卡马西平改性释药系统的构建与评价
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摘要
口服给药是临床上最方便、最常用、病人顺应性最好的给药方式。大部分的药物都有上市的口服给药剂型。但是,据估计约有40%的市售药物是难溶性的,而在新药筛选中这类药物约达到了总数的70%以上。难溶性药物口服吸收的速度和程度受到胃肠道中诸多因素的影响。尤其是像环孢菌素、灰黄霉素、伊曲康唑等药物,它们属于药剂学分类系统中的Ⅱ类药物,在胃肠液中溶解度小、溶出速率慢但通透性高。其在消化液中的溶出速度就成为了其体内吸收的限速步骤,因此,提高Ⅱ类药物的溶出速率就成为了改善其生物利用度的关键。
卡马西平(Carbamazepine,CBZ),化学名为5H-二苯并[b,f]氮杂卓-5-甲酰胺,其表观油水分配系数为2.45且几乎不溶于水(120μg·mL-1,250℃),是典型的生物药剂学分类系统中的Ⅱ类药物。卡马西平在临床上用于治疗癫痫、三叉神经痛以及躁狂抑郁等疾病已有四十余年的时间。卡马西平一般作为口服固体制剂应用,但是由于其在消化液中的溶出是该药吸收的限速步骤,造成了药物在胃肠道中吸收缓慢且不规则,生物利用度低,血药浓度的个体差异大,而且治疗窗狭窄(4-12μg·mL-1),极易产生毒副作用。此外,卡马西平具有四种晶型,不同的晶型在体内的溶解度和吸收速率也有明显的差异。因此提高卡马西平的溶解度和溶出速率对改善卡马西平的生物利用度和临床疗效,减少用药量与用药次数,减小个体差异,避免毒副作用,具有极其重要的意义。环糊精包合物,固体分散体,纳米乳剂,微球,无定形纳米微粉等释药系统已经被研究并成功用来改善该药的生物药剂学特性,特别是无定形态药物制剂更是成为近年来该领域的研究热点。
固体药物的无定形状态是药物分子排列的无序状态,这种物质状态可以促进药物的快速吸收,增加药物的生物利用度,同时也有可能改变药物的疗效。与有序的晶型状态相比无定形状态具有更高的分子流动性,表面自由能和墒。最常用的制备无定形态药物的方法包括直接法,比如骤冷、喷雾干燥和研磨等,还有通过特殊工艺,将原料药与适当的辅料同时加工成含无定形态药物的制剂。然而,由于无定形态药物呈高能状态,因此处于热力学和动力学的不稳定状态,极易向低能稳定的晶体状态转变。此外,储存条件(时间,温度和湿度)的改变也会导致无定形态药物重结晶的发生。在大多数情况下,为了提高无定形态药物及其制剂的物理稳定性,制备时通常将药物与聚合物辅料结合以减小药物分子的自由运动空间,同时还可以提高制剂的玻璃化转变温度,通过干扰药物分子间的相互作用,减缓药物的结晶过程。同一药物的无定形态制剂,在不同的制备工艺下,也可表现出不同的性质。因此,制备具有较高的固体溶解度,良好的相容性和稳定的动力学特性的固体药物的无定形剂型是新药研发过程中的重要研究内容。
超速薄膜冷冻法(Thin film freezing, TFF)是基于表面冷冻薄膜技术的一种革新。液滴在冷固体表面的碰撞和凝固已经被应用于电器和半导体产业来制备薄层冻结物料。近年来这个技术才被用来改善难溶性药物的溶解度和生物利用度。TFF主要是将药物和辅料的溶液滴加于用液氮制冷的不锈钢转子的表面,溶液在转子的表面形成一系列的冷冻圆形薄片,以液氮收集薄片后,冷冻干燥即得所需的无定形态纳米微粉。该方法可以大幅提高药物的溶解度从而增加药物的体内吸收和生物利用度。
本课题的主要目的是通过超速薄膜冷冻法构建可供口服给药的三种卡马西平改性释放纳米微粉并将优选处方制备为口服胶囊制剂,建立卡马西平体内外分析方法,考察其药剂学特性和体内药代动力学特征,从而评估超速薄膜冷冻法对于制备难溶性药物口服无定形态制剂的潜在应用价值。
本研究的主要内容包括处方前研究、改性释放卡马西平纳米微粉的工艺筛选与处方研究,卡马西平改性释放胶囊制剂的研制,HPLC-UV建立生物样品分析方法以及Sprague-Dawley(SD)大鼠体内的药代动力学和生物利用度的研究等。
采用HPLC-UV建立了体外样品中卡马西平的分析方法,方法学考察符合要求。处方前研究结果表明,卡马西平在胃肠道各pH值条件下的溶解度相近,可认为其溶解度不受介质pH值的影响。卡马西平在不同pH值条件下的lgP介于1～1.5之间,提示该药容易被胃肠道上皮细胞吸收,其低溶解度所导致的较慢的溶出速率应该是致使卡马西平口服生物利用度低的主要原因。
对卡马西平改性释药体系进行处方筛选,主要包括：(1)辅料种类的筛选；(2)药物与辅料比例的筛选。以研磨的方法制备药物与辅料的物理混合体系。本研究选用的辅料有：(1)速释辅料,主要包括聚乙烯吡咯烷酮K30(PVP K30),羟丙甲纤维素(HPMC E3);(2)肠溶辅料,主要包括羟丙基甲基纤维素邻苯二甲酸酯(HP-55),聚丙烯酸树脂(Eudragit(?) L100-55)和醋酸羟丙甲纤维素琥珀酸酯(HPMCAS AS-MF);(3)控释辅料,主要包括聚丙烯酸树脂(Eudragit(?) RS-PO),醋酸纤维素(CA)。药物与每种辅料的比例依次为1：4,1：3,1：2,1：1,2：1,3：1和4：1。以药物与辅料物理混合体系的玻璃态转化温度(Tg)为评价指标,采用差示扫描量热分析法对药物与辅料的相容性进行研究比对。结果表明,药物与所选用的所有辅料在任何实验比例下都是相容的,药物与辅料的混合体系的Tg随着体系中药物比例的增加均大体出现降低的趋势。其中,尤其以HPMCAS AS-MF和Eudragit(?) RS-PO作为辅料时,下降趋势特别明显。当以HP-55和HPMCAS AS-MF为辅料时,无论以何种比例混合,体系的Tg始终处于较低水平。这些辅料对提高药物的Tg,改变药物的动力学特性贡献较小,可能会对最终载药体系的稳定性带来隐患。
卡马西平改性释放纳米微粉的研究
1.卡马西平速释纳米微粉的制备工艺及药剂学特性的研究
以超速薄膜冷冻法成功的制备了卡马西平速释纳米微粉。样品DSC观察显示,两种样品在以药物辅料比例为1：2时是完全可混容的。但是,在一些结果中可以观测到重结晶的放热曲线,表明样品在制备过程中发生了相变。XRD结果表明卡马西平在药物载体比例至少1：1时处于无定形状态。在SEM观察下,微粉为疏松多孔状结构。选择CBZ-HPMC E3(1:1)和CBZ-PVPK30(2：1)两种处方在胃肠道模拟介质中进行溶出研究,至少有85%的药物在2h内全部溶出,这可能与微粉的理化特性及辅料的亲水性有关。
2.卡马西平迟释纳米微粉的制备工艺及药剂学特性的研究
