pH-independent release of a basic drug from pellets coated with the extended release polymer dispersion Kollicoat SR 30 D and the enteric polymer dispersion Kollicoat MAE 30 DP.

The objective of this study was to obtain pH-independent release profiles from coated pellets containing drugs with pH-dependent solubility. pH-independent release of the basic model drug verapamil HCl was achieved by coating with a combination of the neutral polymer dispersions Kollicoat SR 30 D (aqueous dispersion of polyvinyl acetate) and the enteric polymer dispersion Kollicoat MAE 30 DP (aqueous dispersion of methacrylic acid and ethyl acrylate copolymer; methacrylic acid copolymer type C). The two polymers where applied either as separate layers (enteric polymer + extended release polymer or vice versa) or as a polymer blend. A careful balance of the ratios of the polymers allowed the achievement of a pH-independent release. Higher amounts of the enteric polymer in the polymer blend resulted in a reversal of the pH-dependency, e.g. a faster release at pH 6.8 than in 0.1 N HCl.     

Physicochemical and release properties of pellets coated with Kollicoat SR 30 D, a new aqueous polyvinyl acetate dispersion for extended release

Kollicoat^® SR 30 D is a new aqueous colloidal polyvinyl acetate dispersion used for extended release coatings. Kollicoat^® SR 30 D is stable against sedimentation, has a low viscosity (54 mPas) and a negative zeta potential of −23.2 mV because of the presence of the anionic surfactant, sodium dodecyl sulfate. Because of its low minimum film formation temperature (MFT = 18 °C), plasticizer addition and a thermal after-treatment (curing) of coated pellets was not required. Coated pellets showed no aging or curing effect. The rate of release could be easily adjusted by varying the coating level. A subcoating layer of the hydrophilic polymer, polyvinyl alcohol, between an ibuprofen-containing core and the Kollicoat^® SR coating prevented the diffusion of the lipophilic, low melting ibuprofen into the polymer coating during storage. The drug release from Kollicoat^® SR 30 D coated pellets was almost independent of the pH and ionic strength of release medium.     

Preparation of floating pellets with verapamil hydrochloride

The aim of this paper is to prepare a floating drug formulation in a gelatin capsule filled with tens of pellets with verapamil hydrochloride (VH) in a dose of 40 mg. The better solubility of VH in an acidic environment of the stomach may result in a greater amount of the drug absorbed. Pellets were prepared by wet granulation of a powder mixture, spheronization of the granulated mass and coating of the cores with aqueous dispersions of polymethylmethacrylate. Sodium hydrocarbonate contained in pellet cores ensures the flotation effect. Proper rate of VH release from pellets was obtained by a coating film of 25-105 microm thickness. Pellets of 1.25-1.6 mm size with a film of 75-85 microm thickness of considerably constant rate released the whole dose of VH in 6 h. During that time the pellets floated on the surface of the receptor solution.     

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.     

Chitosan/Kollicoat SR 30D film-coated pellets of aminosalicylates for colonic drug delivery

The purpose of the study was to (i) prepare the chitosan/Kollicoat SR 30D film-coated pellets for colonic drug delivery, and (ii) evaluate the colonic delivery and efficacy of these coated pellets in the rat. The pellets were coated to different film thickness with chitosan/Kollicoat SR 30D formulations. In vitro drug release was assessed in simulated gastrointestinal (GI) tract conditions. Biodistribution of aminosalicylates (5-ASA) in GI tract and plasma was measured after oral administration of coated or uncoated 5-ASA pellets. Efficacy of the coated or uncoated 5-ASA pellets was tested in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced rat colitis model. Healing of induced colitis was assessed by measuring the myeloperoxidase activities, colon wet weight/body weight, and damage score. The coating was susceptible to bacteria digestion, resulting in an increase in the release of 5-ASA from the coated pellets. After administration of the coated pellets, the drug concentration in the large intestine was higher than those of uncoated pellets. In plasma, the observed mean C_max from the coated pellets was significantly lower than that of the uncoated pellets. Chitosan/Kollicoat SR 30D film-coated pellets could deliver the 5-ASA to the targeted site, providing effective treatment for inflammatory bowel disease. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:186–195, 2010     

