摘要:

AbstractA biophysical model was developed, usingAscaris suumas a model gastrointestinal nematode, to provide quantitative perspectives into the microenvironmental pH within the water-filled, porous, negatively charged cuticle matrix of gastrointestinal nematodes. The central features of the model include (a) the constant rate of excretion of organic acid metabolites across the cuticle, (b) the relationship between cuticle pH and pKaof the organic acids that determines the fraction of unionized and ionized species, and (c) the concentration gradient, mean concentration and buffer capacity within the cuticle that maintain the cuticle pH. The model may be used to predict the extent to which transcuticular absorption of weakly basic and acidic anthelmintics will be affected by transcuticular excretion of organic acid metabolites. Coupled with established models for drug absorption by nematodes and the host gastrointestinal tract, the cuticle pH model provides new insights to the design of drugs with physicochemical properties that favor absorption by nematodes.

ISSN:1061-186X    

DOI:10.3109/10611869409015888

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

AbstractDrug-loaded proteinoid microspheres were freeze-dried to facilitate shipping and handling and to enable long term storage. Heparin was chosen as the model drug in developing the optimum lyophilization process. The factors influencing the integrity of either heparin-loaded or unloaded (‘empty’) proteinoid microspheres during freeze-drying were determined, with emphasis on: selecting an optimum freezing and resuspending temperature; choosing an appropriate cryoprotectant and its optimum concentration in the formulation; and, designing a suitable method for formulating the microspheres. Freezing at/below -70°C was found to minimize damage to the microspheres. Addition of sugars, such as trehalose and lactose, as cryoprotectants, further increased the stability of the heparin-loaded microspheres during freeze-drying. The optimum trehalose or lactose concentrations were determined to be 5% (w/v). Using the optimumized lyophilization process described in this manuscript, microspheres remained intact during freeze-drying. The freeze-dried microspheres were stable for at least three months post-lyophilization.

ISSN:1061-186X    

DOI:10.3109/10611869409015889

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

AbstractPrototype controlled release formulations of ticlopidine hydrochloride were developed, but when administered to humans, these formulations significantly reduced the bioavailability of intact drug in plasma. In order to examine the intestinal permeability characteristics and gastrointestinal metabolism of14C-ticlopidine, we employed anin vitrodiffusion cell system to directly measure the permeation of ticlopidine across various segments of monkey and rabbit intestine. High pressure liquid chromatography was used to determine the amount of intact ticlopidine on both the mucosal and serosal sides of the intestinal tissue.Simulations based upon the known pharmacokinetics of ticlopidine were conducted using STELLA®, a modeling program, to provide insight as to the nature of the decreased bioavailability of these ticlopidine CR dosage forms. These simulations indicate that the absorption of intact ticlopidine is a non-linear phenomena, with inordinately large increases in absorbed intact drug with increases in dose. Conversely, decreases in drug available for immediate absorption, as with the controlled release dosage forms, lead to non-linear decreases in bioavailability. Such a finding is very consistent with the extensive first-pass metabolism suggested from the tissue permeability studies.

ISSN:1061-186X    

DOI:10.3109/10611869409015890

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

AbstractA novel controlled drug release system. Time-Controlled Explosion System (TES) has been developed. TES has a four-layered spherical structure, which consists of core, drug, swelling agent and water insoluble polymer membrane. TES is characterized by a rapid drug release with a precisely programmed lag time; i.e. expansion of the swelling agent by water penetrating through the outer membrane, destruction of the membrane by stress due to swelling force and subsequent rapid drug release. For establishing the concept and development strategy, TES was designed using metoprolol and polystyrene balls (size: 3.2 mm in diameter) as a mo.del drug and core particles. Among the polymers screened, low-substituted hydroxypropylcellulose (L-HPC) and ethylcellulose (EC) were selected for a swelling agent and an outer water insoluble membrane, respectively. The release profiles of metoprolol from the system were not affected by the pH of the dissolution media. Lag time was controlled by the thickness of the outer EC membrane; thus, a combination of TES particles possessing different lag times could offer any desired release profile of the model compound, metoprolol.

ISSN:1061-186X    

DOI:10.3109/10611869409015891

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

AbstractPresent paper proposes a new system to administer triamterene, a sparing potassium diuretic which presents absorption problems when administered as a free powder, due to its low solubility in water.To increase the dissolution rate and subsequent oral bioavailability of this drug, it has been formulated as solid dispersion. This method involves preparation by the melting carrier method using D-mannitol as matrix. These systems were subjected to USP XXII dissolution rate determination. The results revealed a marked dissolution rate increase of included triamterene in solid dispersions when compared with micronized drug. Furtherin vivoassays have demonstrated the absorption efficiency for the proposed systems when referred to pure drug.In vitro-in vivocorrelation between the parameter T80%(from dissolution rate studies) and the pharmacokinetic one Ke, has found to be acceptable. All the results obtained make this system suited for further formulation in the pharmaceutical industry.

