奥沙西罗亲水凝胶骨架片制备及体外释药特性研究

目的制备奥沙西罗亲水凝胶骨架缓释片,考察处方、工艺以及释放条件对体外释药行为的影响,解析其机理。方法以羟丙甲纤维素(HPMC)为骨架材料,乙基纤维素(EC)为阻滞剂,采用湿颗粒压片法制备奥沙西罗亲水凝胶骨架片,考察HPMC用量、HPMC黏度、EC用量、制备方法、压片压力、释放介质及转速对奥沙西罗骨架片体外释药的影响。结果奥沙西罗骨架片体外释药符合Higuchi方程,药物释放机制是骨架溶蚀和药物扩散的综合效应;HPMC用量与黏度、阻滞剂用量、制备方法、压片压力对释放速率均有显著性影响;释放介质的pH值及转速对释放速率无显著性影响。结论调整处方HPMC用量可制得12 h给药1次的骨架缓释片。     

聚氧乙烯骨架缓释片的处方及体外释药机制研究

目的 以聚氧乙烯(PEO)为亲水凝胶骨架制备缓释片剂,并考察其体外释药机制。方法 基于两种规格PEO的用量比与释药速率之间的关系,优化缓释片处方。通过考察片剂的体外释放度和溶蚀比探讨其释药机制,并对不同溶解度药物的体外释放行为进行比较。结果 缓释片体外释药速率与PEO用量比呈线性关系,所得优化处方在12 h内以接近恒速释药,其体外释药与溶蚀过程基本同步,且在所考察用量范围内不同溶解度药物的体外释放度相近。结论 PEO制成的亲水凝胶骨架片缓释性能良好,其体外释药是药物扩散和骨架溶蚀协同作用的结果。     

聚氧乙烯骨架缓释片的处方及体外释药机制研究

目的以聚氧乙烯（PEO）为亲水凝胶骨架制备缓释片剂,并考察其体外释药机制。方法基于两种规格PEO的用量比与释药速率之间的关系,优化缓释片处方。通过考察片剂的体外释放度和溶蚀比探讨其释药机制,并对不同溶解度药物的体外释放行为进行比较。结果缓释片体外释药速率与PEO用量比呈线性关系,所得优化处方在12h内以接近恒速释药,其体外释药与溶蚀过程基本同步,且在所考察用量范围内不同溶解度药物的体外释放度相近。结论PEO制成的亲水凝胶骨架片缓释性能良好,其体外释药是药物扩散和骨架溶蚀协同作用的结果。     

阿昔莫司缓释片的体外释放度及释放机制的初步研究

目的：研制凝胶骨架型阿昔莫司缓释片，考察其体外释放度，并对药物的释放机制进行初步研究。方法：以羟丙基甲基纤维素(HPMC)为骨架材料，将阿昔莫司制成凝胶骨架型缓释片，考察HPMC种类及用量、填充剂种类及用量和制备工艺等因素对阿昔莫司缓释片体外释放速率的影响。结果：HPMC的种类、用量和片剂表面积对阿昔莫司体外释放速率有明显的影响；填充剂的种类及制备工艺对释放速率基本无影响；篮法、桨法及转速对释放速率基本无影响。阿昔莫司缓释片的释放机制为非纯Fickian扩散(non—Fickian)机制，即为药物扩散和骨架溶蚀协同作用的结果，其中扩散机制起主要支配作用。结论：用高黏度HPMC作为亲水凝胶骨架片基质能达到较好的缓释作用。     

神衰果素亲水凝胶缓释骨架片的制备及释药机理的研究

目的制备神衰果素亲水凝胶缓释骨架片.方法以羟丙基甲基纤维素(HPMC)作为缓释材料,采用粉末直接压片工艺制备神衰果素亲水凝胶缓释骨架片,考察HPMC的用量、规格、不同的释药条件对释药速率的影响,并对释药机制作了初探.结果神衰果素亲水凝胶缓释骨架片的体外释药为非Fick扩散,HPMC的用量对药物的释放有较大影响,而HPMC的规格,释放介质的pH值对药物释放影响不大.结论以HPMC作为缓释材料,采用粉末直接压片法制备神衰果素亲水凝胶缓释骨架片,工艺简单,体外缓释效果好.     

