Characterisation of quaternary polymethacrylate films containing tartaric acid, metoprolol free base or metoprolol tartrate

The aim of this study was to better understand the interactions between metoprolol tartrate and quaternary polymethacrylate (Eudragit RL and Eudragit RS) films. For reasons of comparison, polymeric films containing the free base metoprolol or free tartaric acid were also prepared. Systems containing various amounts of the free base, free acid and the salt were characterised using polarising light microscopy, X-ray powder diffraction, differential scanning calorimetry and mechanical analysis (puncture test). The free base is the most efficient plasticiser of the three species for Eudragit RL and Eudragit RS, but with limited solubility in the polymers. Due to its hydrophobicity, it can interact with the hydrophobic polymer backbones. In contrast, in salt containing films, ionic interactions between the positively charged quaternary ammonium groups and the negatively charged tartrate anions apparently occur, this being suggested by the different effects on Eudragit RL versus RS, which have different contents of quaternary ammonium groups. Importantly, the combination of acid and base as a salt avoids drug precipitation at higher metoprolol contents. The obtained new insight into the occurring drug-polymer interactions can help to facilitate the development/optimisation of this type of dosage forms.     

Synthesis and biological activities of diquaternary dipiperazinium salts containing dithiocarboxyl groups.

A series of diquaternary dipiperazinium salts containing dithiocarboxyl groups 6a-f and 9 were synthesized and evaluated for their analgesic and sedative activities. The result showed that the presence of two quaternary ammonium cations and the distance between them are very important for the activities of the salts. Compound 6b exhibited the best activities (at dose 2 mg/kg, analgesic, 57%; sedative, 59%) among compounds 6a-f. Compound 9 not only showed the most potent analgesic (85.4%, dose 1 mg/kg) and sedative (93.1%, dose 1 mg/kg) activities, but also exhibited anticancer activity against KB (68.7%, dose 10 microM).     

Functional group contribution of bile salt molecules to partitioning of a quaternary ammonium N,N-dimethyl derivative of propranolol

A quaternary ammonium N,N-dimethyl derivative of propranolol was extracted from pH 7.4 phosphate buffer into 1-octanol as ion-pairs with 12 different bile salts. The binding number, n, and the extraction constant, Ke, were determined. To obtain group contribution values of the bile salt molecule from the ion-pair extraction data, multiple linear regression analysis by the Free-Wilson technique was applied. The results showed that the fundamental premise of the functional group's contribution to the ion-pair extraction is valid. The functional groups of counterions contribute to the partitioning of the ammonium compound independently and additively in this system.     

Novel Chromatographic methods for monitoring quaternary ammonium compounds in biological fluids

Three novel Chromatographic methods for the determination of quaternary ammonium compounds with biomedical applications are presented and their sensitivity, selectivity, reproducibility and applicability for different groups of the compounds are compared. The first one is a gas Chromatographie method for those compounds with three identical short-chain alkyl groups attached to the nitrogen atom and describes a reproducible dealkylation in the injection port of the gas Chromatograph to their respective tertiary amines. An alkali-flame ionisation detector is used as a sensitive and selective detector. The second one is a method for quaternary ammonium compounds with an ester function and is based on hydrolysis and derivatisation of the resulting acids with pentafluorobenzyl bromide, followed by gas chromatography with electron capture detection. The third method is based on ion-pair adsorption high performance liquid chromatography by adding an inorganic counter-ion to the mobile phase.     

Formation and urinary excretion of cyproheptadine glucuronide in monkeys, chimpanzees, and humans

The urinary excretion of cyproheptadine glucuronide (a quaternary ammonium glucuronide) was studied in monkeys, chimpanzees, and humans after a single 5-mg oral dose of cyproheptadine. Humans and chimpanzees excreted, over a 48-hr period, an average 12.4 and 8.6% of the dose, respectively, as cyproheptadine glucuronide. Various species of monkeys excreted less than 0.5% of the dose as the quaternary ammonium glucuronide conjugate. According to these and previously published data, these unusual drug metabolites are excreted in the urine in relatively large amounts only in higher primates.     

The size of hydroxyl groups in solution and the changes in size associated with the ionization of phenolic, carboxylic and amino groups in phenolic quaternary ammonium salts, nicotine and some amino acids: possible implications for drug-water and drug-receptor interactions.

