Solid Dispersion Pellets Research Articles

Understanding the Conditions Under Which Drugs are Transferred from the Stomach Through the Upper Small Intestine After a High-Calorie, High-Fat Meal

Information on the conditions under which drugs are transferred from the stomach through the upper small intestine after a high-calorie, high-fat meal is very limited. To simulate the drug presence after disintegration and arrival in the antral region, paracetamol solution and Sporanox® amorphous solid dispersion pellets at two dose levels were administered to the antrum of 8 healthy adults 30 min after administration of a high-calorie, high-fat meal on a crossover basis. The overall median buffer capacity of antral contents was estimated to be 18.0 and 24.0 mmol/ml/ΔpH when titrating with NaOH and HCl, respectively. The corresponding values for the contents of upper the small intestine were 14.0 and 16.8 mmol/ml/ΔpH, respectively. The drug transfer process from the antrum through the upper small intestine occurred with apparent first-order kinetics. The best estimate for the antral emptying half-life was 39min and 45min for paracetamol and itraconazole, respectively, the apparent volume of contents of the upper small intestine was more than double compared with previously reported values in the fasted state, the half-life of drug elimination from the upper small intestine was similar to recent estimates for highly permeable drugs in the fasted state, and the apparent volume of antral contents during the first couple of hours post drug administration was 303mL. Information collected in this study could increase the reliability of in silico and/or in vitro modelling approaches applied in clinical drug development.

Green Tea Extract Solid Dispersion Pellets with Enhanced Permeability for Hyperlipidemia

Green tea extract, rich in polyphenols like catechins, has been reported to have pharmacological benefits in patients with hyperlipidemia. The minimal membrane permeability of green tea limits its use in terms of bioavailability. To improve the permeability of green tea catechins in order to enhance theiranti-hyperlipidemia activity, a surfactant-based polymer was used to formulate a solid dispersion of green tea and convert it into commercially acceptable pellets. Green tea extract solid dispersions (GTE-SDs) were prepared withsolvent evaporation method using Soluplus® as a carrier. The GTE-SDs were evaluated for ex vivo permeation studies and characterized using FTIR, DSC, and XRD for confirming the formation of SD. The GTE-SDs exhibiting enhanced ex vivo permeation of EGCG were converted into a pellet formulation using the extrusion spheronization technique while being optimized using a 32 full factorial design. Soluplus® exhibited a four-fold improvement in the ex vivo permeation of EGCG from GTE-SD pellets (33.27%) as compared to GTE (10.43%) (p-value < 0.0001). In male Wistar rats, optimized GTE-SD pellets reduced the lipid blood profiles as compared to GTE (p-value < 0.0001). Thus, GTE-SD pellets can serve as an effective drug delivery platform for hyperlipidemia.

Preparation, optimization and bioavailability studies of the bergenin solid dispersion pellets

In this study, the bergenin solid dispersion pellets (BN-SDP) were prepared using fluidized bed technology by spraying the bergenin (BN) and PVP K30 mixed solution onto the blank pellets. The preparation technology was also optimized by the central composite design response surface methodology. The three significant parameters including air inlet speed, temperature, and injection speed were obtained as 11.6 m/s, 34.3 °C, and 9.0 mL/min, respectively, and drug loading around 12.5%. In vitro results showed that the cumulative release percentages of the BN-SDP were 100% within 20 min. Furthermore, the FTIR, XRD, and DSC findings presented a clear binding pattern between BN and PVP K30 along with amorphous properties in the BN-SDP. The Tmax was earlier for BN-SDP and the Cmax increased one time with BN as a reference, On the other hand, the AUC0-∞ were 536.15 ± 20.64 μg·h/mL and 361.70 ± 35.93·μg h/mL for the BN-SDP and BN, respectively. The oral bioavailability of BN-SDP was enhanced by 1.48 folds in comparison with BN suspension, indicating the solid dispersion technology can increase the oral bioavailability of the BN.

Curcumin Pellets of Carboxymethylated Tamarind Seed Polysaccharide for the Treatment of Inflammatory Bowel Disease

Background and Objectives: Inflammatory Bowel Disease (IBD) is a group of inflammatory conditions of the colon and small intestine. Crohn's disease and ulcerative colitis are the principal types of inflammatory bowel disease. IBD is a complex disease which arises as a result of the interaction of environmental and genetic factors leading to immunological responses and inflammation in the intestine. Curcumin, a yellow coloring agent is used as a remedy for the treatment and prevention of inflammatory disease. Curcumin is safe, non-toxic, and mediates its anti-inflammatory effects through the down-regulation of inflammatory transcription factors, cytokines, redox status, protein kinases, and enzymes that all promote inflammation. Methods: An attempt was made to formulate sustained release pellets of curcumin using Carboxymethyl Tamarind Seed Polysaccharide (CMTSP). Solid dispersion of curcumin prepared using soluplus and incorporated into pellets for enhanced solubility and bioavailability. A central composite design was applied to study the effect of independent variables (amount of microcrystalline cellulose MCC and CMTSP) on crushing strength and drug release of pellets. In vivo study of solid dispersion loaded pellets revealed the presence of more amount of drug in plasma than pure drug loaded pellets. Result: Dissolution and absorption of curcumin were found to be increased by 1.5 and 2 fold, respectively. Conclusion: Carboxymethyl tamarind seed polysaccharide can be used successfully for colon targeted drug delivery system in the form of pellets. The percent permeability of pellets prepared by using solid dispersion was found to be more than pellets prepared by using pure drug. Curcumin has an advantageous safety profile as well as low relativecost, making it an attractive option for IBD patients. Keywords: Soluplus, carboxymethyl tamarind seed polysaccharide, extrusion-spheronization, solid dispersion pellets, inflammatory bowel disease, curcumin.

DESIGN AND STATISTICAL EVALUATION OF A MULTIUNIT DELIVERY SYSTEM CONTAINING NISOLDIPINE-SOLUPLUS® SOLID DISPERSION FOR HYPERTENSION CHRONOTHERAPY

<p><strong>Objective: </strong>To study the mechanism and factors affecting the design of an industrially scalable formulation in a combined drug delivery module containing solid dispersion (SD) multiunit pellets with novel polymer Soluplus® in a modified release system to address chronotherapeutic needs of hypertension therapy.</p><p><strong>Methods: </strong>Nisoldipine-Soluplus® SD pellet formulations were prepared using the central composite design of experiments (CCD) to study the effect of inert core level and drug to polymer ratio. The solid dispersions were formed on inert pellets surface by fluidized bed coating and characterized by dissolution efficiency and time for 90% drug release. The data was statistically analyzed to develop a response surface for optimum SD formulation in pellets. The SD pellets were characterized by FTIR, DSC and SEM. The optimum formulation of SD coated pellets was further coated with Eudragit S100-L100 polymer mix and characterized for dissolution in multimedia and two-step dissolution for lag time.</p><p><strong>Results: </strong>A response surface was developed for highest dissolution efficiency (%DE) and least time to release 90% drug (T<sub>90</sub>). The model was significant, and the role of core pellets was found to be more significant than the drug-polymer ratio. The study of the desirability function indicated that a polymer content of 75% and inert core level to yield 23% net weight gain, provided optimum dissolution enhanced SD pellets. The drug was found to exist in amorphous form. The final capsules containing Eudragit S100-L100 coated delayed release SD pellets showed a lag time of 2 h and a definite pH-gradient towards drug release.</p><p><strong>Conclusion: </strong>The findings from this study helped to understand the mechanism, design and factors affecting drug release from a delayed release SD system for a poorly soluble drug for potential hypertension chronotherapy.</p>

Application of ethyl cellulose, microcrystalline cellulose and octadecanol for wax based floating solid dispersion pellets

