Etude des facteurs conditionnant l'absorption percutanee des alcools incorpores dans des melanges eau-monooleate de sorbitanne polyoxyethylene-myristate d'isopropyle

Percutaneous absorption of ethanol, butanol and octanol is studied in vitro on skin of hairless rats. Alcohols are introduced in various vehicles prepared with water-isopropyl myristate-polyoxyethylene sorbitan monooleate (Tween 80).In aqueous or isopropyl myristate solution, the permeability constant of alcohols increases in the same way as their partition coefficient, stratum corneum/vehicle. The addition of Tween 80 to the aqueous or isopropyl myristate solutions reduces the permeability constant of alcohols when they are initially poorly soluble in the pure solvent. The intensity of the effect is proportional to the quantity of surface-active agent added to the solvent and decreases with the stratum corneum/vehicle partition coefficient.In ternary systems with an external aqueous phase, results are similar to those obtained with water-Tween 80 solution. So percutaneous absorption of alcohols in a two phase mixture seems to be a function of the affinity of alcohols for the aqueous phase which are in contact with the stratum corneum.Absorption of alcohols is not modified by the viscosity of the various vehicles studied.     

An investigation of the interfacial interaction between poly(acrylic acid) and glycoprotein

The swelling behaviour of poly(acrylic acid) microspheres, produced from poly(acrylic acid) crosslinked with maltose, was investigated as a function of time by using a laser diffraction spectrometer. Swelling was also studied in various pH glycoprotein solutions. Microscopy revealed confirmatory evidence of interfacial film formation when microsphere hydration occurred in a pH 5 glycoprotein solution. ATR-FTIR spectroscopy was used to determine the diffusion coefficient of water through the interfacial film existing at the poly(acrylic acid) glycoprotein solution interface. Both processes exhibited a pH dependency with rates decreasing in the sequence pH 7>6>5=4.     

Impregnation and release of aspirin from chitosan/poly(acrylic acid) graft copolymer microspheres

The purpose of this study was to produce aspirin-impregnated microspheres of chitosan/poly(acrylic acid) copolymer in order to evaluate the release characteristics as a function of pH, simulating the fluids in the gastrointestinal tract. Chitosan microspheres were obtained by the coacervation-phase separation method, induced by the addition of a non-solvent (NaOH 2.0 M solution). The microspheres were cross-linked with glutaraldehyde, reduced with sodium cianoborohydride and grafted with poly(acrylic acid). The impregnation of aspirin into chitosan/poly(acrylic acid) copolymer microspheres was achieved by the dissolution of the drug in water:ethanol (2:1), which was adsorbed by the microspheres for 24h at 25 degrees C. The efficiency of aspirin impregnation was high (approximately 94%). The approach employed herein in the production of aspirin-impregnated microspheres using chitosan/poly(acrylic acid) can be a suitable drug-release control system.     

Impregnation and release of aspirin from chitosan/poly(acrylic acid) graft copolymer microspheres

The purpose of this study was to produce aspirin-impregnated microspheres of chitosan/poly(acrylic acid) copolymer in order to evaluate the release characteristics as a function of pH, simulating the fluids in the gastrointestinal tract. Chitosan microspheres were obtained by the coacervation-phase separation method, induced by the addition of a non-solvent (NaOH 2.0 M solution). The microspheres were cross-linked with glutaraldehyde, reduced with sodium cianoborohydride and grafted with poly(acrylic acid). The impregnation of aspirin into chitosan/poly(acrylic acid) copolymer microspheres was achieved by the dissolution of the drug in water:ethanol (2:1), which was adsorbed by the microspheres for 24 h at 25 °C. The efficiency of aspirin impregnation was high (~94%). The approach employed herein in the production of aspirin-impregnated microspheres using chitosan/poly(acrylic acid) can be a suitable drug-release control system.     

The retention of 14C-labelled poly(acrylic acids) on gastric and oesophageal mucosa: an in vitro study.

Polymers that bind from solution onto gastric mucosa can be used either as a means of facilitating localised drug delivery, or can act as therapeutic agents in their own right (e.g. by forming a protective layer or by inhibiting enzymes). In our previous study [Int. J. Pharm. 236 (2002) 87], the binding and retention of labelled poly(acrylic acid)s on sections of gastric mucosa from pigs was evaluated using 'dynamic flow' conditions and a high molecular weight poly(acrylic acid) was found to bind most avidly. In the current study, 3% solutions of 'low', 'high' and 'ultra high' molecular weight polymers were evaluated in the 'dynamic flow' model for their ability to bind to tissues from the fundic and pyloric regions of the stomach and the oesophagus of pigs. All the polymers tested were retained on each mucosa for extended periods; the high and ultra high molecular weight polymers showed the greatest retention. Examination of the kinetics of polymer elution suggested that two fractions exist, 'bound' and 'unbound' polymer, showing differing retention profiles. The high molecular weight polymer showed the greatest retention on pyloric tissue, particularly on the upper sections. The retention of the ultra high and high molecular weight polymer was similar on the fundic and oesophageal mucosa, and the distribution was even across the tissue. It was concluded that poly(acrylic acid) binding from solution presents a therapeutic opportunity, and the differences in binding and retention of the polymers on the different mucosae could present an opportunity for targeting.     

Mucopolysaccharides in aqueous solutions: effect of ionic strength on titration curves

We study the changes taking place in hyaluronic acid, chondroitin 4-sulfate (C4-S) and condroitin 6-sulfate (C6-S), at ionic strengths of 0.10, 0.15, and 0.20 in NaCl, in a neutralization process in aqueous solution. We apply the equation of Henderson Hasselbalch modified for polyelectrolytes and evaluate the changes in the electrostatic free energy starting from the pK curves as a function of the dissociation degree. For a dissociation degree next to 0.4 corresponding to the -COOH group of the hyaluronic acid, we observed a change in the conformation of the three glycosaminoglycans studied. This conformational change takes place as a consequence of the break of intramolecular links and the beginning of the ionization process. The macromolecules in solution show a structure of random coil sufficiently expanded so that the interaction among the close ionizable groups is negligible.     

An in vitro model for investigating the gastric mucosal retention of 14C-labelled poly(acrylic acid) dispersions

Polymers that bind from solution onto gastric mucosae can be used as a means of facilitating localised drug delivery, or act as therapeutic agents in their own right (e.g. by forming a protective layer or by inhibiting enzymes). Previous workers have used semi-quantitative methods to identify the ability of commercially available poly(acrylic acid)s to bind to gastric mucosa. In this study, the binding and retention of labelled poly(acrylic acid)s to sections of gastric mucosa from the pyloric region of pigs stomach were evaluated using 'static' and 'dynamic flow' test systems. Dispersions (3%) of 'low', 'high' and 'ultra high' (cross-linked) polymers were seen to adhere to porcine pyloric mucosa after exposure and rinsing in the 'static' system. The high molecular weight polymer showed the greatest retention in the 'dynamic' test system when washing continuously with simulated gastric acid. Changing the pH of the dispersions from 4.3 to 6.2 had little effect on polymer retention. It was concluded that polymers that were sufficiently mobile in solution to spread on, and interact with, the mucosal surface, but had a sufficiently high molecular weight to form viscous solutions and/or bioadhere to the mucosa, may be retained on the mucosal surface for the longest periods.     

Effect of some anionic polymers on pH of triethanolamine aqueous solutions

One of the suggested approaches in the management and prophylaxis of acne involves binding of free fatty acids in the form of soap with alcoholamines. Due to a possible irritating effect of alcoholamines associated with a relatively high pH of their aqueous solutions, complexation of alcoholamines with acid polymers is advocated. Triethanolamine is one of the best recognized alcoholamines. It was conventionally neutralized with Carbopols, Eudragits, alginic acid and pectin. During neutralization of polymer dispersions with triethanolamine, variations in the course of the neutralization curve have been observed among individual macromolecular compounds. The pH of 0.1 mol/l triethanolamine solution reaches 10.51, while following a complete neutralization with anionic polymers, such as Carbopols, Eudragits, alginic acid and pectin, pH ranges from 3.88 for systems neutralized with alginic acid to 8.50 for the system neutralized with Eudragit S-100. Complexation of triethanolamine with anionic polymers decreases its pH, and it is possible to find such pH range in which pH of the preparation containing the polymer and triethanolamine will correspond to the physiological pH of the skin.     

Studies of neutralizing properties of antacid preparations. Part 3: Constant pH neutralization of hydrochloric acid by hydrotalcite

The neutralization reaction of hydrochloric acid by powdered hydrotalcite (HT) was studied by pH-stat method in the range of pH from 3.0 to 4.8. The neutralization process was examined by monitoring the appearance of aluminium and magnesium ions in the reaction medium, by determination of the chloride concentration in solution and by IR analysis of partially neutralized HT. The mechanism of acid neutralization of HT is discussed.     

