Amphiphilic amino acid copolymers as stabilizers for the preparation of nanocrystal dispersion

The recent advance of particle size engineering in nanometer ranges has widened the formulation opportunities of relatively water-insoluble drugs. However, the ‘nanoformulation’ suffers from a lack of systematic understanding about the requirements of polymeric stabilizers. Furthermore, the polymers that can be used for the preparation of nanocrystals are so limited that finding a proper stabilizer for a given formulation is often difficult. In this study, amino acid copolymers whose properties can systematically be tailored are developed, and their morphological and compositional effects are investigated. Copolymers containing lysine (K) as their hydrophilic segments, and phenylalanine (F) or leucine (L) as their hydrophobic segments successfully produce stable nanocrystals (200–300 nm) in water, while copolymers of K and alanine (A) could not generate nanosized particles. Not the morphology but the hydrophobicity of copolymers seems to be a critical parameter in the preparation of drug nanocrystals by wet comminution. The effective stabilization performance of copolymers requires the hydrophobic moiety content to be higher than 15 mol%. Comminution for only 5 min is long enough for nanocrystal preparation, and the crystallinity of drug is found intact after the processing.     

临床随访研究中样本含量的估计

目的:介绍临床随访研究中生存分析资料的log-rank检验所需样本含量的估计法.方法:以离散性Markov链拟合生存过程,据此计算log-rank统计量的数学期望和方差,导出样本含量估计公式.结果:实例分析表明,该法能较好反映实际情况,应用灵活.结论:本法是一种有效、可行的样本含量估计法,值得推荐.     

An overview on in situ micronization technique – An emerging novel concept in advanced drug delivery

The use of drug powders containing micronized drug particles has been increasing in several pharmaceutical dosage forms to overcome the dissolution and bioavailability problems. Most of the newly developed drugs are poorly water soluble which limits dissolution rate and bioavailability. The dissolution rate can be enhanced by micronization of the drug particles. The properties of the micronized drug substance such as particle size, size distribution, shape, surface properties, and agglomeration behaviour and powder flow are affected by the type of micronization technique used. Mechanical communition, spray drying and supercritical fluid (SCF) technology are the most commonly employed techniques for production of micronized drug particles but the characteristics of the resulting drug product cannot be controlled using these techniques. Hence, a newer technique called in situ micronization is developed in order to overcome the limitations associated with the other techniques. This review summarizes the existing knowledge on in situ micronization techniques. The properties of the resulting drug substance obtained by in situ micronization were also compared.     

Sample size determination using an interim analysis

Interim analyses are often employed to terminate comparative clinical trials for ethical or economic reasons when the evidence indicates that one treatment is superior to the other. Here an interim analysis is proposed for the situation where a one-sided test is to be performed. The proposed interim analysis consists of a one-sided test to terminate the clinical trial if it appears that the null hypothesis of interest is true. By noting that incorporation of a single interim analysis is similar to the two-stage procedure used for constructing a test procedure with power independent of the unknown variance, it also includes estimation of the variance, which can be used to control the power of the test if the trial is not terminated. Various properties of this two-stage procedure and derivation of the constants needed for its implementation are presented.     

Correlation between the median particle size of chewed frankfurter sausage and almonds during masticatory performance test

The correlation between chewing and gastric function is best reflected when the same food type is used during both tests. We proposed frankfurter sausage as test food for masticatory performance as it can also be used in gastric emptying test. The suitability of frankfurter sausage to determine masticatory performance, however, has never been examined. To examine the correlations between the median particle size of frankfurter sausage and almonds (as standard test food) after different numbers of chewing cycles. Twenty‐seven subjects performed masticatory performance tests by chewing 2 types of test foods, that is, a piece of almond or 5‐g frankfurter sausage cubes placed in a sealed latex bag, for 5 and 15 chewing cycles. For each individual, right and left sides were tested separately. Chewed samples obtained from both sides were pooled. Median particle sizes were determined using a multiple sieving method. Spearman’s rank correlation was used to examine any correlation between median particle sizes of the 2 test foods after 5 and 15 cycles. Median particle sizes after 5 and 15 cycles were 2.04 ± 0.87 and 0.95 ± 0.58 mm for almonds and 4.16 ± 0.19 and 3.73 ± 0.25 mm for frankfurter sausage, respectively. Significant correlations were observed between the median particle size of chewed frankfurter sausage after 15 cycles and that of chewed almonds after 5 and 15 cycles (r = .76, P < .01 and r = .52, P = .01, respectively). Frankfurter sausage chewed for 15 cycles may be suitable for the determination of masticatory performance in conjunction with gastric emptying test.     

A Review of: “The Statistical Analysis of Recurrent Events,by R. J. Cook and J. F. Lawless”

In a classical drop-loser (or drop-arm) design, patients are randomized into all arms (doses) and at the interim analysis, inferior arms are dropped. Therefore, compared to the traditional dose-finding design, this adaptive design can reduce the sample size by not carrying over all doses to the end of the trial or dropping the losers earlier. However, all the doses have to be explored. For unimodal (including linear or umbrella) response curves, we proposed an effective dose-finding design that allows adding arms at the interim analysis. The trial design starts with two arms, depending on the response of the two arms and the unimodality assumption; we can decide which new arms to be added. This design does not require exploring all arms (doses) to find the best responsive dose; therefore, it can further reduce the sample size from the drop-loser design by as much as 10–20%.     

一种生物气溶胶旋风式分离采集装置的设计与验证

目的:设计一种生物气溶胶旋风式分离采集装置,为小粒径生物气溶胶分离采集和分析提供有效手段。方法:对经典旋风式分离采集装置结构参数进行优化,借助Fluent软件对筒体直径等关键结构参数对粒径分离效果的影响进行模拟仿真,确定生物气溶胶旋风式分离采集装置的最优结构参数,之后采用高纯铝材料制作生物气溶胶旋风式分离采集装置。采用TSI9310尘埃粒子计数器和六级安德森采样器对设计的生物气溶胶旋风式分离采集装置的粒径分离效果进行实验验证。结果:设计的生物气溶胶旋风式分离采集装置筒体直径为18 mm,该装置对于粒径小于3.3μm的生物气溶胶粒子基本无阻留,对于粒径大于3.3μm的粒子,分离阻留效率随粒径的增加逐渐增大。结论:生物气溶胶旋风式分离采集装置可以有效分离小粒径生物气溶胶粒子、阻留大粒径生物气溶胶粒子,达到粒径分离效果。     

Optimization of the High-Shear Wet Granulation Wetting Process Using Fuzzy Logic Modeling

A fuzzy model has been developed for the optimization of high-shear wet granulation wetting on a plant scale depending on the characteristics of pharmaceutical active substance particles. The model optimized on the basis of experimental data involves a set of rules obtained from expert knowledge and full-scale process data. The skewness coefficient of particle size distribution and the tapped density of the granulated mixture were chosen as the model input variables. The output of the fuzzy ruled system is the optimal quantity of wetting liquid. In comparison to manufacturing practice, a very strong sensitivity of the optimal quantity of the added wetting liquid to the size and shape of the active substance particles has been identified by fuzzy modeling.     

Book review of Child and adolescent obesity: Causes and consequences,prevention and management. Edited by W. Burniat,T. J. Cole,I. Lissau and E. M. E. Poskitt. (Cambridge University Press,Cambridge, 2002). [pp. 436]. ISBN: 0521 652375. £70.00 hbk.

Background: Bone mineral density (BMD), bone mineral content (BMC), and bone size have been widely studied individually as important risk factors for osteoporotic fracture, but little is known about the correlation and the degree of sharing genetic and environmental factors between the pairs of the three phenotypes.

Aim: The study investigated genetic correlation (ρ_G), environmental correlation (ρ_E) and phenotypic correlation (ρ_P) between BMD, BMC and bone size.

Subjects and methods: Bivariate variance decomposition analyses were performed in 904 subjects from 287 Chinese nuclear families.

Results: Significant ρ_E, ρ_G and ρ_P were detected between BMD, BMC and bone size, except for ρ_E between BMD and bone size at the hip (ρ_E?=?0.121, p?=?0.361). Common shared genetic factors explained 86.1% and 60% of BMD and BMC genetic variations at the spine and hip, respectively. However, the genetic and environmental correlations between BMD and bone size were limited. ρ_E and ρ_G at the spine were 0.392 and 0.381, and at the hip were 0.121 and ?0.205, respectively. Only 14.5% and 4.2% of variations between BMD and bone size at the spine and hip may be due to the shared genetic factors.

Conclusion: The obtained results suggested that bone size may be used as another surrogate phenotype independently of BMD for eventual elucidation of the pathogenesis of osteoporosis because of the limited correlations between BMD and bone size.

Résumé. Arrière plan: La densité minérale osseuse (DMO), le contenu minéral de l’os (CMO) et la taille de l’os, ont fait l’objet de nombreuses études au niveau individuel, en relation avec le risque de fracture ostéoporotique, mais la corrélation et les responsabilités relatives des facteurs génétiques et environnementaux entre les paires de ces trois phénotypes sont encore peu connues.

Objectif: L’étude porte sur la corrélation génétique (ρ_G), environnementale (ρ_E) et phénotypique (ρ_p) entre DMO, CMO et taille de l’os.

Sujets et méthodes: Des analyses bivariées de décomposition de la variance ont été effectuées sur 904 sujets de 287 familles nucléaires chinoises.

Résultats: Des ρ_G, ρ_E, ρ_p ont été détectées entre DMO, CMO et taille de l’os, à l’exception de ρ_E entre DMO et taille de l’os à la hanche (ρ_E?=?0,121, p?=?0,361). Des facteurs génétiques communs expliquent respectivement 86,1% et 60% des variations génétiques de DMO et CMO du rachis et de la hanche. Les corrélations génétiques et environnementales entre DMO et taille de l’os sont cependant limitées. Les ρ_G, ρ_E, au rachis sont respectivement 0,392 et 0,381 et sont 0,121 et -0,205 à la hanche. Seulement 14,5% et 4,2% des variations entre DMO et taille de l’os au rachis et à la hanche peuvent être dus à des facteurs génétiques communs.

Conclusion: Les résultats suggèrent que par suite des corrélations limitées qui lient la DMO et la taille de l’os, cette dernière peut être utilisée comme phénotype de substitution, indépendamment de la DMO, pour l’élucidation de la pathogenèse de l’ostéoporose.

Zusammenfassung. Hintergrund: Knochendichte (bone mineral density, BMD), Knochenkalkgehalt (bone mineral content, BMC), und Knochengröße (bone size) sind als bedeutsame individuelle Risikofaktoren für osteoporotische Frakturen umfangreich untersucht worden, aber es ist wenig über die Korrelation und das Ausmaß der beteiligten genetischen und Umwelt-Faktoren zwischen jeweils zwei der drei phänotypischen Parameter bekannt.

Ziel: Die Studie untersucht die genetische Korrelation (ρ_G), die umweltbedingte Korrelation (ρ_E) und die phänotypische Korrelation (ρ_P) zwischen BMD, BMC and Knochengröße.

Probanden und Methoden: Bivariate Varianz-Dekompositionsanalysen wurden bei 904 Probanden aus 287 Chinesischen Kernfamilien untersucht.

Ergebnisse: Signifikante ρ_E, ρ_G and ρ_P wurden zwischen BMD, BMC und Knochengröße entdeckt, mit Ausnahme von ρ_E zwischen BMD und Knochengröße im Hüftbereich (ρ_E?=?0,121, p?=?0,361). Gemeinsame genetische Faktoren erklärten jeweils 86,1% und 60% der genetischen Variation von BMD und BMC an Wirbelsäule und Hüfte. Allerdings waren die genetischen und umweltbedingten Korrelationen zwischen BMD und Knochengröße gering. ρ_E und ρ_G an der Wirbelsäule waren 0,392 und 0,381, und an der Hüfte jeweils 0,121 und –0,205. Nur 14,5% und 4,2% der Variation zwischen BMD und Knochengröße im Bereich von Wirbelsäule und Hüfte könnten durch gemeinsame genetische Faktoren bedingt sein.

Zusammenfassung: Die dargestellten Ergebnisse legten nahe, dass Knochengröße möglicherweise ein weiterer Ersatzparameter ist, der, wegen der begrenzten Korrelation zwischen BMD und Knochengröße, unabhängig vom BMD genutzt werden könnte, um die Pathogenese der Osteoporose aufzuklären.

Resumen. Antecedentes: La densidad mineral ósea (DMO), el contenido mineral del hueso (CMH) y el tamaño del hueso han sido ampliamente estudiados de manera individual como importantes factores de riesgo de fractura osteoporótica, pero se conoce poco acerca de la correlación y del grado en que se comparten los factores genéticos y ambientales entre estos tres fenotipos, considerados dos a dos.

Objetivo: El estudio investigó la correlación genética (ρ_G), la correlación ambiental (ρ_E) y la correlación fenotípica (ρ_P), entre la DMO, el CMH y el tamaño del hueso.

Sujetos y métodos: Se realizaron análisis bivariados de descomposición de la varianza en 904 sujetos de 287 familias nucleares chinas.

Resultados: Se detectaron significativas ρ_E, ρ_G y ρ_P entre la DMO, el CMH y el tamaño óseo, excepto para la ρ_E entre la DMO y el tamaño óseo en la cadera (ρ_E=0,121, p=0,361). Los factores genéticos comunes compartidos explicaban el 86,1% y el 60% de la DMO y las variaciones genéticas del CMH en la espina dorsal y la cadera, respectivamente. Sin embargo, las correlaciones genéticas y ambientales entre la DMO y el tamaño del hueso fueron limitadas. Las ρ_E y ρ_G en la espina dorsal fueron de 0,392 y 0,381, y en la cadera de 0,121 y -0,205, respectivamente. Sólo el 14,5% y el 4,2% de las variaciones entre la DMO y el tamaño del hueso en la espina dorsal y la cadera podían ser debidas a los factores genéticos compartidos.

Conclusión: Los resultados sugieren que el tamaño del hueso puede utilizarse como otro fenotipo sustitutivo, con independencia de la DMO, en el eventual esclarecimiento de la patogénesis de la osteoporosis, debido a las limitadas correlaciones entre la DMO y el tamaño del hueso.     

泉州女性青年服装号型数据库建立

笔者选取600名泉州地区女性青年作为样本进行测量实验,确定15个测量变量,派生13个变量,对数据进行统计,采用聚类分析法将女性青年上下半身体型各归为5类,通过计算出各类体型测量部位的中间体数据与分档档差,进一步确定与建立女性青年服装号型人体数据库。