Novel silicones for transdermal therapeutic system, 4. Modified route to prepare oligodimethylsiloxane containing a cationic end-group,and its property as transdermal penetration enhancer

A modified route to prepare oligodimethylsiloxane (ODMS) containing a quaternary salt at the one chain end was investigated, for the development of a silicone-based transdermal penetration enhancer. p-(Chloromethyl)phenethyl-terminated ODMS (CMP-ODMS) was prepared by hydrosilylation of p-chloromethylstyrene with hydrosilyl-terminated ODMS, as an intermediate. Then, CMP-ODMS was reacted with pyridine or ethyldimethylamine to afford a quaternary ODMS salt quantitatively. The enhancing activity of drug penetration was evaluated by measuring the amount of indomethacin permeating through the skin, using a two-chamber diffusion cell having an isolated rabbit abdominal skin mounted between half cells. The obtained polymers effectively enhanced the drug penetration through the skin, whereupon the permeation coefficients were 2 to 15 times that measured without enhancer. Also, the enhancing activities were influenced by the chemical structure of polar and non-polar end-groups.     

Preparation of oligodimethylsiloxanes with sugar moiety at a terminal group as a transdermal penetration enhancer

Oligodimethylsiloxanes (ODMSs) containing glucose or cellobiose moiety at a terminal group were prepared to develop a silicone‐based transdermal penetration enhancer. Glucopiranosyl‐terminated ODMS was prepared by the hydrosilylation of hydrosilyl‐terminated ODMS with 1‐allyl‐β‐D‐glucose tetraacetate followed by hydrolysis of the acetyl groups with sodium methoxide, to afford glucopiranosyl‐terminated ODMS with a ether linkage between glucopiranosyl and ODMS components (GlcO‐ODMS), and by the coupling reaction of iodopropyl‐terminated ODMS with 2‐(2,3,4,6‐O‐tetraacetyl‐β‐D‐glucopyranosyl)thiopseudourea hydrobromide followed by the similar hydrolysis to afford glucopiranosyl‐terminated ODMS with a thioether linkage (GlcS‐ODMS). Cellobiosyl‐terminated ODMS (Cell‐ODMS) was also prepared by the similar procedure as GlcO‐ODMS. The enhancing activity of GlcO‐ODMS, GluS‐ODMS and Cell‐ODMS on the drug permeation through the rabbit abdominal skin was evaluated by in vitro experiments using a two‐chamber diffusion cell and antipyrine as a model drug. The permeation of antipyrine through the skin was increased by the addition of GlcS‐ODMS and GlcO‐ODMS but not by Cell‐ODMS.     

Oligomer-oligomer incompatibility, 3. End-group effects

In order to investigate the influences of different end-groups on oligomer miscibility with other substances, oligo(propylene glycol)s bearing ? OH groups (OPG-OH) studied in the previous paper², were acetylated at both ends (OPG-AC). The limits of miscibility of OPG-AC with oligo(dimethylsiloxane) (ODMS) were measured turbidimetrically. A simple and reliable method for the determination of the critical points from turbidity data is presented. The observed upper critical temperatures (T_c) increase with degree of oligomerization of ODMS (ranging from 1 to 5), whereas T_c shows a minimum when the degree of oligomerization of the OPG-AC is raised (from 1 to 57,5). For lower mol. wt. oligoglycols, the T_c-values of ODMS/OPG-AC are lower by ca. 50 K as compared with those of ODMS/OPG-OH. The different end-groups play a minor role with respect to the pressure influences (up to 1 500 bar the miscibility increases in all cases). For OPG-AC the chain length of optimum miscibility with a given ODMS is found at considerably lower values than for OPG-OH. The theoretical evaluation of the experimental material on the basis of the lattice theory yields a reduction in the enthalpies of mixing up to 10% and an increase in the volumes of mixing (<0) up to 50% when ? OH is replaced by ? AC. For the treatment of end-group effects, the solubility parameter theory, when combined with the concept of molar attraction constants, presents several advantages: In particular it is possible to describe the phase separation behaviour of the different oligomer mixtures simply by means of solubility parameters and molar volumes of the different segments and end-groups and to forecast the presence or absence of a chain-length of optimum miscibility.     

