Effect of bases with different solubility on the release behavior of risperidone loaded PLGA microspheres

Poly (D, L-lactide-co-glycolide) (PLGA) microspheres are attractive delivery vehicles due to their excellent sustained release capabilities. One major problem with PLGA microspheres is that the hydrophobic properties of PLGA generally cause a lag period in the process of drug release, leading to fluctuation of drug concentration in the blood and various resulting adverse reactions. Herein, Mg(OH)?, an inorganic base, and arginine, an organic base, were separately co-encapsulated into risperidone-loaded PLGA microspheres at varying concentration using the solvent evaporation method to improve release profiles from the microspheres. High encapsulation efficiencies were obtained in all formulations. The surface of base-free microspheres was smooth, whereas a few pores formed in base co-encapsulated microspheres. After 7-days degradation, many inter-connecting pores were formed in the interior of the microspheres containing 10 mg Mg(OH)?. The final pH in the microspheres with Mg(OH)? was higher than in those with arginine after 28-days degradation. The initial release of risperidone from microspheres containing Mg(OH)? was higher than from those containing arginine, and the latter release exhibited a more uniform pattern. Microspheres with 5mg and 10mg arginine exhibited zero-order release kinetics. However, both bases eliminated the lag phase of release. These results indicate that the incorporation of bases has potential in addressing the problem of the lag period in drug release from PLGA microspheres, and improving release behavior toward an ideal model.     

Polycarbonate microspheres containing mitomycin C and magnetic powders as potential hepatic carcinoma therapeutics

The polycarbonate copolymer poly(trimethylene carbonate-co-5,5-dimethyl trimethylene carbonate) (P(TMC-co-DTC)) was synthesized by the polymerization of trimethylene carbonate (TMC) and 5,5-dimethyl trimethylene carbonate (DTC) using tin (II) 2-ethylhexanoate [Sn(Oct)(2)] as a catalyst. In vitro degradation tests indicated this polycarbonate copolymer degraded slowly in phosphate buffer saline solution (PBS, 0.1 mol/L, at 37°C). Magnetic polymer microspheres (MMC-PC-M) generated from the P(TMC-co-DTC) copolymer and containing Fe(3)O(4) magnetic ultrafine powders and an anticancer drug, mitomycin C (MMC) were prepared by a solvent evaporation technique. These anticancer magnetic polycarbonate microspheres showed strong magnetic responsiveness and high MMC loading capacity. In vitro drug release studies indicated that these microspheres sustained steady release rates of MMC in PBS. In vitro cytotoxicity assays demonstrated the microspheres were strongly inhibitory to human hepatic carcinoma (Bel-7204) cells. In vivo site-specific therapy in nude mice with human hepatic carcinoma indicated that the microspheres possessed markedly high antitumor activity against human hepatic carcinoma (Bel-7204).     

The influence of chitosan on in vitro properties of Eudragit RS microspheres

Eudragit RS microspheres containing chitosan hydrochloride were prepared by the solvent evaporation method using acetone/liquid paraffin solvent system and their properties were compared with Eudragit RS microspheres without chitosan, prepared in our previous study. Different stirring rates were applied (400-1200 rpm) and drug content, Higuchi dissolution rate constant, surface and structure characteristics of the microspheres were determined for each size fraction. An increase in average particle size with a reduction of stirring rate appeared in limited interval in both series. The average particle size of microspheres without chitosan, prepared at the same stirring rate, was smaller. Pipemidic acid content increased with increasing fraction particle size, but not with increasing stirring rate as it was observed for microspheres without chitosan. We presume that high pipemidic acid content in larger microspheres is a consequence of cumulation of undissolved pipemidic acid particles in larger droplets during microspheres preparation procedure. Pipemidic acid release was faster from microspheres with chitosan and no correlation between Higuchi dissolution rate constant and stirring rate or fraction particle size was found, though it existed in the system without chitosan. Structure and surface characteristics of microspheres observed by scanning electron microscope (SEM) were not changed significantly by incorporation of chitosan. But in contrast with microspheres without chitosan, the surface of chitosan microspheres was more porous after three hours of dissolution. It is supposed that the influence of particle size fraction and stirring rate on release characteristics is expressed to a great extent through porosity and indirectly through total effective surface area, but the incorporation of highly soluble component i.e. chitosan salt hides these effects on drug release. In conclusion, changes in biopharmaceutical properties due to varying stirring rate and fraction particle size exhibited the same direction as those reported for the microspheres without chitosan, although they are less expressed because of increased experimental variability, likely caused by chitosan.     