Chelation in Metal Intoxication XXIX: α-Mercapto-β-aryl Acrylic Acids as Antidotes to Mercury (II) Toxicity

Abstract: α-Mercapto-β-(2-furyl) acrylic acid (MFA), α-mercapto-β-(phenyl) acrylic acid (MPA), α-mercapto-β-(2-hydroxyphenyl) acrylic acid (MHA), α-mercapto-β-(4-methoxyphenyl) acrylic acid (MMA), β-1,2-phenylene di-α-mercapto acrylic acid (1, 2-PDMA) and β-1, 4-phenylene di-α-mercapto acrylic acid (1, 4-PDMA) enhanced faecal excretion and reduced liver, spleen and blood burden of inorganic mercury when administered (0.5 m mol/kg, in two split doses) 24 hr after Hg (II) (1 mg/kg) in rats. MFA, MPA, MHA and MMA were also effective in lowering renal Hg mainly from the cytosol, without any significant increase in urinary excretion of Hg. The results indicate that all the mono-mercapto acrylic acids including MFA were more effective than di-mercapto acrylic acids and act through the mechanism characteristic of thiol chelators, that is, mobilization of Hg as their complexes, contrary to the reported observation that MFA acts through the induction of metallothionein.     

In vitro acid reactivity of three commercial antacid tablets.

The in vitro acid reactivity of three commercial brands of aluminum and magnesium hydroxide antacid tablets was determined by two methods. A pH-stat test was used to examine the rate and extent of acid neutralization at a constant pH of 3.0. A modified Rossett-Rice test was used to record the length of time during which the antacid products maintained the pH of a simulated gastric solution at between 3.0 and 5.0. Acid neutralization by product A was faster and more complete than that by product B or C. The percent of theoretical acid consuming capacity at 30 minutes of product A (86.8%) was significantly greater than that of product B (56.1%) and product C (57.0%) tablets. The 32-minute Rosett-Rice time A was significantly longer than the 16- and 12-minute times of products B and C, respectively. The differences observed may be attributed to different reactivities of the raw materials used in the products, or formulation and processing variables. It is not known how the data relate to in vivo performance.     

Drug release from the enzyme-degradable and pH-sensitive hydrogel composed of glycidyl methacrylate dextran and poly(acrylic acid)

Hydrogels composed of glycidyl methacrylate dextran (GMD) and poly(acrylic acid, PAA) were prepared by UV irradiation method for colon-specific drug delivery. GMD was synthesized by coupling of glycidyl methacrylate to dextran in the presence of 4-(N,N-dimethylamino)pyridine. GMD was photo-polymerized by ammonium peroxydisulfate as initiating system in phosphate-buffered solution (0.1 M, pH 7.4). And then, acrylic acid monomer was added and subsequently heat-polymerized by 2,2'-azobisisobutyronitrile as an initiator. The hydrogels exhibited high swelling ratio (about 20) at 37 degrees C, and showed a pH-dependent swelling behavior. In addition, the swelling ratio of the hydrogel was remarkably enhanced to about 45 times in the presence of dextranase at pH 7.4. The swelling-deswelling behavior proceeded reversibly for the GMD/PAA hydrogels between pH 2 and pH 7.4. Release of 5-aminosalicylic acid from the GMD/PAA hydrogels was evaluated in simulated gastrointestinal pH fluids in the absence or presence of dextranase. We concluded that the hydrogels prepared could be used as a dual-sensitive drug carrier for sequential release in gastrointestinal tract.     

新型丙烯酸树脂肠溶包衣材料的合成与应用

用自由基溶液共聚合的方法合成了3种有不同羧基含量的pH敏感性甲基丙烯酸甲酯(MMA)和甲基丙烯酸(MAA)二元共聚物以及MMA,MAA与丙烯酸丁酯(BA)三元共聚物;将合成物用作萘普生微丸的包衣材料进行包衣,测定萘普生包衣微丸在不同pH缓冲溶液中的溶出度。结果表明:通过改变反应单体中MAA的含量,可制备有不同酸值的丙烯酸树脂;包衣微丸的萘普生溶出度与溶出介质的pH值和包衣材料的酸值密切相关,萘普生在其用作包衣材料制备的微丸中只有在较高pH值的缓冲介质中才有较高的溶出度和溶出速率;MMA,MAA和BA的三元共聚物本身具有可塑性,在用作包衣时可不再外加增塑剂。     