The present study aimed to develop and optimize the wax based floating sustained-release dispersion pellets for a weakly acidic hydrophilic drug protocatechuic acid to achieve prolonged gastric residence time and improved bioavailability. This low-density drug delivery system consisted of octadecanol/microcrystalline cellulose mixture matrix pellet cores prepared by extrusion-spheronization technique, coated with drug/ethyl cellulose 100cp solid dispersion using single-step fluid-bed coating method. The formulation-optimized pellets could maintain excellent floating state without lag time and sustain the drug release efficiently for 12h based on non-Fickian transport mechanism. Observed by SEM, the optimized pellet was the dispersion-layered spherical structure containing a compact inner core. DSC, XRD and FTIR analysis revealed drug was uniformly dispersed in the amorphous molecule form and had no significant physicochemical interactions with the polymer dispersion carrier. The stability study of the resultant pellets further proved the rationality and integrity of the developed formulation.

Novel patchouli alcohol ternary solid dispersion pellets prepared by poloxamers.

The present study investigates the possibility of using poloxamers as solubility and dissolution rate enhancing agents of poorly water soluble bioactive constituent patchouli alcohol (PA) that can be used for the preparation of immediate release pellets formulation. Two commercially available grades poloxamer 188 (P 188) and poloxamer 407 (P 407) were selected, and solid dispersions (SDs) containing different weight ratio of PA and poloxamers, and the combination of P 188 and P 407 as dispersing carriers of ternary solid dispersions (tSDs) were prepared by a low temperature melting method and solidified rapidly by dropping into the 10-15 °C condensing agent atoleine. Both PA/P 188 and PA/P 407 binary solid dispersions (bSDs) could remarkably promote the dissolution rate of PA, increasing approximately 16 times in bSDs with poloxamers in comparison with pure PA within 180 min. P188 contributed to a faster dissolution rate than P 407, however, P 407 had a better solubility. It is interesting to note that the incorporation of P 188 in PA/P 407 bSD pellets could strongly enhance the dissolution rate of PA. DSC and FTIR were used to explore the characteristics of PA-SD pellets. The enhancement of dissolution from the SDs may be attributed partly to the reduction in particle size in PA crystalline due to the formation of eutectic system with poloxamers. Moreover, a simple, accurate in-vitro dissolution test method for volatility drug was established, and the process of PA-SD pellets preparation was simple, rapid, cost effective, uncomplicated and potentially scalable.

The role of lipid-based nano delivery systems on oral bioavailability enhancement of fenofibrate, a BCS II drug: comparison with fast-release formulations.

The aim of this study was to compare various formulations solid dispersion pellets (SDP), nanostructured lipid carriers (NLCs) and a self-microemulsifying drug delivery system (SMEDDS) generally accepted to be the most efficient drug delivery systems for BCS II drugs using fenofibrate (FNB) as a model drug. The size and morphology of NLCs and SMEDDS was characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Their release behaviors were investigated in medium with or without pancreatic lipase. The oral bioavailability of the various formulations was compared in beagle dogs using commercial Lipanthyl® capsules (micronized formulation) as a reference. The release of FNB from SDP was much faster than that from NLCs and SMEDDS in medium without lipase, whereas the release rate from NLCs and SMEDDS was increased after adding pancreatic lipase into the release medium. However, NLCs and SMEDDS increased the bioavailability of FNB to 705.11% and 809.10%, respectively, in comparison with Lipanthyl® capsules, although the relative bioavailability of FNB was only 366.05% after administration of SDPs. Thus, lipid-based drug delivery systems (such as NLCs and SMEDDS) may have more advantages than immediate release systems (such as SDPs and Lipanthyl® capsules).

Binary lipids-based nanostructured lipid carriers for improved oral bioavailability of silymarin

The main purpose of this study was to prepare binary lipids-based nanostructured lipid carriers to improve the oral bioavailability of silymarin, a poorly water-soluble liver protectant. Silymarin-loaded nanostructured lipid carriers were prepared by the method of high-pressure homogenization with glycerol distearates (Precirol ATO-5) and oleic acid as the solid and liquid lipids, respectively, and lecithin (Lipoid E 100) and Tween-80 as the emulsifiers. The silymarin-nanostructured lipid carrier prepared under optimum conditions was spherical in shape with mean particle size of ∼78.87 nm, entrapment efficiency of 87.55%, loading capacity of 8.32%, and zeta potential of -65.3 mV, respectively. Invitro release of silymarin-nanostructured lipid carriers was very limited even after 12 h, while invitro lipolysis showed fast digestion of nanostructured lipid carriers within 1 h. Relative oral bioavailability of silymarin-nanostructured lipid carriers in Beagle dogs was 2.54- and 3.10-fold that of marketed Legalon® and silymarin solid dispersion pellets, respectively. It was concluded that nanostructured lipid carriers were potential drug delivery systems to improve the bioavailability of silymarin. Other than improved dissolution, alternative mechanisms such as facilitated absorption as well as lymphatic transport may contribute to bioavailability enhancement.

Bile salt/phospholipid mixed micelle precursor pellets prepared by fluid-bed coating

Bile salt/phospholipid mixed micelles (MMs) are potent carriers used for oral absorption of drugs that are poorly soluble in water; however, there are many limitations associated with liquid formulations. In the current study, the feasibility of preparing bile salt/phospholipid MM precursor (preMM) pellets with high oral bioavailability, using fluid-bed coating technology, was examined. In this study, fenofibrate (FB) and sodium deoxycholate (SDC) were used as the model drug and the bile salt, respectively. To prepare the MMs and to serve as the micellular carrier, a weight ratio of 4:6 was selected for the sodium deoxycholate/phospholipids based on the ternary phase diagram. Polyethylene glycol (PEG) 6000 was selected as the dispersion matrix for precipitation of the MMs onto pellets, since it can enhance the solubilizing ability of the MMs. Coating of the MMs onto the pellets using the fluid-bed coating technology was efficient and the pellets were spherical and intact. MMs could be easily reconstituted from preMM pellets in water. Although they existed in a crystalline state in the preMM pellets, FB could be encapsulated into the reconstituted MMs, and the MMs were redispersed better than solid dispersion pellets (FB:PEG = 1:3) and Lipanthyl®. The redispersibility of the preMM pellets increased with the increase of the FB/PEG/micellar carrier. PreMM pellets with a FB:PEG:micellar carrier ratio of 1:1.5:1.5 showed 284% and 145% bioavailability relative to Lipanthyl® and solid dispersion pellets (FB:PEG = 1:3), respectively. Fluid-bed coating technology has considerable potential for use in preparing sodium deoxycholate/phospholipid preMM pellets, with enhanced oral bioavailability for poorly water-soluble drugs.

Micronization of Solid Dispersion Pellets: Physical Characterization and Improved Dissolution

Micronization of Solid Dispersion Pellets: Physical Characterization and Improved Dissolution

Novel Tanshinone II A ternary solid dispersion pellets prepared by a single-step technique: In vitro and in vivo evaluation

Novel Tanshinone II A (TA) ternary solid dispersion (tSD) pellets with the combination of polyvinylpyrrolidone and poloxamer 188 as dispersing carriers were prepared by a single-step technique. A formulation screening study showed that the addition of poloxamer 188 to binary TA-PVP system could remarkably promote the dissolution rate of TA from 60% to 100% after 60min. Scanning electron microscopy study revealed a smooth surface and a tightly packed coating structure. Differential scanning calorimetry analysis confirmed the formation of solid dispersions. In vivo test showed that TA tSD pellets presented significantly larger AUC0–t, which was 0.76 times more than that of binary solid dispersion (bSD) pellets, 2.87 times more than that of physical mixtures (PMs) and 5.40 times more than that of TA. Cmax of TA tSD pellets also increased by 1.82–8.97-fold as that of bSD pellets, PMs and TA. TA tSD pellets generated obviously shortened Tmax of (3.80±0.398)h, compared to bSD pellets with (4.15±0.456)h, PMs with (4.65±0.226)h and TA with (5.52±0.738)h. In conclusion, the addition of poloxamer 188 to pellets containing PVP-based solid dispersions could achieve complete dissolution, accelerated absorption rate and superior oral bioavailability. The fluid-bed technique becomes an alternative approach to obtain solid dispersion-coated pellets.

In Vitro Evaluation and Pharmacokinetics in Dogs of Solid Dispersion Pellets Containing Silybum marianum Extract Prepared by Fluid-Bed Coating

The solid dispersion of a poorly water-soluble Silybum marianum extract (SME) was prepared by a one-step fluid-bed coating technique depositing onto non-pareil pellets. In vitro evaluation indicated that this technique was highly efficient and reproducible producing pellets with acceptable appearance, flowability, friability, uniformity of drug content and enhanced dissolution. Physical characterization by DSC, powder X-ray diffractometry and FT-IR suggested the formation of a solid dispersion and possible interaction between PVP and the flavonolignans. Stress testing showed that the drug content and dissolution profiles of the SME solid dispersion pellets were sensitive to heat and humidity, while they are not affected under accelerated and long-term testing conditions. The relative bioavailability of solid dispersion pellets in dogs based on quantification of silibinin was about five-fold that of the SME suspension confirming enhanced oral bioavailability. It was concluded that the solid dispersion pellets prepared by fluid-bed coating showed favorable in vitro characteristics and enhanced oral bioavailability.

Enhanced dissolution of silymarin/polyvinylpyrrolidone solid dispersion pellets prepared by a one-step fluid-bed coating technique

Solid dispersion systems have been widely used to enhance the dissolution and oral bioavailability of poorly water-soluble drugs. However, the formulation process development and scaling-up present a number of difficulties greatly limiting the commercial applications. In this study, solid dispersions of silymarin (SM) with polyvinylpyrrolidone (PVP) were prepared by a one-step fluid-bed coating technique. The process involved the spray application of the ethyl alcohol solution of SM and PVP and subsequent deposition of the coprecipitates onto the non-pareil pellets in drying air flow in a fluid-bed coater. The central composite design/response surface methodology was employed to investigate the effects of the two independent variables, PVP/SM ratio and coating weight gain, on the dissolution of SM. The results demonstrated that the dissolution of PVP/SM solid dispersions was enhanced greatly at PVP/SM ratios of over 4/1. The results of the central composite design suggested that both PVP/SM ratio and coating weight gain affected the dissolution rate significantly. Second-order or third-order polynomial non-linear equations were employed to estimate the relationship between dissolution responses and the two independent variables. Response surface graphs were delineated based on the best-of-fit equations and the optimal experimental range was identified as: PVP/SM, 4/1−5/1; coating weight gain, 80%−120%. The results indicate that the fluid-bed coating technique has the potential use in the preparation of solid dispersions.

Solid dispersion of ketoprofen in pellets

The formulation of ternary solid dispersions of ketoprofen with Macrogol and kollagen hydrolizate derivative as carriers was elaborated on the basis of the results of the experiments in which different methods of solid dispersion preparation (melting, solvent method, different cooling), different concentrations of drug/carriers and molecular weight of Macrogol were tested. The best solid dispersion consisted of: ketoprofen–Macrogol 6000-KLH T (1+8.9+0.1) was chosen to formulate the pellets on the basis of the pharmaceutical availability of ketoprofen from solid dispersion and the physical chemical studies: thermomicroscopic, DSC and X-ray diffraction. The pellets were prepared by the extrusion and spheronization method. The mechanical properties of the pellets as well as ketoprofen released from pellets containing solid dispersion, in comparison with physical mixtures and the drug alone, were evaluated. The increase in the amount of released ketoprofen from solid dispersion pellets was 3.8-times greater than from the pellets containing the drug alone. The stability of solid dispersion pellets was satisfactory.