Polymeric prodrugs, 8. Synthesis and hydrolytic behaviour of dextran-bound anticancer agents

3-Chloro-2-hydroxypropyl ether of dextran ( 3a ) and succinyldextran ( 4a ) were prepared and used for coupling the anticancer agents 6-purinethiol and 5-fluorouracil. The “in vitro” drug liberation was measured at pH 7,2 and 8,8. The release rate from the dextran conjugates was compared with that of the poly(1-vinyl-2-pyrrolidone-co-maleic acid) derivatives of these drugs. The effect of the macromolecular chain on the hydrolytic behaviour of the polymer-bound drugs was clearly detected.     

Characterization of chemical stimuli for the penetration ofschistosoma mansoni cercariae

The mode of action of chemical substances which trigger the penetration ofS. mansoni cercariae into agar substrata is studied. The effectiveness of these substances is largely independent of their polarity and water solubility. Thus, they do not seem to act by a passive membrane permeation process, but they may interact with specific receptor sites, which are characterized. The receptor sites seem to respond to the following chemical characteristics of the stimulating aliphatic hydrocarbon chain: Carboxylic end group, lipophilic end group, chain length,cis- double bond. The penetration stimulating substances cause, even in cercariae in free water, a transformation of the tegument, manifested as a reduction of the Cercarienhüllen-Reaktion and a loss of osmotic protection.     

Carboxyl-terminated poly(vinyl alcohol). Chain transfer of methyl propionate to vinyl acetate

Poly(vinyl acetate) was prepared at 60°C with benzoyl peroxide by using methyl[carbonyl-¹⁴C] propionate as chain transfer agent and solvent. The resulting polymer was hydrolysed to poly(vinyl alcohol) (PVAL) having carboxyl end groups and the average number of carboxyl groups per chain was unambiguously determined by comparing the activity of the polymer to that of the methyl propionate. An average density of 1,5 carboxyl groups per chain was found for poly(vinyl alcohol) prepared from poly(vinyl acetate) of DP 80 – 90. Other methods of end group analysis for carboxyl groups in PVAL are discussed.     

Biokinetics of transdermal therapeutic medicinal form of phenazepam

We studied the rate of phenazepam absorption into the blood and its transport to the brain from a transdermal therapeutic system and bioavailability of the drug in this system. Hydrogel matrix consisting of polyvinyl alcohol and 1,2-propylene glycol was used for application. Transdermal application of 0.1–0.4 mg phenazepam in a dose of 14 mg/kg provided a stable level of this drug during application interval (1–48 h), while its bioavailability for blood plasma and brain was 0.63 and 0.2, respectively (determined for 0.4 mg phenazepam). The rate of drug penetration into the blood and brain was 46 and 60 ng/ml/h, respectively. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 130, No. 12, pp. 633–635, December, 2000     

Synthesis and copolymerization of macromonomers based on 2-nonyl- and 2-phenyl-2-oxazoline

Several macromonomers were prepared by cationic ring-opening polymerization of 2-nonyl- and 2-phenyl-2-oxazoline using different techniques of functionalization. Introduction of the unsaturated functional group directly via a suitable termination agent proved to be superior to the use of a phenol-functionalized initiator and to the introduction of hydroxyl end groups via hydrolysis of the reactive cationic chain end and subsequent esterification with methacryloyl chloride. The macromonomers were characterized by spectroscopic techniques as well as GPC. One of the 4-vinylbenzyl-terminated macromonomers was copolymerized with MMA in different ratios. The copolymerization parameter r₁ was determined to be 0.75. The resulting graft copolymers were characterized regarding number of grafts per chain, molar mass, and glass transition temperature.     

Oligomer-oligomer incompatibility, 2. Oligo(dimethylsiloxane)/oligo(propylene glycol)

The demixing behavior of 20 representatives of the system oligo(dimethylsiloxane)/oligo(propylene glycol) (ODMS/OPG)

1 The prefix “oligo” has been chosen for all products, since the addition or removal of a few monomeric units changes the physical properties considerably (cf. Tab. I), even in the case of the highest molecular weight sample.

is investigated at pressures up to 1 500 bar. The degrees of oligomerization range from 2 to 5 for the first and from 1 to 57, 6 for the second component. The experimental results are compared with those for the previously studied system oligoisobutene/oligo(propylene glycol) (OIB/OPG). In both cases the observed upper critical temperatures T_c increase with the number of monomeric units of the less polar component, whereas they run through a minimum when the number of monomeric units of the glycol is raised. For the present system the T_c values are found to be considerably higher than that of OIB/OPG and the optimum compatibility can normally be observed already between 1 and 7 propylene glycol units as against 50 in the case of OIB/OPG. In the low pressure region T_c of ODMS/OPG is decreased by pressure for all representatives of this system, while enhanced incompatibility has been found with OIB/OPG. For ODMS/OPG the special features of the critical lines are determined by the chain length of OPG, for OIB/OPG by that of OIB. For ODMS/OPG the initial reduction of T_c by pressure is most pronounced with the highest molecular weight oligo(propylene glycol), for which it amounts up to 0,3 K/bar; with increasing pressure and decreasing chain length the effects become smaller. For the lowest molecular weight sample of OPG the critical lines show a vertex at 700–1000 bar. In any case the two systems under consideration behave in an increasingly similar manner as the pressure is raised. The theoretical evaluation and discussion of the above results is performed by analogy with that of the first paper in this series.     