以超速薄膜冷冻法成功的制备了卡马西平迟释纳米微粉。样品DSC观察显示,三种样品在以药物辅料比例为2：1时是完全可混容的。特别是以HPMCAS AS-MF为载体,药物辅料比例高达4：1时仍然是可混容的。但是,在一些结果中仍可以观测到重结晶的放热曲线,表明迟释的样品在制备过程中也发生了相变。XRD结果表明卡马西平在药物辅料比例至少3：1时处于无定形状态。在SEM观察下,微粉仍为疏松多孔状结构。此外,三种样品的引湿性增加但总体变化不大。选择CBZ-HPMCAS AS-MF (2:1), CBZ-L100-55(2：1)和CBZ-HP-55(2:1)三种处方在胃肠道模拟介质中进行溶出研究,前2h在酸性介质中至少有40%的药物溶出,当转换为碱性介质时,高达85%的药物在15min内快速溶出,这是由肠溶辅料的溶解特性决定的。
3.卡马西平控释纳米微粉的制备工艺及药剂学特性的研究
以超速薄膜冷冻法成功的制备了卡马西平控释纳米微粉。样品DSC观察显示,两种样品在以药物载体比例为1：1时是完全可混容的。但是,不可避免地还是在一些结果中观测到重结晶的放热曲线,表明控释的样品在制备过程中也发生了相变。XRD结果表明卡马西平在药物载体比例至少1：1时处于无定形状态。在SEM观察下,微粉依然为疏松多孔状结构。此外,两种样品的引湿性不同且相差较大。选择CBZ-RS-PO(2：1)和CBZ-CA(1：2)两种处方在胃肠道模拟介质中进行溶出研究,表明药物的溶出具有控制释放的特性且溶出不受介质酸碱性的影响,这与控释辅料的不溶性相关。
卡马西平改性释放纳米微粉于室温下真空干燥器中储存,在0、1、3、6个月时分别以XRD、药物的含量及含水量和体外溶出考察微粉的稳定性。根据考察结果,选取三个处方CBZ-HPMC E3(1:1), CBZ-L100-55(2:1)和CBZ-CA(1：2)进行下一步胶囊制剂的研究。
为了获得更长期的物理化学稳定性,便于口服给药,将三种稳定的卡马西平改性释放纳米微粉,硅化微晶纤维素,硬脂酸镁和羧甲基淀粉钠以不同的比例,通过干法制粒压片和研磨的方法成功制备了三种卡马西平改性释放胶囊制剂。制备前后,卡马西平在载药系统中为无定形状态,相关质量指标未发生明显改变；初步稳定性实验显示其稳定性良好；体外释药试验结果表明,制备前后制剂释放规律基本相同,具有明显的速释,迟释和控释特征,制剂学特性良好。
采用HPLC-UV建立了大鼠血浆中卡马西平及其活性代谢产物10,11-环氧化卡马西平(CBZ-E)的含量检测的分析方法,方法学考察符合《化学药物非临床药代动力学研究技术指导原则》要求。用PK Solver2.0药动学处理软件对大鼠口服卡马西平原料药和三种改性释放胶囊(30mg·Kg-1)后的血药浓度数据进行处理,求算药动学参数。对于卡马西平,CBZ-HPMC E3胶囊,CBZ-L100-55胶囊和CBZ-CA胶囊生物利用度分别为原料药组的2.4倍,2.6倍和2.5倍；三组胶囊制剂的Cmax均高于原料药组；原料药组的MRT值最长,CBZ-CA的较短,CBZ-HPMCE3的最短；原料药组,CBZ-HPMC E3胶囊,CBZ-L100-55胶囊和CBZ-CA胶囊的tmax值分别为2h,1.5h,6h和1h；对于卡马西平的活性代谢产物CBZ-E, CBZ-HPMCE3胶囊,CBZ-L100-55胶囊和CBZ-CA胶囊生物利用度分别为原料药组的2.7倍,3.2倍和3.0倍；三组胶囊制剂的Cmax也均高于原料药组；原料药组的MRT值最长,CBZ-CA的较短,CBZ-HPMC E3的最短；原料药组,CBZ-HPMC E3胶囊,CBZ-L100-55胶囊和CBZ-CA胶囊的tmax值分别为3h,6h,8h和4h；与原料药相比,纳米微粉改性释放胶囊可缩短卡马西平及CBZ-E的t1/2并增大AUC,尽管原料药组MRT最长,但其Cmax最低AUC最小。该实验表明,对于低溶出速率和体内药动学参数欠佳的水难溶性药物-卡马西平,采用纳米微粉体系可改善其药动学特征。
本文成功地以超速薄膜冷冻法构建了供口服给药的卡马西平改性释药纳米微粉,包括CBZ-HPMC E3(1:1), CBZ-L00-55(2:1)和CBZ-CA (1:2).为增加制剂的稳定性,便于口服给药,应用干法制粒压片法和研磨的方法制备了供口服给药的卡马西平改性释放胶囊,并对其进行了体内外评价。卡马西平在载药系统中始终为无定形状态,溶解度和溶出速率增加,具备良好的制剂学特性。大鼠口服给药后能够极大的改善卡马西平及其活性代谢产物10,11-环氧化卡马西平的生物利用度。本文研究证实,改性释放纳米微粉可增加卡马西平的溶出度和溶出速率并提高其口服生物利用度,是一种具有巨大研究价值和发展前景的新型口服给药系统,而超速薄膜冷冻技术则是改善包括卡马西平在内诸多难溶性药物体内外功效的重要途径。
Oral route of administration is the most convenient, common and preferred for clinical therapy and a lot of drugs has been prepared as oral dosage form. However, approximately70%of new drug candiates being developed by the pharmaceutical industry in recent years are poorly water soluble. Currently, almost40%of immediate release drugs in the market are practically insoluble. Their oral bioavailability is affected by a variety of factors which influence their absorption from the gastrointestinal tract. Of particular interest is the poorly water soluble, highly permeable active pharmaceutical ingredients (APIs) which categorized into the biopharmaceutics classification system (BCS) class Ⅱ. For instance, cyclosporine, griseofulvin, and itraconazole are defined as this class. Generally, the limiting factor to the in vivo absorption of BCS Class Ⅱ drugs after oral administration is their inadequate dissolution rates. Therefore, an enhancement of the dissolution rate is thought to be a key determinant for improving the oral bioavailability of BCS class Ⅱ drugs.