非诺洛芬钙亲水凝胶缓释骨架片释药机理的研究

目的　研究非诺洛芬钙亲水凝胶缓释骨架片的释放机理。方法　以羟丙基甲基纤维素(HPMC)为亲水骨架材料,通过对Peppas经验式中n值的详细考察,研究非诺洛芬钙缓释骨架片在不同条件下的溶蚀度与释放度。结果　在各种条件下,非诺洛芬钙骨架片的释放与溶蚀均呈零级动力学过程,且二者间呈线性关系。结论　非诺洛芬钙骨架片的释放机理为:前40min,以扩散和溶蚀协同作用方式释放;50min后,以溶蚀机制释放。     

聚氧乙烯亲水凝胶骨架片的溶蚀行为

目的研究聚氧乙烯(PEO)亲水凝胶骨架片的溶蚀行为。方法直接压片法制备PEO高分子素片，并测定单一和混合PEO骨架片在水中的溶蚀速率，通过实验和建立数学模型的方法探讨PEO相对分子质量与溶蚀速率的关系。结果实验结果表明PEO骨架片的溶蚀速率与重均分子量遵循经验方程：k∝(_w)^{-1.130 4}，该式中的指数(-1.130 4)与理论推导值(-1.241)有较好的吻合，该方程可以有效预测重均分子量范围在97.98×10⁴～553.36×10⁴的单一和混合PEO骨架片的溶蚀速率。结论PEO是一种优良的亲水骨架材料，本实验获得的溶蚀规律对于PEO亲水凝胶骨架片的设计将具有积极的指导意义。     

新型缓释骨架材料聚氧化乙烯与HPMC凝胶层结构的差异比较

比较聚氧化乙烯(PEO)和羟丙甲纤维素(HPMC)缓释骨架片吸水膨胀后凝胶层结构的差异,探讨PEO作为新型骨架材料的优势。通过考察PEO和HPMC骨架片在不同释放时间点的吸水性和膨胀性,解释凝胶层结构的差异。PEO分子量型号对骨架片凝胶层结构和凝胶层厚度有显著影响,但考察的三种型号HPMC骨架片其凝胶层结构和凝胶层厚度无显著性差异。结果显示,PEO是一种优良的亲水骨架材料,相对于HPMC而言,具有更强的调节释药行为的能力。     

吡嘧司特钾水凝胶骨架缓释片的研究

目的研制吡嘧司特钾(TBX)水凝胶缓释骨架片.方法以羟丙甲基纤维素(HPMC)为骨架材料,考察HPMC用量、黏度及压片压力等对主药体外释放速度的影响,优化处方工艺.结果所得片剂体外释放实验表明10h累积释放度＞75%,其释放行为符合Hguchi方程.HPMC的用量、黏度、制备方法及压片片力的大小等对TBX的释放速率均有显著影响.结论用高黏度的HPMC作为亲水凝胶骨架片的基质能达到较好的缓释作用.     

石杉碱甲凝胶骨架缓释片药物释放因素的研究

目的考察影响石杉碱甲(hupcrzine—A，Hup—A)亲水凝胶骨架片体外释药的各种因素。方法以羟丙基甲基纤维素(HPMC)和乙基纤维素(EC)为骨架材料，湿法制粒压片制备缓释骨架片，并考察HPMC和EC的用量、粘度、HPMC粒度、压片压力及其他辅料对石杉碱甲亲水凝胶骨架片体外释药的影响。结果石杉碱甲亲水凝胶骨架片体外释药符合Higuchi方程。HPMC粒度、粘度、压片压力及辅料种类对石杉碱甲的释放速率没有显性影响。HPMC用量及EC的粘度、用量对石杉碱甲的释放速率有显性影响。结论HPMC及EC用量、EC粘度为影响石杉碱甲亲水凝胶骨架片释放速率的主要因素。     

Probing the dynamics of matrix hydration in the presence of electrolytes

The aim of our work was to probe the mechanisms associated with induced matrix stiffening via textural analysis as a consequence of in situ electrolyte interactions within hydroxypropylmethylcellulose (HPMC) and polyethylene oxide (PEO) matrices in relation to their role in controlling the release of highly soluble drugs such as diltiazem hydrochloride (>50% water soluble at 25°C). The dynamics of HPMC and PEO matrix swelling during hydration in the presence of appropriate electrolytes intended to induce constant drug release rates from simple monolithic systems are influenced by continuously shifting peripheral matrix stiffening toward the matrix core in a manner dependent on electrolyte content and hydration time. Matrix erosion for HPMC and PEO controls (i.e., without electrolyte) follow linear dissolution kinetics (r² > 0.97), while formulations with electrolyte characteristically undergo a square root of time decline in weight. The swelling potential of the electrolyte-containing matrices, influenced by the boundary infiltration process, reflected considerable suppression during the first 2 hr of exposure to medium, while subsequent events differed in both polymers. In view of these differences, simultaneous measurements in textural transitions and electrolyte conductivity showed that PEO has a higher affinity for water molecules than does HPMC.     

Extended release of flurbiprofen from tromethamine-buffered HPMC hydrophilic matrix tablets

Abstract

The pH-dependent solubility of a drug can lead to pH-dependent drug release from hydrophilic matrix tablets. Adding buffer salts to the formulation to attempt to mitigate this can impair matrix hydration and negatively impact drug release. An evaluation of the buffering of hydrophilic matrix tablets containing a pH-dependent solubility weak acid drug (flurbiprofen), identified as possessing a deleterious effect on hydroxypropyl methylcellulose (HPMC) solubility, swelling and gelation, with respect to drug dissolution and the characteristics of the hydrophilic matrix gel layer in the presence of tromethamine as a buffer was undertaken. The inclusion of tromethamine as an alkalizing agent afforded pH-independent flurbiprofen release from matrices based on both HPMC 2910 (E series) and 2208 (K series), while concomitantly decreasing the apparent critical effect on dissolution mediated by this drug with respect to the early pseudo-gel layer formation and functionality. Drug release profiles were unaffected by matrix pH-changes resulting from loss of tromethamine over time, suggesting that HPMC inhibited precipitation of drug from supersaturated solution in the hydrated matrix. We propose that facilitation of diffusion-based release of potentially deleterious drugs in hydrophilic matrices may be achieved through judicious selection of a buffering species.     

Electrolyte-induced compositional heterogeneity: a novel approach for rate-controlled oral drug delivery

In this work a new approach for in situ interactions between drug and electrolyte(s) is devised to control the release of highly water soluble drugs from oral hydrophilic monolithic systems. The model drug diltiazem hydrochloride (water solubility in excess of 50% at 25 degrees C), in conjunction with specific electrolytes, was principally employed in the design of swellable tablet formulations comprised of hydrophilic polymers such as hydroxypropylmethlcellulose (HPMC) or poly(ethylene oxide) (PEO). Electrolytes such as sodium bicarbonate or pentasodium tripolyphosphate were used to modulate intragel pH dynamics, swelling kinetics, and gel properties. Through in situ ionic interactions (an intragel matrix system composed of different chemical species that promote competition for water of hydration), a compositionally heterogeneous structure referred to as a "metamorphic scaffold" was established. It is shown that this latter structure results in the inhibition of drug dissolution, induction of a differential swelling rate, and attainment of "matrix stiffening" and axially provides a uniform gel layer. Presence of such phases in matrix structure and its influence on swelling dynamics enabled control of diltiazem hydrochloride release in a zero-order manner in different pH environments over a 24-h period. From kinetic analysis using the power law expressions [M(t)/M(infinity) = k(1)t(n), M(t)/M(infinity) = k(1)t(n) + k(2)t(2)(n)] and Hopfenberg model [M(t)/M(infinity) = 1 - (1 - k(1)t)(n)], it became apparent that the dynamics of matrix relaxation and controlled erosion were major factors involved in the release mechanism, while the composite rate constant k(1) (in Hopfenberg model) decreased by approximately 2-fold in the presence of electrolyte(s). These findings indicated that the dynamics of swelling and gel formation in the presence of ionizable species within hydrophilic matrices provide an attractive alternative for zero-order drug delivery from a simple monolithic system.     

Development of a controlled release low dose class II drug-Glipizide

The purpose of this study was to develop a new monolithic matrix system to completely deliver glipizide, a Biopharmaceutics Classification System (BCS) Class II drug in a zero order manner over an extended time period. Two approaches were examined using drug in formulations that contain swellable hydroxypropylmethylcellulose (HPMC) or erodible polyethylene oxide (PEO). The matrices were prepared by dry blending selected ratios of polymers and ingredients using direct compression technique. Dissolution was assessed using modified USP apparatus II. Glucotrol XL push-pull osmotic pump (PPOP) was used as the reference. The interrelationship between matrix hydration, erosion and textural properties were determined and analyzed under the dissolution test conditions. Linear and reproducible release similar to that of Glucotrol XL was achieved for optimized matrices (f2>50) independent of hydrodynamic conditions. The kinetics of drug delivery was directly related to the synchronization of swelling, erosion and fractional release. HPMC matrices showed a significantly greater degree of hydration and swelling and stronger texture property relative to PEO matrices. Results indicate that in the case of low dose/low soluble drug, total drug release in a zero order manner heavily depends on the synchronization of erosion and swelling fronts during the entire dissolution study.     

Assembled modules technology for site-specific prolonged delivery of norfloxacin

The aim of this research was to design and study norfloxacin (NFX) release in floating conditions from compressed hydrophilic matrices of hydroxypropylmethylcellulose (HPMC) or poly(ethylene oxide) (PEO). Module assembling technology for drug delivery system manufacturing was used. Two differently cylindrical base curved matrix/modules, identified as female and male, were assembled in void configuration by friction interlocking their concave bases obtaining a floating release system. Drug release and floatation behavior of this assembly was investigated. Due to the higher surface area exposed to the release medium, faster release was observed for individual modules compared to their assembled configuration, independently on the polymer used and concentration. The release curves analyzed using the Korsmeyer exponential equation and Peppas & Sahlin binomial equation showed that the drug release was controlled both by drug diffusion and polymer relaxation or erosion mechanisms. However, convective transport was predominant with PEO and at low content of polymers. NFX release from PEO polymeric matrix was more erosion dependent than HPMC. The assembled systems were able to float in vitro for up to 240min, indicating that this drug delivery system of norfloxacin could provide gastro-retentive site-specific release for increasing norfloxacin bioavailability.     

羟丙基甲基纤维素骨架片的水渗透、骨架膨胀和药物释放性质

当HPMC骨架与水接触时,可以观察到水渗透进入HPMC骨架的过程。HPMC取代度类型对水渗透作用的影响集中表现在最初较短的一段时间内,这段时间是指HPMC形成水凝胶的时间。水凝胶形成后,水渗透进入凝胶的速率是恒定的。HPMC对水渗透作用的影响取决于其分子量。当HPMC骨架中加入药物后,水渗透进入骨架的能力会变弱。当水渗透进入HPMC骨架时,骨架可发生明显的膨胀,其轴向膨胀比径向膨胀大得多,骨架的膨胀主要由HPMC产生,骨架中HPMC含量越高,其膨胀程度越大。水渗透、骨架膨胀与药物释放之间存在线性相关性。     

Thermogravimetric investigation of the hydration behaviour of hydrophilic matrices

This article proposes thermogravimetric analysis (TGA) as a useful method to investigate the hydration behaviour of hydrophilic matrix tablets containing hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (NaCMC) or a mixture of these two polymers and four drugs with different solubility. The hydration behaviour of matrix systems was studied as a function of the formulation composition and of the dissolution medium pH. TGA results suggest that the hydration of matrices containing HPMC is pH‐independent and not affected by the characteristics of the loaded drug; this confirms HPMC as a good polymer to formulate controlled drug delivery systems. On the other hand, the performances of NaCMC matrix tablets are significantly affected by the medium pH and the hydration and swelling of this ionic polymer is influenced by the loaded drug. For systems containing the two polymers, HPMC plays a dominant role in the hydration/dissolution process at acidic pH, while at near neutral pH both the cellulose derivatives exert a significant influence on the hydration performance of systems. The results of this work show that TGA is able to give quantitative highlights on the hydration behaviour of polymeric materials; thus this technique could be a helpful tool to support conventional hydration/swelling/dissolution studies. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2070–2079, 2010     

二甲双胍亚硝胺杂质研究及亲水凝胶骨架材料的筛选

目的 探讨不同亲水凝胶骨架材料与盐酸二甲双胍(metformin hydrochloride,MET)降解生成N-二甲基亚硝胺(N-dimethylnitrosamine,NDMA)之间的相关性,筛选合适的骨架材料用于制备MET缓释片。方法 以高效液相色谱-三重四极杆串联质谱为NDMA监测手段,通过原辅料相容性考察确定产生NDMA风险较低的骨架材料,而后考察溶胀性能,确定溶胀作用与参比制剂相似的骨架材料,将筛选出的骨架材料制备缓释片后考察其体外溶出和剂量倾泻的行为。结果 原辅料相容性考察发现羟丙甲纤维素(hypromellose,HPMC)是引起MET降解产生NDMA的主要原因,并筛选出溶胀作用与HPMC相似的卡波姆,以其为骨架材料制备缓释片可获得与参比制剂相似的溶出曲线,且剂量倾泻风险较低,产品稳定性良好。结论 卡波姆可作为HPMC的替代材料,用于制备MET缓释片。     

Influence of hydroxypropyl-beta-cyclodextrin complexation on piroxicam release from buccoadhesive tablets.

Interaction of piroxicam (PX) and hydroxypropyl-beta-cyclodextrin (HPbetaCD) was investigated in solution and in the solid state. Solubility studies demonstrated the formation of the PX-HPbetaCD inclusion complex with 1:1 stoichiometry. Equimolecular PX-HPbetaCD solid systems were prepared and characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, and X-ray diffractometry. Modification of the release of a sparingly water-soluble drug, PX, from hydrophilic matrices using cyclodextrin complexation was evaluated. The buccoadhesive controlled release tablets for the delivery of PX were prepared by direct compression of hydroxypropylmethyl cellulose (HPMC) and Carbopol 940 (C940), which showed superior bioadhesion properties compared to HPMC. The tablets were evaluated for their dissolution, swelling and mucoadhesive properties. The in vitro release results demonstrated that matrix tablets containing the PX-HPbetaCD solid complex displayed faster PX release compared to those containing a physical mixture or "free" drug. Differences in release rates of PX from the tablets could be attributed to the presence of the polymers and to cyclodextrin complexation. The effect of the polymers on PX release can affect the drug solubility (complexation) and polymer water uptake (swelling). Higher polymer water uptake may result in higher drug solubility and diffusivity in a hydrated polymeric environment. Drug complexation affected also its diffusivity through the semipermeable membrane.