克拉霉素漂浮-生物粘附微囊的制备及性能研究

选用乳化-溶剂挥发法制备乙基纤维素载药微球(EMs), 并通过内部凝胶化法进行包衣制得海藻酸钠-乙基纤维素载药微囊(AEMs), 最后通过离子交联法进一步包衣制得壳聚糖-海藻酸钠-乙基纤维素载药微囊(CAEMs). 研究克拉霉素漂浮\|生物粘附微囊的制备工艺, 并考察微囊的体外漂浮性能、 粘附性能及体内滞留性能. 结果表明, CAEMs球形度较好, 药物包封率为72.3%~78.2%, 载药量为7.1%~12.7%. 在pH=5的醋酸缓冲液中, 6 h时的累积释放率为56.6%~70.6%, 漂浮率大于70%, 4 h时的体内滞留率为60.5%. CAEMs有望通过延长药物胃内滞留时间, 在临床用于根除幽门螺旋杆菌, 从而降低消化道溃疡的复发率.     

Preparation of clarithromycin. Selective 6-O-methylation of the novel erythromycin A 9-O-(2-pyrimidyl)oxime

A new method for the preparation of clarithromycin is described through the highly regioselective O-methylation at C(6)-OH of the novel derivative 9-pyrimidyloxime erythromycin A. The facile synthesis of 6,11-O-dimethyl- and 6,11,12-O-trimethyl erythromycin A is also reported. These compounds are useful as standards to assess clarithromycin purity in quality control processes.     

Construction of a Novel Carbon Paste Clarithromycin Sensor for Low Level Concentration Measurement,Applications to Pharmaceutical and Biological Analysis

A potentiometric carbon paste sensor was fabricated for determination of clarithromycin based on incorporation of the ion association complex of the clarithromycin‐phosphotungstate. The proposed sensor exhibited a Nernstian slope of 59.2±0.3 mV per decade for clarithromycin over a wide concentration range of 7.4×10^?7 to 1.5×10^?3 M, with a low detection limit of 5.0×10^?7 M. The proposed sensor manifested advantages of very fast response, long life time and, most importantly, excellent selectivity for clarithromycin relative to a wide variety of common foreign inorganic cation, and also biological species. The sensor was successfully applied to determine clarithromycin in clarithromycin tablet, blood serum and urine samples. The inclusion complex formation between β‐cyclodextrin and clarithromycin was studied by the proposed sensor. The influence of the temperature on the response of the sensor was investigated and the temperature coefficient of the sensor was calculated.     

Study on the interaction between clarithromycin and bovine serum albumin in the imitated physiology solution

The interaction between clarithromycin (CAM) and bovine serum albumin (BSA) was investigated using linear-sweep voltammetry in pH 7.4 phosphate buffer solution where CAM caused two irreversible reduction waves P2 and P3 on mercury electrode. The study showed that the formation constant and formation ratio for the interaction between CAM and BSA were 1.51×1012 and 3:1 for P2,4.53×105 and 1:1 for P3, respectively. The ion strength enhanced the hydrophobic interaction between CAM and BSA.     

From (E)- and (Z)-ketoximes to N-sulfenylimines, ketimines or ketones at will. Application to erythromycin derivatives

Reactions of (E)- and (Z)-ketoximes with trialkylphosphines and diphenyl disulfide (PhSSPh) have been compared to gain insight into the mechanisms involved and their potential applications. N-Sulfenylimine isomers and ketimines have been spectroscopically characterised. Both the E and Z isomers of erythromycin A oxime, when treated with Bu₃P and PhSSPh (1:4:8 ratio), give the same N-phenylsulfenyl ketimine (of configuration E) as the major compound, whereas with Bu₃P or Me₃P and PySeSePy (1:8:4 ratio) afford the imine in good yield. Clarithromycin oxime behaves similarly.     

