难溶性药物的增溶及其缓/控释制剂研究进展

目前由高通量药物筛选而得的活性物质约有40％是水难溶性的，难溶性药物（poorly water—soluble drug）因其在水中溶解度小，药物难以被机体吸收，体内消除速度较快，血药浓度容易出现峰谷现象，口服制剂生物利用度低，且难以实现剂型的多样化。已报道的增溶技术如固体分散技术、环糊精包合技术、胶束增溶、微乳增溶、超微粉碎等已用于增加难溶性药物的溶解度，提高其口服制剂的生物利用度。缓／控释制剂（sustained or controlled release dosage forms）具有减少用药总剂量和用药次数，避免血浓峰谷现象，降低毒副作用，提高病人顺应性等优点，在临床上的应用日益广泛。目前应用增溶技术和缓／控释技术提高难溶性药物的溶解度和生物利用度，研制难溶性药物的缓／控释制剂以成为药剂学研究的热点方向。本文就难溶性药物的增溶及其缓／控释制剂的研究进展做如下综述。     

难溶性药物增溶研究进展

如何增加难溶性药物的溶解度,改善其生物利用度,一直是药剂学研究的重要内容。该文就近年来应用广泛的纳米混悬剂、渗透泵、自微乳化技术、固体分散体、固体脂质纳米粒、液固压缩技术等一些新方法新技术在增加难溶性药物溶解度及改善生物利用度方面的应用进行综述。     

纳米晶体技术在水难溶性药物口服制剂中应用的研究进展

目的综述水难溶性药物纳米晶体的制备方法,稳定剂在纳米晶体形成过程中的主要应用原理及产品物理性质的表征,为改善水难溶性药物溶解度或口服生物利用度提供理论依据。方法查阅国内外相关文献27篇,回顾纳米晶体技术的发展历程,提供药物纳米晶体技术的最新研究进展。结果药物纳米晶体不仅制备工艺简单,性质考察方便;还能够提高难溶性药物在胃肠道中的溶解度,改善难溶性药物的口服生物利用度。结论药物纳米晶体技术具有实际生产意义和广阔的应用前景。     

难溶性药物新型速崩片的研究进展

摘 要难溶性药物由于其溶解度低,导致吸收差,生物利用度低,临床应用受到很大局限。运用各种增溶技术,增加难溶性药物的溶解度,进而提高其生物利用度十分必要。然而现有的增溶技术常常会造成增溶后含药量低、粘度高等问题,容易造成服用量的增大以及制剂困难。速崩片可通过局部快速释放达到提高患者顺应性以及增溶的目的。本文针对近年来出现的难溶性药物速崩片增溶技术,综述了固体分散体速崩片、包合物速崩片、乳剂冻干片、自微乳分散片、纳米混悬剂冻干片、微丸速崩片、水分散体冻干片等制剂新技术在增加难溶性药物溶解度、改善生物利用度、提高患者用药依从性等方面的应用。     

不同pH的溶出介质对HPMC骨架片释药的影响

目的探讨溶出介质的pH对难溶性药物的HPMC骨架片释药的影响.方法以甲氧苄胺嘧啶、卡马西平、磺胺甲恶唑和茶碱四种难溶型性药物为模型药物,测定四种pH缓冲溶液介质(pH1.0,pH4.0,pH6.0,pH7.5)下的药物的溶解度和释放度.结果难溶性药物的HPMC骨架片释药随着其溶解度的增加而加快.结论难溶性药物HPMC骨架片释药的差异主要与药物在不同pH的溶出介质中的溶解度有关.     

不同pH的溶出介质对HPMC骨架片释药的影响

目的　探讨溶出介质的pH对难溶性药物的HPMC骨架片释药的影响。方法　以甲氧苄胺嘧啶、卡马西平、磺胺甲恶唑和茶碱四种难溶型性药物为模型药物,测定四种pH缓冲溶液介质(pH1.0 ,pH4 .0 ,pH6 .0 ,pH7.5 )下的药物的溶解度和释放度。结果　难溶性药物的HPMC骨架片释药随着其溶解度的增加而加快。结论　难溶性药物HPMC骨架片释药的差异主要与药物在不同pH的溶出介质中的溶解度有关。     

固体分散技术在中药制剂中的应用

固体分散技术具有增加中药难溶性成分的溶解度和溶出速率,延缓、控制药物的释放,增加药物的稳定性,提高药物的生物利用度等优点,广泛应用于中药多种剂型的制备。随着固体分散技术的进一步发展以及新载体材料、新设备的采用,固体分散技术必将在中药的剂型发展与创新中做出更大的贡献。     

