Croscarmellose Sodium as Pelletization Aid in Extrusion-Spheronization.

Only few excipients are known to be suitable as pelletization aids. In this study, the potential use of croscarmellose sodium (CCS) as pelletization aid was investigated. Furthermore, the impact of cations on extrusion-spheronization (ES) of CCS was studied and different grades of CCS were tested. The influence of different cations on the swelling of CCS was investigated by laser diffraction. Mixtures of CCS with lactose monohydrate as filler with or without the inclusion of different cations were produced. The mixtures were investigated by mixer torque rheometry and consequently extruded and spheronized. Resulting pellets were analyzed by dynamic image analysis. In addition, mixtures of different CCS grades with dibasic calcium phosphate anhydrous (DP) and a mixture with praziquantel (PZQ) as filler were investigated. Calcium and magnesium cations caused a decrease of the swelling of CCS and influenced the use of CCS as pelletization aid since they needed to be included for successful ES. Aluminum, however, led to an aggregation of the CCS particles and to failure of extrusion. The inclusion of cations decreased the uptake of water by the mixtures which also reduced the liquid-to-solid-ratio (L/S) for successful ES. This was shown to be dependent on the amount of divalent cations in the mixture. With DP or PZQ as filler, no addition of cations was necessary for a successful production of pellets, however the optimal L/S for ES was dependent on the CCS grade used. In conclusion, CCS can be used as a pelletization aid.

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.

Applicability of image analysis to support QbD driven development of pellets.

OBJECTIVE: The stages of preparing high drug loaded pellets were investigated using static and dynamic imaging techniques to provide a greater understanding and ease the scale up process. SIGNIFICANCE: An example of a real case laboratory and production scale quality by design (QbD) based development of pellets is demonstrated. Potential process analytical technology (PAT) approaches by dynamic image analysis (DIA) are presented in various process phases. METHODS: Pellets were prepared at laboratory and production scale (high shear granulation, extrusion/spheronization, drying, and coating). The influence of process parameters on pellet properties (aspect ratio (AR), yield, pellet size, and their distribution) was investigated using static and DIA. During coating, we focused on the coating thickness and identification of potential agglomeration. RESULTS AND CONCLUSION: The effects of kneading time, amount of water, extrusion screen plate (ESP) opening diameter and thickness on pellet properties were confirmed in accordance with literature. In terms of screw speed, spheronization speed and time, no considerable influence on pellet properties was observed in the range of studied process parameters, thereby confirming the design space. In addition to the ESP thickness and opening diameter, quality of the ESP impacts the pellet properties. Lastly, coating thickness measurements with dynamic and static image analysis were comparable and an exemplary case of in-line agglomeration detection was presented. Real-time evaluation with PATVIS APA is an effective PAT tool for the evaluation of spheronization (pellet size distribution, AR, and yield) and coating (coating thickness, agglomeration detection).

Liqui-Tablet: the Innovative Oral Dosage Form Using the Newly Developed Liqui-Mass Technology.

In this study, an attempt was made to produce Liqui-Tablets for the first time. This was carried out through the compaction of naproxen Liqui-Pellets. The incentive to convert the novel Liqui-Pellet into Liqui-Tablet was due to the array of inherent advantages of the popular and preferred tablet dosage form. The study showed that naproxen Liqui-Tablet could be successfully produced and the rapid drug release rate (100% drug release ~ 20 min) could be achieved under pH 1.2, where naproxen is insoluble. It was observed that the different pH of the dissolution medium affected the trend of drug release from formulations with varying amounts of liquid vehicle. The order of the fastest drug-releasing formulations was different depending on the pH used. The presence of Neusilin US2 showed considerable enhancement in the drug release rate as well as improving Liqui-Tablet robustness and hardness. Furthermore, images from X-ray micro-tomography displayed a uniform distribution of components in the Liqui-Tablet. The accelerated stability studies showed acceptable stability in terms of dissolution profile.

Fabrication and evaluation of fast disintegrating pellets of cilostazol.

