无定形固体分散体的溶出与吸收研究进展

无定形固体分散体是提高难溶性药物生物利用度最有效的策略之一,但其易受到处方因素、制备工艺、存储条件和溶出条件等因素的影响从而在储存期或溶出过程中结晶,丧失溶出优势。此外,体内外环境的差异、表观浓度与透膜通量之间的差异、体内吸收过程的复杂性等影响因素使得无定形固体分散体的体外溶出不能完全准确预测体内吸收,给固体分散体产品开发带来了极大挑战。本文总结了关于无定形药物固体分散体溶出与吸收的研究进展,期望为难溶性药物无定形固体分散体制剂的开发提供参考。     

药物研究与开发中的高通量结晶技术

1　前言药物固体剂型 (片剂、颗粒剂,胶囊等 )使用方便,贮存稳定,是市场上主要剂型。一种活性药物组分 (activepharmaceuticalingredients, APIs)可能存在多种固体形式,包括多晶型、溶剂化物、水合物、共晶、无定形固体和盐 (可能形成水合物、溶剂化物、多晶型、共晶和无定形固     

固体自乳化药物传递系统的研究概况

综述固体自乳化药物传递系统的定义与特点、处方组分、制备工艺、药物体外释放和体内吸收的影响因素及质量评价指标。固体自乳化药物传递系统为一种新型制剂，可以显著提高难溶性药物的口服生物利用度，还可以通过添加各种固体辅料或采用包衣技术制备缓控释产品。     

浅谈固体自乳化药物传递系统固化技术

查阅最近的国内外文献，综述固体自乳化药物传递系统定义及特定，固体自乳化药物传递系统的各种固化技术。作为一种新型制剂，固体自乳化药物传递系统有着良好的开发前景。     

固体自微乳药物递送系统的研究进展

作为一种新型的药物递送系统,固体自微乳药物递送系统可以显著提高水难溶性药物的口服生物利用度,且具有液态自微乳和固体制剂二者的优势。通过设计不同的辅料处方和包衣技术,可以控制药物释放使其具有靶向性,来达到不同的给药目的。固体自微乳药物递送系统的应用前景广阔,具有研究意义。本文对固体自微乳载体、固化技术、固体自微乳新制剂的应用进行了总结归纳,为提高水难溶性药物释放的固体自微乳化技术的研究提供了参考。     

固体脂质纳米粒的研究新进展

固体脂质纳米粒是近年来很受重视的一种新型药物传递载体,具有靶向、控释、提高药物稳定性、毒性小、可大批量生产等优点,是一种极有发展前景的新型给药系统.现综述了近年来国内外固体脂质纳米粒的制备技术、作为药物载体的应用、存在问题以及发展前景.     

超临界二氧化碳制备布地奈德-聚氧乙烯固体分散体及体外评价

本文以水难溶性药物布地奈德为模型药物，研究超临界流体技术制备布地奈德-聚氧乙烯固体分散体的方法及其影响因素。采用超临界二氧化碳静态法制备布地奈德-聚氧乙烯固体分散体，用粉末X射线衍射法、差示扫描量热法、溶解度法和体外溶出实验进行固体分散体的物相鉴别。在40 ℃，20 MPa条件下，布地奈德-聚氧乙烯N750(1∶10)是形成固体分散体的最佳条件，布地奈德与聚氧乙烯载体形成氢键，以无定形状态存在于载体中，溶解度和体外溶出速率显著提高。超临界流体技术是制备固体分散体的一种可行方法。     

植入剂在癌症治疗中的应用进展

植入剂为一种无菌固体制剂，由药物和赋形剂藉熔融、热压，辐射等方法制成。植入释放系统具有长效和恒释作用。由于聚合物骨架的阻滞作用，系统中药物常呈恒速释药，故可维持稳定的血药浓度，减少药物的毒副作用。它适用于半衰期短．代谢快，不适于通过其它途径给药的药物。近年来，在抗肿瘤治疗中植入剂获得了广泛的关注和较深入的研究。     

溶剂蒸发法和热熔挤出法制备苯扎贝特固体分散体

以水难溶性药物苯扎贝特为模型药物,以聚维酮(PVP K30)或新型辅料Soluplus(R)为载体,分别采用溶剂法和热熔挤出法制备了苯扎贝特固体分散体.采用差示扫描量热法、傅里叶变换红外光谱法和X射线粉末衍射法对固体分散体进行了表征并考察了溶出度.结果显示,药物以无定形或分子状态存在于固体分散体中,两种工艺以及两种载体...     