ISSN:1061-186X    

DOI:10.3109/10611869409015892

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

AbstractDue to their poor bioavailability after oral administration, the use of gangliosides in medicine is limited to the parenteral route of administration. In the present study, the association with poly(alkylcyanoacrylate) nanospheres and nanocapsules of monosialoganglioside GM1 and other chemically modified gangliosides was investigated with the aim of developing a colloidal drug delivery system suitable for use by the oral route. Our results show that gangliosides can be successfully associated with a biodegradable cyanoacrylic carrier either in the form of nanospheres or as nanocapsules, avoiding any degradation of the ganglioside molecule during the polymerization process. However, the drug-loading was found to be more efficient for nanocapsules. The amount of GM1 incorporated into nanospheres appeared to be dependent on the alkyl chain length of the cyanoacrylic polymer; this amount was however too low for pharmaceutical purposes. In contrast, nanocapsules allowed the attainment of very high drug encapsulation levels, especially with lipophilic derivatives of GM1, where an increase of lipophilicity has been obtained by chemical esterification of the sialic acid residue. Drug release experiments performed in the absence of enzymes indicated that nanocapsules were stable in acid medium, in which no drug release was observed, while their behaviour in basic medium was found to be affected by the composition of the oily phase and the oil/polymer ratio.

ISSN:1061-186X    

DOI:10.3109/10611869409015893

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

AbstractSilica nanoparticles, radiolabeled with75Selenium were coated with 14 types ofω-functionalized surfactants covalently bound to the particle surface. The particles were suspended in phosphate buffered saline (PBS) and injected intravenously via the tail vein of Wistar rats. The animals were sacrificed after 5 different time points (30 min, 2 h, 6 h, 24 h, and 7 d), and two samples of each organ and two blood samples were weighed into vials. The radioactivity of each sample was measured in a LKB-Wallac CliniGamma counter. Coated silica nanoparticles accumulated in the liver at much lower levels than other colloidal drug carriers after short time periods (30 min). The liver accumulation increased after longer time periods due to a natural redistribution process. Surface modification by increasing the hydrophilicity and thickness of coating yielded higher and longer persisting concentrations in the intestine, blood, and the muscles. Initially increased lung concentrations were decreasing with time, propably due to migration of the alveolar phagocytes.

ISSN:1061-186X    

DOI:10.3109/10611869409015894

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

AbstractThe metabolism of Phe-Pro was investigated in Caco-2 cell monolayers, a model of small intestinal epithelium. The results indicate that the majority of Phe-Pro was hydrolyzed during passage from the apical (AP) to basolateral (BL) side. The enzyme responsible for the hydrolysis is prolidase, a cytosolic enzyme. Through kinetic studies of a supernatant enzyme preparation, a Kmof 30.4μM and Vmaxof 38.9 nmol/min per mg of protein were obtained. The enzyme catalyzed hydrolysis was inhibited by proline (66%), Zn++(86%), Cu++(100%), Fe+++(100%), PCMB (89%), and captopril (66%), but not by leucine. We also studied the transcellular transport of Phe-Pro by measuring the amount of Phe in the receiver media. In the presence of a proton gradient (AP pH6, BL pH7.4), the appearance rate of Phe in the BL media after Phe-Pro was loaded apically was at least 100 times faster than that in the AP media after Phe-Pro was loaded basolaterally. The former is also higher than the appearance rate of Phe without a transepithelial proton gradient (pH 6–pH 6) or against a proton gradient (pH7.4–pH6). The rate of appearance of Phe in the BL media (pH7.4) after Phe-Pro was loaded on the AP side (pH 6) was decreased by the presence in the AP media of proline (42%), leucine (40%), and captopril (17%), but not by Zn++. In conclusion, the transmembrane uptake of Phe-Pro is dependent on a proton gradient, and the intracellular metabolism of Phe-Pro is complete via hydrolysis by prolidase.

ISSN:1061-186X    

DOI:10.3109/10611869409015895

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

AbstractOn December 9th and 10th, 1993, the GTRV (Groupe Thématique de Recherche sur les Vecteurs) held a successful symposium in Nancy (France). GTRV is a non profit-making French research association focusing on drug targeting. Based on a multidisciplinary approach, the GTRV rallies scientists both from Universities and well-known French public research organizations (CNRS and INSERM) as well as from the Pharmaceutical and Cosmetic industries. The GTRV is composed of more than 400 members, approximately 40% are from industry. Although most of GTRV members are French, it also includes scientists from other countries (Canada, Switzerland and EC countries).

ISSN:1061-186X    

DOI:10.3109/10611869409015896

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor