Enteric-coated Pellets Research Articles

Evaluation of toxicity using zebrafish embryo model and preparation of enteric-coated pellets containing Panax notoginseng saponins

Panax notoginseng saponins (PNS) extracted from the root of Panax notoginseng (Burk.) F. H. Chen are the main biologically active substances. However, PNS have low permeability and degradation in the acid gastric environment, leading to their limited bioavailability. This study aimed to determine the acute toxicity of PNS in zebrafish larvae and prepare enteric-coated pellets of PNS to enhance their permeability and stability. The survival proportion, the morphological abnormalities, and the heartbeat of zebrafish embryos were performed at treated doses of PNS ranging from 0.01 to 50 μg/ml. Administration of PNS at doses greater than 10 μg/ml may result significantly in morphological alterations such as pericardial edema and curved tail. The core pellets containing PNS, polyethylene glycols, and absorption enhancers were fabricated by the dripping method. Then, the dripping pellets were coated using Eudragit L100 as an enteric coating polymer. The characterizations of core pellets and enteric-coated pellets were evaluated. The produced dripping pellets showed advantageous features, such as ease of preparation, excellent uniformity, notable friability, high dissolution rate, and good stability. In addition, absorption enhancers were successfully incorporated into the core pellets to improve the permeability of PNS. Differential scanning calorimetry, X-ray powder diffraction, and Fourier-transform infrared spectroscopy profiles revealed that the drug was maintained in an amorphous state and did not interact with the excipients during the pellet preparation process. Histological evaluation showed that dripping pellets caused a minor effect on the surface of the jejunal mucosa. The enteric-coated pellets displayed smooth surface morphology, desirable sphericity, good flowability, uniform content, and stability in an acidic pH 1.2 environment and rapid drug release in a pH 6.8 buffer solution. Based on the findings, the enteric-coated pellets may improve the absorption and stability of PNS.

Bicarbonate buffer dissolution test with gentle mechanistic stress for bioequivalence prediction of enteric-coated pellet formulations

This study aimed to develop a dissolution test that can predict the bioequivalence (BE) of enteric-coated pellet formulations. The original duloxetine hydrochloride capsule (reference formulation (RF); Cymbalta® 30 mg capsule) and four generic test formulations (two capsules (CP) and two orally disintegrating tablets (OD)) were used as model formulations. Clinical BE studies were conducted on 24–47 healthy male subjects under fasting conditions. Dissolution tests were performed using a compendial paddle method (PD) (paddle speed: 50 rpm) and a flow-through cell method (FTC) (flow rate: 4 mL/min). For a further test, cotton balls were added to the vessel to apply gentle mechanistic stress to the formulations, and paddle speed was reduced to 10 rpm (paddle with cotton ball method (PDCB)).All the dissolution tests were conducted with 0.01 M HCl (pH 2.0) for 0.5 h followed by 10 mM bicarbonate buffer solutions (pH 6.5) for 4 h. One each of the two CP and two OD showed BE with RF. PDCB was able to discriminate between BE and non-BE formulations, while this was not possible with PD and FTC. In PDCB, the cotton balls intermittently moved the pellets near the vessel bottom. PDCB is useful for predicting BE during formulation development.

Duloxetine hydrochloride enteric-coated pellets in capsules with delayed release: formulation and evaluation

ABSTRACT The primary purpose of this study is to develop and evaluate an effective and reliable delayed-release dosage form of Duloxetine hydrochloride enteric-coated pellets in capsules. Duloxetine hydrochloride dissolves in an acidic environment, yet pellets maintain their enteric coating due to the Wurster expansion process for the Fluidized Bed Processor. Four distinct layers comprise enteric-coated pellets: a pharmaceutical layer, a barrier layer, an enteric layer, and a coating on the inert core pellets. A suspension layering approach protects the acidic environment from the drug by coating it with an enteric layer composed of hydroxyl propyl methyl cellulose phthalate HP55. We also determined the bulk and tapped densities, Hausner’s ratio, compressibility index, and moisture content of all formulations. The produced pellets are being evaluated for in-vitro release tests using UV-Visible spectroscopy. The zero-order model, the first-order model, and Higuchi’s square root equation, Hixson-Crowell, Korsemeyer peppas, and the Weibull model were used to evaluate the released kinetics models. Investigations using FT-IR (infrared spectroscopy) are still being undertaken to determine the drug’s compatibility with various excipients. Formulation ‘F7’ exhibited highest similarity factor of 56.1. Stability tests conducted over a three-month period under accelerated settings established that the optimized formulation is stable.

Lowly-buffered biorelevant dissolution testing is not necessarily biopredictive of human bioequivalence study outcome: Relationship between dissolution and pharmacokinetics

It has been revealed that buffer capacity of aspirated human intraluminal fluid is much lower than that of in vitro compendial dissolution media. Since buffer capacity significantly alters the dissolution profile of certain drug products, dissolution testing in highly buffered media dictates poor predictability of in vivo drug performance. To mitigate this inconsistency, low buffer capacity medium was suggested as an in vivo representation (biorelevant dissolution testing). The purpose of this study was to characterize the dissolution profiles of enteric-coated drug products in different buffer capacity media in a flow through cell dissolution apparatus, and to evaluate the in vivo predictability of human bioequivalence study outcomes conducted in the fasted state. It was confirmed that the lower the buffer capacity of dissolution media, the higher the discriminatory power of esomeprazole magnesium hydrate enteric-coated pellets, reflecting human bioequivalence failure. In the meantime, two duloxetine hydrochloride enteric-coated pellets also exhibited distinct dissolution profiles in such a lowly buffered medium despite the fact that these two are bioequivalent in human. Biopharmaceutical and pharmacokinetic characteristics comparison suggested that low intestinal permeability and small systemic elimination rate of duloxetine hinders the clear impact of different dissolution profile on its in vivo performance. These data suggest that dissolution comparison in physiologically-relevant low buffer capacity media is not always indicative of human bioequivalence. Instead, biopharmaceutical and pharmacokinetic aspects must be taken into consideration to make biorelevant dissolution testing biopredictive.

Formulation of enteric-coated pellets containing diclofenac sodium by coating technology

Background: Diclofenac sodium (DS) is a non-steroidal anti-inflammatory drug (NSAIDs) that has strong anti-inflammatory and analgesic effects, but it has many serious side effects on the gastrointestinal tract. Enteric-coated DS pellets have many advantages such as limited drug release in the stomach, with Eudragit L100 coating to help drug release in the intestines, avoiding side effects in the gastrointestinal tract. The aim of this study was to formulate enteric-coated pellets and to evaluate the physico-chemical properties of prepared pellets. Materials and methods: DS, HPMC, Eudragit L100 were used in this study. DS pellets were prepared using sugar spheres layered with DS followed by an enteric coat of Eudragit L100. Results: Prepared enteric-coated DS pellets by layering method using HPMC as a binding agent and Eudragit L100 as enteric-coated membrane to help pellets ensure the release of drug in the gastrointestinal tract. Pellets have a nice shape, the size range of 0.7-1 mm, the layering efficiency of 36.69%, the drug content of 8.84% ± 0.43% (w/w). The drug release was 3.59% after 2h in acidic environment of pH 1.2 and 84.9% after 1h in phosphate buffered saline of pH 6.8. Conclusions: Enteric-coated pellets of DS were successfully prepared by using coating technology. Key words: diclofenac sodium, pellet, coating technology

Preparation and Evaluation of Dual–release Esomeprazole Magnesium Pulsed Capsules Filled with Two Kinds of Enteric-coated Pellets

Preparation and Evaluation of Dual–release Esomeprazole Magnesium Pulsed Capsules Filled with Two Kinds of Enteric-coated Pellets

FORMULATION AND EVALUATION OF PROBIOTIC AND PREBIOTIC LOADED PELLETS BY EXTRUSION AND SPHERONIZATION FOR IMPROVED STORAGE VIABILITY

Objective: The present study aims to prepare stains-loaded enteric-coated pellets by extrusion and spheronization technique for acidic environment protection and improve the viability of the strains during storage. Methods: Lactobacillus casei and Lactobacillus plantarum strains are proven to have various therapeutic and prophylactic uses in human beings, but low stability during storage and transit to site of action has limited their action. Pellets were prepared by incorporating probiotic strains D1-D9 (L. casei) and E1-E9 (L. plantarum) by further enteric-coating the pellets, which were evaluated for particle size, loss on drying, friability, micromeritic properties, viability, disintegration, survivability in acidic and bile juices, and stability studies for 90 d respectively. Results: The method employed for preparing the pellets showed good % yields with a particle rage of 1400-850 µm. LoD values were in the range of 3.07±0.30% to 2.13±0.11%; all the prepared pellets showed good flow properties and friability in an acceptable range. SEM images revealed that enteric-coated pellets had smooth and uniformly surfaces. The viability results ranged from 8.78±0.31 to 8.53±0.15 log CFU/g and 8.47±0.15 to 8.85±0.22 log CFU/g for both L. casei and L. plantarum enteric coated pellets, respectively. The Disintegration time for the pellets was<15 min in all the formulations. The enteric-coated probiotic pellets provided adequate protection against the acidic environment. Studies of survivability in simulated gastrointestinal conditions demonstrated that formulations D7 and E7 showed higher viability among the formulations at the end of 3 h. The stability studies showed that the formulations with a higher concentration of Inulin and pectin combination proved better viability of L. casei and L. plantarum strains in the formulation during 90 d of stability study. Conclusion: This study suggested that using extrusion and spheronization techniques can be employed to prepare pellets with prebiotics (Inulin and Pectin) which can be utilized to formulate probiotic dosage forms with improved viability in physiological conditions and real-time storage conditions

Hot-melt extrusion technique: A novel continuous manufacturing method for enteric-coated pellets

The technology of hot-melt extrusion (HME) is becoming a progressively appealing way to develop different drug delivery systems. A wide range of pharmaceutical dosage forms and formulations from oral to topical and parenteral can be prepared. The dosage forms formulated using HME technique are composite mixtures of active pharmaceutical agents, active excipients, and other processing aids. HME has many advantages over traditional techniques of pharmaceutical development, such as non-solvent technology, lower processing requirements, uninterrupted activity, and greater possibility of uniform suspension and increased bioavailability. This paper addresses enteric-coated pellet pharmaceutical applications and its process techniques using the HME technology and its applications in pharmaceutical industries for an efficient pathway for a novel drug delivery system.

Factors Contributing to Drug Release From Enteric-Coated Omeprazole Capsules: An In Vitro and In Vivo Pharmacokinetic Study and IVIVC Evaluation in Beagle Dogs.

This study was performed to explore factors influencing the release of the proton pump inhibitor omeprazole from enteric-coated capsules in vitro and absorption in vivo in beagle dogs. Enteric-coated pellets with different enteric coating materials and coating levels were designed and prepared. All self-prepared formulations were characterized in vitro as well as in vivo and compared to the brand and generic commercial products. Evaluation of the corresponding release profiles suggested that coating material was the most critical factor. Enteric coating level determined the lag time before initiation of drug release, and subcoating level affected the drug release rate. Pharmacokinetic studies were performed in beagle dogs to further confirm the influence of formulation factors on drug absorption. Medium at pH 6.8 was a more biorelevant condition for in vitro drug release tests, although medium at pH 6.0 was better for discriminating release profiles of different formulations. A multiple level C in vitro/in vivo correlation was preliminarily established by which Tmax and Cmax of omeprazole formulations could be predicted with release parameters such as Tlag and T25. These results may facilitate quality evaluation and potentially improve the clinical efficacy of generic omeprazole products.

Preparation of defatted walnut meal hydrolysate-loaded enteric-coated pellets with enhanced oral absorption efficiency

The goal of this study was to enhance the absorption efficiency of walnut peptides (WPs) by employing an enteric-coated pellet formulation. Firstly, defatted walnut meal hydrolysate (DWMH) and microcrystalline cellulose (MCC) were mixed with sodium caprate to prepare the core pellets by extrusion/spheronization. The granulation process was optimized by a single-factor experiment and used to obtain uniform and spherical core pellets with a high yield of 74.3%. Afterwards, enteric coating of the core pellets was conducted using a bottom-spray fluid-bed coater. The in vitro release study of the optimum product showed that less than 10% of WPs were released from the enteric-coated pellets in simulated gastric fluid after 2 h, and complete release of WPs was achieved in simulated intestinal fluid after 45 min. Moreover, the bioactivity of WPs was retained following absorption from the enteric-coated formulation. Finally, the absorption efficiency of WPs from DWMH-loaded enteric-coated pellets was investigated in rats using an in situ intestinal perfusion experiment. It was revealed that the enteric-coated pellet formulation can significantly enhance the intestinal absorption of WPs. In conclusion, enteric coating of the pellets and co-delivery of an absorption enhancer could be an effective strategy for producing oral formulations of bioactive peptides.

Gastric retention pellets of edaravone with enhanced oral bioavailability: Absorption mechanism, development, and in vitro/in vivo evaluation

Absorption mechanism of edaravone (EDR) was studied to inform the preparation of gastric retention pellets with the aim to enhance its oral bioavailability. Three different models, namely, Caco-2 cells model, in situ single-pass intestinal perfusion model, and everted gut sac model in rats, were employed to characterize the gastrointestinal absorption kinetics of EDR. And it was found that passive transfer plays a vital role for the transport of EDR, and acidic condition is preferable for EDR absorption. Further, it is likely that EDR acts as a substrate for P-glycoprotein and multidrug-resistance protein. And hence, an orally available gastric retention pellets were developed accordingly. Pharmacokinetic experiments performed with rats and beagles showed that the absolute bioavailability of EDR solution and enteric-coated pellets following oral administration were 33.85% ± 2.45% and 7.64% ± 1.03%, indicating that stomach absorption is better than intestinal adsorption for EDR. However, the gastric retention pellets resulted in 68.96% absolute bioavailability and about 200% relative bioavailability in comparison to EDR solution, which was 9 times that of enteric-coated pellets. The present work demonstrates that gastric retention pellets has excellent potential as oral administration route for EDR.

Process, optimization, and characterization of budesonide-loaded nanostructured lipid carriers for the treatment of inflammatory bowel disease

The major challenge involved in the treatment of inflammatory bowel disease is targeted delivery of the drug at the site of inflammation. As nanoparticles possess the ability to accumulate at the site of inflammation, present investigation aims at development of Budesonide-loaded nanostructured lipid carrier systems (BDS-NLCs) for the treatment of inflammatory bowel disease. BDS-NLCs were prepared by employing a high pressure homogenization technique. Various preliminary trials were performed for optimization of the NLCs in which different processes, as well as formulation parameters, were studied. The BDS-NLCs was optimized statistically by applying a 3-factor/3-level Box–Behnken design. Drug concentration, surfactant concentration, and emulsifier concentration were selected as independent variables, and % entrapment efficiency and particle size were selected as dependent variables. The best batch comprises of 10%, 7%, and 20% w/w concentration of drug, surfactant, and emulsifier, respectively, with % entrapment efficiency of 92.66 ± 3.42% and particle size of 284.0 ± 4.53 nm. Further, in order to achieve effective delivery of nanoparticulate system to colonic region, the developed BDS-NLCs were encapsulated in Eudragit® S100-coated pellets. The drug release studies of pellets depict intactness of BDS-NLCs during palletization process, with f2 value of 75.879. The in vitro evaluation of enteric-coated pellets revealed that a coating level of 15% weight gain is needed in order to impart lag time of 5 h (transit time to reach colon). The results of the study demonstrate that the developed BDS-NLCs could be used as a promising tool for the treatment of inflammatory bowel disease.

Esomeprazole magnesium enteric-coated pellet-based tablets with high acid tolerance and good compressibility

The aim of this study was to develop esomeprazole magnesium (EMZ-Mg) enteric-coated pellets and pellet-based tablets, as well as to investigate the effects of pellet size and compression method on acid tolerance, content uniformity, compressibility, and stability of preparations. This study used two types of pellet cores, namely, microcrystalline cellulose (MCC) core with a particle size of 150–300 μm and sucrose core with a particle size of 600–700 μm. Enteric-coated pellets, which consisted of a drug-free core, a drug layer, a sub-coating layer (hydroxypropyl methylcellulose, 6 cps), and an enteric-coating layer (Eudragit®L30D-55), were prepared by using a bottom-spray fluidized bed-coating technique. Pellet-based tablets were prepared by using a direct compression method or a wet granulation method. The acid tolerances of the two types of enteric-coated pellets (MCC and sucrose cores) reached up to 98% in simulated gastric fluid (pH 1.0) within 2 h, and the dissolution rates in simulated intestinal fluid (pH 6.8) reached up to 85% of the labeled amount within 15 min. When compressed into tablets, the pellets based on MCC core (smaller particle size) displayed a significantly higher acid tolerance (up to 92%) compared with the pellets based on sucrose core (larger particle size). In addition, the MCC core-based tablets (F8), especially those prepared by using a granulation method, showed higher drug content uniformity and compressibility than the sucrose core-based tablets (F10), and no lamination phenomenon was observed during compression. The crystallinity of EMZ-Mg was altered during drug layering process, and some physicochemical interactions were observed between the drug and excipients. Moreover, the two types of enteric-coated pellets showed a relatively high stability after storage under high temperature and strong light. However, they showed poor stability under high humidity, resulting in remarkable degradation of active compound. The EMZ-Mg enteric-coated pellets and pellet-based tablets were successfully developed, and reduction in pellet size and wet granulation reduced the differences in content uniformity and better protected the pellet coating from damages during compression.

Formulation Optimization Utilizing D-Optimal Experimental Design of Oral Capsules Containing Enteric-Coated Pellets of Lansoprazole and<i> in vivo </i>Bioequivalence

An optimized formulation of capsules containing Lansoprazole enteric-coated pellets using D-Optimal design with a polynomial statistical model were prepared by using Eudragit?L100 as an enteric coated polymer to provide resistance to simulated gastric acid dissolution in buffer media. D-Optimal experimental design was used to determine the optimal level for three coating layers that were applied to formulate the enteric-coated pellets including a drug loading layer, a sub-coating, and an outer enteric coating. Dissolution studies were performed on the prepared Lansoprazole capsules. Less than 5 percent of Lansoprazole was released in 60 minutes in an acidic dissolution medium (pH 1.2) and greater than 90 percent of active ingredient was released in the next 60 minutes in a buffer dissolution medium (pH 6.8). The Lansoprazole capsules were stable with no observable change in physico-chemical properties in accelerated and normal storage conditions for 6 and 18 months, respectively. The pharmacokinetic parameters Cmax, Tmax, AUC0-t, and AUC0-∞ were determined after administration of the D-Optimal design optimized capsules of LPZ to healthy beagle dogs and were statistically compared to Gastevin? capsules as a reference (KRKA, Slovenia) using the non-compartmental method with the aid of WinNonlin 5.2 software. The analysis of variance showed that the two formulations did not demonstrate bioequivalence using a 90% confidence interval range (80% - 120%) of Cmax, AUC0-t, and AUC0-∞. No significant difference in Tmax was found at the 0.95 significance level using the Wilcoxon signed-rank test. D-Optimal Experimental Design provided definitive direction for an optimal formulation of capsules containing enteric-coated pellets of lansoprazole loaded within the coating of pellets that provided similar bioequivalence to Gastevin.