The present study was designed to formulate and develop fast disintegrating pellets of poorly soluble model drug (cilostazol) by reducing the proportion of micro-crystalline cellulose with pre-gelatinized starch (PGS), lactose and chitosan. The bioavailability enhancement of a model drug was achieved by preparing inclusion complex with Captisol® (Sulfobutyl Ether ß cyclodextrin - SBE-ß-CD). Extrusion-spheronization technique was used to formulate pellets. Placket-Burman design was used for the initial screening of most significant factors such as screen size (mm), ratio of micro crystalline cellulose: PGS + lactose + chitosan and % of HPMC which affects pellet properties. The inclusion complex of drug and Captisol® (SBE-ß-CD) was prepared by Solvent Evaporation method and were incorporated into pellets in a predefined proportion. Formulation was optimized by using 32 full factorial design, the optimized batch was selected on the basis of dependent variables such as % yield, pellet size, disintegration time and % Cumulative drug release (%CDR), the obtained results were 87.15%, 0.75 mm, 13 min and 91.024% respectively. Differential scanning calorimetry (DSC) and Fourier transform infrared spectrometry (FTIR) study revealed no significant interaction between drug and polymer. Scanning electron microscopy (SEM) confirmed uniform and spherical shaped pellets having pores on the surface which facilitates wicking action and fast disintegrating property of pellets. A design space was constructed to meet the desirable target and optimized batch. The scope of study can further extended to hydrophobic molecules which may useful due to rapid disintegration and enhanced dissolution rate.

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.

Liquisolid Pellets and Liqui-Pellets Are Not Different.

Our research group has pioneered the development of liquisolid pellets as a new drug delivery system targeting at the improvement of the dissolution rates of poorly water-soluble drugs, combining the technological and biopharmaceutical advantages of both multiparticulate and liquisolid systems. Recently, Lam and collaborators claimed the invention of "liqui-pellets" as "the emerging next-generation oral dosage form which stems from liquisolid concept in combination with pelletization technology". However, the concept of liqui-pellet is not novel. As we demonstrate in this commentary, liqui-pellets are the same type of preparation as our previously and extensively reported liquisolid pellets. Liquisolid pellets have been disclosed in a patent application and public peer-reviewed articles covering the concept, preparation and challenges associated with these systems. There are no technical differences that justify excluding our previous reports as the first reports on liquisolid pellets or liqui-pellets. This commentary highlights the similarities between liquisolid pellets and liqui-pellets, focusing on the anteriority of liquisolid pellets as disclosed by our group.

Development of multiple-unit pellet system tablets by employing the SeDeM expert diagram system II: pellets containing different active pharmaceutical ingredients.

The SeDeM Expert Diagram System (SeDeM EDS) was originally developed to provide information about the suitability of powders to produce direct compressible tablets. Multiple-unit pellet systems (MUPS) are dosage forms consisting of pellets compressed into tablets or loaded into hard gelatin capsules. The aim of this study was to apply the SeDeM EDS to different size pellets (i.e. 0.5, 1.0, 1.5, 2.0, and 2.5 mm) containing different APIs (i.e. doxylamine, ibuprofen or paracetamol) to determine which properties should be corrected to yield MUPS tablet formulations. The SeDeM parameter tests were conducted on the pellets, selected excipients, intermediate blends, and final blends. The study showed that the properties of the pellets depended on the active ingredient and pellet size. The SeDeM compressibility indices indicated that the final pellet blends should be suitable for compression into MUPS tablets. MUPS tablets were prepared from the final blends and evaluated in terms of physico-chemical properties and dissolution profiles. Only three of the MUPS tablet formulations containing ibuprofen and one MUPS tablet formulation containing paracetamol failed content uniformity. The water solubility of the APIs as well as the pellet size (surface area exposed to the dissolution medium) attributed to the difference in drug dissolution rate.

Quality by Design Approach for the Development of Self-Emulsifying Systems for Oral Delivery of Febuxostat: Pharmacokinetic and Pharmacodynamic Evaluation.

The goal of the present investigation is to formulate febuxostat (FXT) self-nanoemulsifying delivery systems (liquid SNEDDS, solid SNEDDS, and pellet) to ameliorate the solubility and bioavailability. To determine the self-nanoemulsifying region, ternary plot was constructed utilizing Capmul MCM C8 NF® as an oil phase, Labrasol® as principal surfactant, and Transcutol HP® being the co-surfactant. Liquid SNEDDS (L-SNEDDS) were characterized by evaluating droplet size, zeta potential, % transmission, and for thermodynamic stability. In vitro dissolution study of FXT loaded L-SNEDDS (batch F7) showed increased dissolution (about 48.54 ± 0.43% in 0.1 N HCl while 86.44 ± 0.16% in phosphate buffer pH 7.4 within 30 min) compared to plain drug (19.65 ± 2.95% in 0.1 N HCl while about 17.61 ± 2.63% in phosphate buffer pH 7.4 within 30 min). Single pass intestinal permeability studies revealed fourfold increase in the intestinal permeability of F7 compared to plain drug. So, for commercial aspects, F7 was further transformed into solid SNEDDS (S-SNEDDS) as readily nanoemulsifying powder form (SNEP) as well as pellets prepared by application of extruder spheronizer. The developed formulation was found superior to pure FXT with enhanced oral bioavailability and anti-gout activity (with reduced uric acid levels), signifying a lipidic system being an efficacious substitute for gout treatment.