主链含酪氨酸的聚磷酸酯抗肿瘤药物的研究

通过含酪氨酸的聚磷酸酯与药物分子进行大分子反应，制备了含５－氟尿嘧啶或氨甲蝶呤的聚磷酸酯。所得聚磷酸酯均具有两亲性，部分聚磷酸酯在水中能形成胶束。研究了这些聚合物的体外降解和释药性能，体外抗肿瘤实验表明，有些聚磷酸酯药物具有较强的抗肿瘤活性。     

ERYTHROMYCIN POLYLACTIC ACID MICROSPHERES FOR LUNG TARGETING

AIM：To prepare polylactiv acid microspheres of Erythromycin for Lung targeting.METHEDS:The orthogonal test design was used to optimize the technology of preparation.The character of the microspheres,drug release in vitro,stabiligy and tissue distribution were examined. RESULTS:The Erythromycin polylatic acid microspheres was regular in its morphology.Drug was enveloped in microspheres but not physically mixed with PDLLA.The average particle size was 11.65μm with over 94% of the microspheres being in the range of 5-20μm;The drug loading and the incorporation efficiency were 18% and 60% respectively.The microspheres were stable for three month at 4℃ and room temperature.The in vitro release properties could be expressed by the Higuchi′s equation:y=28.067+3.8515t^1/2(r=0.9834).Comparing with injection,the drug in microspheres was more concentrated in lung tissue.CONLUSION:Erythromycin polylactic acid microspheres showed significant sustained release and lung targeting.     

Synthesis and photochemical properties of photoactivated antitumor prodrugs releasing 5-fluorouracil

A new family of antitumor prodrugs (1-3) of 5-fluorouracil (5-FU) possessing photolabile 2-nitrobenzyl chromophores have been designed and synthesized to investigate the efficiency and mechanism of photoactivated 5-FU release upon UV-irradiation at lambda(ex)= 365 nm. The photoactivated prodrug 3 derived from conjugation of 2 with a tumor-homing cyclic peptide Cys-Asn-Gly-Arg-Cys (CNGRC) was so designed as to manifest a tumor-targeting function.     

Thermal characteristics of poly (DL-lactic acid) microspheres containing neurotensin analogue.

The thermal characteristics of poly (DL-lactic acid) (DL-PLA) microspheres containing a hexapeptide (NA: H(CH3)-Arg-Lys-Pro-Trp-tert-Leu-Leu-OEt) with neurotensin activity were investigated. PLA microspheres with a drug content of 1.5-11.0% were prepared by a novel o/w (oil-in-water) solvent evaporation method. Both DL-PLA and NA were amorphous in form, and an increase in heat capacity at glass transition temperature (Tg) of the polymer was observed in DL-PLA microspheres containing NA. The Tg of DL-PLA (PLA2000 bulk) was 307.8 K, while Tg of microspheres containing NA (content 6.0%) shifted to 321.2 K. The Tg of PLA2000 microspheres was found to increase with an increase in the content of NA, and its increasing tendency reached a plateau at an NA content of greater than 6%. The apparent activation energy of glass transition of PLA2000 bulk and the microspheres was calculated to be 86.3 and 99.3 kcal/mol, respectively. As a result of the release test after storage at 4 degrees C and 40 degrees C for 1 month, nearly the same release profiles of NA from PLA2000 microspheres were found. The release rate of NA after the initial release became slow after storage at 45 degrees C for 1 month. This may be attributed mainly to a decrease in surface area caused by the formation of agglomerates of PLA2000 microspheres under conditions near Tg.     