Mecanisme de l'action analgesique des morphiniques: Inhibition de la liberation d'acetylcholine au niveau du systeme nerveux central

Mechanism of the analgesic action of morphine-like drugs: inhibition of acetylcholine release at the level of the central nervous systemThe localisation in the central nervous system of cytoglycopenic substances such as 2-deoxy-D-glucose or insulin is accompanied by a vagal stimulation, expressed in the periphery by an increase of digestive secretions. The same localization in the central nervous system of morphine-like analgesics has led to the study of a possible interference, at that level, of these two types of agonists.The external pancreatic secretion of rats, anesthetized with urethane, was primarily used as a control of possible changes of the vagal stimulation of central origin, induced by 2-deoxy-D-glucose.The hypersecretion produced by this agent is suppressed by a previous injection of morphine, methadone, or codeine. Phenobarbital and imipramine decrease the induced hypersecretion of the pancreas. In the case of the first group, the antagonists nalorphine or naloxone reversed the observed effects, while they do not act on the effects in the second group. Morphinic tolerance also prevents the appearance of the inhibitory effect.Thebain, chlorpromazine, prochlorperazine, metoclopramide, and a soluble derivative of aspirin do not modify the centrally induced vagal pancreatic hypersecretion.These facts combine in favour of a primary action of the acute effects of central analgesics at the cholinergic receptors of the brain. The morphine-like derivatives interrupt (probably at the hypothalamus) the cholinergic transmission of painful stimuli to the cortex, thus suppressing the perception of pain. Moreover, it is likely that other direct or indirect effects of morphine-like drugs on the cerebral amines contribute to the centrally induced inhibitory action of transmission of painful sensations.The lack of activity of aspirin on pancreatic secretion is in keeping with the hypothesis ascribing the antalgic action to a peripheral effect.Relevant effects of psychotropic agents and of the antiemetic studied elsewhere are discussed.     

Quantitative Determination of the Extent of Neutralization of Carboxylic Acid Functionality in Carbopol® 974P NF by Diffuse Reflectance Fourier Transform Infrared Spectrometry Using Kubelka-Munk Function

Purpose. The purpose of this study was to develop an analytical method for the quantitative determination of the extent of neutralization of the carboxylic acid function in Carbopol^® 974P NF using Diffuse Reflectance Fourier Transform Infrared Spectroscopy (DRIFT) with Kubelka-Munk function analysis. Methods. Carbopol^® 974P NF is a high molecular weight, chemically crosslinked polymer of acrylic acid, that has the C=O stretching band of the unionized carboxylic acid function at 1695 cm^–1. The quantitative determination of the extent of neutralization of the carboxylic acid function in Carbopol^® 974P NF is based upon the asymmetrical C =O stretching of the carboxylate anion at 1570 cm^–1 measured by DRIFT Spectroscopy. Results. To overcome spectral differences arising from sample preparation (powders, granules and tablets) and in an effort to increase the precision of the analytical method, the following approaches were used: (1) an internal standard, (2) first derivative of the spectrum to eliminate the effect of baseline drift and (3) the ratio of the first derivative of the C=O stretch of the carboxylate anion peak (1570 cm^–1) in the neutralized Carbopol^® 974P NF to that of the peak of the internal standard (866 cm^–1). The above data treatment techniques proved to be superior to the usual methods of peak height or peak area. The calibration curve of the ratio of the first derivative (1570 cm^–1/866 cm^–1) was a linear function of the mass of sodium carboxylate over the range from 0.0% to 100.0% neutralization of the carboxylic acid function in Carbopol^® 974P NF (Fig. la). No particle size or sample preparation effects were noted within the experimental error. Conclusions. DRIFT Spectroscopy using the Kubelka-Munk function is a powerful tool for the routine determination of the extent of neutralization of the carboxylic acid function in Carbopol^® 974P NF in complex pharmaceutical formulations.     