Study on enantiomeric separation of basic drugs by NACE in methanol‐based medium using erythromycin lactobionate as a chiral selector

A wide variety of chiral selectors have been employed in CZE, and among them macrocyclic antibiotics including glycopeptides, ansamycins, aminoglycosides and polypeptides exhibited prominent enantioselective properties toward abundant racemic compounds. Compared with CZE, the use of macrocyclic antibiotics as chiral selectors in NACE has not been reported previously. In this study, an approach to the enantioseparation of basic drugs by means of NACE with erythromycin lactobionate (EL) belonging to the group of macrolide antibiotics has been investigated. Especially different from the above four classes of antibiotics, there are no reports concerned with the use of macrolides which belong to macrocyclic antibiotics as chiral selectors in CE. In this work EL is first used as a chiral selector in NACE for the enantiomeric separations of two racemic basic drugs that possess high separability consisting of propranolol and duloxetine. Furthermore, EL possesses advantages such as high solubility and low viscosity in the solvent and very weak UV absorption. The chiral separations were achieved using Tris‐boric acid as the BGE and methanol as the organic medium. In the course of this work we observed that both migration time and enantioseparation were influenced by several parameters such as the pH and composition of the BGE, EL concentration, capillary temperature and applied voltage. Consequently, these parameters were systematically optimized in order to obtain the optimum enantioseparations.     

Extractive Spectrophotometric Methods for Determination of Clarithromycin in Pharmaceutical Formulations Using Bromothymol Blue and Cresol Red

Two simple and sensitive extractive spectrophotometric methods have been described for the analysis of clarithromycin in pure form and in pharmaceutical formulations. The methods involved formation of yellow colored chloroform extractable ion‐association complexes of clarithromycin with bromothymol blue (BTB) and cresol red (CR) in buffered aqueous solution at pH 4. The extracted complexes showed maximum absorbance at 410 and 415 nm for BTB and CR, respectively. Beer's law is obeyed in the concentration ranges 0.1–20 μg mL^?1 and 2.0–20 μg mL^?1 of clarithromycin with molar absorptivity of 2.01 × 10⁴ and 4.378 × 10³ for BTB and CR, respectively. The composition ratio of the ion‐association complex was clarithromycin: BTB and CR = 1:1 as established by Job's method. The methods have been applied to the determination of drug in commercial formulations. The results of analysis were validated statistically and through recovery studies.     

Electrochemiluminescence Detection of Clarithromycin in Biological Fluids after Capillary Electrophoresis Separation

Abstract

A sensitive analytical method for the determination of clarithromycin in biological fluids with electrochemiluminescence detection after capillary electrophoresis separation was proposed in this paper, based on the enhancing effect of clarithromycin on electrochemiluminescence of tris(2,2-bipyridyl) ruthenium(II) (Ru(bpy)₃ ²⁺). Various factors influencing the separation and detection of clarithromycin were examined to establish the detection system. Under the optimized conditions, the electrochemiluminescence intensity is proportional with the concentration of the analyte over the range of 0.1–10 µM with a detection limit of 30 nM (S/N = 3). The proposed method has been successfully applied for clarithromycin content determination in spiked human plasma and urine samples.     

克拉霉素的示波极谱测定及其电化学行为

在 0 .0 5mol LNaOH(pH 1 2 .7)介质中 ,克拉霉素在滴汞电极上产生一灵敏的还原峰 ,峰电位Ep=- 1 .35V(vs.SCE)。其一阶导数峰电流ip′与克拉霉素浓度在 8.0× 1 0 -6～ 4.8× 1 0 -5mol L范围内有良好的线性关系 (r=0 .9991 ) ,检出限为 4 .0× 1 0 -6mol L。此法已用于片剂的测定。用线性扫描和循环伏安法研究了体系性质 ,结果表明 ,克拉霉素的电极过程为具有吸附的不可逆过程     

A New Crystal Structure of Clarithromycin

Abstract A new crystal structure of clarithromycin single acetonitrile solvate designated “Form III” was first determined by single crystal X-ray diffraction. The compound crystallized in the monoclinic system, P2 ₁ space group with a = 10.644(2) ?, b = 18.099(4) ?, c = 11.628(2) ?, α = γ = 90°, β = 95.38(3)°, V = 2230.1(8) ?³, Z = 2, D _c = 1.175 g/cm³, μ = 0.087 mm⁻¹, F(000) = 860, R ₁ = 0.034, wR ₂ = 0.062, S = 0.875, (Δ/σ)_max = 0.001 for 2,709 observed reflections (I > 2σ (Ι)). Form III of clarithromycin, contrary to Form I, is more thermodynamically stable than Form II used currently on the market. Graphical abstract A New Crystal Structure of Clarithromycin Jian-Hua Liang, Guo-Wei Yao A crystal structure of clarithromycin single acetonitrile solvate was first determined by single crystal X-ray diffraction.