Quality by Design Approach for Developing Lipid-Based Nanoformulations of Gliclazide to Improve Oral Bioavailability and Anti-Diabetic Activity.

The aim of the current investigation was to generate a self-nanoemulsifying drug delivery system (SNEDDS) of gliclazide (GCZ) to address the poor solubility and bioavailability. Ternary phase diagram was created with Capmul MCM C8 NF (oil), Cremophor RH 40 (surfactant), and Transcutol HP (co-surfactant) to distinguish the self-emulsifying region. A D-optimal design was employed with three variables, such as oil, surfactant, and co-surfactant, for further optimization of liquid (L)-SNEDDS. GCZ-loaded L-SNEDDs were analyzed for globule size, polydispersity index (PDI), and solubility. In vitro dissolution of optimized L-SNEDDS exhibited (F5) faster drug release (97.84%) within 30 min as compared to plain drug (15.99%). The optimized L-SNEDDS was converted to solid (S)-SNEDDS as a self-nanoemulsifying powder (SNEP) and pellets by extrusion-spheronization. Optimized S-SNEDDS were characterized using Fourier-transform infrared spectroscopy (FTIR), X-ray diffractometry (XRD), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). In vitro dissolution of SNEP (S3) and pellet were 90.54 and 73.76%, respectively, at 30 min. In vivo studies showed a twofold rise in bioavailability through SNEDDS with a significant decline in blood glucose levels compared to plain drug suspension suggesting a lipid-based system as an alternative approach for treating diabetes.

Utilizing mixer torque rheometer in the prediction of optimal wet massing parameters for pellet formulation by extrusion/spheronization.

In this study, we aimed to optimize theophylline pellet formulations using a two-factor three-level full-factorial design (32) by monitoring the concentration of two pellet excipients, polyvinyl pyrrolidone K30 (PVP) binder solution (X1) and the hydrophilic excipient mannitol (X2). Their impact on pellet characteristics (responses) were evaluated. Increasing PVP concentration in the binder solution resulted in an increase in the wet mass torque value. The effect of mannitol, however, was antagonistic. Moreover, the pellet particle size was significantly influenced by the level of mannitol, PVP solution, and quadratic effect of mannitol. Mannitol significantly antagonized the pellet particle size. Furthermore, increased mannitol concentrations significantly enhanced drug dissolution rate from the pellets, whereas PVP concentration in the binder solution significantly reduced the drug dissolution rate. In conclusion, wet granulations can be controlled by monitoring the composition of the binder solution and pellet composition.

Effect of lipid and cellulose based matrix former on the release of highly soluble drug from extruded/spheronized, sintered and compacted pellets.