共无定形技术改善葛根素水溶性及增溶机制研究

葛根素(PUE)为异黄酮类成分,具有广泛的药理活性,但其低水溶性限制了其口服固体制剂的开发。本研究以烟酰胺(NIC)为配体通过减压旋蒸法制备了PUE-NIC共无定形体系,同时联合粉末X-射线衍射(PXRD)、差示扫描量热法(DSC)和红外光谱(FT-IR)等多种手段对其进行表征,并对其溶出行为及增溶机制进行了系统的研究。结果表明,PUE-NIC共无定形仅存在单一的玻璃化转变温度(35.1℃),为单一均相二元体系。与PUE晶体相比,在溶出过程中,共无定形不仅发生"液-液相分离"(LLPS)现象,PUE与NIC还可形成摩尔比为1∶1与1∶2的Ap型络合物,这有利于显著增加PUE的溶解度,并能维持长时间的药物过饱和态优势,有利于药物吸收。     

On the role of salt formation and structural similarity of co-formers in co-amorphous drug delivery systems

Co-amorphous drug delivery systems based on amino acids as co-formers have shown promising potential to improve the solubility and bioavailability of poorly water-soluble drugs. Potential salt formation is assumed to be a key molecular interaction responsible for amorphous stability and increased solubility. However, little is known about the importance of the overall structure of the co-former. In this study, the structurally related amino acids arginine (basic) and citrulline (neutral) were chosen together with four model drugs (acidic furosemide and nitrofurantoin; basic cimetidine and mebendazole) to investigate the importance of salt formation versus structural similarity of co-formers. Drug-amino acid mixtures were ball milled at a molar ratio of 1:1. Generally, arginine showed a higher tendency to successfully form co-amorphous systems with the model drugs compared with citrulline, irrespective of assumed salt formation. Salt forming mixtures showed much higher T_gs, faster dissolution rates, higher solubility and physical stability compared to the corresponding non-salt forming mixtures. In conclusion, structural similarity of the co-formers does not lead to similar co-former performance for a given drug. Salt formation is not a prerequisite for the formation of a co-amorphous system, but if a co-amorphous salt system is formed, improved dissolution rate and physical stability are observed.     

A theoretical and spectroscopic study of co-amorphous naproxen and indomethacin

Co-amorphous drug systems were recently introduced as potential drug delivery systems for poorly water soluble drugs in order to overcome problems associated with amorphous materials. The improved physical stability and dissolution of these systems was attributed to molecular interactions between the co-amorphous partners, such as hydrogen bonds. However, molecular level characterization with vibrational spectroscopy of even the amorphous drugs alone presents a significant challenge. This becomes even more complicated when more than one compound is present in the material under investigation. In this study, the co-amorphous drug mixture containing naproxen (NAP) and indomethacin (IND) was investigated using infrared spectroscopy (IR) and quantum mechanical calculations. The structures of both drugs were optimized as monomer, homodimer and heterodimer using density functional theory and used for the calculation of IR spectra. Conformational analysis confirmed that the optimized structures were suitable for the theoretical prediction of the spectra. Vibrational modes from the calculation could be matched with experimentally observed spectra for crystalline and amorphous NAP and IND, and it could be shown that both drugs exist as homodimers in their respective individual amorphous form. With the results from the experimental single amorphous drugs and theoretical homodimers, a detailed analysis of the experimental co-amorphous and theoretical heterodimer spectra was performed and evaluated. It is suggested that NAP and IND exist as heterodimers in the co-amorphous mixture when quench cooled together from the melt in a 1:1 molar ratio.     

