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.     

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。     

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.     

Evaluation of Drug-Containing Polymer Films Prepared from Aqueous Latexes

Polymeric films containing salicylic acid or propranolol HC1 were prepared by casting and drying a drug-containing, aqueous colloidal polymer dispersion (Eudragit NE 30D) as an alternative to films cast from organic polymer solutions. The drug was either dissolved (salicylic acid) or dissolved/ dispersed (propranolol HC1) in the polymeric matrix. Incompatibilities (flocculation or coagulation) between salts of basic drugs and two ethylcellulose latexes were overcome by substituting the anionic surfactants with a nonionic surfactant (Pluronic P103). The drug release was studied as a function of drug loading, film thickness, amount of hydrophilic additive (hydroxypropyl methylcellulose), and storage humidity. The release of propranolol HC1 (monolithic dispersion) was a combination of diffusion through the polymer and pores or channels; the extent of each release mechanism depended on the drug loading. On DSC thermograms, melting transitions were obtained with monolithic dispersions but not with monolithic solutions. The heat of fusion was linearly correlated to the amount of drug in the films. The amount of drug remaining in the film after the dissolution study was not detectable and corresponded to the drug dissolved in the polymer. The drug release increased with increased drug loading and increased amount of hydroxypropyl methylcellulose but was independent of film thickness and relatively insensitive to different storage humidities.     

Constant Potassium Chloride Release from Microporous Membrane-Coated Tablets Prepared with Aqueous Colloidal Polymer Dispersions

To achieve constant drug release and to avoid the use of organic solvents, potassium chloride tablets were coated with aqueous latexes containing dispersed pore-formers with pH-dependent solubility characteristics. The pore-forming agent, dibasic calcium phosphate, was insoluble in the latex but soluble at low pH. Upon contact with simulated gastric fluids, it leached out rapidly to form a rate-controlling, microporous membrane. The release of potassium chloride was linear with time up to 75–80% drug released. It increased with increasing level of pore-former and decreasing membrane thickness but was independent of the degree of agitation and the pH of the dissolution medium after leaching of the pigments. Upon storage at different relative humidities, moisture uptake of the film coat and variations in the release profiles over time were minimal.     

流化床制备胃漂浮型控释甲硝唑微丸

为治疗胃内幽门螺旋菌感染,需制备胃漂浮型控释制剂。采用流化床制备甲硝唑控释微丸,以NaHCO3作产气介质,产生浮力,以EC为主要成膜材料,控制药物释放。根据体外溶出对时间的曲线筛选处方。所得微丸以近似零级动力学进行释药,其溶出速率常数为0．15(t≤6h),释放持续时间达10h以上。约80％的微丸可稳定飘浮8h以上,达到了控释与漂浮的双重要求。     

流化床制备胃漂浮型控释甲硝唑微丸

为治疗胃内幽门螺旋菌感染,需制备胃漂浮型控释制剂。采用流化床制备甲硝唑控释微丸,以NaHCO_3作产气介质,产生浮力,以EC为主要成膜材料,控制药物释放。根据体外溶出对时间的曲线筛选处方。所得微丸以近似零级动力学进行释药,其溶出速率常数为0.15(t≤6h),释放持续时间达10h以上。约80％的微丸可稳定飘浮8h以上,达到了控释与漂浮的双重要求。     

Effect of Polymer Blending on the Release of Ganciclovir from PLGA Microspheres

Purpose The aim of the study is to investigate the effect of polymer blending on entrapment and release of ganciclovir (GCV) from poly(d,l-lactide-co-glycolide) (PLGA) microspheres using a set of empirical equations. Methods Two grades of PLGA, PLGA 7525 [d,l-lactide:glycolide(75:25), MW 90,000–126,000 Da] and Resomer RG 502H [d,l-lactide:glycolide(50:50), MW 8000 Da], were employed in the preparation of PLGA microspheres. Five sets of microsphere batches were prepared with two pure polymers and their 1:3, 1:1, and 3:1 blends. Drug entrapment, surface morphology, particle size analysis, drug release, and differential scanning calorimetric studies were performed. In vitro drug-release data were fitted to a set of empirical sigmoidal equations by nonlinear regression analysis that could effectively predict various parameters that characterize both diffusion and degradation cum diffusion-controlled release phases of GCV. Results Entrapment efficiencies of GCV ranged from 47 to 73%. Higher amounts of GCV were entrapped in polymer blend microspheres relative to individual polymers. Triphasic GCV release profiles were observed, which consisted of both diffusion and degradation cum diffusion-controlled phases. In vitro GCV release was shortest for Resomer RG 502H microsphere (10 days) and longest for PLGA 7525 microspheres (90 days). Upon blending, the duration of release gradually decreased as the content of Resomer RG 502H in the matrix was raised. Equations effectively estimated the drug-release rate constants during both the phases with high R² values (>0.990). GCV release was slower from the blend microsphere during the initial diffusion phase. Majority of entrapped drug (70–95%) was released during the matrix degradation cum diffusion phase. Conclusions Drug entrapment and release parameters estimated by the equations indicate more efficient matrix packing between PLGA 7525 and Resomer RG 502H in polymer-blended microspheres. The overall duration of drug release diminishes with rising content of Resomer RG 502H in the matrix. Differential scanning calorimetry studies indicate stronger binding between the polymers in the PLGA 7525/Resomer RG 502H∷ 3:1 blend. Polymer blending can effectively alter drug-release rates of controlled delivery systems in the absence of any additives.     

法莫替丁缓释微丸的悬浮包衣法制备

采用淀粉和蔗糖为赋形剂制备法莫替丁含药微丸，以乙基纤维素为包衣材料，采用悬浮包衣法制备了法莫替丁缓释微丸，并用正交设计筛选出了最佳制备工艺参数。释放度研究结果表明：在进风温度为45℃，喷雾压力为147kPa及输液速度为10ml/min的条件下进行包衣，可制得在12h内释药符合Higuchi模型动力学过程的缓释微丸。     

An Organic Acid-Induced Sigmoidal Release System for Oral Controlled-Release Preparations

To achieve time-controlled or site-specific drug delivery in the gastrointestinal tract, a sigmoidal release system (SRS) was developed, which achieved a prolonged lag time, followed by rapid release. The theophylline beads with a thick Eudragit RS film coating showed very low drug release in water, whereas the release rate increased considerably in organic acid solutions. A hydration study of Eudragit RS films suggested that the increase in drug release was attributable to structural changes of the film induced by polymer-acid interactions. When succinic acid was incorporated into the core of Eudragit RS-coated theophylline beads, the drug release profile showed a typical sigmoidal pattern. SRS beads containing acetaminophen were also prepared by the same technique. Again, a sigmoidal release pattern was observed in which the lag time was prolonged with an increase in the coating level, whereas the drug release rate thereafter was almost constant irrespective of the coating level. Acetaminophen-containing SRS beads with different coating thickness were orally administered to beagle dogs. The drug plasma concentration curves showed lag periods similar to the in vitro lag time.     

Mechanical Properties of Dry and Wet Cellulosic and Acrylic Films Prepared from Aqueous Colloidal Polymer Dispersions Used in the Coating of Solid Dosage Forms

The mechanical properties of dry and wet polymeric films prepared from various aqueous polymeric dispersions were evaluated by a puncture test. They were studied with respect to type of polymer dispersion [cellulosic: Aquacoat and Surelease; acrylic: Eudragit NE, L, RS, and RL 30 D], plasticizer type (water-soluble or water-insoluble), drying or curing conditions, method of film preparation (pseudolatex- vs solvent casting) and ratio of Eudragit RS/RL 30 D in mixed Eudragit RS/RL films. Dry and wet mechanical strengths of the polymeric films depended primarily on the types of the colloidal polymer dispersion and the plasticizer. Films prepared from ethylcellulose dispersions resulted in very weak and brittle films when compared to the acrylic films. Pseudolatex-cast ethylcellulose films showed lower puncture strength and elongation values when compared to those of the solvent-cast films. Curing of the pseudolatex-cast ethylcellulose films had minimal effects on their mechanical properties. Eudragit L 30D, an enteric polymer dispersion, resulted in brittle films in the dry state, but in very flexible films in the wet state because of the plasticization effect of water. Wet Eudragit RS 30 D polymer films plasticized with water-insoluble plasticizers were significantly more flexible than the corresponding wet films plasticized with water-soluble plasticizers. The water-soluble plasticizers leached from the films during exposure to the aqueous medium, while the water-insoluble plasticizers were almost completely retained within the wet films. The low permeability of a water-soluble drug, chlorpheniramine maleate, and the weak mechanical properties of Aquacoat films could suggest osmotic driven/rupturing effects as the release mechanisms from Aquacoat-coated dosage forms.     

Sustained Local Anesthetic Release from Bioerodible Polymer Matrices: A Potential Method for Prolonged Regional Anesthesia

Polyanhydride polymer matrices have been used successfully for sustained release of a number of drugs in vitro and in vivo. Dibucaine free base, dibucaine HC1, and bupivacaine HC1 were incorporated into polymer matrices with copolymer l,3-bis(p-carboxyphenoxy)propane-sebacic acid anhydride (1:4). Drug release was measured in vitro following incubation of the drug-polymer matrices in phosphate buffered solution, pH 7.4, at 37°C, to approximate in vivo conditions. Local anesthetics were released in a sustained manner yielding 90% cumulative drug release over periods ranging from 3 to 14 days. The kinetics of release varied with both the choice of local anesthetic and the method of drug incorporation into the matrix (hot melt versus compression molding). Polymer local anesthetic matrix devices (PLAM), loaded by hot melt incorporation with 20% bupivacaine, were implanted in vivo adjacent to the sciatic nerve in three rats. Reversible neural blockade was observed for 4 days in all animals. Polymer implants without local anesthetic showed no neural blockade. This technology could lead to methods of prolonged blockade of peripheral nerves or of sympathetic ganglia, which may be utilized for the management of postoperative pain, sympathetically maintained pain, or certain forms of chronic pain.     

儿童微粉包衣制剂技术研究进展

目前国内儿童专用口服制剂数量较少,儿童用成人药现象普遍,开发新型儿童专用制剂很有必要。微粉包衣制剂技术能掩盖药物不良味道,提高制剂的依从性和便利性,适用于开发儿童制剂。本文总结儿童微粉包衣制剂技术研究应用现状和发展前景,为微粉包衣技术在儿童口服制剂领域的应用提供参考。     

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.     

控释包衣膜中增塑剂含量的HPLC测定

建立了高效液相色谱法测定控释包衣膜中增塑剂含量,采用Hypersil C18柱,甲醇为流动相,检测波长为217和260nm,分别测定柠檬酸三乙酯（TEC）,柠檬酸三丁酯（TBC）,三醋酸甘油酯（TR）,邻苯二甲酸二甲酯（DMP）,邻苯二甲酸二乙酯（DEP）,邻苯二甲酸二丁酯（DBP）的含量,其中DMP,DEP和DBP在5－87ug/ml,TEC,TBC,TR在130－2300ug/ml浓度范围内与峰高呈良好的线性关系（r=0.9999),方法的日内及日间精密度,回收率均符合药物分析要求。     

粉末包衣技术在药物制剂领域的应用研究进展

粉末今的一个重要分支,其在药物制剂领域的应用优势突出,近年来受到药剂学研究者的广泛关注。分类综述目前应用于药物制剂的几种主要粉末包衣技术,包括属于物理化学法中的凝聚法、以及物理机械法中的喷雾干燥法、喷雾冷凝法、干法包衣技术和气流悬浮包衣技术,并探讨粉末包衣技术的主要功用,如用于制备缓控释制剂、药物粉末表面改性、改善口服制剂感官效果和提高药物及制剂稳定性等。     

Investigation and Comparison of Performance of Effervescent and Standard Pneumatic Atomizer Intended for Soluble Aqueous Coating

Effervescent atomizers belong to the group of internal mixing atomizers. The effervescent approach might be a potential alternative to traditional atomization techniques, e.g., for applications where low atomization air consumption is advantageous In this paper, performance of one proposed design of the effervescent atomizer is investigated and compared to that of a standard pneumatic atomizer. The purpose of the comparison is to evaluate the actual potential of the specific effervescent atomizer in pharmaceutical relevant aqueous coating applications. Aqueous solutions of Hypromellose 5 as well as Povidone K-90F were characterized in terms of rheological properties and surface tension. Solutions were atomized by means of a standard Schlick pneumatic atomizer as well as a customized inside-out type effervescent atomizer. Spray droplet size distributions were recorded by a Spraytec instrument. Increased shear viscosity in the range 24–836 mPa.s had a modest effect on spray mean diameters for pneumatic sprays of the Newtonian solutions of Hypromellose 5. In contrast, mean droplet diameters increased by a factor of 3–5 in pneumatic sprays of Povidone K-90F solutions 11–175 mPa.s in viscosity, where non-Newtonian behavior was observed. Further, sprays of all solutions of Povidone K-90F have considerably larger mean droplet size. The effervescent atomizer atomized low viscosity solutions of Povidone K-90F more efficiently than Hypromellose 5 solutions of corresponding shear viscosity. However, atomization of high viscosity Povidone K-90F results in a coarser spray than that of the corresponding Hypromellose 5 solution. Viscosity, visco-elasticity, and surface tension of solutions all seem to affect atomization efficiency. The pneumatic atomizer was not sensitive to changes in airflow above 8.4 kg/h and liquid flow only had a considerable effect at suboptimal air flows. In its current design the effervescent atomizer improved efficiency throughout the investigated range of air flow of 0.18–0.84 kg/h and consistently produced smaller drops at liquid flow of 10 g/min compared to 35 g/min. In spite of the very low level of air consumption, the effervescent atomizer can produce fine sprays. Within its working range, the standard pneumatic atomizer, however, is capable of producing sprays of even smaller mean droplet size. All together this suggests the described effervescent atomizer as an alternative for applications where advantages of reduced atomization air flow outweigh the disadvantages of a less fine spray, e.g., in coating of attrition- prone substrate.     

Engineering and Development of Chitosan-Based Nanocoatings for Ocular Contact Lenses

This article reports on electrohydrodynamic atomization to engineer on-demand novel coatings for ocular contact lenses. A formulation approach was adopted to modulate the release of timolol maleate (TM) using chitosan and borneol. Polymers polyvinylpyrrolidone and poly (N-isopropylacrylamide) were utilized to encapsulate TM and were electrically atomized to produce optimized, stationary contact lens coatings. The particle and fiber diameter, thermal stability, material compatibility of the formed coatings, their in vitro release-modulating effect, and ocular tolerability were investigated. Results demonstrated highly stable nanomatrices with advantageous morphology and size. All formulations yielded coatings with high TM encapsulation (>88%) and excellent ocular biocompatibility. Coatings yielded biphasic and triphasic release, depending on composition. Kinetic modeling revealed a noticeable effect of chitosan; the higher the concentration, the more the release of TM because of chitosan swelling, with the mechanism changing from Fickian diffusion (1% w/v; n = 0.5) to non-Fickian (5% w/v, 0.45 < n < 0.89). The use of electrohydrodynamic atomization has not yet been explored in depth within the ocular research remit, engineering on-demand lens coatings capable of sustaining TM release. This is likely to offer an alternative dosage form for management of glaucoma with particular emphasis on improving poor patient compliance.     

马钱子碱新型壳聚糖纳米粒体外肝癌细胞摄取特性的研究

水凝胶是一种亲水性三维空间网络结构,与合成高聚物相比,天然高分子材料如壳聚糖、透明质酸、海藻酸钠等具有良好的生物相容性和生物可降解性,更适宜用作水凝胶基质。脂质体是一种由脂质双分子层形成的球形囊泡,脂质体水凝胶给药系统不仅可发挥脂质体缓控释、刺激响应性释放药物的特点,而且水凝胶屏障可提高脂质体的稳定性,药物可通过口服、注射、局部透皮等多种给药途径进入体内发挥药效,广泛用于药物传递系统和组织工程。综述多种以天然高分子材料为凝胶骨架,且其内含有载药脂质体、类脂囊泡等的水凝胶系统研究进展,对开发新型缓控释制剂、提高水溶性药物透皮吸收和生物利用度、研究智能刺激响应性给药系统等方面具有重要参考价值。

     

Formulation and evaluation of novel tableted chitosan microparticles for the controlled release of clozapine

Controlled release formulations of clozapine microparticulated tablets were prepared by using chitosan. Microparticles were characterized for particle size and size distribution. Microparticles were compressed into tablets using the directly compressible excipients. SEM photographs of the fractured part of the tablet revealed the presence of discrete particles in the tablets, suggesting that the system chosen is ideal for tableting. Drug release from the tableted microparticles exhibited an initial burst effect, but the release decreased with increasing extent of cross-linking. Tablets were coated with chitosan or cellulose acetate, which significantly lowered the initial burst effect when compared to uncoated tablets. Drug release from chitosan-coated tablets was slightly higher than the tablets coated with cellulose acetate. Tablets prepared were effective in delivering clozapine over a period of 12?h.