Evaluation of the drug release patterns and long term stability of aqueous and organic coated pellets by using blends of enteric and gastrointestinal insoluble polymers

The major aim of this study was to identify an efficient tool to adjust drug release patterns from aqueous and organic ethylcellulose (a gastrointestinal insoluble polymer) coated pellets and to evaluate the long term stability of the film coatings. Drug release was monitored during open and closed storage at 25 °C/60% RH (ambient conditions) and 40 °C/75% RH (stress conditions) for up to 24 months. Release of vatalanib succinate, a poorly soluble drug that demonstrates pH-dependent solubility, from pure ethylcellulose coated pellets was slow irrespectively of the type of coating and release medium. By addition of the enteric polymer methacrylic acid/ethyl acrylate copolymer (applied as aqueous Kollicoat MAE 30 DP dispersion or organic solution of Kollicoat MAE 100 P) to ethylcellulose broad ranges of drug release patterns could be achieved. For aqueous film coatings the addition of Kollicoat MAE 30 DP to ethylcellulose dispersions resulted in unaltered drug release kinetics during closed storage at ambient and stress conditions. The storage stabilizing effect of the added enteric polymer might be explained by the more hydrophilic nature of Kollicoat MAE 30 DP compared to ethylcellulose trapping water during film formation and improving polymer particle coalescence. However, during open storage of aqueous coated ethylcellulose:Kollicoat MAE 30 DP pellets at stress conditions drug release decreased due to further gradual polymer particle coalescence. In contrast, drug release rates from organic coated ethylcellulose:Kollicoat MAE 100 P pellets stored at ambient and stress conditions did not change which could be explained by differences in the film formation process. This clearly indicates that the presented concept of the addition of methacrylic acid/ethyl acrylate copolymer to ethylcellulose film coatings in combination with an organic coating process is able to achieve broad ranges of drug release patterns and to overcome storage instability.     

pH-Sensitive Polymer Blends Used as Coating Materials to Control Drug Release from Spherical Beads: Elucidation of the Underlying Mass Transport Mechanisms

Purpose To elucidate the drug release mechanisms from pellets coated with pH-sensitive polymer blends.Methods Verapamil hydrochloride-loaded beads were coated with various blends of a water-insoluble and an enteric polymer, ethylcellulose:Eudragit L and Eudragit NE:Eudragit L, respectively. Both experimental and theoretical techniques were used to characterize the systems before and upon exposure to 0.1 M HCl and phosphate buffer (pH 7.4).Results Using analytical solutions of Fick’s second law of diffusion, optical and scanning electron microscopy, and mechanical and gravimetric analysis, new insight into the underlying drug release mechanisms could be gained. More importantly, the latter can be effectively altered by varying the type of polymer blend and blend ratio. For example, at low pH drug release is primarily controlled by diffusion through the intact film coatings in Eudragit NE:Eudragit L blends, whereas crack formation is of major importance in ethylcellulose:Eudragit L-coated systems. At high pH, the (partial) leaching of the enteric polymer out of the coatings plays an important role. In all cases, the observed drug release profiles could be explained based on the occurring mass transport processes.Conclusions The obtained new knowledge can be used to effectively adjust desired drug release mechanisms and, thus, release patterns.     

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.     

Development of a novel osmotically driven drug delivery system for weakly basic drugs

The drug substance SAG/ZK has a short biological half-life and because of its weakly basic nature a strong pH-dependent solubility was observed. The aim of this study was to develop a controlled release (cr) multiple unit pellet formulation for SAG/ZK with pH-independent drug release. Pellets with a drug load of 60% were prepared by extrusion/spheronization followed by cr-film coating with an extended release polyvinyl acetate/polyvinyl pyrrolidone dispersion (Kollidon SR 30 D). To overcome the problem of pH-dependent drug release the pellets were then coated with a second layer of an enteric methacrylic acid and ethyl acrylate copolymer (Kollicoat MAE 30 DP). To increase the drug release rates from the double layered cr-pellets different osmotically active ionic (sodium and potassium chloride) and nonionic (sucrose) additives were incorporated into the pellet core. Drug release studies were performed in media of different osmotic pressure to clarify the main release mechanism. Extended release coated pellets of SAG/ZK demonstrated pH-dependent drug release. Applying a second enteric coat on top of the extended release film coat failed in order to achieve pH-independent drug release. Already low enteric polymer levels on top of the extended release coated pellets decreased drug release rates at pH 1 drastically, thus resulting in a reversal of the pH-dependency (faster release at pH 6.8 than in 0.1N HCl). The addition of osmotically active ingredients (sodium and potassium chloride, and sucrose) increased the imbibing of aqueous fluids into the pellet cores thus providing a saturated drug solution inside the beads and increasing drug concentration gradients. In addition, for these pellets increased formation of pores and cracks in the polymer coating was observed. Hence drug release rates from double layered beads increased significantly. Therefore, pH-independent osmotically driven SAG/ZK release was achieved from pellets containing osmotically active ingredients and coated with an extended and enteric polymer. In contrast, with increasing osmotic pressure of the dissolution medium the in vitro drug release rates decreased significantly.     

聚合物水性分散体在茶碱控释小丸包衣上的应用

将Ｓｕｒｃｌｅａｓｅ、Ｓｕｒｅｔｅｒｉｃ、Ｏｐａｒｌｒｙ等聚合物水性分散体应用于茶碱小丸的包衣,得到释放度符合美国药典要求的控释小丸。     

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.     

Mechanisms Controlling Theophylline Release from Ethanol-Resistant Coated Pellets

Purpose

To elucidate the mass transport mechanisms controlling drug release from recently proposed, ethanol-resistant, polymeric film coatings.

Methods

Theophylline matrix pellets were coated with ethylcellulose: guar gum blends. Drug release from single pellets and ensembles of pellets was measured in various release media. Changes in the systems’ morphology, composition and mechanical properties were monitored using SEM, gravimetrical analysis and a texture analyzer. Based on the obtained experimental results a mechanistically realistic mathematical model was identified and used to quantitatively predict drug release from coated pellets in ethanol-free and ethanol-containing bulk fluids.

Results

Drug diffusion though the intact polymeric film coatings is likely to be the dominant mass transport mechanism in the investigated systems, irrespective of the ethanol content in the surrounding environment. An appropriate solution of Fick’s law could be used to quantitatively predict theophylline release from pellets coated with different ethylcellulose:guar gum blends at different coating levels. Importantly, independent experiments confirmed the theoretical predictions.

Conclusions

In silico simulations can help facilitating the optimization of the novel ethanol-resistant polymeric film coatings, avoiding time-consuming and cost-intensive series of trial-and-error experiments. The presence/absence of ethanol does not affect the underlying drug release mechanisms.     

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.     

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.     

Dry polymer powder coating and comparison with conventional liquid-based coatings for Eudragit) RS, ethylcellulose and shellac.

Drug-layered pellets were coated with micronized polymer powders (Eudragit) RS, ethylcellulose, and shellac) by a dry powder coating technique as an alternative to organic- and aqueous-based coatings (Eudragit) RS 30D, Aquacoat) ECD) were investigated. High plasticizer concentrations (40%) and a thermal after-treatment (curing) were necessary for the coalescence of the polymer particles and good film formation. Ethylcellulose required a higher curing temperature and time than Eudragit) RS because of its higher glass transition temperature (133 versus 58 degrees C). A smaller polymer particle size also promoted film formation. In general, pellets coated with polymer powders required higher coating levels to obtain similar drug release patterns as pellets coated with organic polymer solutions and aqueous polymer dispersions.     

药物制剂中薄膜包衣微丸的研究与应用

综述近年来薄膜包衣微丸在药物制剂中的研究与应用。微丸属于多单元型药物传递系统，具有众多优点。而将微丸制备技术和薄膜包衣技术相结合制成的具有特殊释药性质的薄膜包衣微丸，已经成为缓、控释制剂研究领域的热点。     

A novel powder coating process for attaining taste masking and moisture protective films applied to tablets

A novel powder coating process was developed for the application of taste masking and moisture protective films on tablets while avoiding the use of solvents or water. The coalescence of particles to form a polymeric film was investigated through studies of dry powder layering of micronized acrylic polymer (E PO) to produce free films. Theophylline containing tablets were coated with the same acrylic polymer in a laboratory scale spheronizer using a powder coating technique. The dry powder layer delayed the onset of drug release in pH 6.8 medium, depending on the coating level, while no delay was observed in pH 1.0 medium. The presence of hydrophilic polymers in the acrylic coating layer decreased the lag time for drug release in pH 6.8 medium, while only the presence of HPMC in the film slowed the drug release rate in acidic medium. The dry coating process was demonstrated to be a reliable alternative to solvent or aqueous film coating technologies for applying taste masking and moisture protective film coats onto compressed tablets. A controlled drug release profile was achieved in pH 6.8 media.     

5-氨基水杨酸时控结肠定位控释微丸及其制剂的研制

目的制备5-氨基水杨酸微丸及其时控结肠定位控释释药系统的研究。方法首先采用挤出滚圆机制备了含药微丸,然后使用流化床包衣设备将微丸包衣,以羟丙甲纤维素和微粉硅胶的混合物包衣作为溶胀控释层,以乙基纤维素水分散体Surelease包衣作为时滞包衣层,并将包衣微丸装入肠溶胶囊。用释放度测定法研究微丸的释放行为。结果药物通过时滞层破裂开始释放,该层厚度增加可显著延长释药时滞。调节羟丙甲纤维素的型号、包衣增重及羟丙甲纤维素与微粉硅胶两者比例,可以控制药物释放速度。在模拟胃肠道pH情况下延迟5 h释药,之后的10 h内释药完全。结论可通过调整溶胀控释层包衣混合物的比例、型号、包衣厚度及时滞层的包衣厚度,制备5-氨基水杨酸时控结肠定位控释释药系统。     

Jet milling--a new technique for microparticle preparation

The effect of an aqueous amylopectin subcoating on the acidic resistance and dissolution behaviour of enteric-coated pellets was studied. Freely water-soluble riboflavin sodium phosphate (RSP) was used as a model drug, and microcrystalline cellulose (MCC) and lactose as fillers in the pellet cores. The pellets were subcoated with 5% aqueous amylopectin solution or with 5% hydroxypropyl methylcellulose (HPMC) solution, and subsequently film-coated with aqueous dispersion of cellulose acetate phthalate (CAP). Drug release of enteric-coated pellets was investigated by confocal laser scanning microscopy (CLSM). Dissolution tests showed that amylopectin subcoating improved the acidic resistance of the enteric-coated pellets in 0.1 N hydrochloric acid (HCl) compared with HPMC subcoating. As the amylopectin subcoating load was increased to 4% and the aqueous CAP coating load to 35%, the coated pellets resisted in 0.1 N HCl solution for approximately 1 h (the amount of drug released was below 10%), and they dissolved in the SIF without enzymes in less than 10 min. Confocal microscopy images and profiles of mean fluorescence intensities of RSP (obtained in the range of the interface of the pellet core and the film and the film coating surface) showed consistent results with dissolution tests. It seems that amylopectin subcoating can prevent the influx of the dissolution medium into the pellet core, and thus decrease the premature dissolution and release of the drug from the enteric-coated pellets in 0.1 N HCl solution. The drug release mechanism appeared to be osmotically driven release, and followed by diffusion through the polymer film.     

Plasma enhanced chemical vapor depositions to encapsulate crystals in thin polymeric films: a new approach to controlling drug release rates

An RF plasma discharge was employed to deposit thin polymeric films on drug particles. This study utilized acetylsalicylic acid (aspirin) crystals and allyl alcohol as polymerizable monomer for this new approach to controlling drug release rates. Release rates of coated and uncoated particles were measured in aqueous solution at a pH of 1.0. The drug release rates could be varied over wide ranges by appropriate control of the polymeric films. These controls included film composition, extent of polymer cross-linking and film thickness. A 360 degrees rotating plasma reactor was employed to provide effective agitation and mixing of the drug particles during the coating operation. The plasma discharge was operated in a pulsed mode to provide improved control of the polymer film compositions and, at the same time, minimize undesirable decomposition of drug molecules. Overall, the results obtained clearly indicate that the pulsed RF plasma coating process developed represents a viable, one-step, solventless route to controlled drug release.     