Co-amorphous Formation Induced by Combination of Tranilast and Diphenhydramine Hydrochloride

In this study, we investigated the formation of a co-amorphous system of tranilast (TRL) and diphenhydramine hydrochloride (DPH), which are drugs used for treating allergies and inflammation. The crystallization from undercooled melts of the drugs and drug mixtures was evaluated by thermal analysis. Both drugs in the amorphous state underwent crystallization on heating, although the mixture remained in the amorphous state, indicating the formation of a co-amorphous system. The physicochemical properties of co-amorphous TRL-DPH prepared by the melting-cooling process were studied. The glass transition temperature of co-amorphous TRL-DPH deviated from the theoretical value. The enthalpy relaxation rate of the amorphous drugs, which reflected the molecular mobility, was reduced by the formation of a co-amorphous system. The intermolecular interactions between TRL and DPH in the co-amorphous system were measured by the change in the IR spectra. These results were consistent with the high physical stability. The co-amorphous sample remained in the amorphous state for over 30 days at 40°C, whereas the amorphous drugs showed rapid crystallization. Our findings demonstrate that TRL and DPH form a co-amorphous system, which dramatically decreases their crystallization without an excipient.     

Nanocarriers

The use of nanoparticulate pharmaceutical carriers to enhance the in vivo efficiency of many drugs well established itself over the past decade both in pharmaceutical research and clinical setting. The current level of engineering pharmaceutical nanocarriers in some cases allows for drug delivery systems (DDS) to demonstrate a combination of some desired properties. However, looking into the future of the field of drug delivery, we have to think about the development of the next generation of pharmaceutical nanocarriers combining different properties and allowing for multiple functions.     

Drug-eluting implants for osteomyelitis

Osteomyelitis, an inflammatory process accompanied by bone destruction, is caused by infective microorganisms. The high success rates of antimicrobial therapy by conventional routes of administration in controlling most infectious diseases have not yet been achieved with osteomyelitis for several reasons. Local and sustained availability of drugs have proven to be more effective in achieving prophylactic and therapeutic outcomes. This review introduces osteomyelitis--its prevalence and pathogenesis, the present options for drug delivery and their limitations, and the wide range of carrier materials and effective drug choices, with major focus on the pharmaceutical concepts involved in drug delivery system design and development. With increasing numbers of orthopedic surgeries and the advent of combination devices that provide support and deliver drugs, local drug delivery for osteomyelitis is a topic of importance for both social and commercial interests.     

Amino acids as co-amorphous stabilizers for poorly water-soluble drugs – Part 2: Molecular interactions

The formation of co-amorphous drug–drug mixtures has proved to be a powerful approach to stabilize the amorphous form and at the same time increase the dissolution of poorly water-soluble drugs. Molecular interactions in these co-amorphous formulations can play a crucial role in stabilization and dissolution enhancement. In this regard, Fourier-transform infrared spectroscopy (FTIR) is a valuable tool to analyze the molecular near range order of the compounds in the co-amorphous mixtures. In this study, several co-amorphous drugs – low molecular weight excipient blends – have been analyzed with FTIR spectroscopy. Molecular interactions of the drugs carbamazepine and indomethacin with the amino acids arginine, phenylalanine, and tryptophan were investigated. The amino acids were chosen from the biological target site of both drugs and prepared as co-amorphous formulations together with the drugs by vibrational ball milling. A detailed analysis of the FTIR spectra of these formulations revealed specific peak shifts in the vibrational modes of functional groups of drug and amino acid, as long as one amino acid from the biological target site was present in the blends. These peak shifts indicate that the drugs formed specific molecular interactions (hydrogen bonding and π–π interactions) with the amino acids. In the drug–amino acid mixtures that contained amino acids which were not present at the biological target site, no such interactions were identified. This study shows the potential of amino acids as small molecular weight excipients in co-amorphous formulations to stabilize the amorphous form of a poorly water-soluble drug through strong and specific molecular interactions with the drug.     