将难溶性药物制成单层渗透泵片的中间技术-固体分散体技术

对于难溶性药物而言,不能像水溶性药物一样,按照普通的方法制成释药完全的单层渗透泵片。本论文主要介绍通过固体分散体技术提高难溶性药物的溶解度,再制备成单层渗透泵制剂,进而提高药物的溶解度及其体内生物利用度。     

纳米技术在口服难溶性药物的研究进展

据报道,有〉70%的化学合成药物存在难溶性问题[1],约40%的新化学实体（NCEs）因其难溶性而无法进入临床试验,使其应用受到很大程度的限制[2]。口服给药不仅方便且患者顺应性高,是新药首选的给药途径之一。但对于生物药剂学分类系统中的第Ⅱ类药物（即穿膜性好,但溶解度低而言,因在胃肠道中溶解度低或溶出速率慢,可能导致口服生物利用度低。因此,解决因药物难溶性引起的口服低吸收问题,可提高这类药物的口服生物利用度。解决药物难溶性主要有两条途径：①提高溶解度,增加药物溶出：提高难溶性药物溶解度或溶出速率的常用方法有成盐、改变药物晶型、使用增溶剂或减小粒径等;②应用纳米给药系统,将药物包入载体内部,使药物以载药传递体形式被肠道吸收。     

自乳化释药系统与液固压缩技术联合开发难溶性药物新剂型的进展

提高难溶性药物溶解度,改善难溶性口服药物的生物利用度,一直是药剂学的热点和难点。本文旨在通过对自乳化释药系统和液固压缩技术的介绍,并阐述2种技术联合开发难溶性药物新剂型的优势,说明固体自乳化释药系统可以作为液体自乳化释药系统的提高或者替代,其具有降低生产成本,简化工业生产,提高稳定性与患者耐受性等方面的优势。     

Inorganic-polymer nanohybrid carrier for delivery of a poorly-soluble drug, ursodeoxycholic acid

Delivery of poorly soluble drugs has been problematic due to its low absorption profile and bioavailability. In this work, ursodeoxycholic acid (UDCA), a poorly-soluble drug, was intercalated into inorganic nanovehicle, layered double hydroxides (LDHs), with a molecular level to enhance its solubility in biological fluid. The UDCA-loaded nanovehicle (i.e., UDCA-LDHs) was also coated with an anionic polymer, Eudragit(?) S100, to increase the dissolution rate of UDCA. According to the powder X-ray diffraction (PXRD) patterns of UDCA-LDHs, the gallery height of LDHs was expanded from 3.6? to 28.3?, indicating that the UDCA molecules were successfully intercalated into the interlayer space of LDHs. Fourier transform infrared (FT-IR) spectra also revealed that the UDCA molecules were well stabilized in the LDHs through electrostatic interaction. The in vitro dissolution test in a simulated biological fluid (pH=6.8) showed that the total dissolved fraction of UDCA for the first 2h was about 60.2% for the Eudragit(?) S100 coated UDCA-LDHs, which was a dramatic increase as compared with 19.0% dissolution from intact UDCA. It is, therefore, concluded that LDHs nanovehicle coated with an anionic polymer is a promising delivery system for improving aqueous solubility of poorly soluble drugs.     

芦丁的溶解度及油水分配系数研究

目的研究芦丁在不同介质中的溶解度和油水分配系数,为设计芦丁渗透泵控释制剂提供基础。方法以饱和法测定溶解度,以超声振摇法测定芦丁在正辛醇和水相中的萃取平衡浓度比,计算油水分配系数（P）。结果芦丁在水中的溶解度为194.57mg/L,在2%十二烷基硫酸钠（SDS）溶液中的溶解度为863.17mg/L,在其他不同pH的磷酸盐缓冲溶液中随着pH的升高逐渐升高;油水分配系数随着pH的升高而逐渐降低。结论芦丁为难溶性药物,其溶解度和油水分配系数都与pH有一定的关系;芦丁溶解度和油水分配系数的测定可为进一步研究芦丁渗透泵片提供基础。     

微管蛋白抑制剂SUD-35固体分散体的制备、鉴定及初步体外药效学研究

目的将难溶性微管蛋白抑制剂SUD-35制备成固体分散体,以增加其溶解度及溶出速率。方法以聚乙二醇6000为载体,溶剂-熔融法制备SUD-35固体分散体。采用差示扫描量热分析与X-射线衍射观察药物在载体中的存在状态,并进行溶解度和体外溶出度研究。采用MTT法对SUD-35固体分散体对小鼠白血病L1210细胞药效进行测定。结果 SUD-35固体分散体中SUD-35的溶解度和溶出速率相对原料药和物理混合物均有明显提高,差示扫描量热分析与X-射线衍射结果显示SUD-35以无定型状态存在于固体分散体中,细胞药效结果显示SUD-35固体分散体对小鼠白血病L1210细胞增殖抑制率强于SUD-35纯药。结论聚乙二醇6000为载体制备SUD-35固体分散体,可显著提高SUD-35的溶解度及溶出速率。     