Size in solution can be expressed either as the apparent molal volume at infinite dilution (phi 0v) amd the concentration parameter (j) or as the partial molal volume of the solute at infinite dilution (V0(2)) and the concentration parameter for the solute or solvent (qs or qw). Although calculated differently, these are derived from the same results and are equivalent. From measurement with phenolic quaternary ammonium salts, including compounds with high nicotine-like activity, the apparent size of the hydroxyl group in water is small and variable. Phenolic groups are slightly larger than alcoholic groups, which should be better hydrogen donors. By measuring the volume change associated with ionisation it is possible to measure the size of charged groups such as phenate and carboxylate; these are much smaller than phenolic and carboxyl. Ammonium groups, however, are only slightly smaller than the corresponding amines. The zwitterion forms of amino acids are associated with a minimum in volume but the volume changes increase with chain length from glycine to gamma-aminobutyric acid. Groups separated by less than this distance interact in their effects on water. Decreases in volume or unexpectedly small increments in apparent molal volume represent decreases in entropy which must be taken into account in drug-water-receptor interactions. Although they may be offset by enthalpy changes, they should favour binding because there is more scope for an increase in entropy. This might explain the association of the small apparent size in water of the hydroxyl group in many compounds with its effects of their affinity for receptors.     

Synthesis and evaluation of functional hyperbranched polyether polyols as prospected gene carriers

Hyperbranched polyether polyols have been partially functionalized with quaternary or tertiary ammonium groups. Five derivatives have been prepared bearing 4, 8 and 12 quaternary or 4 and 21 tertiary ammonium groups. The resulting dendritic polymers interact with plasmid DNA affording the corresponding polyplexes. The complexes were physicochemically characterized while their transfection ability was assessed by gel retardation assay, ethidium bromide exclusion assay and cell culture transfection. All the investigated polymers were shown to have marginal to low cytotoxicity in mammalian cells. Transfection efficiency comparable to that of polyethylenimine was exhibited by selected quaternized polymers. However, the introduction of tertiary amino groups on polyglycerol did not improve the transfection of the ineffective parent polymer, despite the fact that the derivatives obtained exhibited additional buffering capacity (sponge effect). The observed transfection efficiency for the quaternized polymers has been attributed to the destabilization of the lysosomal membrane originating from the interaction between the cationic polymers and the anionic moieties located at the membrane. These results are encouraging for the prospective application of these polyols as gene delivery vectors.     

On the mechanism of potentiation of the activity of acetylcholinesterase by some quaternary ammonium compounds

Tetraethylammonium iodide (TEA) increases the maximum velocity of acetylcholine hydrolysis nearly 2-fold whereas it shows purely competitive kinetics when the dipropyl-analogue of acetylcholine (2-acetoxyethyldi-n-propylmethylammonium iodide) is the substrate. Unlike acetylcholine, the dipropyl-analogue does not have deacetylation as its rate determining step and this is further evidence that quaternary ammonium compounds potentiate acetylcholinesterase by accelerating the deacetylation step. The effects of 22 quaternary ammonium compounds on the rate of hydrolysis of acetylcholine, phenyl acetate and dimethylcarbamylacetylcholinesterase have been examined. The acceleration of deacylation by quaternary ammonium compounds was found to have a high degree of structural specificity. Possible mechanisms for this phenomenon are discussed in the light of the structure-action results.     

Effects of cholinesterase inhibitors on the spasmogenic action of acetate esters on rat uterus

Acetate esters, such as phenyl acetate and aspirin, induced atropine-sensitive contractions of isolated uterus only when choline was present. These contractions were selectively and reversibly inhibited by carbamate-type cholinesterase inhibitors, such as neostigmine and eserine, and quaternary ammonium compounds, such as tetraethylammonium and decamethonium. After treatment with organophosphorus cholinesterase inhibitors, such as di-isopropyl fluorophosphate and tetraethyl pyrophosphate, the uterus failed to respond to the acetate esters, even when high concentrations of choline were present. The inhibition of the response of the uterus by organophosphates was effectively removed by pyridine-2-aldoxime methiodide. Pretreatment of the uterus with neostigmine or simultaneous addition of high concentrations of quaternary ammonium compounds prevented the inhibition by organophosphates. The inhibition produced by neostigmine was also reduced by simultaneous addition of quaternary ammonium compounds. These findings suggest that some esterase having an anionic site and an esteratic site, probably cholinesterase, may mediate in the uterine contractions induced by acetate esters in the presence of choline, and that inhibition by organophosphates, carbamates and quaternary ammonium compounds of cholinesterase activity in the preparation may impede the initiation of contractions by the acetate esters in the presence of choline.     

Quantitative correlations between chemical structure and affinity for acetylcholine receptors.

