Novel drug delivery system by chitin derivative

A porous chitin foam was regenerated from chitin dope in calcium chloride dihydrate saturated methanol. The porous chitin foam was shown to have cationic property, because chitin foam tended to adsorb anionic dyes through ionic binding and hydrophobic interaction. A pendant type of polymeric drug was prepared applying peptide spacer composed of phenylalanine at amino end and two step hydrolyses of polymeric drug were shown to release active drug at the final step using lysozyme and chymotrypsin in vitro.     

几种常见药物的高分子衍生物的合成

小分子药物高分子化能延长药效,减小副作用,是改进现有药物的重要方法之一。目前研究的高分子药物大致有两类:(1)高分子本身有药效;(2)高分子本身无药效,但可释放出小分子药物。例如,Vogl等合成的5-乙烯基水杨酸甲酯聚合物本身有抗紫外辐射功能,李福绵等合成的聚甲基丙烯酸-β-(乙酰水杨酰氧)乙酯等本身虽不是药,但可释放出阿斯匹林。我们希望合成出兼有以上两类特点的高分子药物,为此合成了几种常见药物的高分子衍生物:聚甲基丙烯酸水杨酸酯(PSAMA),聚甲基丙烯酸对乙酰胺基苯酯(PAPMA),聚甲基丙烯酸磺胺嘧啶酰胺(PSDMA)和聚甲基丙烯酸乳酸酯(PLAMA)。     

Block ionomer complex micelles based on the self-assembly of poly(ethylene glycol)-block-poly(acrylic acid) and CdCl₂ for anti-tumor drug delivery

A novel block ionomer complex micelles as drug carrier is developed utilizing self-assemble of poly(ethylene glycol)-block-poly(acrylic acid) (PEG-b-PAA) and cadmium chloride. This micelles are characterized to be have good bio-compatibility, hydrophilicity, passive targeting and sustained slow release property which shows great potential for liver cancer therapy. Block ionomer complex micelles based on PEG-b-PAA and cadmium chloride can self-assemble in distilled water, and Cd(2+) agent is entrapped into the core stabilized by PEG shells. Results showed the block ionomer complex micelles to be spherically shaped. Cadmium was incorporated easily into the ionic core with remarkably high efficiency (34.25% weight (wt)/wt). The cadmium-loaded polymeric micelles exhibited sustained and slow release behavior of cadmium and a potent cytotoxicity against SMMC-7721 in vitro. This novel block ionomer complex micelles with cores of metal antitumor drug indicates to be potential carriers for effective drug delivery.     

Immobilization of a primary amine-containing drug,adriamycin

Literature reports have described the covalent coupling of the primary amine-containing anticancer drug, adriamycin, to polymeric supports through the amine group on the drug. These reports also have described drug mechanism studies with the immobilized adriamycin, where the release of the drug would undermine the validity of the conclusions. In the present paper, detailed experimental conditions are given for preparation of nonwater-soluble particles of polyvinyl alcohol by crosslinking water-soluble polyvinyl alcohol with 1,4-benzenedicarboxaldehyde, and for activation with cyanuric chloride and covalent attachment of adriamycin. The expected stability of this drug-support linkage against hydrolytic cleavage is compared mechanistically to that expected for less stable coupling through a carbamate linkage or for less stable coupling via an azomethine link.     

TIN-PROTOPORPHYRIN: A POTENT PHOTOSENSITIZER OF BILIRUBIN DESTRUCTION

Abstract— Tin(IV)-protoporphyrin chloride, a proposed chemotherapeutic agent for prevention of neonatal hyperbilirubinemia, is a potent photosensitizer of bilirubin destruction in vitro at visible wavelengths (410, 540, 580 nm). We speculate that the drug may have phototoxic effects in vivo if it accumulates in light-accessible tissues.     

Formulation characterization and in vitro evaluation of acacia gum–calcium alginate beads for oral drug delivery systems

In the present work, new matrix bead formulations based on linear and branched polysaccharides have been developed using an ionic gelation technique, and their potential use as oral drug carriers has been evaluated. Using calcium chloride as a cross‐linking agent and sodium diclofenac (SD), as a model drug, acacia gum–calcium alginate matrix beads were formulated. The response surface methodology based on 3² factorial design was used as a statistical method to evaluate and optimize the effects of the biopolymers‐blend ratio and the concentration of calcium chloride on the particle size (mm), density (g/cm³), drug encapsulation efficiency (%), and the cumulative drug release after 8 hours (R_8h,%). The optimized beads with the highest drug encapsulation efficiency were examined for a drug‐excipients compatibility by powder X‐ray diffraction, differential scanning calorimetry, thermo‐gravimetric analysis, and Fourier transform‐infrared spectroscopy analyses. The swelling and degradation of the matrix beads were found to be influenced by the pH of medium. Higher degrees of swelling were observed in intestinal pH than in stomach pH. Accordingly, the drug release study showed that the amount of SD released from the acacia gum–calcium alginate beads was higher in intestinal pH than in stomach pH. Therefore, the in vitro drug release from the SD‐loaded beads appears to follow the controlled‐release (Hixson‐Crowell) pattern involving a case‐2 transport mechanism operated by swelling and relaxation of the polymeric blend matrix.     

氯化铕对大黄愈伤组织生长及超微结构的影响

以掌叶大黄的愈伤组织为材料，研究了不同浓度氯化铕对其生长的影响，并利用透射电镜技术研究了氯化铕对大黄细胞超微结构的影响。实验结果表明，低浓度氯化铕促进愈伤组织生长，高浓度则抑制生长，浓度达到１００ｍｇ／Ｌ则可导致大黄外植体全部死亡。氯化铕对大黄的促进作用可被钙调蛋白的拮抗剂氯丙嗪抑制。１０ｍｇ／Ｌ氯化铕可使大黄愈伤组织的细胞形态发生明显变异。     

Synthese de polymeres a proprietes pharmacologiques: Introduction de sequence peptidique en chaine laterale

Amino acids have been introduced on to the side-chains of a polymer. Two schemes have been studied: the first involves the synthesis of a monomer containing the amino acid drug moiety and subsequent polymerization; the second depends upon chemical modification of a polymer with the amino acid drug moiety. The drugs used in this study are steroids (cholesterol testosterone). The amino acid moieties introduced on to the side-chains are L-lysine. The preparation of the drug containing the amino acid is done by reacting the chloroformate derivative of the steroid with the amine function of the lysine subsequent to the blocking of the amino acid as a copper complex. The methacrylic monomer is obtained by reacting methacryloyl chloride with the drug amino acid moiety. The polymers were characterized by i.r., NMR (¹H and ¹³C) and GPC. Pharmacological tests are being performed to observe the effect due to the hydrolysis of the drug or the amino acid drug in living organisms.     

Probing the interaction of kojic acid antibiotics with iron(III) chloride by using electrospray tandem mass spectrometry

Kojic acid, 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one, has been used extensively as a clinical iron-chelating drug although the nature of the complexes of iron and kojic acid has not been established. In this article we demonstrate the complexation of kojic acid with iron(III) chloride by using electrospray ionization mass spectrometry (ESI-MS). The ESI-MS analysis revealed different reactions between iron(III) chloride and kojic acid (M), and the mass spectrum exhibited four complexes: [Fe+2(M-H)]+, [Fe+3(M-H)+H]+, [Fe2+4(M-H)+Cl]+, and [Fe2+5(M-H)]+. All these proposed complexes and the presence of chloride ion in one of the dinuclear complexes have been confirmed by isotopic patterns and fragmentation studies by means of tandem mass spectrometry (MSn).     

Studies in the development of nateglinide loaded calcium alginate and chitosan coated calcium alginate beads

Nateglinide loaded alginate-chitosan beads were prepared by ionic gelation method for controlling the drug release by using various combinations of chitosan and Ca2+ as cation and alginate as anion. IR spectrometry, scanning electron microscopy, differential scanning calorimetry and X-ray powder diffractometry were used to investigate the physicochemical characteristics of the drug in the bead formulations. The calcium content in beads was determined by atomic absorption spectroscopy. The swelling ability of the beads in different media (pH 1.2, 4.5, 6.8) has been found to be dependent on the presence of polyelectrolyte complex of the beads and the pH of the media. The ability to release the Nateglinide was examined as a function of chitosan and calcium chloride content in the gelation medium. It is evident that the rate of drug release and its kinetics could be controlled by changing the chitosan and the calcium chloride concentrations. Calcium alginate beads released more than 95% of drug with in 8 h; whereas coated beads sustained the drug release and released only 75-80% of drug. The drug release mechanism analyzed indicates that the release follows either "anomalous transport" or "case-II transport".     

Microcoated wire sensors for the determination of anticancer drugs cyclophosphamide and ifosphamide in the presence of their degradates

The construction and electrochemical response characteristics of poly (vinyl chloride) and poly (vinyl chloride) carboxylate membrane sensors for the determination of cyclophosphamide and ifosphamide are described. Based on the formation of an ion-pair complex between the drug cation and sodium tetraphenylborate, two poly (vinyl chloride) sensors, namely a cyclophosphamide membrane sensor and ifosphamide membrane sensor were fabricated. They show a linear response for both drugs over the concentration range 10⁻²–10⁻⁴ M with cationic slopes of 56 and 54.6 mV per concentration decade, for sensor 1 and sensor 2, respectively. Based on the interaction between the drug solution and the dissociated COOH groups in the poly (vinyl chloride) carboxylate, sensor 3 was fabricated. It shows a linear response for both drugs over the concentration range 10⁻³–10⁻⁵ M with a cationic slope of 49.7 mV per concentration decade. The direct potentiometric determination of cyclophosphamide and ifosphamide in their pharmaceutical preparations using the proposed sensors gave average recoveries of 101.3±0.6, 100.8±10.7 and 102.0±11.0% for the sensors 1, 2 and 3, respectively, which compares reasonably well with the data obtained using the British Pharmacopoeial method (1993). Sensors 1 and 2 were also used to follow up the stability of the drugs studied in the presence of their degradates. These degradation products have no diverse effect on the responses of sensors 1 and 2.     

Determination of quaternary ammonium surfactants in pharmaceutical formulations by the hypochromic effect

A spectrophotometric procedure for determination of the quaternary ammonium salts cetrimide (N,N,N-trimethyl-l-hexadecylammonium bromide), cetylpyridinium chloride (l-hexadecyl-pyridinium chloride) and sapamine [N-(2-dimethylaminoethyl)oleamide acetate] in bulk form and some pharmaceutical formulations, such as eye-drops, disinfectant solutions, creams and tablets, is described. Following TLC separation when necessary, addition of an aqueous solution of the active surfactant to a standard amount of Bromothymol Blue, buffered at pH 7.5, leads to an equivalent decrease of the absorbance at 610 nm, which can be taken as an analytical measure of the drug concentration. Good mean recoveries have been obtained for standard additions of these analytes to pharmaceutical formulations containing them.     

Novel functional hyperbranched polyether polyols as prospective drug delivery systems

Multifunctional hyperbranched polyether polyols bearing protective poly(ethylene glycol) (PEG) chains with or without the folate targeting ligand at their end have been prepared. Solubilization in these polymers of a fluorescent probe, pyrene, and an anticancer drug, tamoxifen, was physicochemically investigated. It was found that PEG chains attached at the surface of these hyperbranched polymers, in addition to their well-established protective role, enhance the encapsulation efficiency of the polymers. The release of pyrene and tamoxifen observed upon addition of sodium chloride is, in most of the cases, significant only at concentrations exceeding the physiological extracellular concentration. Thus, a significant amount of the probe or drug remains solubilized inside the carriers, which is an encouraging result if the polymers are to be used for drug delivery.     

Acetylcholinesterase responsive polymeric supra-amphiphiles for controlled self-assembly and disassembly

We have fabricated enzyme responsive polymeric supra-amphiphiles by mixing a block copolymer of poly(ethylene glycol)-block-poly(acrylic acid) with myristoylcholine chloride in water. The polymeric supra-amphiphiles self-assemble into spherical aggregates with sizes varying from about 40 to 150 nm. Moreover, the spherical aggregates can be disassembled triggered by acetylcholinesterase, an enzyme which can cut off the ester linkage of myristoylcholine chloride. Nile red can be loaded into the spherical aggregates and released in several hours upon the treatment of acetylcholinesterase. The releasing rate is rather fast considering that it takes more than 150 h for Nile red to diffuse out of the spherical aggregates without addition of acetylcholinesterase. It is anticipated that the new enzyme responsive polymeric supra-amphiphile may be explored as a carrier for drug delivery.     

Lipophilicity determination of some monoamine oxidase inhibitors: the effect of methanol and ammonium chloride.

The lipophilicity (RM value) of seventeen monoamine oxidase inhibitory drugs was determined by reversed-phase thin-layer chromatography, and the effect of salt concentration on the reversed-phase retention was studied by adding ammonium chloride to the eluent. Each drug exhibited regular retention behaviour, its RM value linearly decreasing with increasing concentration of methanol in the eluent. Ammonium chloride decreased the retention: the effect was higher at lower salt concentrations, which indicates that the phenomenon is of saturation character. The influence of ammonium chloride depended on the concentration of methanol (on the dielectric constant of the eluent) suggesting that methanol suppresses the dissociation of ammonium chloride resulting in a modified salting-in effect.     

Spectroscopic Probe of the Distribution of Cationic Drug or Dye Between Anionic Polymers

Abstract

Knowledge of the distribution of a drug (or dye) between different biopolymers may be useful in understanding the mechanism of drug action. We have studied the distribution of drugs or dyes between different anionic polymers as model systems. Spectrophotometric and circular dichroism have been used as techniques to monitor the distribution of intercalating, partially intercalating, and nonintercalating cationic dyes or drugs between DNA and other anionic polymers. Both spectrophotometric and circular dichroic evidence indicates that the partially intercalating dye dimethylmethylene blue distributes itself between DNA and heparin with a preference for DNA. In the case of the intercalating drug actinomycin-D, DNA uses its intercalating ability to win heparin in competitive binding of the drug. The picture is somewhat different when pinacyanol (PCYN) chloride, a nonintercalating dye, is used as the ligand in the competitive binding of DNA and poly(styrene sulfonate) (PSS); DNA loses to PSS in competitive binding of this ligand. The equilibrium constant of the distribution of PCYN between DNA and PSS has been determined from a method developed here.     

Action of propranolol on mitochondrial proton fluxes.

The action of propranolol, a Beta-blocking adrenergic agent, on mitochondrial proton fluxes in nonenergized and energized conditions has been studied. 1. The drug inhibited the actions of valinomycin, higericin and FCCP on the inner mitochondrial membrane. 2. It decreased the rate and extent of active energized proton expulsion and passive collapse of the proton gradient so formed. 3. Propranolol was able to increase the permeation of chloride ion through the inner mitochondrial membrane in nonenergized and energized conditions. 4. The drug inhibited mitochondrial contraction but stimulated swelling in various conditions. It is suggested that propranolol is is able to change the proton and chloride permeabilities of mitochondria by perturbing the structure of inner membrane phospholipids, thus enlarging the water-lipid interface.     

高效液相色谱荧光检测法测定药物中的氯乙酰氯

建立测定药物中氯乙酰氯含量的高效液相色谱–荧光检测方法。以吖啶酮乙酰肼为荧光标记试剂,对氯乙酰氯进行柱前衍生。在室温下反应15 min,衍生产率达到最大。衍生溶液在XDB–C18柱上,以水和乙腈为流动相进行分析,激发波长和发射波长分别为255 nm和429 nm。氯乙酰氯浓度在1~1 000 nmol/L范围内与色谱峰面积具有良好的线性关系,线性相关系数r=0.999 9。方法的检出限为0.35 nmol/L,仪器精密度和方法精密度分别为0.52%和0.67%(n=6)。样品加标回收率为92.5%~95.6%。该方法简单、准确,精密度良好,可用于测定药物中氯乙酰氯的残留量。     

Lyotropic liquid-crystalline mesophases and a novel, solid physical form of some water-soluble, reactive dyes

A novel, solid physical form has been observed when some water-soluble, reactive dyes are isolated from aqueous solution, as sodium salts, by the addition of sodium chloride. This quasi-crystalline form has a fibrous morphology, is birefringent but is not crystalline. Dyes of this type are known to form lyotropic liquid-crystalline mesophases in water. Preliminary X-ray diffraction investigations, reported here, for the mesophases formed by two such dyes indicate that they have columnar structures of the type first proposed for the lyotropic mesophases of the disodium chromglycate/water system and subsequently for other drug and dye molecules. X-ray and electron diffraction studies of the quasi-crystalline form show that it has a closely related columnar structure. The quasi-crystalline form is postulated to result from the formation and subsequent precipitation of columnar dye aggregates, as sodium chloride is added to the aqueous dye solution.     

Ion Exchange Controlled Drug Release from Polymerized Ionic Liquids

In this work ion functionalized hydrogels as potent drug delivery systems are presented. The ion functionalization of the hydrogel enables the retention of ionic drug molecules and thus a reduction of burst release effects. Timolol maleate in combination with polymerized anionic 3‐sulfopropylmethacrylate potassium and ibuprofen combined with cationic poly‐[2‐(methacryloyloxy)ethyl] trimethylammonium chloride are investigated in respect to their drug release profile. The results are showing an ion exchange depending release behavior instead of a diffusion‐controlled drug release as it is known from common drug delivery systems. Furthermore, the suitability of such hydrogels for standard methods for sterilization is investigated.