透皮给药研究的新进展

透皮给药安全可控，是无创给药的新途径，有着广阔的市场前景。现有的透皮药物限于小分子和低浓度，角质层屏障使大多数药物难以通过或难以达到有效浓度和有效速率。透皮给药的关键在于促进药物渗透，使药物透皮吸收进毛细血管。促渗手段有：使用化学促渗剂；对药物进行化学修饰制成前体药物；使用物理方法；将药物载入载体。这些方法的原理大致分为三种：改变角质层结构；外力驱动药物；将药物进行修饰或包裹。简要地介绍了增强药物透皮的物理方法和载体方法研究的新进展。     

透皮给药研究的新进展

透皮给药安全可控,是无创给药的新途径,有着广阔的市场前景。现有的透皮药物限于小分子和低浓度,角质层屏障使大多数药物难以通过或难以达到有效浓度和有效速率。透皮给药的关键在于促进药物渗透,使药物透皮吸收进毛细血管。促渗手段有:使用化学促渗剂;对药物进行化学修饰制成前体药物;使用物理方法;将药物载入载体。这些方法的原理大致分为三种:改变角质层结构;外力驱动药物;将药物进行修饰或包裹。简要地介绍了增强药物透皮的物理方法和载体方法研究的新进展。     

The effect of hydrophilic chain length and iRGD on drug delivery from poly(ε-caprolactone)-poly(N-vinylpyrrolidone) nanoparticles

Poly(ε-caprolactone)-b-Poly(N-vinylpyrrolidone) (PCL-b-PVP) copolymers with different PVP block length were synthesized by xanthate-mediated reverse addition fragment transfer polymerization (RAFT) and the xanthate chain transfer agent on chain end was readily translated to hydroxy or aldehyde for conjugating various functional moieties, such as fluorescent dye, biotin hydrazine and tumor homing peptide iRGD. Thus, PCL-PVP nanoparticles were prepared by these functionalized PCL-b-PVP copolymers. Furthermore, paclitaxel-loaded PCL-PVP nanoparticles with satisfactory drug loading content (15%) and encapsulation efficiency (>90%) were obtained and used in?vitro and in?vivo antitumor examination. It was demonstrated that the length of PVP block had a significant influence on cytotoxicity, anti-BSA adsorption, circulation time, stealth behavior, biodistribution and antitumor activity for the nanoparticles. iRGD on PCL-PVP nanoparticle surface facilitated the nanoparticles to accumulate in tumor site and enhanced their penetration in tumor tissues, both of which improved the efficacy of paclitaxel-loaded nanoparticles in impeding tumor growth and prolonging the life time of H22 tumor-bearing mice.     

Enhancing the transdermal delivery of rigid nanoparticles using the simultaneous application of ultrasound and sodium lauryl sulfate

The potential of rigid nanoparticles to serve as transdermal drug carriers can be greatly enhanced by improving their skin penetration. Therefore, the simultaneous application of ultrasound and sodium lauryl sulfate (referred to as US/SLS) was evaluated as a skin pre-treatment method for enhancing the passive transdermal delivery of nanoparticles. We utilized inductively coupled plasma mass spectrometry and an improved application of confocal microscopy to compare the delivery of 10- and 20-nm cationic, neutral, and anionic quantum dots (QDs) into US/SLS-treated and untreated pig split-thickness skin. Our findings include: (a) ～0.01% of the QDs penetrate the dermis of untreated skin (which we quantify for the first time), (b) the QDs fully permeate US/SLS-treated skin, (c) the two cationic QDs studied exhibit different extents of skin penetration and dermal clearance, and (d) the QD skin penetration is heterogeneous. We discuss routes of nanoparticle skin penetration and the application of the methods described herein to address conflicting literature reports on nanoparticle skin penetration. We conclude that US/SLS treatment significantly enhances QD transdermal penetration by 500-1300%. Our findings suggest that an optimum surface charge exists for nanoparticle skin penetration, and motivate the application of nanoparticle carriers to US/SLS-treated skin for enhanced transdermal drug delivery.     