The affinity constants (log K, pA2) of 128 quaternary ammonium compounds belonging to several different series have been correlated linearly with the hydrophobicity (piR) constant, the dipole moment (muR), and the number of hydroxyl groups (nOH) of the side chain; the dependence on the hydrophobicity constant of the quaternary ammonium head (pi-N identical to) is shown to be parabolic. A correlation coefficient of 0.96 is obtained for all the compounds using only 4 independent variables (6 terms). Based on the quantitative correlation obtained, intermolecular forces involved in the drug-receptor interaction are discussed. Further molecular modifications to enhance the affinity to cholinergic receptors are suggested.     

Muscarinic ganglionic stimulants: conformationally restrained analogues related to [4-[[N-(3-chlorophenyl)carbamoyl]oxy]-2-butynyl]trimethylammonium chloride

The synthesis of a series of tertiary and quaternary cyclic analogues (isoarecolinol, dihydroisoarecolinol, arecolinol, and 3-pyrroline-3-carbinol derivatives) of [4-[[N-(3-chlorophenyl)carbamoyl]oxy]-2-butynyl]trimethylammonium chloride (McN-A-343) (1), a selective stimulant of muscarinic receptors in sympathetic ganglia (so-called M1 receptors), is reported. The compounds 3-10 were tested for muscarinic ganglion-stimulating activity by recording blood pressure responses in pithed rats. All tertiary compounds tested had no ganglion-stimulating activity. Among the series of quaternary derivatives, only the isoarecolinol analogues 4a and 4b showed considerable ganglion-stimulating effects, whereas the dihydroisoarecolinol (8), the arecolinol (6a, 6b), and the 3-pyrroline-3-carbinol derivatives (10) were much less potent. Our experiments therefore demonstrate that in this series a quaternary nitrogen atom, unsaturation at C2 of the ammonium side chain, and a certain spatial arrangement of the ammonium and the phenylcarbamate groups are essential for potent M1-receptor stimulating activity.     

抗高血压药物——噻吩、呋喃、苯骈呋喃季铵盐和胍类衍生物的合成

导致血压升高的拟交感胺,不仅具有苯乙胺结构,且一般为伯胺或仲胺。若分子中的胺基由伯、仲胺变为叔胺、季铵时,其药理作用会由升压转为降压,其中季铵盐的降压作用尤为明显。溴苄之铵(Ⅰ)即属此类降压药。     

Uptake of quaternary ammonium compounds into rat intestinal brush border membrane vesicles

In order to elucidate the mechanism by which quaternary ammonium compounds are transported across the gastro-intestinal epithelium, transport of five quaternary ammonium compounds through rat intestinal brush border membrane vesicles was investigated. Transport across the intestinal brush border membrane is only observed when the organic cations possess a hydrophobic tail and their charge is somehow screened by the presence of a bulky group around the charged atom. Transport appeared to be a passive process. Uptake was stimulated by a transmembrane electrical potential difference, but not by an excess of anions like I^? or taurocholate. The implications for the in vivo absorption of quaternary ammonium compounds and for their use as probes for measuring the transmembrane electrical potential difference are briefly discussed.     

中和剂消除增效复合胺消毒剂抑菌活性的研究

目的 选择合适的中和剂消除增效复合胺消毒剂的抑菌作用,避免样品中微生物限度检查造成假阴性.方法 参照《中国药典》2020年版四部微生物限度有关规定,联合薄膜过滤法,分别采用3种中和剂配方去除季铵盐类消毒剂抗菌活性.结果 采用组合配方中和剂(聚山梨酯、皂苷、卵磷脂、组氨酸比例30 ∶ 30∶ 3 ∶ 1)并联合薄膜过滤法...     

Tumour gene expression from C12 spermine amphiphile gene delivery systems

Gene therapy requires safe and efficient gene delivery systems. Towards this aim both the gene formulation and tumour transfection ability of C12 spermine amphiphiles were tested. Five amphiphiles were synthesised and characterised: 1-[N,N-bis(3-aminopropyl)-1,4-butane diamine] dodecane (12G0--a C12 spermine amphiphile), a poly(ethylene glycol) (PEG, MW = 2 kDa) derivative of 12G0, 1,12-[N,N-bis(3-aminopropyl)-1,4-butane diamine] dodecane (12G1--a C12 spermine bolaamphiphile) and N-methyl quaternary ammonium derivatives of both 12G0 (12QG0) and 12G1 (12QG1). All amphiphiles except 12G0, which precipitates, yield nanoparticles in aqueous media with and without DNA. Thus when 12G0 is substituted with either quaternary ammonium or PEG groups it forms nanoparticles both with and without DNA. The minimum nitrogen, phosphate ratio required to completely condense DNA (NP) was inversely proportional to the particles' zeta potential (zeta), NP = 1626/zeta(0.98). Biological testing showed that both PEG and quaternary ammonium groups diminished the membrane lytic ability of these C12 amphiphiles. On intratumoural injection, while PEG groups hamper gene transfer, the quaternary ammonium amphiphile (12QG0) produces tumour confined gene expression that is 80% of that produced by linear poly(ethylenimine) (LPEI, MW = 22 kDa); while the intratumoural injection of LPEI produced significant gene expression in the liver and lung, making 12QG0 suitable for the administration of cytotoxic tumouricidal genes.     

