine is mainly excreted via the kidney as inactive metabolites. Slow tissue redistribution is probably the reason for the terminal elimination half-life of 15-20 h. There was a good correlation between the estimated tissue concentration and the reduction in blood pressure in patients. The use of the sustained-release pellet formulation can prevent plasma level peaks and thereby lessen the typical side effects of dihydropyridine calcium antagonists. The pharmacokinetics of nilvadipine were not affected by impaired renal function, and although the bioavailability was increased in liver cirrhosis, there was no accumulation after repeated doses. There was no effect on plasma digoxin levels. The plasma concentration of nilvadipine can be affected by either activation or inhibition of the cytochrome P450 system. The use of a sustained-release once-a-day formulation to lower the peaks in plasma levels along with nilvadipine's long terminal half-life means that this well-tolerated pharmaceutical formulation can be employed in clinical trials for the treatment of hypertension and expected to work over 24 h.

Scintigraphic and pharmacokinetic assessment of a multiparticulate sustained release formulation of diltiazem

The in vivo behaviour of a sustained release multiparticulate form of diltiazem (240 mg) has been evaluated by gamma scintigraphy in eight subjects under fasting or fed conditions. The gastric emptying of the pellet formulation was significantly influenced by the presence of food. Transit through the small intestine was unaffected by food and in the majority of cases, the formulation reached the caecum about 3–4 h after leaving the stomach. Post-prandial administration of the sustained release pellet formulation did not affect the bioavailability of the drug. The type of oral formulation (i.e. solution or pellets) appeared to affect the rate, but not the extent, of absorption with the relative bioavailability (pellets to solution) being greater than 90%.

Factors affecting drug release from a pellet system coated with an aqueous colloidal dispersion

The formulation of sustained-release pellets of dextromethorphan hydrobromide is described. The system used consisted of drug-coated sugar spheres which were then overcoated with the rate-controlling membrane. The membrane was produced by spray-coating with an aqueous dispersion of ethylcellulose containing hydroxypropyi methylcellulose. It is shown that adequate post-coating conditioning is important to ensure consistency of release rates. Conditioning at 60° C for at least l h is necessary in order to ensure that the formulations produced show no ageing effects in release rates. Drug release could be made pH-independent by a choice of proper formulation.

Urinary pharmacokinetics of orally administered ketoprofen in man.

The urinary pharmacokinetics of ketoprofen were compared after administration of single doses of standard ketoprofen capsules or two sustained-release pellet formulations of ketoprofen to nine healthy volunteers, using a specific and sensitive high-performance liquid chromatographic assay procedure. The sustained-release pellet formulation with the faster in vitro release characteristics was shown to be bioequivalent to ketoprofen capsules ('Orudis'). The mean (+/- standard deviation) apparent elimination half-life of ketoprofen after this sustained-release formulation was 7.4 +/- 3.1 h, compared with 4.1 +/- 0.85 h after ketoprofen capsules. The sustained-release formulation with the slower in vitro dissolution characteristics also exhibited slower in vivo dissolution, but was only 65% bioavailable, compared to ketoprofen capsules. A disproportionately large degree of elimination of free ketoprofen was observed between 0-6 h after dosing with ketoprofen capsules. This result could be explained by a saturable mechanism in the metabolism of ketoprofen to its glucuronide. however, since the renal excretion of free ketoprofen is not a major route of ketoprofen elimination, relatively large alterations in this parameter will not markedly alter elimination half-life or area under the plasma ketoprofen concentration against time curve. Thus, the clinical significance of such a mechanism is probably negligable.