Aqueous Ethylcellulose Dispersion Research Articles

Appraisal of Surelease Clear E-7–19040, an Ethylcellulose Aqueous Dispersion, as a Release Modifier for the Hydrophilic Core

Appraisal of Surelease Clear E-7–19040, an Ethylcellulose Aqueous Dispersion, as a Release Modifier for the Hydrophilic Core

Photochromic Microcapsules for Textile Materials by Spray Drying—Part 1: Production and Characterization of Photochromic Microcapsules

This study, which is the first in a three-part series, deals with the encapsulation of photochromic dyes by spray drying. An aqueous ethyl cellulose dispersion and a spirooxazine-based photochromic dye were used as a shell and core material, respectively. The effects of main encapsulation parameters, such as solvent type, inlet temperature, feed rate, solid content, and aspirator rate were investigated. The encapsulation results were evaluated by scanning electron microscopy (SEM) images, particle size measurements, thermogravimetric analysis (TGA) and X-ray diffraction (XRD). The microcapsules obtained from a water-ethanol mixture exhibited photochromic properties. For microcapsule production, the optimum feed rate, total solid content, and aspirator rate were determined. Capsule formation improved with increased inlet air temperature. Spray drying to produce photochromic microcapsules could be a practical method for production of photochromic smart textiles.

Preparation and in vitro/in vivo evaluation of a clonidine hydrochloride drug–resin suspension as a sustained-release formulation

Objective The purpose of the present study was to prepare a clonidine hydrochloride (CH) sustained-release suspension. Methods The processes involved in the drug formulation included drug loading, impregnating, and suspension preparation. Clonidine hydrochloride drug–resin complexes (CH-DRC) were prepared using the bath method and the CH-DRC impregnated before the microencapsulation process. Based on the bottom spray fluidized bed coating method, the CH microencapsulated drug–resin complexes (CH-MC) were also prepared using Surelease® (the suspension of ethyl cellulose aqueous dispersion) as the coating material. The effects of coating (process/formulation) on the in vitro release of coating microcapsule were evaluated via single factor investigation and orthogonal design optimization. The CH-MC with optimized formulation was further dispersed in a suitable medium to obtain a sustained-release suspension. Rats were given commercial CH ordinary tablets and the CH sustained-release suspension via intragastric administration. The plasma concentration–time curve and related pharmacokinetic parameters were investigated using the non-compartment model. Results The T max of the CH sustained-release suspension was delayed from 2 h to 5 h compared with the CH ordinary tablets. Similarly, the C max was reduced from 32.138 µg·mL−1 to 18.150 µg·mL−1 with the concentration–time curve being more gentle compared with the commercially CH ordinary tablets. After oral administration, the relative bioavailability of CH sustained-release suspension (AUC0–24 of 137.703 µg·h·mL−1) to its CH ordinary tablets (AUC0–24 of 123.337 µg·h·mL−1) was 111.65%. Conclusions The findings showed that the CH sustained-release suspension for oral administration was successfully formulated.

Taste Masking of Granulated Acetaminophen by Water Insoluble Ethylcellulose Coating.

Bitter tasting of drugs leads to non-compliance especially in the case of pediatric patients due to their inability to swal-low medication. In this study, we aimed to mask the bitter taste of acetaminophen (APAP) particles through coating. A pH independent water insoluble ethylcellulose polymer was used to coat the APAP. The coating of water insoluble ethylcellulose on APAP can have a significant impact on the dissolution profile. Various grades of APAP were used for coating; fine grade, Compap L90% having wide particle size distribution (PSD), and a special granular (SG) APAP 1680 having narrow PSD. Coating was performed using top spray (Vector) for Compap L90% and SG APAP 1680 grade of APAP. Bitter taste of SG APAP was masked after spraying dispersion equivalent to a weight gain of 10% compared to 35% used for Compap L90%. Using bottom spray (Wurster coater, GPCP 2.0), coating was performed on SG APAP 1680 grade of APAP by spraying aqueous dispersion of ethylcellulose (Surelease) equivalent to a weight gain of 10%. The scalability of the top spray process was also evaluated in GPCG 30 and bitter taste was masked by using Surelease dispersion equivalent to a weight gain of 6%. Coated APAP was examined for particle size (PS), particle size distribution (PSD), flowability, and drug release profile. Dissolution was performed using USP apparatus 2 and 4 in phosphate buffer and evaluated for mechanism of drug release. Particle size obtained for coated SG APAP 1680 via top and bottom spray process was 404 µm d(90) and 487 µm d(90) respectively. The results of the study demonstrated the potential of Surelease dispersion in taste masking. The use of SG APAP 1680 having narrow PSD allowed taste masking to achieve at low weight gain without greatly affecting the dissolution profile.

Formulation and evaluation of new oxycodone extended release multiple unit pellet system

Abstract The goal of the present study is to prepare a stable, multiple-unit, extended-release dosage form containing oxycodone pellets coated with aqueous ethylcellulose (EC) dispersion, Surelease E-7-19050. The application of 18% w/w of EC leads to the similar drug release with the hydrophobic, non-swelling, matrix reference product containing 20 mg of oxycodone. Increasing the compression force to 9 kN and including more than 50% w/w of oxycodone pellets into the formulation resulted in faster drug release, indicating the damaging to the EC film coating. The physical appearance of the final formulation, assay of oxycodone, moisture content, and dissolution data over the stability period showed that the multiple-unit pellet system (MUPS) is efficient for the production of highly stable product.

Water-insoluble polymers as binders for pellet drug layering: Effect on drug release and performance upon compression.

The objective of this study was to investigate the applicability of water-insoluble polymers as binders for pellet drug layering to extend the drug release. Carbamazepine was layered on sugar cores in fluidized bed coater using isopropanol (IPA):water solution or aqueous dispersion of ethylcellulose, polyvinyl acetate or ammonium-methylmethacrylate copolymer. Carbamazepine release was extended with all investigated water-insoluble polymers used as binder, without an additional coating layer. Drug release from pellets layered using IPA:water polymer solutions was dependent on polymer properties such as lipophilicity and pore-forming components, while from those layered with aqueous polymer dispersions, the release was dependent on the completeness of film formation during drug layering. Curing effect was observed only for pellets layered with Aquacoat® ECD and Eudragit® RS 30D. The drug release was not affected by compression when pellets were prepared with the flexible polymers Kollidon® SR or Kollicoat® SR 30D, however, it increased when brittle polymers such as ethylcellulose or Eudragit® RS were used. This problem could be minimized by using a higher amount of the binder, addition of a plasticizer or using polymers of higher viscosity grade. In conclusion, the use of water-insoluble polymers as binder for pellet drug layering is an effective tool to extend the drug release without additional coating step.

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

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

Mechanical particle coating using ethylcellulose nanoparticle agglomerates for preparing controlled release fine particles; effect of coating temperature on coating performance

This study describes the effect of coating temperature on the performance of mechanical particle coating using ethylcellulose, which was done to produce controlled-release particles (diameters less than 100 μm) with different release rates. First, theophylline crystals were spheronized using a mechanical powder processor, yielding theophylline spheres (used as core particles). Second, ethylcellulose aqueous dispersion was powdered by spray-freeze drying to prepare colloidal agglomerates (used as coating powder). Finally, the spheres and agglomerates were mechanically mixed at various temperatures using the processor to produce composite particles. The ethylcellulose agglomerates were pulverized during processing to coat the theophylline spheres effectively. When the coating temperature was higher than the glass transition temperature (Tg) of ethylcellulose, the amount of coated polymer increased significantly due to plastics deformation, causing thickening of the coated layer. The porosity of the coated layer decreased upon coalescence of coated polymer particles due to plastic deformation, which prevented the appearance of cracks in the film during curing. Therefore, controlled-release fine particles with various release rates can be produced effectively by mechanical particle coating at temperatures higher than the Tg of the polymer.

Development study of pectin/Surelease® solid microparticles for the delivery of L-alanyl-L-glutamine dipeptide

In this study, microparticles comprising L-alanyl-L-glutamine (AGP) were developed. A combination of pectin and Surelease® (ethylcellulose aqueous dispersion) was responsible for sustained AGP release properties in the gastrointestinal tract. A multiparameter optimization was conducted using a 23 factorial design. A broad array of formulation attributes were investigated (morphology, size, polydispersity, and entrapment efficiency) to identify suitable formulation candidates. Afterwards, two preparations (f7 and f8) varying in their pectin:Surelease® ratio were selected for further characterization (TG/DSC, XRD, FTIR, in vitro release and in vivo study). The factorial design revealed a strong influence of drying temperature on particle size and AGP entrapment efficiency. Thermal and spectroscopic analyses confirmed stability of the formulations at up to 200 °C as well as an effective encapsulation of the dipeptide. A small but not significant difference in the in vitro release profiles was found. However, in the in vivo test, formulation f8 presented a quicker effect of AGP in comparison to f7 in an animal model of insulin-induced hypoglycemia, suggesting that the higher concentration of the hydrophilic polymer pectin in f8 contributes to a faster release and bioavailability. Therefore, this study showed the possibility of encapsulating AGP using pectin and Surelease® with preserved activity of the dipeptide, and depending on the intended time and duration for action, other polymer ratios can be tested.

Multivariate analysis as a method to understand variability in a complex excipient, and its contribution to formulation performance

A key part of the Risk Assessment of excipients is to understand how raw material variability could (or does) contribute to differences in performance of the drug product. Here we demonstrate an approach which achieves the necessary understanding for a complex, functional, excipient. Multivariate analysis (MVA) of the certificates of analysis of an ethylcellulose aqueous dispersion (Surelease) formulation revealed low overall variability of the properties of the systems. Review of the scores plot to highlight batches manufactured using the same ethylcellulose raw material in the formulation, indicated that these batches tend to be more closely related than other randomly selected batches. This variability could result in potential differences in the quality of drug product lots made from these batches. Manufacture of a model drug product from Surelease batches coated using different lots of starting material revealed small differences in the release of a model drug, which could be detected by certain model dependent dissolution modeling techniques, but they were not observed when using model-independent techniques. This illustrates that the techniques are suitable for detecting and understanding excipient variability, but that, in this case, the product was still robust.

Oral sustained-release suspension based on a lauryl sulfate salt/complex

The objective of this study was to evaluate the feasibility of lauryl sulfate (LS) salt/complex as a novel carrier in oral sustained-release suspensions. Mirabegron, which has a pH-dependent solubility, was selected as the model drug. Sodium lauryl sulfate (SLS) was bound to mirabegron in a stoichiometric manner to form an LS salt/complex. LS salt/complex formulation significantly reduced the solubility of mirabegron and helped mirabegron achieve sustained-release over a wide range of pH conditions. Microparticles containing the LS salt/complex were prepared by spray drying with the aqueous dispersion of ethylcellulose (Aquacoat® ECD). The diameter of the microparticles was less than 200μm, which will help avoid a gritty taste. In vitro results indicated the microparticles had slower dissolution profiles than the LS salt/complex. The dissolution rate could be controlled flexibly by changing the amount of Aquacoat® ECD. The microparticle suspension retained the desired sustained-release property and dissolution profile after being stored for 30days at 40°C. In addition, the suspension displayed sustained-release behavior in dogs without a pronounced Cmax peak, which will help prevent side effects. These results suggest that microparticles containing LS salt/complex may be useful as a novel sustained-release suspension for oral delivery.

Development and characterization of crosslinked hyaluronic acid polymeric films for use in coating processes

The aim of this work was to develop and characterize new hyaluronic acid-based responsive materials for film coating of solid dosage forms. Crosslinking of hyaluronic acid with trisodium trimetaphosphate was performed under controlled alkaline aqueous environment. The films were produced through casting process by mixing crosslinked or bare biopolymer in aqueous dispersion of ethylcellulose, at different proportions. Films were further characterized regarding morphology by scanning electron microscopy, robustness by permeation to water vapor transmission, and ability to hydrate in simulated gastric and intestinal physiological fluids. The safety and biocompatibility of films were assessed against Caco-2 and HT29-MTX intestinal cells. The permeation to water vapor transmission was favored by increasing hyaluronic acid content in the final formulation. When in simulated gastric fluid, films exhibited lower hydration ability compared to more extensive hydration in simulated intestinal fluids. Simultaneously, in simulated intestinal fluids, films partially lost weight, revealing ability for preventing drug release at gastric pH, but tailoring the release at higher intestinal pH. The physiochemical characterization suggests thermal stability of films and physical interaction between compounds of formulation. Lastly, cytotoxicity tests demonstrated that films and individual components of the formulations, when incubated for 4h, were safe for intestinal cells Overall, these evidences suggest that hyaluronic acid-based responsive films, applied as coating material of oral solid dosage forms, can prevent the premature release of drugs in harsh stomach conditions, but control the release it in gastrointestinal tract distal portion, assuring safety to intestinal mucosa.

Blends of hydrophobic and swelling agents in the swelling layer in the preparation of delayed-release pellets of a hydrophilic drug with low MW: Physicochemical characterizations and in-vivo evaluations

In this study, a hydrophobic material, ethylcellulose, which was used as its aqueous suspension Surelease®, was combined with a swelling agent as the swelling layer to prepare delayed-release pellets for Danshensu, which is a hydrophilic drug with low MW. A rupturable, delayed-release pellet consists of a drug core, a swelling layer containing a swelling agent (cross-linked sodium carboxymethyl cellulose) with a hydrophobic agent (Surelease®), and a controlled layer composed by an insoluble, water-permeable polymeric coating (aqueous ethylcellulose dispersions) was developed in a fluidised bed. Results showed that blending Surelease® into the swelling layer could effectively extend the release of Danshensu from the pellets, which may be attributed to the slowed swelling rate by reduction of water penetration and improvement of mechanical integrity of the swelling layer. Drug in the delayed pellets showed sustained release in beagle dogs after oral administration with comparable in-vivo exposure to the uncoated drug pellets. In conclusion, blends of hydrophobic and swelling agents in the swelling layer in double-membrane pellets could achieve a delayed drug-release profile in vitro, as well as delayed and sustained absorption in vivo for highly soluble, low-MW drug. The present study highlighted the potential use of a delayed-release system for other hydrophilic, low-MW drugs to meet the formulation requirements for chronopharmacological diseases.

Preparation of naproxen–ethyl cellulose microparticles by spray-drying technique and their application to textile materials

The objective of this study is to develop a new textile-based drug delivery system containing naproxen (NAP) microparticles and to evaluate the potential of the system as the carrier of NAP for topical delivery. Microparticles were prepared by spray-drying using an aqueous ethyl cellulose dispersion. The drug content and entrapment efficiency, particle size and distribution, particle morphology and in vitro drug release characteristics of microparticles were optimized for the application of microparticles onto the textile fabrics. Microparticles had spherical shape in the range of 10–15 μm and a narrow particle size distribution. NAP encapsulated in microparticles was in the amorphous or partially crystalline nature. Microparticles were tightly fixed onto the textile fabrics. In vitro drug release exhibited biphasic release profile with an initial burst followed by a very slow release. Skin permeation profiles were observed to follow near zero-order release kinetics.

Ethanol-resistant ethylcellulose/guar gum coatings – Importance of formulation parameters

Recently, ethylcellulose/guar gum blends have been reported to provide ethanol-resistant drug release kinetics from coated dosage forms. This is because the ethanol insoluble guar gum effectively avoids undesired ethylcellulose dissolution in ethanol-rich bulk fluids. However, so far the importance of crucial formulation parameters, including the minimum amount of guar gum to be incorporated and the minimum required guar gum viscosity, remains unclear. The aim of this study was to identify the most important film coating properties, determining whether or not the resulting drug release kinetics is ethanol-resistant. Theophylline matrix cores were coated in a fluid bed with blends of the aqueous ethylcellulose dispersion “Aquacoat®ECD30” and guar gum. The polymer blend ratio, guar gum viscosity, and degree of dilution of the final coating dispersion were varied. Importantly, it was found that more than 5% guar gum (referred to the total polymer content) must be incorporated in the film coating and that the apparent viscosity of a 1% aqueous guar gum solution must be greater than 150cP to provide ethanol-resistance. In contrast, the investigated degree of coating dispersion dilution was not found to be decisive for the ethanol sensitivity. Furthermore, all investigated formulations were long term stable, even upon open storage under stress conditions for 6months.

Ethanol-resistant polymeric film coatings for controlled drug delivery

The sensitivity of controlled release dosage forms to the presence of ethanol in the gastro intestinal tract is critical, if the incorporated drug is potent and exhibits severe side effects. This is for instance the case for most opioid drugs. The co-ingestion of alcoholic beverages can lead to dose dumping and potentially fatal consequences. For these reasons the marketing of hydromorphone HCl extended release capsules (Palladone) was suspended. The aim of this study was to develop a novel type of controlled release film coatings, which are ethanol-resistant: Even the presence of high ethanol concentrations in the surrounding bulk fluid (e.g., up to 40%) should not affect the resulting drug release kinetics. Interestingly, blends of ethylcellulose and medium or high viscosity guar gums provide such ethanol resistance. Theophylline release from pellets coated with the aqueous ethylcellulose dispersion Aquacoat® ECD 30 containing 10 or 15% medium and high viscosity guar gum was virtually unaffected by the addition of 40% ethanol to the release medium. Furthermore, drug release was shown to be long term stable from this type of dosage forms under ambient and stress conditions (without packaging material), upon appropriate curing.

A Novel Multilayered Multidisk Oral Tablet for Chronotherapeutic Drug Delivery

A Multilayered Multidisk Tablet (MLMDT) comprising two drug-loaded disks enveloped by three drug-free barrier layers was developed for use in chronotherapeutic disorders, employing two model drugs, theophylline and diltiazem HCl. The MLMDT was designed to achieve two pulses of drug release separated by a lag phase. The polymer disk comprised hydroxyethylcellulose (HEC) and ethylcellulose (EC) granulated using an aqueous dispersion of EC. The polymeric barrier layers constituted a combination of pectin/Avicel (PBL) (1st barrier layer) and hydroxypropylmethylcellulose (HPMC) (HBL1 and HBL2) as the 2nd and 3rd barrier layers, respectively. Sodium bicarbonate was incorporated into the diltiazem-containing formulation for delayed drug release. Erosion and swelling studies confirmed the manner in which the drug was released with theophylline formulations exhibiting a maximum swelling of 97% and diltiazem containing formulations with a maximum swelling of 119%. FTIR spectra displayed no interactions between drugs and polymers. Molecular mechanics simulations were undertaken to predict the possible orientation of the polymer morphologies most likely affecting the MLMDT performance. The MLMDT provided two pulses of drug release, separated by a lag phase, and additionally it displayed desirable friability, hardness, and uniformity of mass indicating a stable formulation that may be a desirable candidate for chronotherapeutic drug delivery.

Encapsulation of a pressure-sensitive adhesive by spray-drying: microparticles preparation and evaluation of their crushing strength

An industrial pressure-sensitive adhesive was microencapsulated by spray-drying using an aqueous colloidal ethylcellulose dispersion (Aquacoat® ECD) plasticised by triacetin to form the wall material. Unloaded (0:100) and adhesive-loaded (25:75) particles were produced in a Büchi B-191 mini spray-dryer with product yields of 62% and 57%, respectively. Microparticles were spherical and narrow sized with mean D3,2 diameters of 3.165 ± 0.001 and 5.544 ± 0.105 µm, respectively. The microparticles were found to redisperse well in water and exhibit enough stability in neutral and alkaline aqueous media to be further used in a coating slip. Crush tests on single microparticles with diameters ranging from 2 to 12 µm were performed using a nanoindenter. They revealed that the crushing force of both kinds of microparticles increased linearly with their diameter and that the adhesive loading reduced the mechanical strength of the prepared microparticles.

Real-time predictions of drug release and end point detection of a coating operation by in-line near infrared measurements

The aim of this work was to carry out real-time near infrared (NIR) predictions of drug release from sustained release coated tablets and to determine end point of coating operation.In-line measurements were ensured by implementation of a NIR probe inside a pan coater. Tablets were coated using a functional aqueous dispersion of ethylcellulose blended with PVA–PEG graft copolymer to obtain a controlled drug release dosage form over 16h. Samples were collected at regular intervals and subjected to a standardized curing step. Percentages of released drug at 4h, 8h and 12h were selected to describe the controlled drug release of cured tablets. These dissolution criteria were used as reference values to calibrate NIR spectral information and to develop three partial least squares regressions.Low predictive errors of 1.7%, 1.9% and 1.5%, respectively, were obtained. The coating operation was stopped while desired dissolution criteria were achieved, corresponding to a coating level around 10%.The present study demonstrated that real-time NIR measurements could be performed on non-finished drug products to predict dissolution properties of cured coated tablets. This novel and innovative approach fulfils the expectations of ICH Q8 guideline on pharmaceutical development, in terms of process understanding and process analytical technology (PAT) control strategy. This approach should be however adapted to curing operation to allow a real-time release testing.

Evaluating tamsulosin hydrochloride-released microparticles prepared using single-step matrix coating

The objective of the present study was to determine the optimum composition for sustained-release of tamsulosin hydrochloride from microparticles intended for orally disintegrating tablets. Microparticles were prepared from an aqueous ethylcellulose dispersion (Aquacoat®), and an aqueous copolymer based on ethyl acrylate and methyl methacrylate dispersion (Eudragit® NE30D), with microcrystalline cellulose as core particles with a fluidized bed coating process. Prepared microparticles were about 200μm diameter and spherical. The microparticles were evaluated for in vitro drug release and in vivo absorption to assess bioequivalence in a commercial product, Harnal® pellets. The optimum ratio of Aquacoat® and Eudragit® NE30D in the matrix was 9:1. We observed similar drug release profiles in microparticles and Harnal® pellets. Higuchi model analysis of the in vitro drug release from microparticles was linear up to 80% release, typical of Fickian diffusion sustained-release profile. The in vivo absorption properties from microparticles were comparable to Harnal® pellets, and there was a linear relationship between in vitro drug release and in vivo drug release. In conclusion, this development produces microparticles in single-step coating, that provided a sustained-release of tamsulosin hydrochloride comparable to Harnal® pellets.