摘要:

AbstractPolymethylmethacrylate, a biocompatible polymer, was selected for the development of indomethacin‐ and ibuprofen‐loaded oral microparticulate dosage forms. Microparticles were prepared by an emulsion‐solvent evaporation method using aqueous phase as dispersion medium to minimize the use of hazardous organic solvents.Among the different emulsion stabilizers, methylcellulose, in a concentration range of 0·01‐0·1% w/v, was found suitable for the formation of discrete microparticles. Indomethacin‐loaded microparticles were spherical in shape which was not influenced by variation in concentration of methylcellulose. Ibuprofen‐loaded microparticles were, however, irregular in shape irrespective of methylcellulose concentration but tended to become spherical at low drug load. Actual drug content in the microparticles was almost equal to theoretical drug load and was not influenced significantly by change in methylcellulose concentration.Thus, polymethylmethacrylate microparticles, having a high degree of drug incorporation efficiency, can be prepared by solvent evaporation technique using methylcellulose; the shape of the microparticles is independent of methylcellulose concentration but is related to the solubility of the drug in the pol

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00596.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractThis paper describes the production and characterization of polyacrylic polymer microparticles by using an oil‐in‐oil system. Microparticles were designed for oral administration of tetracycline. Eudragit L 100, Eudragit S 100 and Eudragit RS 100 microparticles were produced by an oil‐in‐oil‐based in‐liquid drying process using as external phase light mineral oil.Microparticle morphology was characterized by optical and electron microscopy. The release kinetics of the antibiotic from microspheres were determined by using two different experimental approaches, a flow‐through cell method and a dialysis method. The oil‐in‐oil method here described allows the production of microparticles with a high encapsulation efficiency and appropriate dimensional and morphological characteristics for oral administration. Release profile data indicate that tetracycline is released from microparticles with a rate adequate for a sustained enteric delivery. In addition the release pattern of the drug is influenced by the type of Eudragit used for microparticle production.Our results suggest that tetracycline‐containing microparticles represent an interesting system for the sustained release of orally admini

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00597.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractThe objective of this research is to develop a microencapsulation system suitable for protein drugs which are unable to withstand the harsh processing conditions involved in most microencapsulation techniques.A novel non‐cross‐linked albumin/acacia complex coacervate gel‐microencapsulation system was developed without the use of harsh processing conditions such as chemical cross‐linking agents, organic solvents and the application of heat. This system was compared with chemically cross‐linked albumin/acacia‐coacervate microgels and interfacial polymerized nylon microcapsules with respect to entrapment of protein (β‐glucuronidase) and retention of enzyme activity.The effects of pH, temperature and ionic strength on the stability of β‐glucuronidase were investigated to determine enzyme compatibility with different processing conditions. Oppositely charged albumin and acacia formed spontaneous microgel coacervate‐microcapsules under specific pH, ionic strength and concentration conditions. Total enzyme entrapment efficiency was highest in the nylon microcapsules. However, enzyme activity was highest in the non‐cross‐linked albumin/acacia microcapsules followed by cross‐linked albumin/acacia microcapsules and then the nylon‐microcapsules. Enzyme activity decreased with time in aqueous solution but was maintained in the albumin/acacia microcapsules over a ten‐day study period. This may be due in part to the presence of albumin, as aqueous albumin solutions showed higher activity than those prepared without albumin over a ten‐day study period. Stabilization of coacervate microcapsules was achieved without the use of chemical cross‐linking agents.This method resulted in the preparation of β‐glucuronidase microcapsules with significantly higher enzyme activity than that of mic

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00598.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractThe value of pharmaceutical proteins depends upon the retention of their native structure. A powerful technique to investigate the conformation of proteins is Fourier‐transform infrared (FTIR) spectroscopy, which can be applied to both liquids and solids. Herein, using the model pharmaceutical protein, excipient‐free recombinant methionyl human growth hormone (rhGH), we have examined the amide III band region, which is sensitive to changes in the secondary structure.Gaussian curve‐fitting analysis of rhGH vibrational spectra in solution yields a high degree of α‐helix content, comprising half of the overall secondary structure, and virtually no β‐sheets, consistent with the four antiparallel α‐helices in the molecule as elucidated from the crystal structure. The remainder of the secondary structure is comprised of extended chain and other disordered structures. The IR spectra of rhGH was also measured in the lyophilized solid pressed into pellets with KBr.The data indicate that rhGH undergoes a dramatic change in the secondary structure upon lyophilization, namely, α‐helices decrease by half with increases in β‐sheet and unordered structures. The data were not significantly influenced by the conditions used in processing the protein‐in‐KBr pellet. In addition, we measured the spectrum of the dried powder alternatively, using an FTIR microscope, and found the structure much more similar to that obtained for the protein‐in‐KBr pellet than for the aqueous solution. The secondary structural reorganization was reversible, as determined from the protein spectra follo

