International Journal of Pharmaceutics (v.230, #1-2)
Correlation of ‘in vitro’ release and ‘in vivo’ absorption characteristics of rifampicin from ethylcellulose coated nonpareil beads by B Sreenivasa Rao; A Seshasayana; S.V Pardha Saradhi; N Ravi Kumar; Cheruvu P.S Narayan; K.V Ramana Murthy (1-9).
The purpose of this study was to investigate the possibility to develop different levels of correlation between in vitro dissolution parameters and in vivo pharmacokinetic parameters for three rifampicin formulations. A level A correlation of in vitro release and in vivo absorption could be obtained for individual plasma level data by means of the Wagner and Nelson method. Linear correlation could be obtained when percent dose released in vitro was plotted vs percent dose absorbed in vivo with correlation coefficients between 0.954, 0.983 and 0.997 for the formulations studied. A second level correlation between mean in vitro dissolution time (MDT) and mean in vivo residence time (MRT) was performed with a correlation coefficient of 0.536, 0.420 and 0.335. Finally, it was also possible to establish a good in vitro–in vivo correlation when the T 50%hrs (time taken to release 50% of rifampicin) in vitro and C max, T max or AUC in vivo were compared.
Keywords: Rifampicin; Release in vitro; Absorption in vivo; In vitro–in vivo correlation;
pH-sensitive nanoparticles of poly(amino acid) dodecanoate complexes by Sascha General; Andreas F Thünemann (11-24).
Nanoparticles were formed by the complexation of poly(l-arginine) (PLA), poly(l-histidine) (PLH) and poly(l-lysine) (PLL) with dodecanoic acid (C12). Dynamic light scattering, ζ potential measurements, atomic force microscopy, fluorescence, and circular dichroism spectroscopy were used for their characterization. It was found that the diameters of the poly(l-arginine) dodecanoate (PLA-C12), poly(l-histidine) dodecanoate (PLH-C12), and poly(l-lysine) dodecanoate (PLL-C12) complex nanoparticles were in the range 120–200 nm. Furthermore, the pH-sensitive dissolution and the surface charges can be adjusted by choosing PLA, PLH and PLL. The particle stability against basic pH values increases with increasing pK a value of the poly(amino acid) in the series PLH-C12, PLL-C12 and PLA-C12. The particles as such show a core-shell morphology. Their cores are formed by stoichiometric poly(amino acid) dodecanoate complexes while the shells stabilizing the particles are formed by cationic poly(amino acid) chains in an uncomplexed state. The particles were tested as containers for hydrophobic molecules such as pyrene, which served as a fluorescence probe for measuring the polarity within the particles, and Q10 which functioned as a model drug. The maximum uptake of Q10 into the nanoparticles is about 13% (w/w), thereby making the complexes attractive as simple drug carriers for controlled release purposes. Circular dichroism measurements revealed that the poly(amino acid) chains of PLA-C12 and PLL-C12 adopt predominantly an α-helix and that of PLH-C12 a β-sheet.
Keywords: pH-sensitive; Nanoparticles; Poly(amino acids); Self-assembly; Secondary structure;
Pharmaceutical applications of size reduced grades of surfactant co-processed microcrystalline cellulose by S.R Levis; P.B Deasy (25-33).
New grades of ultra-fine microcrystalline cellulose (MCC), without (grade X) or with variable percentage sodium lauryl sulphate (SLS; grades Y), were prepared by an ultrasonic homogenisation process from Avicel® PH-101 (grade C), prior to recovery by spray-drying. Both new grade types were found to be inferior compared with grade C in a tableting application for paracetamol, resulting largely from poor flow of the feed material. However, both new grades proved superior to grade C in an aqueous extrusion/spheronisation application for the preparation of indomethacin pellets, producing smoother pellets in greater yield. Grade Y was particularly effective at delaying drug dissolution, due mainly to decreased porosity in the pellets formed and retardation of their break-up.
Keywords: Microcrystalline cellulose; Ultra-fine grades; Paracetamol tablets; Indomethacin pellets; Spheronisation aid;
Characterization of soft gelatin capsules by thermal analysis by S Nazzal; Y Wang (35-45).
Thermal analysis of soft gelatin capsule was used as a diagnostic tool to evaluate the effect of temperature and humidity stress conditions as well as formulation water, propylene glycol and ethanol on the softening of the gelatin shells. Results obtained using modulated and conventional DSC given as ΔT m (change in gel–sol transition temperature) were compared with the results obtained using manual hardness tester given as % hardness loss. No difference between the two methods was observed in their ability to determine the extent of softening due to formulation water, propylene glycol and ethanol content. Thermal analysis and shifts in the reversible heat flow determined using MDSC provided additional insight into the structural changes and extent of deformation within the gelatin network upon exposure to formulation ingredients, temperature and humidity. Modulated thermal analysis is, therefore, a useful tool for screening the variables influencing the hardness of gelatin capsules.
Keywords: Soft gelatin capsule; Modulated differential scanning calorimetry; Hardness; Thermal analysis; Formulation;
S-adenosyl-l-methionine N-ole-1-oyltaurate: pharmacokinetic of the orally administered salt in rats by A Morana; A.De Rosa; M Cartenı̀; M Parlato; M.De Rosa (47-55).
A pharmacokinetic study based on the distribution of radioactivity from the double labelled S-adenosyl-l-methionine (SAM) has been carried out by oral administration of the liposoluble stable salt [methyl-14C, 8-3H]SAM N-ole-1-oyltaurate to rats. The SAM sulfate p-toluensulfonate salt, the only SAM salt at present commercialized as drug, was chosen as reference compound to have a comparative pharmacokinetic analysis. The metabolism of the SAM is characterised by a differential use of the two labelled moieties by the various organs, liver being the most active in metabolizing the sulfonium compound with a preferential uptake of the methyl-14C fragment. The radioactivity detected after the administration of [methyl-14C, 8-3H]SAM N-ole-1-oyltaurate is, in all the organs examined, two times higher than the [methyl-14C, 8-3H]SAM sulfate p-toluensulfonate compound, attesting that the liposoluble [methyl-14C, 8-3H]SAM N-ole-1-oyltaurate is provided with better bioavailability.
Keywords: [methyl-14C, 8-3H]SAM; N-ole-1-oyltaurate; Pharmacokinetic; Rats;
Dextrins as potential carriers for drug targeting: tailored rates of dextrin degradation by introduction of pendant groups by Dale Hreczuk-Hirst; Daniella Chicco; Lisa German; Ruth Duncan (57-66).
There is a recognised need to identify new biodegradable polymers suitable for development as targetable drug carriers. The aim of this study was to determine the rate of degradation of two dextrin fractions (Mw 15.5 and 51 KDa) by α-amylase and liver lysosomal enzymes (tritosomes). Also experiments were conducted to discover whether backbone modification by succinolyation (1–34 mol%) or pendant group incorporation (e.g. doxorubicin) could be used to tailor the rate of polymer degradation. Dextrin (α-1,4 polyglucose) is a natural polymer used clinically as a peritoneal dialysis solution and as a controlled drug delivery formulation. Size exclusion chromatography (SEC) showed that dextrin was degraded rapidly (within 20 min) by rat plasma and porcine pancreatic α-amylase. In contrast over 48 h no degradation was observed in the presence of tritosomes. The rate of α-amylase degradation of succinoylated dextrins (Mw∼51 KDa) was dependant on the degree of modification (dextrin >1>5>15>34 mol% succinoylation). Dextrin–doxorubicin conjugates were prepared from the 15 and 34 mol% succinoylated intermediates to have a doxorubicin loading of 8 and 12 wt.%, respectively. These doxorubicin conjugates were more stable than their parent intermediates, and SEC showed an apparently higher molecular weight. The drug conjugates did however degrade slowly over 7 days to release oligosaccharide–doxorubicin species. This fundamental study demonstrates the possibility of controlling the rate of dextrin enzymolysis by backbone modification and thus affords the potential to rationally design dextrin–drug conjugates for specific applications as targetable carriers.
Keywords: Dextrins; Drug–polymer conjugates; Succinoylation; Biodegradable polymers;
Determination of the disappearance rate of iodine-125 labelled oils from the injection site after intramuscular and subcutaneous administration to pigs by Susan Weng Larsen; Elise Rinvar; Ove Svendsen; Jens Lykkesfeldt; Gitte Juel Friis; Claus Larsen (67-75).
The rate of disappearance of clinically used vegetable oils, Viscoleo, sesame oil, castor oil and isopropyl myristate, from the injection site after intramuscular (i.m.) or subcutaneous (s.c.) administration to pigs were determined by using a non-invasive gamma-scintigraphy method. All the oil vehicles were spiked with 2.5% (v/v) 125I-triolein and six injections of 1.9 ml were given to each of 12 pigs. No significant difference (ANOVA) in disappearance rate of each individual oil vehicle from the different injection sites was observed after administration of the oils: i.m. in the lower back, s.c. in the neck and s.c. in the mid-back. Likewise, no inter-individual difference between the pigs was observed. The half-life of 14 days for Viscoleo was significantly smaller than those of the other oil vehicles (P<0.0001), i.e. 23, 20, 20 days for sesame oil, castor oil and isopropyl myristate, respectively. Due to the spreading effect of the oils and reflux of the oils through the injection canal, the half-lives were calculated omitting the data for the first sampling day.
Keywords: Parenteral depots; Disapperance rates; Pig; I.m administration; S.c. administration; Gamma-scintigraphy;
Erratum to “Quaternary ammonium palmitoyl glycol chitosan—a new polysoap for drug delivery” by Ijeoma F. Uchegbu; Lubana Sadiq; Mahmoud Arastoo; Alexander I. Gray; Wei Wang; Roger D. Waigh; Andreas G. Schätzleinä (77).
Author index vol's 212–230 (83-103).
Subject index vol's 212–230 (105-121).