Preparation of Controlled-Release Coevaporates of Dipyridamole by Loading Neutral Pellets in a Fluidized-Bed Coating System

Purpose. The purpose of this study was to demonstrate that it is possible to prepare controlled-release drug-polymer coevaporates on an industrial scale, omitting the recovery problems and the milling and sieving processes encountered when coevaporates are prepared by the conventional solvent-evaporation technique. Methods. Controlled-release coevaporates were prepared by spraying organic solutions of dipyridamole-Eudragit^® blends onto neutral pellets using the fluidized-bed coating method. Enteric acrylic polymers Eudragit^® L100-55, L, and S were used as dispersing agents and drug/polymer ratio 2:8 was selected for all formulations. Polarized light microscopy, X-ray diffraction spectroscopy, and differential scanning calorimetry were used to determine whether the drug was amorphous or crystalline in the coating films. Moreover, in vitro dissolution tests were performed on the dipyridamole coated pellets in test media simulating the pH variations in the GI tract and the results were compared to the release data obtained from coevaporates prepared by the conventional solvent-evaporation method. Results. All the results clearly indicate that dipyridamole is amorphous in the coating films deposited on neutral pellets as well as in coevaporate particles obtained by the conventional solvent-evaporation method. When the release patterns of the dipyridamole coated pellets are compared to those of the drug coevaporate particles prepared with the same enteric acrylic polymers, the results show similar dissolution trends. Conclusions. The results obtained indicate that pelletization can be considered as a method of choice for pilot plant and/or full-scale production of controlled-release dosage forms based on the formation of amorphous solid dispersions.     

Bead Coating. I. Change in Release Kinetics (and Mechanism) Due to Coating Levels

Beads containing 50% acetaminophen (APAP) and 50% microcrystalline cellulose (Avicel PH 101) were prepared and then coated using an aqueous ethylcellulose based dispersion (Aquacoat) to evaluate the effect of the coating level on drug release. The APAP release was shown to be dependent on levels of the coating and a change in mechanism was suggested. Drug release from incompletely coated beads at low levels of coating can be described with the square root of time model, while drug release from beads with a high level of coating appears to be best described by zero-order release. At low coating levels, the drug release rate constant based on the square root relationship seems to be linear with the coating level. At high coating levels, drug release rate in terms of a zero-order model appears to be proportional to the reciprocal of the coating level.     

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 T_50% 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 elevated 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.     

混合水分散体肠溶迟释薄膜性能研究

目的 采用肠溶型水分散体Eudragit?L30D-55和控释型水分散体Kollicoat?SR30D混合制备一种全新的对周围环境pH值具有响应的,同时具有迟释性能的聚合物薄膜。方法 采用铸膜法制备L30D-55∶SR30D混合水分散体游离膜,采用差示扫描量热法(DSC)测定薄膜玻璃化转变温度(glass transition temperature,Tg),万能材料试验机测试薄膜拉伸性能,杯法考察薄膜透湿性能。考察聚合物比例、附加剂种类和用量对薄膜性能的影响,并以制备泮托拉唑钠(PAZ-Na)肠溶迟释微丸考察包衣膜特性。结果 随着SR30D的增加,薄膜的Tg逐渐降低,强度和刚性变弱,韧性变强,透湿性能先不变后增加。随着增塑剂增加,薄膜刚性减弱,渗透性能增强。不溶性成分的加入可不同程度降低薄膜的渗透性。制备的肠溶迟释微丸在0.1 mol·L^-1盐酸中2 h药物损失量<5%,在pH 6.8缓冲液中可延迟10~20 min开始释放,并至90 min释放完全。结论 L30D-55∶SR30D混合水分散体制备的游离膜和包衣膜具有良好的理化性能,可用于肠溶调释制剂的研究和开发。