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00599.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractThe extent that wet granulation enhanced particulate dispersion in a diazepam mixture was investigated and compared with that of an interactive mixture formulated with the same excipients. Specifically, the influence of diazepam concentration on the extent of drug dispersion was studied.The dissolution profiles of diazepam in the powder mixtures were determined using an automated USP/NF paddle method with phosphate buffer (pH 5; 0·5 M). Diazepam was determined using a validated spectro‐photometric assay. Dissolution data were fitted to a biexponential model using the Marquardt‐Levenberg algorithm for nonlinear least squares parameter estimation. This model described the diazepam dissolution from individually dispersed particles and aggregates, and allowed the estimation of the reciprocal dissolution rate constants and initial concentration of aggregates. The reciprocal dissolution rate constants for the dispersed diazepam particles during the dissolution of the wet granulated mixture were independent of diazepam concentration and were not significantly different from those of the interactive mixture. The reciprocal dissolution rate constants for aggregated particles increased with diazepam concentration for both mixtures but were larger for the granulated mixture indicating that aggregate size distributions were greater in these mixtures. The initial concentration of aggregates increased from about 20 to 60% as the diazepam concentration in the interactive mixture, increased from 2·5 to 10·0%, but was less than 10% and independent of diazepam concentration for the wet granulated mixture.The low, concentration‐independent initial aggregate concentration contributed to the rapid dissolution of the diazepam in all concentrations of the wet granulated

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00600.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractThe complexation ofN(4)‐propylajmalinium bromide—a quaternary semi‐synthetic derivative of the alkaloid ajmaline—with β‐cyclodextrin was examined using the solubility method.The interaction betweenN(4)‐propylajmalinium bromide and β‐cyclodextrin was studied by thin‐layer chromatography, IR and UV spectroscopy and principal component analysis. β‐Cyclodextrin formed inclusion complexes withN(4)‐propylajmaliniun bromide modifying the solubility and activity of the drug.A significant linear correlation between the solubility and specific activity of drug was established, and the medicinal use of the new formulation ofN(4)‐propylajmalini

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00601.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractThe effect of acute noise stress on acetylcholine content of the corpus striatum in rat brain has been studied. Twelve adult male albino Wistar rats were exposed to noise stress (10 000 Hz 100 dB) for 30 min and then killed. Exposure to acute noise stress caused a significant reduction of acetylcholine content from 40·17 ± 0·89 (control) to 31·60±0·9 nmol (g tissue)−1(P<0·001).The significant reduction in the content of the cholinergic neurotransmitter in the corpus striatum in rats exposed to acute noise stress indicates that the noise had affected the cholinergic system in this br

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00602.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractWe have investigated the effect of various antimalarial compounds on the metabolism of diazepam and nordiazepam in‐vitro by human liver microsomes.Production of nordiazepam and C3‐hydroxydiazepam (temazepam) from diazepam, and C3‐hydroxynordiazepam (oxazepam) from nordiazepam was not saturable within the range of substrate concentrations used (5–500 μM diazepam, 5–200 μM nordiazepam).At a fixed low diazepam concentration (20 μM), none of the antimalarial drugs tested had statistically significant effects on the metabolism of diazepam to nordiazepam and temazepam. Similarly, at nordiazepam 140 μM, none of the antimalarial drugs tested had statistically significant effects on the metabolism of nordiazepam to oxazepam.We conclude that in‐vivo, none of the antimalarials investigated are likely to have a clinically significant effect on the metabolism of diazepam

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00603.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractA novel molecular modelling study is described which involves the construction of a substrate‐haem complex (as a representation of the active site) for a P450 based enzyme involving the positioning of the haem about the steroid C(20). The complex was then utilized to study the binding (to the P450 haem) of the steroidal and nonsteroidal reversible inhibitors of the 17,20‐lyase component of the enzyme complex 17α‐hydroxylase/17,20‐lyase to gain insight into its active site.The results of the study appear to agree with a recent report on the binding of the reversible steroidal inhibitor 17‐(3‐pyridyl) androsta‐5,16‐dien‐3β‐ol. Using the substrate‐haem complex, we consider the probable reasons for the observed inhibitory activity within the four enantiomers of ketoconazole and other similar antimycotic compou

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00604.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractThe current therapies for prostate cancer involve either surgical resection or drugs which produce androgen deprivation. These methods, however, induce shrinkage of hyperplastic tissue via the blockade of the action of testosterone, and therefore cause undesirable side‐effects such as gynaecomastia and impotence. The enzyme 5α‐reductase has been under investigation as a possible chemotherapeutic target in the fight against prostate cancer, since it is the enzyme responsible for the conversion of testosterone to the more potent androgen, dihydrotestosterone.In the present study, we have modelled both steroidal and non‐steroidal inhibitors of 5α‐reductase in an attempt to elucidate the essential structural requirements needed in the design of non‐steroidal inhibitors.The study suggests that there is a requirement for groups to mimic the steroid substrate A‐ring, in particular the C(3) carbonyl group; the area about C(3), C(4), C(5) and C(6) of testosterone appears to be sterically hindered, presumably due to the binding of the NADPH moiety; and the area of the active site about the C(17) of the steroid substrate does not appear to possess hydrogen bonding groups and is not restricted. The study also suggests that the two isozyme types possibly vary in the positioning of the reducing NADPH moiety, i.e the preference for the 4‐ and 6‐azasteroids is dependent on the positioning of the NADPH about the steroid backbone.Using data obtained from this study, several non‐steroidal inhibitors have been designed, synthesized and subsequently tested‐some of which have been found to possess goo

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00605.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY