Safety and Robustness of Coated Pellets: Self-Healing Film Properties and Storage Stability

Purpose  Aim of the study was to verify the safety of chlorpheniramine maleate pellets, coated with blends of poly(vinyl acetate) and poly(vinyl alcohol)–poly(ethylene glycol) graft copolymer. Therefore, the impact of mechanical forces and storage conditions on the drug release was investigated. Results  Similar release profiles before and after compression of the pellets to tablets underlined the high film robustness. A damage of the film coat with a razor blade resulted in a premature release, but without a burst. After a similar damage with a needle, the release profile remained almost unchanged, which indicated a swelling based self repair mechanism of the film. Additional studies were dedicated to the storage stability at three different conditions. A slightly delayed release was obtained after 6 months storage at 25°C and a marginally accelerated release was measured after storage at elevated temperatures. No drug migration into the coating layer was detected during storage by confocal Raman microscopy. ¹H-NMR analysis during storage demonstrated, that no polymer or drug degradation had occurred and the plasticizer concentration remained constant. Conclusion  The polyvinyl based coating blend for modified release pellets demonstrated a high safety, due to their high robustness and compressibility as well as their satisfying storage stability. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

High efficiency dry coating of non-subcoated pellets for sustained drug release formulations using amino methacrylate copolymers

Abstract

Dry coating utilizing a fluidized bed was evaluated in order to produce films with sustained drug release using amino methacrylate copolymers as film former. In contrast to other dry coating procedures using amino methacrylate copolymers, the described method enables an appropriate polymer adhesion by the selection of a plasticizer additive mixture in combination with the use of a three-way nozzle for simultaneous application. Well spreading fatty acid esters were found to increase the coating efficiency from 73% to approximately 86%, when they were used in conjunction with the plasticizer. Pellets were used as drug cores without previous treatment. After a curing step at 55?°C, the pellets exhibited a prolongation of the drug release over a period of about 6?h. Mainly the three parameters, coating level, composition of the polymers in the coating mixture, and the type of plasticizer, were found to exert distinct influence on the dissolution profile. Despite the differences in the coating procedure, the dissolution profiles of the coated pellets as well as the influencing parameters were similar to those known from conventional coating techniques.     

Effect of curing conditions and plasticizer level on the release of highly lipophilic drug from coated multiparticulate drug delivery system

The study aimed to investigate the effect of triethyl citrate (TEC) plasticizer level (10, 15, and 20%), curing temperature (40, 50, and 60 degrees C) and time (0 to 168 h) on the release of a highly lipophilic drug bumetanide from pellets coated with methacrylate ester copolymer (Eudragit RS). Bumetanide was layered onto sugar pellets followed by coating with 6% Eudragit RS with and without hydroxypropyl methyl cellulose (HPMC) seal coat using Wurster Fluid Bed equipment. Coated pellets were stored for 3 months at room temperature and the release was tested in USP purified water. At 10% TEC level, increasing curing time and temperature lead to slower drug release. At 15 and 20% TEC levels, curing initially decreased drug release followed by increase in the release at longer curing time and higher temperature. Drug release from coated pellets plasticized with 15% TEC and completely cured followed zero order kinetic models. At plasticizer level of 20%, bumetanide release from the completely cured pellets was better modeled using the Higuchi's equation reflecting possible drug migration during curing. Storage led to an increase in drug release. The use of HPMC seal coat stabilized drug release after storage. It was concluded that bumetanide migration into Eudragit RS film coat was the main cause of the accelerated release after curing and storage. The drug migration during storage at room temperature was prevented by seal coating the pellets with HPMC.     

Development of a Lag Time Coating for Drug-Layered Fish Feed Pellets

The purpose of this work was to develop a release-delaying coat for drug-layered fish pellets, in order to prevent a premature release of the drug in the tank water but allowing a rapid release after uptake by the fish. Blank pellets were prepared in a rotary processor and drug layered in a Wurster coater with bovine serum albumin or riboflavin using hydroxypropyl methyl cellulose (HPMC) as a binder. On the drug- loaded pellets, different mixtures of ethyl cellulose (EC) and HPMC were applied as the release-delaying coat. The aim was to obtain less than 10% drug release during the first 10 min followed by a fast release after the “lag” period, resulting in a sigmoidal release profile. In order to prevent coat bursts it was necessary to increase the amount of plasticizer from 20 to 40% triethylcitrate. To have a complete coat around the pellets, the thickness of the coat (amount EC) was important up to a certain level. The EC/HPMC ratio had a decisive influence on optimizing the permeability of the coating and realizing a sigmoidal release profile. The release rate was studied as a function of several formulation variables and physico-chemical parameters (salinity, pH, and temperature) of the dissolution medium as the coating system is intended for different fish species. Salinity of the water proved to be important as well as the temperature. The developed system seems to be promising for a lot of ichthyologic applications, although it has to be evaluated for each intended drug, keeping in mind the properties of the particles to be coated, the fish species, and the environment.     

Development of a lag time coating for drug-layered fish feed pellets

The purpose of this work was to develop a release-delaying coat for drug-layered fish pellets, in order to prevent a premature release of the drug in the tank water but allowing a rapid release after uptake by the fish. Blank pellets were prepared in a rotary processor and drug layered in a Wurster coater with bovine serum albumin or riboflavin using hydroxypropyl methyl cellulose (HPMC) as a binder. On the drug-loaded pellets, different mixtures of ethyl cellulose (EC) and HPMC were applied as the release-delaying coat. The aim was to obtain less than 10% drug release during the first 10 min followed by a fast release after the "lag" period, resulting in a sigmoidal release profile. In order to prevent coat bursts it was necessary to increase the amount of plasticizer from 20 to 40% triethylcitrate. To have a complete coat around the pellets, the thickness of the coat (amount EC) was important up to a certain level. The EC/HPMC ratio had a decisive influence on optimizing the permeability of the coating and realizing a sigmoidal release profile. The release rate was studied as a function of several formulation variables and physicochemical parameters (salinity, pH, and temperature) of the dissolution medium as the coating system is intended for different fish species. Salinity of the water proved to be important as well as the temperature. The developed system seems to be promising for a lot of ichthyologic applications, although it has to be evaluated for each intended drug, keeping in mind the properties of the particles to be coated, the fish species, and the environment.     

Drug-polymer mixed coating: a new approach for controlling drug release rates in pellets

A new approach to developing a drug-polymer mixed coat for highly water-soluble diltiazem pellets was investigated at different coating levels. Drug layering and the coating procedures were performed using a bottom spray fluidized bed coater. Drug pellets were coated with Eudragit NE40 (NE40) alone and in combination with diltiazem and hydrophilic cellulose derivatives. Dissolution studies revealed that incorporation of hydrophilic substances such as methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), and the drug itself considerably increased the release rates. The release from mixed polymer coatings was fast compared to pellets coated with NE40 only. The major portion of the drug was released in about 2 hours in case of MC and NE40 mixed coat compared to hours from coated pellets containing HPMC or diltiazem. Incorporation of 15% to 25% drug with respect to the polymer coat helped to achieve a drug-release profile at a desirable rate over a 12 hour period. Moreover, the test formulation comprising 25% diltiazem with respect to 7% NE40 had a dissolution profile that matched the commercial product, Herbesser SR capsules. The release of diltiazem from the coated pellets was slightly affected by the pH of dissolution media.     

Characterization of the film formation of the dry coating process.

As the film formation of the dry coating process differs completely from conventional coating methods it is of certain interest to define a parameter like the minimum film formation temperature (MFT) used for aqueous dispersion based processes in order to describe an efficient film formation. Film formation occurs mainly during the curing step following the coating phase. Therefore, the film formation of the dry coating process was analyzed with regard to the two process parameters influencing film formation, namely curing temperature and time. Theophylline pellets were coated using the enteric polymer HPMCAS and TEC/Myvacet as plasticizer composition. The polymer and the plasticizer were applied to the pellets simultaneously, except for the beginning of the coating step when the plasticizer has been sprayed 30 s before powder feeding was started. The coated pellets were cured for five different time periods at eight different temperatures. Drug release was determined in 0.1 N HCl. Their surface and cross-sectional morphologies were examined by scanning electron microscopy. The glass transition temperature of the obtained films as well as of the polymer plasticizer mixture obtained by casting a film using an organic solution of the coating components was determined by thermomechanical analysis. At higher curing temperature and/or extended curing time an enhancement of acid resistance is observed. The glass transition temperature of the coating mixture was determined to be 51.7+/-3.3 degrees C. It is close to the temperature needed for film formation. Enteric resistant pellets are obtained after curing for 0.75 h at 55 degrees C. However, enteric resistance was achieved as well slightly below the glass transition temperature at 45 degrees C applying long curing periods of at least 12 h. This may be caused by the plasticizer gradient along the coat which is caused by spraying the plasticizer 30 s before starting powder feeding. This results in a higher plasticizer concentration of the inner layers of the coat relatively to the outer ones. Due to this film formation starts at the inner layers even below the glass transition temperature. As the plasticizer diffuses to the outer layers during curing according to the plasticizer gradient, film formation proceeds.     