Kollicoat SR 30D游离膜的拉伸性能和透湿性

采用平面铸膜法制备Kollicoat SR 30D游离膜,以自制简易膜拉伸试验装置初步检测膜的机械性能,并考察增塑剂及致孔剂对膜延伸率和膜透湿性的影响.结果表明,增大增塑剂枸橼酸三乙酯(TEC)的用量可使膜延伸率和透湿性明显提高;3种致孔剂(聚乙二醇6000、聚维酮K30和羟丙甲纤维素E5)均能提高薄膜的透湿性,但对膜延伸率无明显改变.进一步研究表明,聚乙二醇用量对以10％ TEC为增塑剂的膜的延伸率和透湿性无明显影响.     

Kollicoat SR30D在盐酸青藤碱微丸型缓释片中的应用

以新型水分散体Kollicoat SR30D为微丸的衣膜材料,制备盐酸青藤碱缓释包衣微丸;随后将其与适宜的辅料混匀后直接压片,制得能缓释12 h的微丸型片剂.考察了增塑剂种类和用量对微丸中药物释放的影响,以及压片过程中填充剂比例对微丸的保护作用.结果表明,以10%柠檬酸三乙酯作增塑剂的Kollicoat SR30D能在流化床包衣过程中形成致密完整的衣膜,无需愈合处理.将包衣增重为18%的微丸与硅化微晶纤维素颗粒以1:3(w/w)混匀,再加入0.5%硬脂酸镁,直接压片可制得缓释12 h的微丸型片剂,且压片前后药物释放行为无显著差异.     

Influence of the components of Kollicoat SR film on mechanical properties of floating pellets from the point of view of tableting

The influence of pellet core ingredients on pellet behaviour, e.g. during compression, is well known. In this study the influence of components of a Kollicoat SR polymer film on mechanical properties was investigated. The aim of this study was to evaluate the influence of polymer film components on the mechanical properties of the pellet as a whole, from the point of view of tableting. Tablets should disintegrate into undeformed pellets floating in this environment for 5-6 h, releasing the model drug--verapamil hydrochloride--if possible in a controlled way. The usefulness of texture analysis and work of compression measurement was also evaluated. Kollicoat SR in the form of a 30D aqueous dispersion was chosen as the main component of the polymer film. Polyvinyl pyrrolidone K-30 as a pore former, and propylene glycol, triethyl citrate and dibutyl sebacate plasticisers were selected as typical additives. The influence of different thickness of polymer film on behaviour during stress was also evaluated. After coating the cores with a 20 microm Kollicoat SR dispersion film, an increase in mechanical strength, in comparison to the pellet core, was observed (2.74 to 3.34 mJ). Addition of porophor increased the work of compression by 50% to 5.1 mJ. The investigation of the influence of plasticiser on film properties proved that the kind of plasticiser used in the polymer film had no effect on the mechanical properties of the film or pellets. Only in the case of the film with triethyl citrate was no distinct of the pellet core found. Pellets coated both with films with triethyl citrate and with dibutyl sebacate, in contrast to pellets with a film coating with propylene glycol, showed a significant decrease of the dissolution rate of verapamil hydrochloride (20, 10 and 40% at 6 hours, respectively). It is possible to compress pellets with a 50 microm polymer film without affecting the dissolution rate, as was confirmed during release studies. When using Kollicoat SR the most appropriate plasticizer seems to be triethyl citrate, and in this case a change of behavior during compression analysis by texture analyzer was observed. But so relationship was found between the type of plasticizer and the work needed to obtain a given deformation.     

Control and stability of drug release from diffusion pellets coated with the aqueous quaternary polymethacrylate dispersion Eudragit RS 30 D.