Interpretation and prediction of inhaled drug particle accumulation in the lung and its associated toxicity

The increasing use of poorly-soluble inhaled dry powder pharmaceuticals means that animal toxicology studies of these drugs frequently produce lung changes related to the physical presence of undissolved particulate material within the alveolar spaces. These changes are independent of any chemically- or pharmacologically-mediated toxicity and present a challenge to drug developers and regulators in that risk depends on the retained lung burden of undissolved drug material, rather than the delivered dose, systemic exposure or duration of dosing as traditionally used in risk assessment for inhaled compounds. The methodology presented uses basic pharmacokinetic principles to estimate lung particulate burdens achieved in rat inhalation toxicity studies for four inhaled compounds which have reached clinical evaluation. The estimated lung particulate burdens and associated histopathological findings were compared with published thresholds for similar effects caused by inert particulates such as titanium dioxide. Results of the analysis illustrate that regardless of the duration of the study, estimated lung burdens in excess of ～1?mg drug per g lung were associated with adverse changes consistent with those described in the literature for inert insoluble particles. For all low solubility inhaled pharmaceuticals so far examined, the calculated steady-state retained lung burden of drug in humans is several orders of magnitude lower than that associated with adverse effects in human or animals.     

Encapsulation of Poorly Soluble Drugs in Polymer-Drug Conjugates: Effect of Dual-Drug Nanoformulations on Cancer Therapy

Purpose

Current cancer chemotherapy is gradually shifting to the application of drug combinations that prevent development of drug resistance. Many anticancer drugs have poor solubility and limited oral bioavailability. Using an innovative approach, we developed dual-drug nanoformulations of a polymeric nanogel conjugate with anticancer 5-FU nucleoside analog, floxuridine (FLOX), and the second anticancer drugs, paclitaxel (PCL), or a geldanamycin analog, 17-AAG, for combination therapy.

Methods

PCL or 17-AAG had been encapsulated in the cholesteryl-polyvinyl alcohol-floxuridine nanogel (CPVA-FLOX) by simple solution mixing and sonication. Dual nanodrugs formed particles with diameter 180 nm and either drug content (5–20%) that were stable and could be administered orally. Their cytotoxicity in human and mouse cancer cells was determined by MTT assay, and cellular target inhibition – by Western blot analysis. Tumor growth inhibition was evaluated using an orthotopic mouse mammary 4T1 cancer model.

Results

CPVA-FLOX was more potent than free drug in cancer models including drug-resistant ones; while dual nanodrugs demonstrated a significant synergy (CPVA-FLOX/PCL), or showed no significant synergy (CPVA-FLOX/17-AAG) compared to free drugs (PCL or 17-AAG). Dual nanodrug CPVA-FLOX/17-AAG effect on its cellular target (HSP70) was similar to 17-AAG alone. In animal model, however, both dual nanodrugs effectively inhibited tumor growth compared to CPVA-FLOX after oral administration.

Conclusion

Oral dual-drug nanoformulations of poorly-soluble drugs proved to be a highly efficient combination anticancer therapy in preclinical studies.     

Solubility of drugs in the presence of gelatin: effect of drug lipophilicity and degree of ionization

The solubility of seven drugs (nitrofurantoin, chlorothiazide, phenobarbital, prednisolone, griseofulvin, diazepam and piroxicam) in the absence and presence of gelatin was measured, at three different pH values (3.7, 5.0 and 7.0) at 37 degrees C. Drugs studied had different physicochemical properties (log P, pK(a), aqueous solubility) and their solubility in presence of 0.1 and 0.5% (w/v) hydrolyzed (and in some cases common) gelatin was estimated. Results show that the solubility of all drugs is significantly enhanced, especially in the presence of 0.5% gelatin. This gelatin-induced enhancement in drug solubility is higher in the pH in which acidic drugs are less ionized, especially for the less lipophilic acidic drugs (nitrofurantoin, chlorothiazide). In all cases, drug solubility in presence of gelatin is correlated with their aqueous solubility. Therefore, the established relationships between aqueous and gelatin solubility can be employed to derive an estimate of the drug solubility in presence of gelatin once its aqueous solubility is known. With the exception of piroxicam which is highly ionized and phenobarbital which is relatively soluble, there seems to be a tendency for larger gelatin-induced increases in solubility as drug lipophilicity increases or aqueous solubility decreases.     

Interpretation and prediction of inhaled drug particle accumulation in the lung and its associated toxicity

1. The increasing use of poorly-soluble inhaled dry powder pharmaceuticals means that animal toxicology studies of these drugs frequently produce lung changes related to the physical presence of undissolved particulate material within the alveolar spaces. These changes are independent of any chemically- or pharmacologically-mediated toxicity and present a challenge to drug developers and regulators in that risk depends on the retained lung burden of undissolved drug material, rather than the delivered dose, systemic exposure or duration of dosing as traditionally used in risk assessment for inhaled compounds.

2. The methodology presented uses basic pharmacokinetic principles to estimate lung particulate burdens achieved in rat inhalation toxicity studies for four inhaled compounds which have reached clinical evaluation.

3. The estimated lung particulate burdens and associated histopathological findings were compared with published thresholds for similar effects caused by inert particulates such as titanium dioxide. Results of the analysis illustrate that regardless of the duration of the study, estimated lung burdens in excess of ～1?mg drug per g lung were associated with adverse changes consistent with those described in the literature for inert insoluble particles.

4. For all low solubility inhaled pharmaceuticals so far examined, the calculated steady-state retained lung burden of drug in humans is several orders of magnitude lower than that associated with adverse effects in human or animals.

     

Spontaneous Crystalline-to-Amorphous Phase Transformation of Organic or Medicinal Compounds in the Presence of Porous Media, Part 3: Effect of Moisture

Purpose

Amorphization of crystalline compounds using mesoporous media is a promising technique to improve the solubility and drug release of poorly-soluble compounds. The objective of this paper is to understand the effect of moisture on the capacity and performance of vapor-phase mediated amorphization.

Methods

Mesoporous silicon dioxide (SiO₂) and crystalline naphthalene were used as the model system. The effect of moisture on the amorphization capacity of naphthalene was determined using adsorption chambers with various levels of relative humidity. Enthalpy and capacity of water vapor adsorption on SiO₂ were measured using isothermal microcalorimetry and thermogravimetry.

Results

Moisture not only suppressed the amorphization capacity of naphthalene, but reversed an already-amorphized formulation as well. On the other hand, through the same competitive interaction, improved drug release and enhanced solubility were obtained. The initial supersaturation was followed by an entropy-driven crystallization. In addition, moisture-induced siloxane bond fracture was found at normal processing conditions, which led to the changes in silica surface chemistry. However, the implication in amorphization has not reached a definitive conclusion.

Conclusions

Humidity during processing and storage must be carefully controlled for this type of amorphous formulation. Further investigation is needed to better understand the moisture-induced changes of silica.     

固体分散技术在制剂领域的研究进展

固体分散体作为一种制剂的中间体,在改善难溶性药物的溶出与提高其生物利用度方面发挥了重要的作用。固体分散技术是提高难溶性药物的溶出与溶解度最具应用潜力的新技术之一,其发展将推动制剂领域日臻完善。重点从固体分散体的载体材料、各种新型制备技术及其比较、固体分散剂型的应用与稳定性问题4个方面展开介绍,阐述了影响固体分散体稳定性的因素,并提出了防止其老化的有效措施,最后对固体分散技术的发展提出了中肯的建议。     

Effect of temperature and fat content on the solubility of hydrochlorothiazide and chlorothiazide in milk

The solubility of hydrochlorothiazide and chlorothiazide in milk has been studied. Experiments were carried out at 5, 15, 25, and 37 degrees C on a buffer solution of pH 6.5, a 2.6% solution of casein, bovine skim milk samples, and bovine milk samples with fat contents of 0.75, 1.70, and 3.50%. The "total" solubility of both drugs in the media studied was higher than the buffer solubility. The highest "total" solubility for both drugs was observed in skim milk. Based on binding data of thiazides to milk, the "total" solubility was split into "free" and "bound" solubility. The increases of solubility noted cannot be explained on the basis of drug-milk binding data. The enhancement of solubility was attributed to the increase of intrinsic solubility of drugs in milk. Results of the thermodynamic analysis of solubility data showed that a different solubilization process of hydrochlorothiazide may be responsible for the high solubility values found in skim milk for this drug. In contrast, the thermodynamic parameters of chlorothiazide in all types of milk are similar, indicating a common solubilization mechanism. The biopharmaceutical significance of the findings is discussed in light of the freeze-dried drug-milk formulations and coadministration of drugs with milk in general.