Drug release mechanisms from Kollicoat SR:Eudragit NE coated pellets

Thin, free films based on Kollicoat SR:Eudragit NE blends were prepared by casting or spraying aqueous dispersions of these polymers, and were thoroughly characterized with respect to their water uptake behavior, water permeability, dry mass loss kinetics, mechanical properties and drug release patterns. A mechanistic mathematical model based on Fick's law of diffusion was used to quantify the experimentally measured release of metoprolol succinate from various types of systems. With increasing Eudragit NE content the films became more hydrophobic, resulting in decreased water permeability as well as water uptake rates and extents. In addition, the dry mass loss upon exposure to the release medium decreased. Consequently, the films' permeability for the drug decreased. Importantly, metoprolol succinate release from thin films was mainly controlled by pure diffusion, allowing for the determination of the apparent diffusion coefficient of the drug in the different polymeric systems. Knowing these values, drug release from coated pellets could be quantitatively predicted, assuming intact film coatings throughout the observation period. Comparison with independent experimental results showed that crack formation set on very rapidly in the polymeric membranes upon exposure to the release medium in the case of sugar starter cores, irrespective of the polymer:polymer blend ratio and investigated coating level. In contrast, the onset of crack formation was delayed as a function of the blend ratio and coating thickness in the case of microcrystalline cellulose starter cores, attracting less water into the pellets core. The obtained new insight into the underlying drug release mechanisms can be very helpful during device optimization and improve the safety of this type of advanced drug delivery systems.     

Oral controlled release optimization of pellets prepared by extrusion-spheronization processing

Controlled release high dosage forms of a typical drug such as Indobufen were prepared as multiple-unit doses by employing extrusion-spheronization processing and subsequently film coating operations. The effects of drug particle size, drug/binder ratio, extruder screen size and preparation reproducibility on the physical properties of the spherical granules were evaluated. Controlled release optimization was obtained on the same granules by coating with polymeric membranes of different thickness consisting of water-soluble and insoluble substances. Film coating was applied from an organic solution using pan coating technique. The drug diffusion is allowed by dissolution of part of the membrane leaving small channels of the polymer coat. Further preparations were conducted to evaluate coatings applied from aqueous dispersion (pseudolatex) using air suspension coating technique. In this system the drug diffusion is governed by the intrinsic pore network of the membrane. The most promising preparations having the desired in vitro release, were metered into hard capsules to obtain the drug unit dosage. Accelerated stability tests were carried out to assess the influence of time and the other storage parameters on the drug release profile.     

Statistical optimisation of diclofenac sustained release pellets coated with polymethacrylic films

The objective of the present study was to evaluate three formulation parameters for the application of polymethacrylic films from aqueous dispersions in order to obtain multiparticulate sustained release of diclofenac sodium. Film coating of pellet cores was performed in a laboratory fluid bed apparatus. The chosen independent variables, i.e. the concentration of plasticizer (triethyl citrate), methacrylate polymers ratio (Eudragit RS:Eudragit RL) and the quantity of coating dispersion were optimised with a three-factor, three-level Box-Behnken design. The chosen dependent variables were cumulative percentage values of diclofenac dissolved in 3, 4 and 6 h. Based on the experimental design, different diclofenac release profiles were obtained. Response surface plots were used to relate the dependent and the independent variables. The optimisation procedure generated an optimum of 40% release in 3 h. The levels of plasticizer concentration, quantity of coating dispersion and polymer to polymer ratio (Eudragit RS:Eudragit RL) were 25% w/w, 400 g and 3/1, respectively. The optimised formulation prepared according to computer-determined levels provided a release profile, which was close to the predicted values. We also studied thermal and surface characteristics of the polymethacrylic films to understand the influence of plasticizer concentration on the drug release from the pellets.     

Mixed polymer coating for modified release from coated spheroids

Modified-release drug spheroids coated with an aqueous mixture of high-viscosity hydroxypropylmethylcellulose (HPMC) and sodium carboxymethylcellulose (NaCMC) were formulated. The preparation of core drug spheroids and the coating procedures were performed using the rotary processor and a bottom-spray fluidized bed, respectively. Dissolution studies indicated that incorporation of suitable additives, such as poly(vinylpyrrolidone) (PVP) and poly(ethylene glycol) 400 (PEG) improved the flexibility and integrity of the coat layer by retarding the drug release. An increase in coating levels applied generally retarded the release rate of the drug. However, the ratio of HPMC to NaCMC in the mixed, plasticized polymeric coat played a more dominant role in determining the dissolution T50% values. The optimal ratio of HPMC to NaCMC for prolonged drug release was found to be 3:1, whereas an increase in the amount of NaCMC in the mixed polymer coat only increased drug release. The synergistic viscosity effect of HPMC and NaCMC in retarding drug release rate was greater in distilled water than in dissolution media of pH 1 and 7.2. Cross-sectional view of the scanning electron micrograph showed that all of the coated spheroids exhibited a well-fused, continuous, and distinct layer of coating film. The drug release kinetics followed a biexponential first-order kinetic model.     

Influence of plasticization time, curing conditions, storage time, and core properties on the drug release from Aquacoat-coated pellets

Theophylline or chlorpheniramine maleate pellets were coated with an aqueous ethylcellulose dispersion, Aquacoat. The influence of the plasticization time, curing conditions, storage time, and core properties on the drug release were investigated. The plasticization time (time between plasticizer addition to the polymer dispersion and the spraying process) did not affect the drug release, when the water-soluble plasticizer triethyl citrate, was used because of its rapid uptake by the colloidal polymer particles. In contrast, with the water-insoluble plasticizer acetyltributyl citrate (ATBC), plasticization time (1/2 h vs 24 h) influenced the drug release, the longer plasticization time resulted in a slower drug release because of a more complete plasticizer uptake prior to the coating step. However a thermal aftertreatment of the coated pellets at eleylated temperatures (curing step) reduced/eliminated the effect of the plasticization time with ATBC. In general, curing reduced the drug release and resulted in stable drug release profiles. The time period between the coating and the curing step was not critical when the pellets were cured for a longer time. The structure of the pellet core (high dose matrix vs low dose layered pellet) strongly affected the drug release. A slow, zero-order drug release was obtained with high dose theophylline pellets, while a more rapid, first-order release pattern was obtained with low dose theophylline-layered nonpareil pellets.     

Influence of plasticizer level on the drug release from sustained release film coated and hot-melt extruded dosage forms

In the current study, the influence of plasticizer level on drug release was investigated for solid dosage forms prepared by hot-melt extrusion and film coating. The properties of two highly water-soluble compounds, diltiazem hydrochloride (DTZ) and chlorpheniramine maleate (CPM), and a poorly water-soluble drug, indomethacin (IDM), were investigated in the melt extrudates containing either Eudragit RSPO or Eudragit RD 100 and triethyl citrate (TEC) as the plasticizer. In addition, pellets containing DTZ were film coated with Eudragit RS 30D and varying levels of TEC using a fluidized bed coating unit. Differential scanning calorimetry (DSC) demonstrated that both CPM and IDM exhibited a plasticization effect on the acrylic polymers, whereas no plasticizing effect by DTZ on Eudragit RSPO was observed. Thermogravimetric analysis (TGA) was used to investigate the thermal stability of the DTZ, Eudragit RSPO and TEC at 140 degrees C, the maximum temperature used in the hot-melt extrusion process. The chemical stability of DTZ and IDM in the extrudate following hot-melt processing was determined by high pressure liquid chromatography (HPLC). Drug release rates of both DTZ and CPM from hot-melt extrudates increased with an increase in the TEC level in the formulations, while the release rate of DTZ from the Eudragit RS 30D-coated pellets decreased with an increase in TEC in the coating dispersion. This phenomenon was due to the formation of a reservoir polymeric structure as a result of the thermal stress and shear stress involved in the hot-melt extrusion process regardless of the TEC level. In contrast, coalescence of the polymer particles in the film coating process was enhanced with higher levels of TEC, as demonstrated by scanning electron microscopy (SEM). The addition of TEC (0% to 8%) in the IDM hot-melt extrudate formulation had no influence on the drug release rate as the drug release rate was controlled by drug diffusion through the inside of the polymeric materials rather than between the polymer particles.     

Effect of Curing Conditions and Plasticizer Level on the Release of Highly Lipophilic Drug from Coated Multiparticulate Drug Delivery System

The study aimed to investigate the effect of triethyl citrate (TEC) plasticizer level (10, 15, and 20%), curing temperature (40, 50, and 60°C) and time (0 to 168h) on the release of a highly lipophilic drug bumetanide from pellets coated with methacrylate ester copolymer (Eudragit RS). Bumetanide was layered onto sugar pellets followed by coating with 6% Eudragit RS with and without hydroxypropyl methyl cellulose (HPMC) seal coat using Wurster Fluid Bed equipment. Coated pellets were stored for 3 months at room temperature and the release was tested in USP purified water. At 10% TEC level, increasing curing time and temperature lead to slower drug release. At 15 and 20% TEC levels, curing initially decreased drug release followed by increase in the release at longer curing time and higher temperature. Drug release from coated pellets plasticized with 15% TEC and completely cured followed zero order kinetic models. At plasticizer level of 20%, bumetanide release from the completely cured pellets was better modeled using the Higuchi's equation reflecting possible drug migration during curing. Storage led to an increase in drug release. The use of HPMC seal coat stabilized drug release after storage. It was concluded that bumetanide migration into Eudragit RS film coat was the main cause of the accelerated release after curing and storage. The drug migration during storage at room temperature was prevented by seal coating the pellets with HPMC.     

Influence of film additives on stabilizing drug release rates from pellets coated with acrylic polymers.

The objective of this study was to investigate the influence of talc and triethyl citrate (TEC) on stabilizing the drug release rates following curing and storage at elevated temperature of pellets coated with an aqueous acrylic polymeric dispersion. Core pellets containing anhydrous theophylline (20%), microcrystalline cellulose, and polyvinylpyrrolidone were prepared by extrusion-spheronization. The aqueous dispersions were prepared by adding up to 30% TEC as a plasticizer and talc up to 200% as an antiadherent to a mixture of Eudragit RS 30D/RL 30D (95:5). The theophylline pellets were coated in a fluidized-bed coating unit and then cured at elevated temperatures. Theophylline pellets were successfully coated with the Eudragit dispersions that contained up to 200% talc, based on the dry polymer weight, and the coating efficiency was greater than 93%. Our results demonstrated that the polymer, which was plasticized by TEC, was able to function as a film-forming agent for dispersions containing high levels of talc. No sticking of the coated pellets was observed during the coating process or during the curing or equilibrating phase, even with high levels of TEC in the film. The dissolution rate of theophylline from the coated pellets was delayed when the film coating dispersion contained high levels of talc. Additionally, the stability of the drug release profiles from the coated pellets after storage was significantly improved. Furthermore, a modified dissolution testing used to simulate mechanical stresses that may be encountered in vivo showed the film coated pellets would have sufficient strength. The results of this study demonstrated that high levels of film additives in the acrylic dispersion contributed to the stabilization of the drug release rates as well as the reproducibility of the coating process.     

Polymer leaching from film coating: effects on the coating transport properties

The release mechanism of metoprolol succinate pellets coated with a blend of a water-insoluble polymer, ethyl cellulose (EC), and a water-soluble polymer, hydroxypropyl cellulose (HPC), is mechanistically explained. The kinetics of drug release and HPC leaching were followed for drug doses. The coating was initially not permeable to the drug, and release started only after a critical amount of the HPC had been leached out. Drug release occurred mainly through pores created in the coating by the HPC dissolution. Single-pellet release experiments were also performed. The coating thickness and size of each pellet were measured. In order to quantitatively characterize the transport properties of the coating of the individual pellets, and to determine the effective diffusion coefficient (D(e)) of the drug in the coating, a mechanistic model was used to fit the single-pellet release data. It was found that D(e) increased with time due to an increase in the amount of HPC leached. It was also found that D(e) was dependent on the coating thickness, and increased more slowly with a thicker coating. This agreed well with the finding that the HPC leaching rate decreased with increasing film thickness.     

Dry Powder Coating of Pellets with Micronized Eudragit® RS for Extended Drug Release

PURPOSE: To develop a novel powder coating technology for extended-release pellets based on the acrylic polymer, Eudragit RS. METHODS: A mixture of micronized Eudragit RS plus talc and a liquid feed (plasticizer plus binder solution) were sprayed separately onto propranolol hydrochloride-loaded pellets in a fluidized bed coater. The coated pellets were heat-cured under different conditions (40 degrees C to 60 degrees C, 2 h to 24 h). The coalescence (film formation) of the polymer particles was studied via the determination of the glass transition and the minimum polymer-softening temperatures (MST). The coated pellets were characterized with respect to their morphologic, release, and stability properties. RESULTS: The optimum plasticizer type and concentration and process temperatures could be identified by the determination of the MST. High concentrations of plasticizer (40% based on the polymer) and a thermal treatment were necessary to achieve complete film formation and extended drug release. Curing the pellets resulted in release profiles, which did not change during storage for 3 years. The coated pellets had a smooth, continuous surface and a dense film structure after curing. CONCLUSIONS: This novel coating technique avoids the use of organic polymer solutions or latex dispersions, has short processing times, and results in stable extended-release profiles.     

白术黄连微丸结肠靶向胶囊的制备及体外释放研究

目的 将中药"白术黄连方"制备成以胃溶微丸和肠溶微丸为基础的结肠靶向胶囊,优化其处方组成和制备工艺,考察其体外释放特性.方法 采用单因素实验和正交实验法优化微丸的处方组成和工艺参数.用挤出-滚圆技术制备素丸,流化床底喷方式进行包衣,考察隔离衣增重、肠溶衣中聚合物比例、增塑剂用量和包衣增重对肠溶微丸释放行为的影响,并对其...     

Polymerized rosin: novel film forming polymer for drug delivery

Polymerized rosin (PR) a novel film forming polymer is characterized and investigated in the present study for its application in drug delivery. Films were produced by a casting/solvent evaporation method from plasticizer free and plasticizer containing solutions. Films prepared from different formulations were studied for their mechanical (tensile strength, percent elongation and Young's modulus), water vapour transmission and moisture absorption characteristics. Neat PR films were slightly brittle and posed the problem of breaking during handling. Hydrophobic plasticizers, dibutyl sebacate and tributyl citrate, improved the mechanical properties of free films with both the plasticizers showing significant effects on film elongation. Release of diclofenac sodium (model drug) from coated pellets was sustained with high coating levels. Concentration of plasticizer was found to affect the release profile. PR films plasticized with hydrophobic plasticizers could therefore be used in coating processes for the design of oral sustained delivery dosage forms.     

Sustained release pellets based on poly(N-isopropyl acrylamide): matrix and in situ photopolymerization-coated systems

The usefulness of poly(N-isopropyl acrylamide), PNIPA, for preparing sustained release matrix or photopolymerization-coated cellulosic pellets was evaluated. Theophylline pellets and granules were prepared using powdered cellulose (PC), poly(vinylpyrrolidone) (PVP), and PNIPA of Mw approximately 330 kDa, Mn approximately 93 kDa and low critical solubility temperature approximately 32 degrees C. The low consistency of wet mass, evaluated by torsion rheometry, due to hydrophilic character of PNIPA at room temperature, favored extrusion-spheronization. Theophylline (20%) pellets prepared with 15% PNIPA, 20% PVP and 45% PC, and granules obtained using 40% PNIPA and 40% PC showed an enhanced, although limited, ability to sustain the release. This effect was notably promoted after compression (which provides slowly eroding tablets) or coating of individualized pellets. A new coating technique consisting in forming the polymer film by photo-polymerization/cross-linking of NIPA monomers on pellets surface, using a photoinitiator and UV-irradiation at 366 nm, was developed. The composition of coating mixture and the time of irradiation were optimized using oscillatory rheometry. Coating did not significantly change the shape, size, or friability of the pellets but remarkably decreased the porosity and sustained drug release for several hours. In situ formation and cross-linking of PNIPA on the pellet appears as a feasible way for controlling drug release.