The interprocess NIR sampling as an alternative approach to multivariate statistical process control for identifying sources of product-quality variability

We are presenting a new approach of identifying sources of variability within a manufacturing process by NIR measurements of samples of intermediate material after each consecutive unit operation (interprocess NIR sampling technique). In addition, we summarize the development of a multivariate statistical process control (MSPC) model for the production of enteric-coated pellet product of the proton-pump inhibitor class. By developing provisional NIR calibration models, the identification of critical process points yields comparable results to the established MSPC modeling procedure. Both approaches are shown to lead to the same conclusion, identifying parameters of extrusion/spheronization and characteristics of lactose that have the greatest influence on the end-product’s enteric coating performance. The proposed approach enables quicker and easier identification of variability sources during manufacturing process, especially in cases when historical process data is not straightforwardly available. In the presented case the changes of lactose characteristics are influencing the performance of the extrusion/spheronization process step. The pellet cores produced by using one (considered as less suitable) lactose source were on average larger and more fragile, leading to consequent breakage of the cores during subsequent fluid bed operations. These results were confirmed by additional experimental analyses illuminating the underlying mechanism of fracture of oblong pellets during the pellet coating process leading to compromised film coating.

Preparation and evaluation of duloxetine hydrochloride enteric-coated pellets with different enteric polymers

The main purpose of the present study was to prepare duloxetine hydrochloride (DXH) enteric-coated pellets using different enteric polymers. Three layers (drug-loaded layer, barrier layer, and enteric-coated layer) were applied to the inert core pellets, successively. The optimal formulation was manufactured by employing suspension layering method in fluidized bed processor (FBP) with varieties of enteric polymers like Aqoat® AS-LF, Eudragit® L30D55 and HPMCP-HP55. The prepared pellets were measured for physical characterization and the in vitro dissolution profile. Scanning electron microscopy (SEM) was conducted to observe the morphology of pellets, and different kinetic models were applied to analyze the release mechanism of Cymbalta® and home-made pellets. The coating weight gain of enteric-coated layer containing Eudragit® L30D55, Aqoat® AS-LF and HP-55 were determined to be 35%, 26% and 24%, respectively. The similarity factors (f2) of self-made capsules with above polymers and commercially available capsules (Cymbalta®) were above 50 in the dissolution medium of pH 6.8 phosphate buffer solution (PBS). SEM figures showed the smooth surfaces of self-prepared pellets using Eudragit® L30D55 and Aqoat® AS-LF, whereas rough surface was found in the HP-55 pellets at day 0, and an impurity was appearing in the condition of 40 °C/75% relative humidity for 1 month. In conclusion, the pellets prepared by utilizing Eudragit® L30D55 and Aqoat® AS-LF were the optimal preparations based on the dissolution profile and stability.

Is it possible to achieve bio-equivalence between an oral solid immediate-release and an analogue enteric-coated formulation?

While bioequivalence between enteric-coated and immediate-release formulations can be achieved in terms of AUC, gastric emptying of enteric-coated dosage forms is a stochastic event, usually leading to lower Cmax values than those observed with the corresponding immediate release. This article examines challenges of developing enteric-coated dosage forms which are bioequivalent to the corresponding immediate-release formulations in terms of both AUC and Cmax using rasagiline as a model compound. In vitro drug release profiles of enteric-coated formulations were obtained and compared to those of the immediate-release formulation by dissolution testing. Pharmacokinetics was evaluated in bioequivalence studies in healthy human volunteers after single oral administration of enteric-coated and immediate-release formulations. The initial enteric-coated pellet formulation prototype was equivalent in terms of AUC, but differed in Cmax ; a second formulation prototype, consisting of a single-unit core and enteric-coating film, proved to be bioequivalent to immediate-release rasagiline tablets in terms of AUC and Cmax . In vitro, it released rasagiline rapidly at a pH of 6.8. Despite differences in gastric emptying between disintegrating immediate-release and enteric-coated solid dosage forms, bioequivalence in pharmacokinetic studies was achieved.

Multiple-unit tablet of probiotic bacteria for improved storage stability, acid tolerability, and in vivo intestinal protective effect

The aim of this study was to formulate probiotics-loaded pellets in a tablet form to improve storage stability, acid tolerability, and in vivo intestinal protective effect. Bacteria-loaded pellets primarily prepared with hydroxypropyl methylcellulose acetate succinate were compressed into tablets with highly compressible excipients and optimized for flow properties, hardness, and disintegration time. The optimized probiotic tablet consisted of enteric-coated pellets (335 mg), microcrystalline cellulose (Avicel PH102, 37.5 mg), and porous calcium silicate (25 mg) and allowed whole survival of living bacteria during the compaction process with sufficient tablet hardness (13 kp) and disintegration time (14 minutes). The multiple-unit tablet showed remarkably higher storage stability under ambient conditions (25°C/60% relative humidity) over 6 months and resistance to acidic medium compared to uncoated strains or pellets. Repeated intake of this multiple-unit tablet significantly lowered plasma level of endotoxin, a pathogenic material, compared to repeated intake of bare probiotics or marketed products in rats. These results, therefore, suggest that the multiple-unit tablet is advantageous to better bacterial viability and gain the beneficial effects on the gut flora, including the improvement of intestinal barrier function.

Novel naproxen/esomeprazole magnesium compound pellets based on acid-independent mechanism: in vitro and in vivo evaluation

The purpose of this study was to develop the novel naproxen/esomeprazole magnesium compound pellets (novel-NAP/EMZ) depending on EMZ acid-independent mechanism which has been proved to be predominate in the mechanism of co-therapy with nonsteroidal anti-inflammatory drug. The novel-NAP/EMZ compound pellets, composed of NAP colon-specific pellets (NAP-CSPs) and EMZ modified-release pellets (EMZ-MRPs), were prepared by fluid-bed coating technology with desired in vitro release profiles. The resulting pellets were filled into hard gelatin capsules for in vivo evaluation in rats and compared with the reference compound pellets, consisted of NAP enteric-coated pellets (NAP-ECPs) and EMZ immediate-release pellets (EMZ-IRPs). The reference compound pellets were prepared simulating the drug delivery system of VIMOVO®. In vivo pharmacokinetics, EMZ-MRPs had significantly larger AUC0–t (p < 0.01), 1.67 times more than that of EMZ-IRPs, and prolonged mean residence time (7.55 ± 0.12 h) than that of IRPs (1.46 ± 0.39 h). NAP-CSPs and NAP-ECPs showed similar AUC0–t. Compared to the reference compound pellets, the novel-NAP/EMZ compound pellets did not show distinct differences in histological mucosal morphology. However, biochemical tests exhibited enhanced total antioxidant capacity, increased nitric oxide content and reduced malondialdehyde level for novel-NAP/EMZ compound pellets, indicating that the acid-independent action took effect. The gastric pH values of novel-NAP/EMZ compound pellets were at a low and stable level, which could ensure normal physiological range of human gastric pH. As a result, the novel-NAP/EMZ compound pellets may be a more suitable formulation with potential advantages by improving bioavailability of drug and further reducing undesirable gastrointestinal damages.

Pharmacokinetic Study of a Diclofenac Sodium Capsule Filled with Enteric-coated Pellets in Healthy Chinese Volunteers by Liquid Chromatography-electrospray Ionization-tandem Mass Spectrometry.

The pharmacokinetic study of a diclofenac sodium capsule filled with enteric-coated pellets (abbreviated as CAPSULE) in healthy Chinese subjects was evaluated using liquid chromatography-electrospray ionization-tandem mass spectrometry with simple sample preparation. In a cross-over study, 12 healthy male volunteers were given 50 mg CAPSULE and diclofenac sodium enteric-coated tablet (abbreviated as TABLET, used as a control dosage form) at fasting. The Cmax, AUC0-t, and Tmax of CAPSULE were 1.01±0.52 μg/mL, 1.54±0.18 μg·h/mL, and 1.50±1.31 h, respectively. When compared with TABLET, the pharmacokinetic study showed that although this CAPSULE exhibited similar AUC (only 10% lower), it presented lower maximum plasma concentration, faster absorption and shorter time to reach maximum concentration. When compared with the previous study in Germany, obvious variations on Tmax were found in Chinese subjects taking CAPSULE, but not TABLET. The results indicated that individual difference should be paid attention when prescribing CAPSULE to Chinese patients.