Synthesis,Structure Elucidation and Antimicrobial Properties of New Bis-1,3,4-Oxadiazole Derivatives

Pharmaceutical Chemistry Journal - Four new 1,3,4-bis-oxadiazole derivatives were synthesized, two of them bearing quaternary ammonium salts. The newly synthesized bis-1,3,4-oxadiazoles were...     

Virucidal activity of some quaternary ammonium compounds.

Four different quaternary ammonium compounds were tested by microtechniques for evaluating their activity against the type species of six viral groups very frequently involved in human and animal pathology. Three disinfectants showed good activity against five of the representative viruses under test, while the fourth proved less effective. Poliovirus type 1 was found to be completely resistant.     

Potentiation of acetylcholinesterase by a series of quaternary ammonium compounds

Eleven spiran, and two non-spiran, quaternary ammonium compounds have been examined and some of these compounds found to potentiate the hydrolysis of acetylcholine by acetylcholinesterase at high substrate concentrations. The experiments were made in three reaction media, each differing in its ionic composition. The results obtained in these media differ both quantitatively and qualitatively. The mechanism of the potentiation is discussed in terms of the effect of quaternary ammonium compounds on the deacetylation step of acetylcholine hydrolysis.     

Synthesis, characterization and evaluation of thiolated quaternary ammonium-chitosan conjugates for enhanced intestinal drug permeation

In a previous report quaternary ammonium-chitosan conjugates (N⁺-Chs) endowed with intestinal drug permeability-enhancing properties were described. They are characterized by short pendant chains of n adjacent diethyl-dimethylene-ammonium groups substituted onto the primary amino group of the chitosan (Ch) repeating units. In the present work two N⁺-Chs, one having DS (degree of substitution) = 59.2 ± 4.5%, n = 1.7 ± 0.1 (N⁺(60)-Ch), the other one having DS = 40.6 ± 1.3%, n = 3.0 ± 0.2 (N⁺(40)-Ch) were used to synthesize novel multifunctional non-cytotoxic Ch derivatives, each carrying thiol along with quaternary ammonium groups (N⁺-Ch–SH), with increased potential to enhance transepithelial drug transport. They have been obtained by transforming the residual free amino groups of N⁺(60)-Ch and N⁺(40)-Ch into 3-mercaptopropionamide moieties. The former yielded 4.5 ± 0.7% thiol-bearing groups, the latter, 5.2 ± 1.1% of such groups, on a Ch repeating unit basis. The multifunctional derivatives have improved the ability of the parent N⁺-Chs to enhance the permeability of the water-soluble macromolecular fluorescein isothiocyanate dextran, MW 4400 Da (FD4) and that of the lipophilic dexamethasone (DMS) across the excised rat intestinal mucosa and Caco-2 cell monolayer, respectively. The data from the present work altogether point to a synergism of quaternary ammonium and thiol groups to improve the intestinal drug absorption enhancing properties of the multifunctional Ch derivatives.     

Mechanism of intestinal transport of an organic cation, tributylmethylammonium in Caco-2 cell monolayers

Many quaternary ammonium salts are incompletely absorbed after their oral administration and may also be actively secreted into the intestine. However, the underlying mechanism(s) that control the transport of these cations across the intestinal epithelium is not well understood. In this study, the mechanism of absorption of quaternary ammonium salts was investigated using Caco-2 cell monolayers, a human colon carcinoma cell line. Tributylmethyl-ammonium (TBuMA) was used as a model quaternary ammonium salts. When TBuMA was administrated at a dose of 13.3 imole/kg via iv and oral routes, the AUC values were 783.7±43.6 and 249.1±28.0 μmole·min/L for iv and oral administration, indicating a lower oral bioavailability of TBuMA (35.6%). The apparent permeability across Caco-2 monolayers from the basal to the apical side was 1.3 times (p<0.05) greater than that from the apical to the basal side, indicating a net secretion of TBuMA in the intestine. This secretion appeared to be responsible for the low oral bioavailability of the compound, probably mediated by p-gp (p-glycoprotein) located in the apical membrane. In addition, the uptake of TBuMA by the apical membrane showed a Na⁺ dependency. Thus, TBuMA appears to absorbed via a Na⁺ dependent carrier and is then secreted via p-gp related carriers.