Mechanochemical solid-state polymerization (XI): effect of water-insoluble pharmaceutical aids on drug release from mechanically synthesized polymeric prodrugs

We discuss here the effect of water-insoluble pharmaceutical aids on the nature of drug release from composite polymeric prodrugs synthesized by mechanochemical solid-state polymerization. Magnesium stearate (Mgst) and hydrogen castor oil (HCO) were used as water-insoluble pharmaceutical aids. Composite polymeric prodrugs were synthesized by the mechanochemical solid-state polymerization of a vinyl monomer of 5-fluorouracil (I) in the presence of Mgst or HCO. The molecular weight of the resulting polymeric prodrugs increased with increasing the content of Mgst or HCO. Prodrug hydrolysis was carried out in a heterogeneous system in phosphate buffer at pH 6.8 and 37 degrees C. The rate of drug release from the composite polymeric prodrug containing Mgst (Poly-Mgst) was faster than that from polymeric prodrug containing no pharmaceutical aids (Poly-Non), while hydrolysis of the composite polymeric prodrug containing HCO (Poly-HCO) was slower than Poly-Non. Scanning electron microscope (SEM) photos showed the surface of Poly-HCO was smoother than that of Poly-Non and Poly-Mgst. It was suggested that the slower drug release from Poly-HCO may be responsible for the smaller specific surface area than that of Poly-Non. It was also shown that the rate of drug release from the composite polymeric prodrugs decreases with increasing the content of Mgst or HCO. Hence, novel composite polymeric prodrugs with a variety of drug release rates can be prepared by mechanochemical solid-state polymerization in a totally dry process.     

含己烷雌酚的聚磷酸酯的合成及其抗肿瘤活性研究

合成了３种主链含己烷雌酚的生物可降解的聚磷酸酯，结构经ＩＲ，＾１ＨＮＭＲ和元素分析鉴定，通过水接触角的测定研究了聚合物的亲水－疏水性能，以ｐＨ值变化表征了聚合物的体外水解速率。初步的体外实验表明，此类聚磷酸酯具有较好的体外抗艾氏腹水癌活性。     

Erufosine (ErPC3) Cationic Prodrugs as Dual Gene Delivery Reagents for Combined Antitumor Therapy

Sixteen cationic prodrugs of the antitumor alkylphospholipid (APL) erufosine were rationally synthesized to provide original gene delivery reagents with improved cytotoxicity profile. The DNA complexation properties of these cationic lipids were determined and associated transfection rates were measured. Furthermore, the self-assembly properties of the pro-erufosine compounds were investigated and their critical aggregation concentration was determined. Their hydrolytic stability under pH conditions mimicking the extracellular environment and the late endosome milieu was measured. Hemolytic activity and cytotoxicity of the compounds were investigated. The results obtained in various cell lines demonstrate that the prodrugs of erufosine display antineoplastic activity similar to that of the parent antitumor drug but are not associated with hemolytic toxicity, which is a dose-limiting side effect of APLs and a major obstacle to their use in anticancer therapeutic regimen. Furthermore, by using lipoplexes prepared from a prodrug of erufosine and a plasmid DNA encoding a pro-apoptotic protein (TRAIL), evidence was provided for selective cytotoxicity towards tumor cells while nontumor cells were resistant. This study demonstrates that the combination approach involving well tolerated erufosine cationic prodrugs and cancer gene therapy holds significant promise in tumor therapy.     

可降解聚合物包覆次血红素六肽微球的制备及生物活性

采用水包油包水(W₁/O/W₂)复乳溶剂挥发法制备了包覆次血红素六肽(DhHP-6)的2种聚酯微球. 通过扫描电子显微镜、 体外缓释行为、 高效液相(HPLC)检测、 酶活力测定和初步的动物实验等表征, 综合评价了载药微球的体外释放及体内生物活性. 实验结果表明, 载药微球球体圆整, 粒径分布均匀, 载药量高, 能够实现体外缓释, 并对细胞过氧化损伤和小鼠脑缺血损伤均有一定的保护作用.     