Synthesis of star-shaped polydimethylsiloxanes containing SiO2 core units

Star-shaped polysiloxanes consisting of SiO₂ cores and polydimethylsiloxane (PDMS) branches were successfully prepared by three methods using functionalized solvent-soluble silicates as a starting material. The first method involved the lithiation of a Si? OH functional silicate with butyllithium, followed by reaction with hexamethylcyclotrisiloxane (D₃) and termination with a chlorosilane to afford a star polymer. In this case, the chain ends were substituted with vinyl or Si? OH functional groups. In the second method, a Si? Cl functional silicate was used as the source of the SiO₂ core. A PDMS chain with a lithium silanolate terminal group was reacted with the Si? Cl functional silicate to provide a star polymer. In the third method, a PDMS chain with a diethylamino group at one chain end was reacted with the Si? OH functional silicate to form a star polymer. The Mark-Houwink constant a of the star polymer was 0,74, which is very close to that of a linear PDMS.     

Studies on the preparation and controlled release of redox/pH-responsive zwitterionic nanoparticles based on poly-L-glutamic acid and cystamine

The enhancement of tumor intracellular drug uptake and resistance against nonspecific protein adsorption are essential for an injectable anticancer drug carrier. In the present study, a new type of redox/pH-responsive zwitterionic nanoparticles (NPs) was prepared using poly-L-glutamic acid and cystamine in aqueous solutions under mild conditions. The NPs showed surface charge convertible feature in response to pH change of the solutions. The NPs demonstrated excellent anti nonspecific protein adsorption. In vitro release profiles of the NPs, they showed redox/pH dual sensitivities in vitro release. The effective intracellular delivery behaviors were verified through investigation of cell viability, and confocal laser scanning microscopy observation of HeLa cells after incubation with the DOX-loaded NPs. The NPs were non-cytotoxic and would have potential applications as a drug delivery vehicle for enhancing intracellular uptake of anticancer drugs.     

基于STC12C5S60S2单片机经皮给药系统的设计

背景：经皮给药技术为蛋白质多肽类药物的导入提供了一种方便有效的方式。 目的：研制一种基于微控制器的经皮给药系统,实现药物经皮无创导入的同时维持药物的活性,提高药物的生物利用度。 方法：经皮给药系统以微控制器为核心,采用电致孔导入技术,电离导入技术和超声波导入技术从不同角度克服皮肤屏障,促进药物经皮吸收,在软硬件上合理的设计实现3种机制的协同作用,提高药物导入的效率。 结果与结论：试制出经皮给药系统样机,该系统操作简便,以无创的方式经皮给药可以提高患者的依从性,通过各治疗参数的调节,可用于多种药物的经皮导入,为实现个体化治疗提供可能。     

<Emphasis Type="Italic">In vitro</Emphasis> and <Emphasis Type="Italic">in vivo</Emphasis> evaluation of Bola-surfactant containing niosomes for transdermal delivery

A novel niosome formulation is proposed for topical drug delivery of ammonium glycyrrhizinate, a natural compound with an efficacious anti-inflammatory activity. Niosomes were made up of a new non ionic surfactant, α,ω-hexadecyl-bis-(1-aza-18-crown-6) (Bola-surfactant)-Span 80-cholesterol (2:3:1 molar ratio). Niosome vesicles were prepared with the thin layer evaporation method and were physico-chemically characterized. The tolerability of Bola-surfactant both as free molecules or assembled ion niosome vesicles was evaluated in vitro on cultured of human keratinocyte cells (NCTC2544). Human tolerability was evaluated on volunteers. The ability of Bola-niosomes to promote intracellular delivery was evaluated by confocal laser scanning microscopy (CLSM) studies. Human stratum corneum and epidermis (SCE) membranes were used in vitro to investigate the percutaneous permeation. The anti-inflammatory activity of ammonium glycyrrhizinate was evaluated in vivo on human volunteers with a chemically induced erythema. Experimental data show that Bola-niosomes are characterized by a mean size of ∼400 nm and are able to provide an encapsulation efficiency of 40% with respect to the drug amount used during preparation. CLSM showed that Bola-niosomes were able to promote the intracellular uptake of the delivered substances. Bola-niosomes were also able to significantly improve (p <0.001) the percutaneous permeation of ammonium glycyrrhizinate with respect to both the aqueous drug solution and a physical mixture between unloaded Bola-niosomes and the aqueous drug solution. Bola-niosomes showed a suitable tolerability both in vitro and in vivo. Ammonium glycyrrhizinate-loaded Bola-niosomes determined a significant (p <0.001) and noticeable improvement of the in vivo anti-inflammatory activity of the drug. An effective example of conjugating innovative colloidal carriers, coming from pharmaceutical nanotechnology, and therapeutically effective natural compounds, coming from traditional medicine, was reported. Part of this research was presented at the 33rd Annual Meeting of the Controlled Release Society in Vienna, Austria, July 22–26, 2006.     