The biodistribution and metabolic fate of [11C]acrylic acid in the rat after acute inhalation exposure or stomach intubation

Rats were nose-exposed to an atmosphere containing gaseous [11C]acrylic acid for 1 min and sacrificed 1.5 and 65 min later. At 1.5 min 28% of the administered radiolabel was associated with the snout of the exposed animal. The biodistribution data indicated the gastrointestinal tract as the major site of absorption of acrylic acid after inhalation exposure. Therefore, rats were also stomach intubated with an aqueous solution of [11C]acrylic acid and sacrificed at 1.5, 10, 20, 40, and 65 min after intubation. The absorption of acrylic acid from the stomach was rapid, as was its subsequent metabolism. Carbon-11 was rapidly eliminated from both nose-exposed and stomach-intubated animals as 11CO2, with about 60% of the administered dose eliminated 1 h after administration. A portion of the radiolabel was also eliminated via the renal system.     

Cation exchange resins as pharmaceutical carriers for methylene blue: Binding and release

Methylene blue is a competitive inhibitor of the glutathione reductase of Plasmodium falciparum and is used in combination with other antimalarial drugs leading to a renaissance of methylene blue in malaria therapy. Its bitter flavour and tissue colouring property impair compliance, especially in children. These problems may be solved by binding the cationic methylene blue to cation exchange materials as pharmaceutical carriers in order to mask the undesirable properties. However, such carriers are only useful if the antimalarial is released under physiological conditions. The binding to seven cation exchange resins was studied. Ion exchangers on acrylic or methacrylic acid basis bound between 1.54 and 2.16 g methylene blue chloride trihydrate per gram ion exchanger. Polymers on divinylbenzene or styrene basis with sulphonic acid groups bound 306 and 384 mg of methylene blue chloride trihydrate per gram ion exchanger. In aqueous solution at pH of 1.5, nearly all bound methylene blue was released. The release of methylene blue from (meth)acrylic acid polymers in the presence of proteins and fat was not affected. From these data ion exchangers present a promising group of pharmaceutical carrier for the safe and compliant drug administration of methylene blue to children.     

Studies of neutralizing properties of antacid preparations. Part 7. 27Al NMR studies of aluminum species formed during acid dissolution of some antacid preparations

Neutralization of some aluminum containing antacid preparations with hydrochloric acid were studied by 27Al NMR spectroscopy. It has been found that the nature and composition of aluminum species produced during the acid dissolution of preparations depends upon the substance used and on the pH at which the neutralization reaction proceeds. The results are consistent with the presence of both monomeric and polymeric species in solution containing aluminum in octahedral and tetrahedral environments.     

(αMe)Aun: a highly lipophilic,chiral, Cα‐tetrasubstituted α‐amino acid. Incorporation into model peptides and preferred conformation

Abstract: Using a chemo‐enzymatic approach we prepared the highly lipophilic, chiral, C^α‐methylated α‐amino acid (αMe)Aun. Two series of terminally protected model peptides containing either d ‐(αMe)Aun in combination with Aib or l ‐(αMe)Aun in combination with Gly were synthesized using solution methods and fully characterized. A detailed solution conformational analysis, based on FT‐IR absorption, ¹H NMR and CD techniques, allowed us to determine the preferred conformation of this amino acid and the relationship between chirality at its α‐carbon atom and screw sense of the helix that is formed. The results obtained strongly support the view that d ‐(αMe)Aun favors the formation of the left‐handed 3₁₀‐helical conformation.     

Polynucleotide analogues. Copolymers of vinyl bases with acrylic acid, methylacrylic acid, acrylamide, and 1-vinylpyrrolidone.

Preliminary studies are reported on the synthesis and testing of substituted vinyl polymers that are designed to have sequence specific affinity for polyribonucleic acids. Copolymers of 1-vinyluracil with acrylic acid, 2-methylacrylic acid, or 1-vinyl-2-pyrrolidone were prepared by gamma-irradiation to give the respective polymers 1,3, and 4. Similarly, 9-vinyladenine yielded copolymeric products 5 and 6 with acrylic acid or 2-methylacrylic acid. Radical initiated polymerization of 9-vinyladenine with acrylamide yielded copolymer 7. The products were characterized by elemental analysis and ultraviolet, infrared, and nuclear magnetic resonance spectroscopy. No hypochromicity could be detected on mixing polymers 1-4 with poly(adenylic acid). The acrylic acid copolymer 2 containing a high ratio of vinyluracil was a potent inhibitor of poly(adenylic acid) coded polylysine synthesis in an in vitro system. Polymers 6 and 7, containing a high proportion of vinyladenine, inhibited poly(uridylic acid) coded poly(phenylalanine) synthesis.