Effect of preparation temperature in solvent evaporation process on Eudragit RS microsphere properties

Eudragit RS 100 microspheres containing ketoprofen as a model drug were prepared by the solvent evaporation method using an acetone/liquid paraffin solvent system. The influence of various preparation temperatures: 10, 25, 35, and 40 degrees C, on particle size and morphology, drug content and release kinetics, and drug crystal state was evaluated. With increasing temperature, microsphere average size was found to increase and particle size distribution to widen significantly. At 10 degrees C particles of irregular shape are formed, whereas higher temperatures gradually improve the sphericity of microspheres. As can be seen from SEM photographs, particle surface roughness decreases as preparation temperature increases. It was found that temperature had no effect either on ketoprofen microencapsulation efficiency or on its crystal state, but it does influence emulsion-stabilizer incorporation. Ketoprofen forms solid solution in Eudragit matrix and maintains amorphous state for significant period of time. Drug release rates from microspheres correlated with microspheres' surface roughness and to a lesser extent with particle size.     

A unique class of duocarmycin and CC-1065 analogues subject to reductive activation

N-Acyl O-amino phenol derivatives of CBI-TMI and CBI-indole2 are reported as prototypical members of a new class of reductively activated prodrugs of the duocarmycin and CC-1065 class of antitumor agents. The expectation being that hypoxic tumor environments, with their higher reducing capacity, carry an intrinsic higher concentration of "reducing" nucleophiles (e.g., thiols) capable of activating such derivatives (tunable N-O bond cleavage) and increasing their sensitivity to the prodrug treatment. Preliminary studies indicate the prodrugs effectively release the free drug in functional cellular assays for cytotoxic activity approaching or matching the activity of the free drug, yet remain essentially stable and unreactive to in vitro DNA alkylation conditions (<0.1-0.01% free drug release) and pH 7.0 phosphate buffer, and exhibit a robust half-life in human plasma (t1/2 = 3 h). Characterization of a representative O-(acylamino) prodrug in vivo indicates that they approach the potency and exceed the efficacy of the free drug itself (CBI-indole2), indicating that not only is the free drug effectively released from the inactive prodrug but also that they offer additional advantages related to a controlled or targeted release in vivo.     

循环应力下PLGA多孔支架对地塞米松的控制释放

摘要 采用喷雾干燥法制备包载地塞米松(Dex)的聚L-丙交酯-b-聚乙二醇(PLLA-PEG)微球, 以热致相分离/粒子洗去法制备聚乙交酯-co-丙交酯(PLGA)多孔支架, 通过复合溶结法将载药微球固定于PLGA多孔支架中, 制得载药微球-支架(记为MS-S). 另外, 在支架制备过程中将Dex直接加入PLGA溶液中, 制得对比的直接载药支架(记为D-S). 以扫描电镜观察微球和支架的微观形貌, 在循环压应力与水浴摇床两种环境下分别对上述两种载药支架进行控制释放Dex的实验, 用紫外-可见光分光光度计测定Dex的累积释放量. 结果表明, Dex及微球的载入对PLGA支架的整体形貌影响较小; 循环压应力显著提高了Dex从载药支架中的释放速率, 与D-S相比, MS-S延缓了药物的释放. 研究模拟体内循环压应力下支架控制释放药物规律对于实现理想的临床效果具有重要意义.     

Preparation and evaluation of nano-hydroxyapatite/poly(styrene-divinylbenzene) porous microsphere for aspirin carrier

A novel vehicle for the delivery of aspirin (ASA) was prepared from porous nano-hydroxyapatite/poly(styrene-divinylbenzene) [nano-HAP/P(St-DVB)] composite microspheres by grafting nano-HAP [Ca10(PO4)6(OH)2] onto porous P(St-DVB) microspheres. Four types of porous composite microspheres were prepared, each with different nano-HAP contents. The ASA-loaded composite microspheres prepared with 10% and 15% nano-HAP (mass ratio) exhibited excellent buoyancy with relatively short instantaneous floating time (within 10 min) and a long sustained floating time (12 h) in simulated gastric juice. They also offered good sustained release of ASA (up to 8 h). Furthermore, these composite microspheres displayed good buffering capacity that prevented the buildup of acidity caused by hydrolysis of ASA, keeping the pH of gastric juice within the normal range (pH 0.9 to 1.5). The results showed that porous nano-HAP/P(St-DVB) composite microspheres prepared with 10% and 15% nano-HAP could be used as a novel drug carrier for ASA, providing a sustained release dose without leading to stomach irritation, a side effect that is often associated with ASA medication.     