The addition within compatibility limits of the pore formers hydroxypropyl methylcellulose (HPMC) and hydroxy ethylcellulose (HEC) to coatings of the quaternary polymethacrylate dispersion Eudragit RS 30 D enables drug release to be controlled without problems. 20 and 15%, respectively, of these pore formers are suitable for release within 8 h of theophylline from pellets with a coating thickness of about 30 microns. A 10% addition of plasticizer, water soluble triethyl citrate (TEC) or water insoluble dibutyl phthalate (DBP), lowers the minimum film forming temperature (MFT) from 48 to 17 and 26 degrees C, respectively. The MFT is scarcely influenced by the pore formers. However, the plasticizers may modify the effect of the pore formers: HPMC is more effective in the presence of DBP. In spite of the preparation of the coatings at a bed temperature about 20 degrees C above MFT, the release from the diffusion pellets is not stable during storage. Only curing in an oven or in the fluidized bed up to a certain limiting release rate at 80 degrees C for 1 h results in stable products. Increased relative humidity allows reduction of the curing temperature. The water soluble additives polyoxy ethylene (PEG) and polyvinyl pyrrolidone (PVP) and insoluble additives are ineffective as pore formers.     

An investigation into the characteristics of chitosan/Kollicoat SR30D free films for colonic drug delivery

The purpose of the study was to establish the physico-mechanical, digestibility, permeability and swelling properties of chitosan/Kollicoat SR30D films as potential coatings for colonic drug delivery. Free films containing different ratios of chitosan to Kollicoat SR30D were prepared by casting/solvent evaporation method. The resultant mixed films were characterized in terms of puncture strength and elongation (%), glass transition temperature, swellability, polymer miscibility, permeability, and digestibility under different media. The mixed films possessed good mechanical properties, which could be used as film-coating materials for drug delivery. The extent of digestion was directly proportional to the amount of chitosan present within the film. No apparent miscibility was detected between the chitosan and Kollicoat SR30D, regardless of the film composition. The films were found to be susceptible to digestion by bacterial or β-glucosidase enzymes in simulated colonic fluid (SCF). The SCF with rat cecal bacterial enzymes had a more profound hydrolytic activity than that with β-glucosidase enzyme for the digestion of chitosan within the mixed films. Overall, the results indicated that such chitosan/Kollicoat SR30D films had potential as a coating system for drug delivery to the colon.     

Pharmacokinetics of verapamil and norverapamil from controlled release floating pellets in humans.

Pharmacokinetics of verapamil (V) in a dose of 40 mg and its metabolite norverapamil (N) from the new oral drug formulation in a form of capsule filled with floating pellets was determined. Conventional 40-mg tablets used in a medical practice served as a reference. Bioavailability studies were carried out in 12 healthy volunteers including six men and six women. In an in vitro test the pellets floated on the surface of the extraction fluid for 6 h. Mean value of maximum plasma concentration (C(max)) of V for floating pellets was 28.27 ng ml(-1) and t(max) 3.75 h. The value of the area under the concentrations versus time, AUC(0-infinity) was calculated as 364.65 ng ml(-1) h, biological half-lives of the absorption and elimination (t(0.5el)) phase were 0.5 h and 10.68 h, respectively. For the reference conventional tablets those values were 33.07 ng ml(-1), 1.21 h, 224.22 ng ml(-1) h, 0.36 h and 6.17 h, respectively. The average concentration of N in plasma was similar to that of V.     

Influence of hydroxyethylcellulose on the drug release properties of theophylline pellets coated with Eudragit RS 30 D.

The objective of this study was to investigate the influence of a hydrophilic polymer, hydroxyethylcellulose (HEC), on the release properties of theophylline from pellets coated with Eudragit RS 30 D, and the physicochemical properties of Eudragit RS 30 D cast films. The release rate of theophylline from Eudragit RS 30 D coated pellets decreased during storage at 25 degrees C/60% RH due to the further coalescence of colloidal acrylic particles. In addition, water-vapor permeability and tensile strength of Eudragit RS 30 D cast film decreased after 1-month storage at 25 degrees C/60% RH. The presence of 10% hydroxyethylcellulose in the coating formulation was shown to stabilize the drug release rate from coated pellets, the water-vapor permeability and the tensile strength of free films. Atomic force microscopy and scanning electronic microscopy were used to demonstrate that the HEC was immiscible with Eudragit RS 30 D in the cast films. The stabilization effect of HEC was investigated and determined to be due to the formation of an incompatible phase between the latex particles which impaired further coalescence of the colloidal acrylic particles.     

盐酸氨溴索包衣小丸的制备及其释药特性

目的：研制盐酸氨溴索（Amb）包衣小丸，评价其体外释药特性及释药机制。方法：Glatt流化床底喷装置中混悬液法上药制备载药小丸，分别以不同eudragit RS100/eudragit RL100配比为包衣材料制备包衣小丸，释放度试验及扫描电镜考察小丸的体外释药特性及释药机制。结果：包衣小丸在扫描电镜下表面光滑圆整，纵切面层次分明；4种小丸配比而成的缓释胶囊释药曲线与进口缓释胶囊兰勃素差异无显著性，且不受介质pH和转篮转速等因素影响；包衣小丸的释药机制可能为浓度梯度作用下Amb按Fick's定律从完整eudragit膜聚合物链间的分子孔隙扩散。结论：Amb包衣小丸具有理想的缓释效果。     

Compressibility of gastroretentive pellets coated with Eudragit NE using a single-stroke and a rotary tablet press

In this study, 15 kinds of powders with different compression mechanisms were used in the process of filling-binding substances in tablets with pellets. Applied substances possessed dominant brittle time-independent mechanism or time-dependent viscoplastic, viscoelastic mechanism of compression. Using 6 kN compression force in a single-stroke tablet press during 150 ms of compression, damage to the polymer film and pellet core was found in all formulations. As a result, the authors observed an increase of releasing rate of verapamil hydrochloride (VH). A larger contact area between powders and pellets and connected with this better protective properties were ensured by powders with time-independent compression mechanism (eg, D-sorbitol or D-mannitol). Unsymmetrically applied compression force was a reason for inconsistent densification and insufficient protection of the pellets. Taking into consideration the low rotation speed of the turret (10 rpm) in the rotary tablet press, the total compaction time was much longer than in the single-stroke tablet press. The compression time in the case of the rotary tablet press should be considered as the sum of the precompression (about 130 ms) and main compression (about 280 ms) phase times. Compression force applied by upper and lower punch in the precompression and main compression phase was affected uniformly on the pellets' surface, and when protected against fragmentation, allowed only some slight deformation. The powders in tablet formulation were fragmentized and rearranged independent of their compression mechanisms. It was found that the releasing rate of VH from pellets compressed by rotary tablet press with 6, 12, and 18 kN of compression force was similar to the releasing rate from uncompressed pellets.     

Optimization of tamsulosin hydrochloride controlled release pellets coated with Surelease and neutralized HPMCP

This study was to optimize the coating level in the development of controlled release pellets coated with Surelease and neutralized hydroxypropyl methylcellulose phthalate (HPMCP) by a computer optimization technique based on a response surface methodology utilizing polynomial equation. A full factorial 3(2) design was used for the optimization procedure with coating level (X(1)) and HPMCP content (X(2)) as the independent variables. The drug release percent at 2, 3 and 5 h were the target responses, which were restricted to 12-39% (Y(1)), 44-70% (Y(2)) and 70-100% (Y(3)), respectively. The quadratic model was well fitted to the data, and the resulting equation was used to predict the responses in the optimal region. It was shown that the optimized coating formulation was achieved at the ratio of 3:1 (Surelease: neutralized HPMCP) with 20% coating level. The optimized formulation showed release profiles and responses, which were close to predicted responses. Therefore, a full factorial 3(2) design and optimization technique can be successfully used in the development of optimized coating formulations based on Surelease and neutralized HPMCP to achieve a controlled release drug delivery system containing tamsulosin hydrochloride.     

盐酸维拉帕米择时缓释微丸的研制及犬体内药代动力学

目的制备盐酸维拉帕米择时缓释微丸(VH-COERP)；研究VH-COERP在犬体内的药代动力学，并与市售的盐酸维拉帕米缓释微丸(VH-DRP)进行比较。方法采用空白丸芯上药法制备含药丸芯，并用流化床对其包衣，其中羟丙基甲基纤维素为内层包衣溶胀层，乙基纤维素水分散体为外层包衣控释层，通过改变内外层衣膜的厚度达到择时缓释的效果。用RP-HPLC测定6只Beagle犬口服VH-COERP后不同时间血浆中盐酸维拉帕米的浓度，并与VH-DRP比较，通过3P97程序计算药代动力学参数。结果溶胀层和控释层的包衣厚度、溶胀层中添加剂的种类会影响药物释放的时滞、释药行为以及最终释药量，所制得的微丸释放不受介质pH及后处理的影响。体外溶出经5 h时滞后缓慢释药达24 h。与VH-DRP相比，VH-COERP体内释药具有明显的时滞(4 h)，达峰时间明显延长(8 h)，相对生物利用度为(94.56±7.64)%。结论VH-COERP在体内外经过明显的时滞后均能缓慢释放，达到了睡前服药，凌晨发挥疗效的目的。     

Influence of an enteric polymer on drug release rates of theophylline from pellets coated with Eudragit RS 30D

The purpose of this research study was to investigate the influence of an enteric polymer on the drug release properties of theophylline pellets coated with Eudragit RS 30D. Theophylline pellets were coated with aqueous colloidal dispersions of Eudragit RS 30D containing various amounts of Eudragit L 100-55. The effect of storage conditions on the release of drug from coated pellets was determined as a function of the pH of the dissolution medium. The results from the dissolution study showed significant changes in the dissolution rate of theophylline from pellets coated with Eudragit RS 30D when cured at 40 degrees C for 4 days. No change in the drug release rate was observed when Eudragit L100-55 was present in the Eudragit RS 30D dispersion. Increasing the ratio of Eudragit L100-55 to Eudragit RS 30D resulted in faster drug release rates from the coated pellets. An increase in the pH of the dissolution medium was found to enhance drug release from the pellets coated with Eudragit RS 30D containing Eudragit L 100-55. Theophylline pellets when coated with Eudragit RS 30D containing the enteric polymer Eudragit L100-55 demonstrated no aging effects when stored at elevated temperatures. The overcoating of the pellets with Eudragit RD 100 did not affect the drug release profiles and prevented the particles from agglomerating during curing and storage.     

氟比洛芬乙基纤维素水分散体包衣小丸的制备及体外释药特性

目的：制备氟比洛芬包衣小丸，评价其体外释药特性。方法：离心造粒法制备空白丸芯及载药小丸；以乙基纤维素水分散体为包衣材料，羟阿基甲基纤维素为致孔剂，流化床制备氟比洛芬包衣小丸；释放度实验考察小丸的体外释药特性。结果：包衣小丸缓释胶囊的释放曲线与进口缓释胶囊ForbensR相似，羟丙基甲基纤维素的用量和介质pH值对释药影响显著，而热处理时间和胶囊壳对释药无显著性影响。结论：氟比洛芬包衣小丸具有较理想的体外缓释效果。     

Electrophoretic properties of acrylic latex suspensions (Kollicoat MAE 30 D) and ibuprofen

We have compared the electrophoretic properties (measured on the electrical surface) of the commercial latex Kollicoat MAE 30 D and the non-steroidal anti-inflammatory drug (NSAID) ibuprofen in preparation for attempts to develop a suitable vehicle for the NSAID to obtain a modified release formulation. Electrophoretic mobility of the latex and the active principle was measured in solutions containing different concentrations of inorganic electrolytes (NaCl, CaCl2 and AlCl3) at different pH values. This was considered an indispensable first step for further characterization of the substance's electrical properties. Suspensions of both the latex and the drug had negative mobility values throughout the range of pH values studied here. Of the electrolytes, neither NaCl nor CaCl2 led to positive mobility, and no isoelectric point could be determined. However, AlCl3 at a concentration of 10(-3) M led to the greatest reduction in mobility. We therefore found that trivalent cations were more effective than divalent cations, which in turn were more effective than monovalent cations, in reducing mobility.