Effect of buparvaquone on the expression of interleukin 2 receptors inTheileria annulata-infected cells

Theileria annulata-infected cells were cultured in the presence or absence of human recombinant interleukin 2 (hrIL-2). This growth factor proved to be capable of enhancing the growth of the infected cells: its effect was marked, particularly when the cells were seeded at low densities, and it varied from cell line to cell line. The infected cells produced a factor that possessed the biological activities of IL-2, since their supernatants could enhance the proliferation of concanvalin A-stimulated (Con A) blasts. The reactivity of the parasitized cells to hrIL-2 was abolished following their treatment with the antitheilerial drug buparvaquone. In addition, the drug inhibited the binding of¹²⁵I-IL-2 toT. annulata-infected cells but failed to suppress its binding to Con A blasts. Northern blot analysis revealed that the drug had no effect on the expression of the alpha chain of the IL-2 receptor (IL-2R). Therefore, it is possible that buparvaquone interferes with the expression of the beta chain of the IL-2R. The role of IL-2 and the IL2R in the permanent proliferation ofT. annulata-infected cells is discussed.This work was supported by grant Ah 41/1-2 from the Deutsche Forschungsgemeinschaft     

Preparation and polymerization of dimethylamino(methyl)styrenes

Three isomers of methylstyrene derivatives with a dimethylamino group in ortho position to the methyl group were prepared through the coupling reaction of the corresponding Grignard reagent and vinyl bromide using a Pd(0) catalyst, and their radical and anionic polymerization was examined. Monomer reactivity ratios in the radical copolymerization with styrene indicate that 3-dimethylamino-4-methylstyrene (3-DMA-4-MS) and 4-dimethylamino-3-methylstyrene (4-DMA-3-MS) have a higher reactivity than styrene, while the reactivity of 3-dimethyl-amino-2-methylstyrene (3-DMA-2-MS) is lower than that of styrene. The ¹³C NMR chemical shift of vinyl carbons as well as the e-values indicate that the electron density at the vinyl carbons of 3-DMA-4-MS and 4-DMA-3-MS is increased by the electron donating effect of the dimethylamino group, which results in lower reactivity of the monomers in anionic polymerization. The anionic copolymerization with 1,1-diphenylethylene gave an alternating copolymer. In the anionic polymerization of 3-DMA-2-MS, proton transfer reaction from the methyl group to the propagating chain end occurred to some extent to incorporate o-phenylene units in the chain.     

Biological monitoring of three antithrombotic drugs: single dose therapy

A randomised study using 40 New Zealand White male rabbits was performed to compare the effects of three antithrombotic drugs on eight clinical haemostatic function tests. The animals were divided into four treatment groups. The treatment groups were saline (control), unfractioned heparin (UFH), low-molecular-weight heparin (LMWH), and recombinant hirudin (r-hirudin).Blood samples were collected 2 and 12 h after administration of the drugs. The following tests were performed: bleeding time (BT), platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen concentration (Fg), antithrombin III (ATIII), and antifactor Xa activity (antiXa activity). Effects attributable to drug treatment for each analyte were determined by comparison with the control group.At 2 h after medication, in the UFH treated group, TT was moderately prolonged (p<0.05) and antiXa activity was significantly higher (p<0.05) than the respective values of the control group. In the LMWH-treated group the antiXa activity was significantly higher (p<0.01) than that of the control group. In the r-hirudin-treated group, the APTT and TT were significantly prolonged (APTT,p<0.01; the TT samples did not clot) when compared to the control group. However, 12 h after administration, no significant differences (p>0.05) between groups were observed for any of the studied analytes. It might be concluded that the antiXa assay has the potential of being a sensitive screen for heparin therapy and that the absence of changes in the bleeding time, antithrombin III, and antiXa assays —with a markedly prolonged thrombin time - indicates that,in vivo, r-hirudin acts as a specific inhibitor of thrombin.