CBZ,5H-Dibenz[b,f]azepine-5-carboxamide, is a model drug belonged to BCS class Ⅱ with an experimental logP value of2.45and practically insoluble in water (120μg/ml). It is widely used as an anticonvulsant drug and in the therapy of trigeminal neuralgia for40years. CBZ is commonly administered orally as a solid, however, due to the limited dissolution rate, its absorption is slow, erratic and unpredictable in humans, leading to incomplete bioavailability and considerable variability in plasma concentration. Furthermore, CBZ exhibits at least four polymorphic forms and variations dissolution and absorption also occurred between them. However, with a narrow therapeutic index, a high dose of CBZ is also required. It is important to improve the dissolution rate of CBZ and thus increase its degree and rate of absorption, and hence its oral bioavailability. This can reduce the necessary dosage and frequency of dosing and probably reduce its side effects. Many different approaches have been applied to increase the bioavailability of CBZ, such as complexation with substituted cyclodextrins, solid dispersion, nanoemulsions or microemulsions, microspheres, conversion to amorphous form and so on. The use of amorphous solid form is arousing more and more interests and attentions in recent years.
Amorphous form is a special physical state of solid compounds that the positions of the molecules or atoms have no long-range order. Sometimes amorphous compounds have better bioavailability, or achieve ultra-fast absorption in situation of acute and intermittent symptoms than that of morphous compounds, thus change drug efficacy. It has higher molecular mobility, free energy and more entropic compared to the corresponding crystalline state with the long range order. The common techniques for producing an amorphous form are mechanical activation, solution-or melt-mediated transformations of bulk material, such as milling, quench cooling of a drug melt, melt extrusion, spray drying, freeze drying. However, due to the higher energetic state, the amorphous form is kinetically and thermodynamically unstable and has the tendency to convert to a more stable, less energetic crystal form(at least if it is a small molecular weight organic). Storage conditions (time, temperature and humidity) have been identified as main factors influencing the rate of recrystallisation. Upon most occasions, in order to enhance the physical stability of the amorphous drugs and dosage forms, the drug is always combined with a polymer by decreasing the free volume, consequently increasing the glass transition temperature (Tg) and slowing down the crystallization process with the disruption of drug-drug interactions. Sometimes, the stability of the same amorphous systems using different preparation techniques may be different in the drug delivery. Therefore, it is a great challenge to obtain the amorphous formulation with a certain degree of solid solubility, miscibility and kinetic stabilization.
Thin film freezing (TFF) particle engineering process to produce pharmaceutical powders is an evolution of earlier freezing processes on cold surfaces to form films. Impingement and solidification of liquefied droplets onto a cold solid surface has been used in the electrical and semi-conductor industries to add thin layers of frozen material onto a surface. Only recently has this application been used as a particle engineering technique to improve the bioavailability of poorly water soluble compounds and biopharmaceuticals. TFF involves applying a API/stabilizers solution onto a cryogenically-cooled solid surface to obtain a solid dispersion/solution, collecting the frozen particles and removing the solvent via lyophilization. Nanostructrued powders with high surface area, increased wettability, amorphous API structure and rapid dissolution rates were obtained successfully.
The major objectives of undertaking this study were to prepare amorphous powder of CBZ by TFF, incorporate TFF carbamazepine formulations(CBZ-TFF) into capsule dosage form for modified release, establish the CBZ determine method by HPLC-UV for in vitro and in vivo samples analysis, study the bioavailability of CBZ-TFF and to evaluate the potential of using TFF as oral amorphous powder engineering process for poorly water soluble drugs.
The major contents include preformulation study, technology and formulation screening of preparation carbamazepine modified release amorphous powders by TFF and then encapsuled into capsules, establishment of HPLC-UV method for biological specimen analysis, single-dose24-h pharmacokinetic studies of Sprague-Dawley(SD) rats oral administration of the three kinds of preparations by rat capsule dosing apparatus.
The established HPLC-UV method for in vitro sample, analysis was investigated and corresponded to technology requirement. The experiment results of preformulation study stated that the equilibrium solubility of CBZ is with small difference under the condition of gastrointestinal pH value. The oil/water partition coefficient of carbamazepine was less influence by pH and the lgP is between1.0to1.5which indicate that CBZ should be easily absorbed by epithelial cells in gastrointestinal tract, which also hinted that the poor oral bioavailability of carbarmazepine was mainly due to the low solubility resulted slow dissolution vdocity.
The formula and preparation of CBZ modified release drug delivery were investigated:(1) polymer type;(2) drug:polymer ratio. The physical mixtures were mixed by geometric dilution and trituration using a ceramic mortar and pestle with CBZ and different kinds of polymers:(1) immediate release polymers, including Polyvinylpyrrolidone K30(PVP K30) and premium hydroxypropyl methylcellulose (HPMC E3);(2) enteric polymers, including hydroxypropyl methyl-cellulose phthalate NF (HP-55), Eudragit(?) L100-55(L100-55) and hydroxypropyl methylcellulose acetate succinate (HPMCAS AS-MF);(3) controlled release polymers, including Eudragit(?) RS-PO (RS-PO) and Cellulose Acetate (CA). The ratio of the drug and each polymer has seven levels:1:4;1:3;1:2;1:1;2:1;3:1;4:1. Differential scanning calorimetry (DSC) was utilized to define the level of CBZ miscibility with each polymer and the glass transition temperature (Tg) was selected as the response variable to optimize the CBZ-TFF formulations. DSC profiles revealed that completely miscible at every level of ratio with drug and each polymer. However, Tg of physical mixtures decreased with increasing CBZ potency, especially for HPMCAS AS-MF and Eudragit(?) RS-PO. The Tg of physical mixtures with HP-55and HPMCAS AS-MF as polymers were always at low level. There is small contribution for improving the Tg of the drug, which maybe cause the instability of the drug systems.