微针与新型经皮给药载体结合的研究进展

经皮给药系统具有给药方便、血药浓度稳定、无首过效应等优点,但皮肤的屏障作用使得药物难以透过皮肤。近年来,出现了很多新型经皮给药的药物载体,如脂质体、醇质体、囊泡等,这些能通过化学方法促进药物的经皮渗透。而微针能穿透皮肤角质层形成微孔通道,通过物理方法促进药物的渗透,将微针与新型经皮给药载体结合能显著提高药物的经皮吸收的速率。本文对微针与新型经皮给药载体结合的最新研究进行了综述,并展望了微针辅助新型药物载体经皮给药的发展前景。     

药物制剂产业化发展的前沿科学技术问题探讨

随着国际医药产业格局的变化,新药投入风险越来越大。与开发一个新分子实体相比,新剂型的创新路径具有周期短、投资少、风险小、回报高等特点。企业逐步从原料药研发向下游制剂和具有自主品牌的高端制剂创新发展。国家政策鼓励药企创新发展制剂技术和药物释放系统(DDS)等,开发新型制剂、改良型制剂(如创新的给药释药系统),以及鼓励中药“经典名方”向高端中药制剂研发,提高已上市药物的安全性、有效性和临床依从性。高端制剂是新药研发的重要方向,也是应对国际、国内药企竞争的发展战略和策略。本文针对中国药物制剂高质量发展所关注的问题,对比分析国内外药物制剂情况,围绕药物制剂发展的挑战、高端制剂、释药技术与药动学、科学技术问题等方面予以评述。     

Sulfonic Acid Derivatives in the Production of Stable Co-Amorphous Systems for Solubility Enhancement

Co-amorphization is a promising approach to stabilize drugs in the amorphous form. Olanzapine, a poorly water-soluble drug was used in this study. Sulfonic acids (saccharin, cyclamic acid and acesulfame), free and in salt forms, were used as co-formers and compared with carboxylic acids commonly used in the preparation of co-amorphous systems. Several manufacturing techniques were tested, and the co-amorphous systems characterized by differential scanning calorimetry, X-ray powder diffraction, thermogravimetry and Fourier-transform infrared spectroscopy. Free sulfonic acids produced co-amorphous systems with the drug, unlike their salts. Spectroscopy data suggests the formation of salts between olanzapine and the sulfonic acids, used as co-formers. The co-amorphous system produced with saccharin by solvent evaporation, showed the most notable solubility enhancement (145 times). The stability of amorphous and co-amorphous olanzapine systems was assessed upon exposure to stress conditions during storage. Amorphized olanzapine readily reconverted back to the crystalline form while sulfonic acids:olanzapine co-amorphous were stable for up to 24 weeks in low/medium humidity conditions (11-75% RH). Results highlight the potential advantages offered by sulfonic acids as co-formers to produce stable and more soluble co-amorphous olanzapine.     

Imaging of Cells and Nanoparticles: Implications for Drug Delivery to the Brain

A major challenge in the development of central nervous system drugs is to obtain therapeutic effective drug concentrations inside the brain. Many potentially effective drugs have never reached clinical application because of poor brain penetration. Currently, devices are being developed that may improve drug delivery into the brain. One approach involves the encapsulation of drugs into nanocarriers that are targeted to the brain, where the drug is released. Alternatively, living cells have been engineered to produce the pharmaceutical of interest at the target site. It is important to follow the fate of these drug delivery devices inside the body to verify their efficiency in reaching the brain. To this end, both ex-vivo approaches and in-vivo imaging techniques are used, including ex-vivo biodistribution, autoradiography, MRI, optical imaging, PET and SPECT. All these methods have their specific advantages and limitations. Consequently, selection of the tracking method should be based on the specific aims of the experiment. Here, we will discuss the methods that are currently applied for tracking brain drug delivery devices, including the most commonly used labels and labeling procedures for living cells and nanocarriers. Subsequently, we will discuss specific applications in tracking drug delivery devices.