Encapsulation of complementary model drugs in spray-dried nanostructured materials

Two model drugs of different physico-chemical and pharmaceutical properties (ibuprofen, acetaminophen) have been incorporated together or separately in silica-based microspheres using sol–gel and spray-drying processes. A variable amount of a neutral surfactant Brij-56© has also been added. The properties of the microspheres vary significantly depending on their composition. Three kinds of texture are identified: (1) silica containing spheroid nano-domains (formed by ibuprofen; diameters between 20 and 100 nm), (2) silica containing worm-like mesophases (formed by Brij-56© and both model drugs, typical correlation distances ~6 nm), (3) silica intimately mixed with the drug (acetaminophen) without visible phase-separation. The kinetics of drug release in simulated intestinal fluid strongly depend on these textures. The association of ibuprofen and acetaminophen in a single type of microsphere and without surfactant favours a concomitant release. Possible mechanisms of materials’ formation are discussed.     

Enhanced absorption and growth inhibition with amino acid monoester prodrugs of floxuridine by targeting hPEPT1 transporters

A series of amino acid monoester prodrugs of floxuridine was synthesized and evaluated for the improvement of oral bioavailability and the feasibility of target drug delivery via oligopeptide transporters. All floxuridine 5'-amino acid monoester prodrugs exhibited PEPT1 affinity, with inhibition coefficients of Gly-Sar uptake (IC50) ranging from 0.7 - 2.3 mM in Caco-2 and 2.0 - 4.8 mM in AsPC-1 cells, while that of floxuridine was 7.3 mM and 6.3 mM, respectively. Caco-2 membrane permeabilities of floxuridine prodrugs (1.01 - 5.31 x 10(-6 )cm/sec) and floxuridine (0.48 x 10(-6 )cm/sec) were much higher than that of 5-FU (0.038 x 10(-6) cm/sec). MDCK cells stably transfected with the human oligopeptide transporter PEPT1 (MDCK/hPEPT1) exhibited enhanced cell growth inhibition in the presence of the prodrugs. This prodrug strategy offers great potential, not only for increased drug absorption but also for improved tumor selectivity and drug efficacy.     

Preparation and characterization of biodegradable microspheres containing hepatitis B surface antigen

Poly-DL-lactide-poly(ethylene glycol) (PELA) microspheres containing Hepatitis B surface antigen (HBsAg) were elaborated by a solvent extraction method based on the formation of a double water/oil/water (w/o/w) emulsion. Microspheres were characterized in terms of morphology, size and size distribution, encapsulation efficiency, and the efficiency of microsphere formation (EMF). Transmission electron microscopy (TEM) and polyacrylamide gel electrophoresis (PAGE) were used to investigate the structural integrality of HBsAg encapsulated in PELA microspheres. The release profile was investigated by the measurement of antigen present in the release medium at various intervals. The PELA-10 microspheres displayed the highest antigen encapsulation efficiency (about 80%), and antigen molecules could be stabilized in the PELA-10 microspheres during the preparation process. It suggested that the PELA microspheres had a great potential as a new polymer adjuvant for HBsAg. The release of Hepatitis B surface antigen from poly-DL-lactide-poly(ethylene glycol) microspheres.     

口服聚酯聚醚疫苗蛋白微球的制备研究

采用本体聚合法合成不同聚醚含量的聚酯聚醚嵌段共聚物聚 ＤＬ 乳酸 聚乙二醇（Ｐｏｌｙ ＤＬ ｌａｃｔｉｄｅ ｂ ｐｏｌｙｅｔｈｙｌｅｎｅｇｌｙｃｏｌ,ＰＥＬＡ）．ＰＥＬＡ及ＰＬＡ包裹人血清白蛋白（ＨＳＡ）微球采用溶剂挥发法双乳液体系（Ｗ１／Ｏ／Ｗ２）制备．微球球形规整,粒径集中在０５～５０μｍ．用ＣＢＢ法检测微球中蛋白含量,蛋白包裹量达２５％,包裹效率近８０％．从双乳液体系中界面张力角度考察了聚合物囊材的性质、稳定剂的种类及Ｗ１／Ｏ的稳定性等对微球粒径及蛋白包裹量的影响．微球体外释放结果表明ＰＥＬＡ蛋白微球的突释现象不明显,释放速度较为恒定．