Studies of CBZ nanostructured aggregate powder for modified release
1. Development and evaluation of CBZ nanostructured aggregate powder for immediate release
Immediate release nanostructured aggregate powder containing amorphous CBZ and immediate release polymers were successfully manufactured using TFF process. The MDSC was used to define the miscibility of CBZ and each polymer. The compositions were completely miscible with1:2CBZ:polymer ratio for two polymers, however, recrystallization exotherms were observed in some formulations which revealed phase separation occurred during power formation. XRD results indicated that carbamazepine was amorphous for each added immediate release polymer with1:1CBZ:polymer ratio at least. The TFF power samples presented as highly regular porous matrix structure under SEM. Dissolution studies on CBZ-HPMC E3(1:1) and CBZ-PVP K30(2:1) compositions were performed under sink conditions in0.1N HCl for2h and then pH6.8phosphate buffer for6h. At lease85%CBZ quickly dissolved within2h, which is a function of the hydrophilic polymers.
2. Development and evaluation of CBZ nanostructured aggregate powder for delayed release
Delayed release micronized powers containing amorphous CBZ and enteric polymers were also successfully manufactured using TFF process. The compositions were completely miscible with2:1CBZ:polymer ratio for three polymers and as high as4:1in HPMCAS AS-MF, however, recrystallization exotherms were also observed in some formulations which revealed phase separation occurred during power formation. XRD results indicated that carbamazepine was amorphous for each added enteric polymer with3:1CBZ:polymer ratio at least. A highly porous structure with more regularly shaped particles of the CBZ-TFF powder was observed under SEM. Furthermore, the wettability of formulations with various polymer types exhibited similar and significantly enhanced. Dissolution rates on CBZ-HPMCAS AS-MF (1:2), CBZ-L100-55(1:2) and CBZ-HP-55(1:2) compositions were studied under sink conditon. At lease40%CBZ dissolved in2h, and changed for the phosphate buffer, samples revealed rapid dissolution with at least80%CBZ dissolved within15min, which maybe caused by the dynamic dissolving characteristic of the enteric polymer.
3. Development and evaluation of CBZ nanostructured aggregate powder for controlled release
Controlled release micronized powers containing amorphous CBZ and controlled release polymers were also successfully manufactured using TFF process. The compositions were completely miscible with1:1CBZ:polymer ratio for two polymers, however, recrystallization exotherms were also observed in some formulations which revealed phase separation occurred during power formation. XRD results indicated that carbamazepine was amorphous for each added polymer with1:1CBZ:polymer ratio at least. A highly porous structure with more regularly shaped particles of the CBZ-TFF powder was observed under SEM. Furthermore, the wettability of formulations with various polymer types exhibited similar and slightly enhanced. Dissolution rates on CBZ-RS-PO (1:2) and CBZ-CA (2:1) compositions were studied under sink conditon. The behavior of the CBZ release in the dissolution medium was less influenced by the pH and samples revealed controlled released dissolution within8h, which maybe because of the insolubility of the controlled released polymers.
The amorphous CBZ-TFF powders for modified release were stored in desiccators under vacuum at room temperature, and the physical stability was assessed by XRD at1,3and6months. There were no characteristic crystalline peak of CBZ detected with the formulations of CBZ-HPMC E3, CBZ-L100-55and CBZ-CA after storage for up to6months, indicating the powders retained amorphous morphology when stored at room temperature and protected from humidity.
The modified release capsules of the CBZ-TFF were prepared by dry granulation tabletting and grinding method using Silicified Microcrystalline Cellulose (SMCC), Magnesium stearate (Mgst) and Sodium Starch Glycolate (SSG) as supporting agents in order to obtain better physical and chemical stabilities. The stability of modified release capsules of the CBZ-TFF were not affected by the preparation procedures with nearly unchanged main quality indexes. The release trail in vitro were investigated and the results showed that the CBZ-TFF nanostructured aggregate powders and CBZ-TFF modified release capsules have similar release kinetic. The three preparations had immediate release, delayed release and controlled release characters, respectively.
Carbamazepine and its major active metabolite carbamazepine-10,11-epoxide (CBZ-E) were determined in the blood plasma by HPLC. The technology investigation coincided with the requirement of SFDA guidance principle of chemicals non-clinic pharrnacokinetics. Pharmacokinetic parameters were derived using a non-compartmental model PK Solver2.0in Microsoft Excel. For carbamzepine, after oral administration (30mg-Kg-1), three kind of modified release delivery systems showed approximately2.4times,2.6times and2.5times bioavailability improvements in terms rate and extent compared with the crude CBZ. The crude CBZ has the longest MRT, the CBZ-CA showed shorter and the CBZ-HPMC E3showed the shortest. The tmax was significantly longer for the crude CBZ than that for the capsules of CBZ-HPMC E3, CBZ-L100-55and CBZ-CA. For CBZ-E, after oral administration (30mg·Kg-1), three kind of modified release delivery systems showed approximately2.6times,3.2times and3.0times bioavailability improvements in terms rate and extent compared with the crude CBZ. The crude CBZ has the longest MRT, the CBZ-CA showed shorter and the CBZ-HPMC E3showed the shortest. The tmax was significantly longer for the crude CBZ than that for the capsules of CBZ-HPMC E3, CBZ-L100-55and CBZ-CA. Based on comparison of the AUCO-co values of carbamazepine and CBZ-E, the crude CBZ showed significantly lower carbamazepine exposure than the delivery systems (CBZ-HPMC E3, CBZ-L100-55and CBZ-CA). There was no significant difference in AUCo-oo among CBZ-HPMC E3, CBZ-L100-55and CBZ-CA. The Cmax of carbamazepine and CBZ-E were significantly lower in the crude carbamazepine than those of the capsules CBZ-HPMC E3, CBZ-L100-55and CBZ-CA. In contrast to the crude CBZ, the CBZ-TFF formulations had shorten t1/2and augmented AUC. No adverse events were observed during the administration. The AUC of the crude CBZ was lower than that of the modified release capsules, including CBZ-HPMC E3, CBZ-L100-55and CBZ-CA. Although the solution has longer MRT the lower Cmax as well as other parameters also lead to a distinct pharmacokinetics profile when compared to the modified release capsules plots. Therefore, these experiments demonstrated that nanostructured aggregate powder prepared by TFF can be used to improve exposure of compounds with low dissolution rate and poor phatmacokinetic characteristics.
In conclusion, we have successfully incorporated carbamazepine, a poorly soluble drug, into modified release systems by a thin film freezing(TFF) process. Three kinds of modified release micronized powders containing amorphous CBZ and polymers-including HPMC E3, L100-55, CA, were successfully prepared and then encapsuled into capsules. The systems ware physically stable for3months at room temperature and the drug dissolution rates from three kinds of capsule preparations were significantly modified and enhanced compared to the crude drug. The amorphous state of the drug and the modified dissolution rate contributed to a significantly enhanced oral bioavailability compared to the crude CBZ. These data collective support that nanostructured aggregate powder prepared by TFF is a promising delivery system to enhance the oral absorption of poorly water soluble drugs.
卡马西平(Carbamazepine,CBZ),化学名为5H-二苯并[b,f]氮杂卓-5-甲酰胺,其表观油水分配系数为2.45且几乎不溶于水(120μg·mL-1,250℃),是典型的生物药剂学分类系统中的Ⅱ类药物。卡马西平在临床上用于治疗癫痫、三叉神经痛以及躁狂抑郁等疾病已有四十余年的时间。卡马西平一般作为口服固体制剂应用,但是由于其在消化液中的溶出是该药吸收的限速步骤,造成了药物在胃肠道中吸收缓慢且不规则,生物利用度低,血药浓度的个体差异大,而且治疗窗狭窄(4-12μg·mL-1),极易产生毒副作用。此外,卡马西平具有四种晶型,不同的晶型在体内的溶解度和吸收速率也有明显的差异。因此提高卡马西平的溶解度和溶出速率对改善卡马西平的生物利用度和临床疗效,减少用药量与用药次数,减小个体差异,避免毒副作用,具有极其重要的意义。环糊精包合物,固体分散体,纳米乳剂,微球,无定形纳米微粉等释药系统已经被研究并成功用来改善该药的生物药剂学特性,特别是无定形态药物制剂更是成为近年来该领域的研究热点。
固体药物的无定形状态是药物分子排列的无序状态,这种物质状态可以促进药物的快速吸收,增加药物的生物利用度,同时也有可能改变药物的疗效。与有序的晶型状态相比无定形状态具有更高的分子流动性,表面自由能和墒。最常用的制备无定形态药物的方法包括直接法,比如骤冷、喷雾干燥和研磨等,还有通过特殊工艺,将原料药与适当的辅料同时加工成含无定形态药物的制剂。然而,由于无定形态药物呈高能状态,因此处于热力学和动力学的不稳定状态,极易向低能稳定的晶体状态转变。此外,储存条件(时间,温度和湿度)的改变也会导致无定形态药物重结晶的发生。在大多数情况下,为了提高无定形态药物及其制剂的物理稳定性,制备时通常将药物与聚合物辅料结合以减小药物分子的自由运动空间,同时还可以提高制剂的玻璃化转变温度,通过干扰药物分子间的相互作用,减缓药物的结晶过程。同一药物的无定形态制剂,在不同的制备工艺下,也可表现出不同的性质。因此,制备具有较高的固体溶解度,良好的相容性和稳定的动力学特性的固体药物的无定形剂型是新药研发过程中的重要研究内容。
超速薄膜冷冻法(Thin film freezing, TFF)是基于表面冷冻薄膜技术的一种革新。液滴在冷固体表面的碰撞和凝固已经被应用于电器和半导体产业来制备薄层冻结物料。近年来这个技术才被用来改善难溶性药物的溶解度和生物利用度。TFF主要是将药物和辅料的溶液滴加于用液氮制冷的不锈钢转子的表面,溶液在转子的表面形成一系列的冷冻圆形薄片,以液氮收集薄片后,冷冻干燥即得所需的无定形态纳米微粉。该方法可以大幅提高药物的溶解度从而增加药物的体内吸收和生物利用度。
本课题的主要目的是通过超速薄膜冷冻法构建可供口服给药的三种卡马西平改性释放纳米微粉并将优选处方制备为口服胶囊制剂,建立卡马西平体内外分析方法,考察其药剂学特性和体内药代动力学特征,从而评估超速薄膜冷冻法对于制备难溶性药物口服无定形态制剂的潜在应用价值。
本研究的主要内容包括处方前研究、改性释放卡马西平纳米微粉的工艺筛选与处方研究,卡马西平改性释放胶囊制剂的研制,HPLC-UV建立生物样品分析方法以及Sprague-Dawley(SD)大鼠体内的药代动力学和生物利用度的研究等。
采用HPLC-UV建立了体外样品中卡马西平的分析方法,方法学考察符合要求。处方前研究结果表明,卡马西平在胃肠道各pH值条件下的溶解度相近,可认为其溶解度不受介质pH值的影响。卡马西平在不同pH值条件下的lgP介于1～1.5之间,提示该药容易被胃肠道上皮细胞吸收,其低溶解度所导致的较慢的溶出速率应该是致使卡马西平口服生物利用度低的主要原因。
对卡马西平改性释药体系进行处方筛选,主要包括：(1)辅料种类的筛选；(2)药物与辅料比例的筛选。以研磨的方法制备药物与辅料的物理混合体系。本研究选用的辅料有：(1)速释辅料,主要包括聚乙烯吡咯烷酮K30(PVP K30),羟丙甲纤维素(HPMC E3);(2)肠溶辅料,主要包括羟丙基甲基纤维素邻苯二甲酸酯(HP-55),聚丙烯酸树脂(Eudragit(?) L100-55)和醋酸羟丙甲纤维素琥珀酸酯(HPMCAS AS-MF);(3)控释辅料,主要包括聚丙烯酸树脂(Eudragit(?) RS-PO),醋酸纤维素(CA)。药物与每种辅料的比例依次为1：4,1：3,1：2,1：1,2：1,3：1和4：1。以药物与辅料物理混合体系的玻璃态转化温度(Tg)为评价指标,采用差示扫描量热分析法对药物与辅料的相容性进行研究比对。结果表明,药物与所选用的所有辅料在任何实验比例下都是相容的,药物与辅料的混合体系的Tg随着体系中药物比例的增加均大体出现降低的趋势。其中,尤其以HPMCAS AS-MF和Eudragit(?) RS-PO作为辅料时,下降趋势特别明显。当以HP-55和HPMCAS AS-MF为辅料时,无论以何种比例混合,体系的Tg始终处于较低水平。这些辅料对提高药物的Tg,改变药物的动力学特性贡献较小,可能会对最终载药体系的稳定性带来隐患。
卡马西平改性释放纳米微粉的研究
1.卡马西平速释纳米微粉的制备工艺及药剂学特性的研究
以超速薄膜冷冻法成功的制备了卡马西平速释纳米微粉。样品DSC观察显示,两种样品在以药物辅料比例为1：2时是完全可混容的。但是,在一些结果中可以观测到重结晶的放热曲线,表明样品在制备过程中发生了相变。XRD结果表明卡马西平在药物载体比例至少1：1时处于无定形状态。在SEM观察下,微粉为疏松多孔状结构。选择CBZ-HPMC E3(1:1)和CBZ-PVPK30(2：1)两种处方在胃肠道模拟介质中进行溶出研究,至少有85%的药物在2h内全部溶出,这可能与微粉的理化特性及辅料的亲水性有关。