BACKGROUND: The study was to develop an extended release (ER) encapsulated and compacted pellets of Atenolol using hydrophobic (wax based and polymeric based) and high viscosity grade hydrophilic matrix formers to control the release of this highly water soluble drug by extrusion/spheronization (ES). Atenolol is used for cardiovascular diseases and available as an immediate release (IR) tablet dosage form. The lipids, Carnauba wax (CW), Glyceryl monostearate (GMS) and cellulose based i.e. Hydroxypropyl methylcellulose (HPMC) and Ethyl cellulose (EC) were used in preparing Atenolol ER pellets. Thermal sintering and compaction techniques were also applied to control the burst release of Atenolol. METHOD: For this purpose, thirty-six trial formulations (F1-F36) were designed by Response Surface Methodology (RSM), using Design-Expert 10 software, keeping (HPMC K4M, K15 M & K100 M), (EC 7FP, 10FP & 100FP), waxes (GMS, & CW), their combinations, sintering temperature and duration, as input variables. Dissolution studies were performed in pH, 1.2, 4.5 and 6.8 dissolution media. Drug release kinetics using different models such as zero order, first order, Korsmeyer-Peppas, Hixon Crowell, Baker-Lonsdale and Higuchi kinetics were studied with the help of DDsolver, an excel based add-in program. RESULTS: The formulations F35 and F36 showed compliance with Korsmeyer-Peppas Super case II transport model (R2 = 0.975-0.971) in dissolution medium pH 4.5. No drug excipient interaction observed by FTIR. Stereomicroscopy showed that sintered combination pellets, (F35), were highly spherical (AR = 1.061, and sphericity = 0.943). The cross-sectional SEM magnification (at 7000X) of F34 and F35 showed dense cross-linking. The results revealed that the optimized formulations were F35 (sintered pellets) and F36 (compacted pellets) effectively controlling the drug release for 12 h. CONCLUSION: Extended-release encapsulated, and compacted pellets were successfully prepared after the combination of lipids CW (10%) and GMS (20%) with EC (10FP 20% & 100FP 20%). Sintering and compaction, in addition, stabilized the system and controlled the initial burst release of the drug. Extended release (ER) Atenolol is an effective alternative of IR tablets in controlling hypertension and treating other cardiovascular diseases.

Approaches to developing fast release pellets via wet extrusion-spheronization.

Microcrystalline cellulose (MCC) is widely regarded as the excellent choice to manufacture pellets via wet extrusion-spheronisation (ES) process due to its excellent water uptake capability, water holding capacity, desirable rheological properties, cohesiveness and plasticity etc. Nevertheless, in spite of all these advantages, limitations associated with the application of MCC also have been reported. The most prevailing limitation is prolonged or incomplete drug release profile due to the lack of disintegration as pellet contracts significantly during the drying process, especially when in combination with poorly soluble drug at a high level. This characteristic limits the application of MCC in immediate release formulations. Over the years, many approaches have been tried to overcome this disadvantage, such as modifying MCC, incorporation of superdisintegrant, increasing the porosity of pellet, partial or complete substitution for MCC, enhancing the solubility of poorly soluble drug (e.g. solid dispersion, self-emulsifying drug-delivery system), etc. In this review, we will provide an updated and integrated discussion of current approaches to prepare fast release pellets via wet ES.

Development of multiple-unit pellet system tablets by employing the SeDeM expert diagram system I: pellets with different sizes.

Multiple-unit pellet systems (MUPS) provide several pharmacokinetic and pharmacodynamic advantages over single-unit dosage forms, however, compression of pellets into MUPS tablets present certain challenges. Although the SeDeM Expert Diagram System (SeDeM EDS) was originally developed to provide information about the most appropriate excipient and the minimum amount thereof that is required for producing direct compressible tablets, this study investigated the possibility to apply the SeDeM EDS in the production of MUPS tablets. In addition, the effect of pellet size (i.e. 0.5, 1.0, 1.5, 2.0, and 2.5 mm) on SeDeM EDS predictions regarding the MUPS tablet formulations was investigated. The compressibility incidence factor values were below the acceptable value (i.e. 5.00) for all the pellet sizes. Kollidon® VA 64 was identified as the most appropriate excipient to improve compressibility. The compression indices, namely, the parameter index (IP), parametric profile index (IPP), and good compression index (GCI) indicated that acceptable MUPS tablets could be produced from the final pellet-excipient blends based on predictions from the SeDeM EDS. These MUPS tablets complied with specifications for friability, hardness, and mass variation. The SeDeM EDS system is therefore applicable to assist in the formulation of acceptable MUPS tablets.

Preparation, Characterization and In Vitro / In Vivo Evaluation of Oral Time-Controlled Release Etodolac Pellets.

The objective of this study was to prepare time-controlled release etodolac pellets to facilitate drug administration according to the body's biological rhythm, optimize the drug's desired effects, and minimize adverse effects. The preparation consisted of three laminal layers from center to outside: the core, the swelling layer, and the insoluble polymer membrane. Factors influenced the core and the coating films were investigated in this study. The core pellets formulated with etodolac, lactose, and sodium carboxymethyl starch (CMS-Na) were prepared by extrusion-spheronization and then coated by a fluidized bed coater. Croscarmellose sodium (CC-Na) was selected as the swelling agent, and ethyl cellulose (EC) as the controlled release layer. The prepared pellets were characterized by scanning electron microscopy and evaluated by a dissolution test and a pharmacokinetic study. Compared with commercial available capsules, pharmacokinetics studies in beagle dogs indicated that the prepared pellets release the drug within a short period of time, immediately after a predetermined lag time. A good correlation between in vitro dissolution and in vivo absorption of the pellets was exhibited in the analysis.

Preparation, Characterization and Pharmacokinetics Evaluation of the Compound Capsules of Ibuprofen Enteric-Coated Sustained-Release Pellets and Codeine Phosphate Immediate-Release Pellets.

The objective of this study was to prepare ibuprofen enteric-coated sustained-release pellets (IB-SRPs) and codeine phosphate immediate-release pellets (CP-IRPs) to play a synergistic role in analgesia. The pellets were developed by extrusion-spheronization and fluidized bed coating technology. The single-factor investigation was used to determine the optimal prescription and process. The sustained-release membrane of IB-SRPs was water-insoluble ethyl cellulose (EC), triethyl citrate (TEC) was used as plasticizer, and hydroxypropyl methylcellulose (HPMCP) was chose as porogen. Besides, the immediate-release layer of CP-IRPs was gastric-soluble coating film. The ibuprofen and codeine phosphate compound capsules (IB-CP SRCs) were prepared by IB-SRPs and CP-IRPs packed together in capsules with the optimum doses of 200 and 13 mg, respectively. The prepared pellets were evaluated by scanning electron microscopy and dissolution test. Pharmacokinetic studies in beagle dogs indicated that the optimized IB-CP SRCs had smaller individual differences and better reproducibility comparing with commercial available tablets. Additionally, IB-CP SRCs achieved consistency with in vivo and in vitro tests. Therefore, IB-CP SRCs could play a great role in rapid and long-term analgesic.

Lipids bearing extruded-spheronized pellets for extended release of poorly soluble antiemetic agent-Meclizine HCl.

BACKGROUND: Antiemetic agent Meclizine HCl, widely prescribed in vertigo, is available only in immediate release dosage forms. The approved therapeutic dose and shorter elimination half-life make Meclizine HCl a potential candidate to be formulated in extended release dosage form. This study was aimed to develop extended release Meclizine HCl pellets by extrusion spheronization using natural and synthetic lipids. Influence of lipid type, drug/lipid ratio and combinations of different lipids on drug release and sphericity of pellets were evaluated. METHODS: Thirty two formulations were prepared with four different lipids, Glyceryl monostearate (Geleol®), Glyceryl palmitostearate (Precirol®), Glyceryl behenate (Compritol®) and Carnauba wax, utilized either alone or in combinations of drug/lipid ratio of 1:0.5-1:3. Dissolution studies were performed at variable pH and release kinetics were analyzed. Fourier transform infrared spectroscopy was conducted and no drug lipid interaction was found. RESULTS: Sphericity indicated by shape factor (eR) varied with type and concentration of lipids: Geleol® (eR = 0.891-0.997), Precirol® (eR = 0.611-0.743), Compritol® (eR = 0.665-0.729) and Carnauba wax (eR = 0.499-0.551). Highly spherical pellets were obtained with Geleol® (Aspect ratio = 1.005-1.052) whereas irregularly shaped pellets were formed using Carnauba wax (Aspect ratio = 1.153-1.309). Drug release was effectively controlled by three different combinations of lipids: (i) Geleol® and Compritol®, (ii) Geleol® and Carnauba wax and (iii) Geleol®, Compritol® and Carnauba wax. Scanning electron microscopy of Compritol® pellets showed smooth surface with pores, whereas, irregular rough surface with hollow depressions was observed in Carnauba wax pellets. Energy dispersive spectroscopy indicated elemental composition of lipid matrix pellets. Kinetics of (i) Geleol® and Compritol® pellets, explained by Korsmeyer-Peppas (R2 = 0.978-0.993) indicated non-Fickian diffusion (n = 0.519-0.597). Combinations of (ii) Geleol® and Carnauba wax and (iii) Geleol®, Compritol® and Carnauba wax pellets followed Zero-order (R2 = 0.991-0.995). Similarity test was performed using combination of Geleol® and Compritol® (i) as a reference. CONCLUSIONS: Matrices for the extended release of Meclizine HCl from extruded-spheronized pellets were successfully formed by using three lipids (Geleol®, Compritol® and Carnauba wax) in different combinations. The encapsulated pellets of Meclizine HCl can be effectively used for treatment of motion sickness, nausea and vertigo for extended period of time.

Synthesis, Comparison, and Optimization of a Humic Acid-Quat10 Polyelectrolyte Complex by Complexation-Precipitation versus Extrusion-Spheronization.

A novel humic acid and polyquaternium-10 polyelectrolyte complex (PEC) was synthesized utilizing two methods and the solubility and permeability of efavirenz (EFV) were established. Complexation-precipitation and extrusion-spheronization were used to synthesize and compare the drug-loaded PECs. The chemical integrity, thermo-mechanical differences, and morphology between the drug-loaded PECs produced by the two methods were assessed by attenuated total reflectance-Fourier transform infrared, differential scanning calorimetry, and SEM. The extent of drug solubilization was determined using the saturation solubility test while the biocompatibility of both PECs was confirmed by cytotoxicity studies on human adenocarcinoma cells (caco2). Bio-relevant media was used for the solubility and permeability analysis of the optimized PEC formulations for accurate assessment of formulation performance. Ritonavir (RTV) was loaded into the optimized formulation to further corroborate the impact of the PEC on the solubility and permeability properties of a poorly soluble and poorly permeable drug. The optimized EFV-loaded PEC and the RTV-loaded PEC exhibited 14.16 ± 2.81% and 4.39 ± 0.57% increase in solubility, respectively. Both PECs were compared to currently marketed formulations. Intestinal permeation results revealed an enhancement of 61.24 ± 6.92% for EFV and 38.78 ± 0.50% for RTV. Although both fabrication methods produced PECs that enhanced the solubility and permeability of the model Biopharmaceutics Classification System Class II and IV drugs, extrusion-spheronization was selected as most optimal based on the higher solubility and permeability improvement and the impact on caco2 cell viability.

[Wetting agent dosage screening for traditional Chinese medicine pellet based on torque rheological property].

With lubricant and bonding effect simultaneously, wetting agent has direct effect on properties of wet mass and extrudate, thus affecting the forming quality of pellets in extrusion-spheronization process. In this research, 25 representative kinds of traditional Chinese medicine(TCM) were selected as model drugs and 20%, 30% and 40% drug loading were set with MCC as their balling agent. The torque rheological curves were measured to get parameters such as maximum torque (Tmax) and corresponding water addition (WTmax) for these 75 raw materials by a mixer torque rheometer (MTR).The results showed that among 75 representative raw materials, 74 ones could be obtained for spherical pellets under the water addition of WTmax-2. corresponding to the second largest torque in torque rheological curve, suggesting that MTR could be used to select the optimal wetting agent dosage of TCM pellets. So the tedious and expensive pre-production work could be considerably reduced when TCM pellets were prepared.

Feasibility studies of concomitant administration of optimized formulation of probiotic-loaded Vancomycin hydrochloride pellets for colon delivery.

Objective of this study was to develop Vancomycin HCl pellets loaded with Saccharomyces boulardii (S.b.) for pH-dependent system and CODES™ for augmenting the efficacy of Vancomycin HCl in the treatment of colitis. Pellets were prepared by extrusion-spheronization. In the pH-dependent system, the pellets were coated with Eudragit FS 30D. These pellets exhibited spherical form and a uniform surface coating. The CODES™ system consisted of three components: core containing mannitol, drug and probiotic, an inner acid-soluble coating layer, and an outer layer of enteric coating material. Statistical factorial design was used to optimize both formulations. Scanning electron micrographs of coated pellets revealed uniform coating. In vitro drug release of these coated pellets was studied sequentially in various buffers with (2%) and without rat cecal content for a period of 12 h. From the optimized pH-dependent formulation, F6 (20% w/w coating level and 15% w/v concentration of polymer), higher amount of probiotic was released in earlier time phase (first 5 h) as compared to the CODES™ and so R5 [containing acid-soluble inner coating layer (15% w/w coating level and 12% w/v concentration of Eudragit E100), and an outer layer of enteric coating material (12% w/w coating level and 10% w/v concentration of Eudragit L100)] was considered as the best formulation after confirming in vivo X-ray studies conducted on rabbits, suggesting that Vancomycin HCl and S.b. may be co-administered as pellets [CODES™] to enhance the effectiveness of Vancomycin HCl in the treatment of colitis without its associated side effects, which can only be confirmed after clinical trials.