2.卡马西平迟释纳米微粉的制备工艺及药剂学特性的研究
以超速薄膜冷冻法成功的制备了卡马西平迟释纳米微粉。样品DSC观察显示,三种样品在以药物辅料比例为2：1时是完全可混容的。特别是以HPMCAS AS-MF为载体,药物辅料比例高达4：1时仍然是可混容的。但是,在一些结果中仍可以观测到重结晶的放热曲线,表明迟释的样品在制备过程中也发生了相变。XRD结果表明卡马西平在药物辅料比例至少3：1时处于无定形状态。在SEM观察下,微粉仍为疏松多孔状结构。此外,三种样品的引湿性增加但总体变化不大。选择CBZ-HPMCAS AS-MF (2:1), CBZ-L100-55(2：1)和CBZ-HP-55(2:1)三种处方在胃肠道模拟介质中进行溶出研究,前2h在酸性介质中至少有40%的药物溶出,当转换为碱性介质时,高达85%的药物在15min内快速溶出,这是由肠溶辅料的溶解特性决定的。
3.卡马西平控释纳米微粉的制备工艺及药剂学特性的研究
以超速薄膜冷冻法成功的制备了卡马西平控释纳米微粉。样品DSC观察显示,两种样品在以药物载体比例为1：1时是完全可混容的。但是,不可避免地还是在一些结果中观测到重结晶的放热曲线,表明控释的样品在制备过程中也发生了相变。XRD结果表明卡马西平在药物载体比例至少1：1时处于无定形状态。在SEM观察下,微粉依然为疏松多孔状结构。此外,两种样品的引湿性不同且相差较大。选择CBZ-RS-PO(2：1)和CBZ-CA(1：2)两种处方在胃肠道模拟介质中进行溶出研究,表明药物的溶出具有控制释放的特性且溶出不受介质酸碱性的影响,这与控释辅料的不溶性相关。
卡马西平改性释放纳米微粉于室温下真空干燥器中储存,在0、1、3、6个月时分别以XRD、药物的含量及含水量和体外溶出考察微粉的稳定性。根据考察结果,选取三个处方CBZ-HPMC E3(1:1), CBZ-L100-55(2:1)和CBZ-CA(1：2)进行下一步胶囊制剂的研究。
为了获得更长期的物理化学稳定性,便于口服给药,将三种稳定的卡马西平改性释放纳米微粉,硅化微晶纤维素,硬脂酸镁和羧甲基淀粉钠以不同的比例,通过干法制粒压片和研磨的方法成功制备了三种卡马西平改性释放胶囊制剂。制备前后,卡马西平在载药系统中为无定形状态,相关质量指标未发生明显改变；初步稳定性实验显示其稳定性良好；体外释药试验结果表明,制备前后制剂释放规律基本相同,具有明显的速释,迟释和控释特征,制剂学特性良好。
采用HPLC-UV建立了大鼠血浆中卡马西平及其活性代谢产物10,11-环氧化卡马西平(CBZ-E)的含量检测的分析方法,方法学考察符合《化学药物非临床药代动力学研究技术指导原则》要求。用PK Solver2.0药动学处理软件对大鼠口服卡马西平原料药和三种改性释放胶囊(30mg·Kg-1)后的血药浓度数据进行处理,求算药动学参数。对于卡马西平,CBZ-HPMC E3胶囊,CBZ-L100-55胶囊和CBZ-CA胶囊生物利用度分别为原料药组的2.4倍,2.6倍和2.5倍；三组胶囊制剂的Cmax均高于原料药组；原料药组的MRT值最长,CBZ-CA的较短,CBZ-HPMCE3的最短；原料药组,CBZ-HPMC E3胶囊,CBZ-L100-55胶囊和CBZ-CA胶囊的tmax值分别为2h,1.5h,6h和1h；对于卡马西平的活性代谢产物CBZ-E, CBZ-HPMCE3胶囊,CBZ-L100-55胶囊和CBZ-CA胶囊生物利用度分别为原料药组的2.7倍,3.2倍和3.0倍；三组胶囊制剂的Cmax也均高于原料药组；原料药组的MRT值最长,CBZ-CA的较短,CBZ-HPMC E3的最短；原料药组,CBZ-HPMC E3胶囊,CBZ-L100-55胶囊和CBZ-CA胶囊的tmax值分别为3h,6h,8h和4h；与原料药相比,纳米微粉改性释放胶囊可缩短卡马西平及CBZ-E的t1/2并增大AUC,尽管原料药组MRT最长,但其Cmax最低AUC最小。该实验表明,对于低溶出速率和体内药动学参数欠佳的水难溶性药物-卡马西平,采用纳米微粉体系可改善其药动学特征。
本文成功地以超速薄膜冷冻法构建了供口服给药的卡马西平改性释药纳米微粉,包括CBZ-HPMC E3(1:1), CBZ-L00-55(2:1)和CBZ-CA (1:2).为增加制剂的稳定性,便于口服给药,应用干法制粒压片法和研磨的方法制备了供口服给药的卡马西平改性释放胶囊,并对其进行了体内外评价。卡马西平在载药系统中始终为无定形状态,溶解度和溶出速率增加,具备良好的制剂学特性。大鼠口服给药后能够极大的改善卡马西平及其活性代谢产物10,11-环氧化卡马西平的生物利用度。本文研究证实,改性释放纳米微粉可增加卡马西平的溶出度和溶出速率并提高其口服生物利用度,是一种具有巨大研究价值和发展前景的新型口服给药系统,而超速薄膜冷冻技术则是改善包括卡马西平在内诸多难溶性药物体内外功效的重要途径。
Oral route of administration is the most convenient, common and preferred for clinical therapy and a lot of drugs has been prepared as oral dosage form. However, approximately70%of new drug candiates being developed by the pharmaceutical industry in recent years are poorly water soluble. Currently, almost40%of immediate release drugs in the market are practically insoluble. Their oral bioavailability is affected by a variety of factors which influence their absorption from the gastrointestinal tract. Of particular interest is the poorly water soluble, highly permeable active pharmaceutical ingredients (APIs) which categorized into the biopharmaceutics classification system (BCS) class Ⅱ. For instance, cyclosporine, griseofulvin, and itraconazole are defined as this class. Generally, the limiting factor to the in vivo absorption of BCS Class Ⅱ drugs after oral administration is their inadequate dissolution rates. Therefore, an enhancement of the dissolution rate is thought to be a key determinant for improving the oral bioavailability of BCS class Ⅱ drugs.
CBZ,5H-Dibenz[b,f]azepine-5-carboxamide, is a model drug belonged to BCS class Ⅱ with an experimental logP value of2.45and practically insoluble in water (120μg/ml). It is widely used as an anticonvulsant drug and in the therapy of trigeminal neuralgia for40years. CBZ is commonly administered orally as a solid, however, due to the limited dissolution rate, its absorption is slow, erratic and unpredictable in humans, leading to incomplete bioavailability and considerable variability in plasma concentration. Furthermore, CBZ exhibits at least four polymorphic forms and variations dissolution and absorption also occurred between them. However, with a narrow therapeutic index, a high dose of CBZ is also required. It is important to improve the dissolution rate of CBZ and thus increase its degree and rate of absorption, and hence its oral bioavailability. This can reduce the necessary dosage and frequency of dosing and probably reduce its side effects. Many different approaches have been applied to increase the bioavailability of CBZ, such as complexation with substituted cyclodextrins, solid dispersion, nanoemulsions or microemulsions, microspheres, conversion to amorphous form and so on. The use of amorphous solid form is arousing more and more interests and attentions in recent years.
Amorphous form is a special physical state of solid compounds that the positions of the molecules or atoms have no long-range order. Sometimes amorphous compounds have better bioavailability, or achieve ultra-fast absorption in situation of acute and intermittent symptoms than that of morphous compounds, thus change drug efficacy. It has higher molecular mobility, free energy and more entropic compared to the corresponding crystalline state with the long range order. The common techniques for producing an amorphous form are mechanical activation, solution-or melt-mediated transformations of bulk material, such as milling, quench cooling of a drug melt, melt extrusion, spray drying, freeze drying. However, due to the higher energetic state, the amorphous form is kinetically and thermodynamically unstable and has the tendency to convert to a more stable, less energetic crystal form(at least if it is a small molecular weight organic). Storage conditions (time, temperature and humidity) have been identified as main factors influencing the rate of recrystallisation. Upon most occasions, in order to enhance the physical stability of the amorphous drugs and dosage forms, the drug is always combined with a polymer by decreasing the free volume, consequently increasing the glass transition temperature (Tg) and slowing down the crystallization process with the disruption of drug-drug interactions. Sometimes, the stability of the same amorphous systems using different preparation techniques may be different in the drug delivery. Therefore, it is a great challenge to obtain the amorphous formulation with a certain degree of solid solubility, miscibility and kinetic stabilization.
Thin film freezing (TFF) particle engineering process to produce pharmaceutical powders is an evolution of earlier freezing processes on cold surfaces to form films. Impingement and solidification of liquefied droplets onto a cold solid surface has been used in the electrical and semi-conductor industries to add thin layers of frozen material onto a surface. Only recently has this application been used as a particle engineering technique to improve the bioavailability of poorly water soluble compounds and biopharmaceuticals. TFF involves applying a API/stabilizers solution onto a cryogenically-cooled solid surface to obtain a solid dispersion/solution, collecting the frozen particles and removing the solvent via lyophilization. Nanostructrued powders with high surface area, increased wettability, amorphous API structure and rapid dissolution rates were obtained successfully.
The major objectives of undertaking this study were to prepare amorphous powder of CBZ by TFF, incorporate TFF carbamazepine formulations(CBZ-TFF) into capsule dosage form for modified release, establish the CBZ determine method by HPLC-UV for in vitro and in vivo samples analysis, study the bioavailability of CBZ-TFF and to evaluate the potential of using TFF as oral amorphous powder engineering process for poorly water soluble drugs.
The major contents include preformulation study, technology and formulation screening of preparation carbamazepine modified release amorphous powders by TFF and then encapsuled into capsules, establishment of HPLC-UV method for biological specimen analysis, single-dose24-h pharmacokinetic studies of Sprague-Dawley(SD) rats oral administration of the three kinds of preparations by rat capsule dosing apparatus.
The established HPLC-UV method for in vitro sample, analysis was investigated and corresponded to technology requirement. The experiment results of preformulation study stated that the equilibrium solubility of CBZ is with small difference under the condition of gastrointestinal pH value. The oil/water partition coefficient of carbamazepine was less influence by pH and the lgP is between1.0to1.5which indicate that CBZ should be easily absorbed by epithelial cells in gastrointestinal tract, which also hinted that the poor oral bioavailability of carbarmazepine was mainly due to the low solubility resulted slow dissolution vdocity.
The formula and preparation of CBZ modified release drug delivery were investigated:(1) polymer type;(2) drug:polymer ratio. The physical mixtures were mixed by geometric dilution and trituration using a ceramic mortar and pestle with CBZ and different kinds of polymers:(1) immediate release polymers, including Polyvinylpyrrolidone K30(PVP K30) and premium hydroxypropyl methylcellulose (HPMC E3);(2) enteric polymers, including hydroxypropyl methyl-cellulose phthalate NF (HP-55), Eudragit(?) L100-55(L100-55) and hydroxypropyl methylcellulose acetate succinate (HPMCAS AS-MF);(3) controlled release polymers, including Eudragit(?) RS-PO (RS-PO) and Cellulose Acetate (CA). The ratio of the drug and each polymer has seven levels:1:4;1:3;1:2;1:1;2:1;3:1;4:1. Differential scanning calorimetry (DSC) was utilized to define the level of CBZ miscibility with each polymer and the glass transition temperature (Tg) was selected as the response variable to optimize the CBZ-TFF formulations. DSC profiles revealed that completely miscible at every level of ratio with drug and each polymer. However, Tg of physical mixtures decreased with increasing CBZ potency, especially for HPMCAS AS-MF and Eudragit(?) RS-PO. The Tg of physical mixtures with HP-55and HPMCAS AS-MF as polymers were always at low level. There is small contribution for improving the Tg of the drug, which maybe cause the instability of the drug systems.
Studies of CBZ nanostructured aggregate powder for modified release
1. Development and evaluation of CBZ nanostructured aggregate powder for immediate release
Immediate release nanostructured aggregate powder containing amorphous CBZ and immediate release polymers were successfully manufactured using TFF process. The MDSC was used to define the miscibility of CBZ and each polymer. The compositions were completely miscible with1:2CBZ:polymer ratio for two polymers, however, recrystallization exotherms were observed in some formulations which revealed phase separation occurred during power formation. XRD results indicated that carbamazepine was amorphous for each added immediate release polymer with1:1CBZ:polymer ratio at least. The TFF power samples presented as highly regular porous matrix structure under SEM. Dissolution studies on CBZ-HPMC E3(1:1) and CBZ-PVP K30(2:1) compositions were performed under sink conditions in0.1N HCl for2h and then pH6.8phosphate buffer for6h. At lease85%CBZ quickly dissolved within2h, which is a function of the hydrophilic polymers.
2. Development and evaluation of CBZ nanostructured aggregate powder for delayed release
Delayed release micronized powers containing amorphous CBZ and enteric polymers were also successfully manufactured using TFF process. The compositions were completely miscible with2:1CBZ:polymer ratio for three polymers and as high as4:1in HPMCAS AS-MF, however, recrystallization exotherms were also observed in some formulations which revealed phase separation occurred during power formation. XRD results indicated that carbamazepine was amorphous for each added enteric polymer with3:1CBZ:polymer ratio at least. A highly porous structure with more regularly shaped particles of the CBZ-TFF powder was observed under SEM. Furthermore, the wettability of formulations with various polymer types exhibited similar and significantly enhanced. Dissolution rates on CBZ-HPMCAS AS-MF (1:2), CBZ-L100-55(1:2) and CBZ-HP-55(1:2) compositions were studied under sink conditon. At lease40%CBZ dissolved in2h, and changed for the phosphate buffer, samples revealed rapid dissolution with at least80%CBZ dissolved within15min, which maybe caused by the dynamic dissolving characteristic of the enteric polymer.
3. Development and evaluation of CBZ nanostructured aggregate powder for controlled release
Controlled release micronized powers containing amorphous CBZ and controlled release polymers were also successfully manufactured using TFF process. The compositions were completely miscible with1:1CBZ:polymer ratio for two polymers, however, recrystallization exotherms were also observed in some formulations which revealed phase separation occurred during power formation. XRD results indicated that carbamazepine was amorphous for each added polymer with1:1CBZ:polymer ratio at least. A highly porous structure with more regularly shaped particles of the CBZ-TFF powder was observed under SEM. Furthermore, the wettability of formulations with various polymer types exhibited similar and slightly enhanced. Dissolution rates on CBZ-RS-PO (1:2) and CBZ-CA (2:1) compositions were studied under sink conditon. The behavior of the CBZ release in the dissolution medium was less influenced by the pH and samples revealed controlled released dissolution within8h, which maybe because of the insolubility of the controlled released polymers.
The amorphous CBZ-TFF powders for modified release were stored in desiccators under vacuum at room temperature, and the physical stability was assessed by XRD at1,3and6months. There were no characteristic crystalline peak of CBZ detected with the formulations of CBZ-HPMC E3, CBZ-L100-55and CBZ-CA after storage for up to6months, indicating the powders retained amorphous morphology when stored at room temperature and protected from humidity.
The modified release capsules of the CBZ-TFF were prepared by dry granulation tabletting and grinding method using Silicified Microcrystalline Cellulose (SMCC), Magnesium stearate (Mgst) and Sodium Starch Glycolate (SSG) as supporting agents in order to obtain better physical and chemical stabilities. The stability of modified release capsules of the CBZ-TFF were not affected by the preparation procedures with nearly unchanged main quality indexes. The release trail in vitro were investigated and the results showed that the CBZ-TFF nanostructured aggregate powders and CBZ-TFF modified release capsules have similar release kinetic. The three preparations had immediate release, delayed release and controlled release characters, respectively.
Carbamazepine and its major active metabolite carbamazepine-10,11-epoxide (CBZ-E) were determined in the blood plasma by HPLC. The technology investigation coincided with the requirement of SFDA guidance principle of chemicals non-clinic pharrnacokinetics. Pharmacokinetic parameters were derived using a non-compartmental model PK Solver2.0in Microsoft Excel. For carbamzepine, after oral administration (30mg-Kg-1), three kind of modified release delivery systems showed approximately2.4times,2.6times and2.5times bioavailability improvements in terms rate and extent compared with the crude CBZ. The crude CBZ has the longest MRT, the CBZ-CA showed shorter and the CBZ-HPMC E3showed the shortest. The tmax was significantly longer for the crude CBZ than that for the capsules of CBZ-HPMC E3, CBZ-L100-55and CBZ-CA. For CBZ-E, after oral administration (30mg·Kg-1), three kind of modified release delivery systems showed approximately2.6times,3.2times and3.0times bioavailability improvements in terms rate and extent compared with the crude CBZ. The crude CBZ has the longest MRT, the CBZ-CA showed shorter and the CBZ-HPMC E3showed the shortest. The tmax was significantly longer for the crude CBZ than that for the capsules of CBZ-HPMC E3, CBZ-L100-55and CBZ-CA. Based on comparison of the AUCO-co values of carbamazepine and CBZ-E, the crude CBZ showed significantly lower carbamazepine exposure than the delivery systems (CBZ-HPMC E3, CBZ-L100-55and CBZ-CA). There was no significant difference in AUCo-oo among CBZ-HPMC E3, CBZ-L100-55and CBZ-CA. The Cmax of carbamazepine and CBZ-E were significantly lower in the crude carbamazepine than those of the capsules CBZ-HPMC E3, CBZ-L100-55and CBZ-CA. In contrast to the crude CBZ, the CBZ-TFF formulations had shorten t1/2and augmented AUC. No adverse events were observed during the administration. The AUC of the crude CBZ was lower than that of the modified release capsules, including CBZ-HPMC E3, CBZ-L100-55and CBZ-CA. Although the solution has longer MRT the lower Cmax as well as other parameters also lead to a distinct pharmacokinetics profile when compared to the modified release capsules plots. Therefore, these experiments demonstrated that nanostructured aggregate powder prepared by TFF can be used to improve exposure of compounds with low dissolution rate and poor phatmacokinetic characteristics.
In conclusion, we have successfully incorporated carbamazepine, a poorly soluble drug, into modified release systems by a thin film freezing(TFF) process. Three kinds of modified release micronized powders containing amorphous CBZ and polymers-including HPMC E3, L100-55, CA, were successfully prepared and then encapsuled into capsules. The systems ware physically stable for3months at room temperature and the drug dissolution rates from three kinds of capsule preparations were significantly modified and enhanced compared to the crude drug. The amorphous state of the drug and the modified dissolution rate contributed to a significantly enhanced oral bioavailability compared to the crude CBZ. These data collective support that nanostructured aggregate powder prepared by TFF is a promising delivery system to enhance the oral absorption of poorly water soluble drugs.
引文
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