International Journal of Pharmaceutics (v.195, #1-2)
Comparison of surface modification and solid dispersion techniques for drug dissolution by C Rouchotas; O.E Cassidy; G Rowley (1-6).
Surface modification and solid dispersion formulations using hydrophilic excipients can significantly alter the dissolution behaviour of hydrophobic drug materials. The effect of these techniques used individually and in combination on the dissolution properties of the hydrophobic drug, phenylbutazone (PB), are compared. PB was treated with a poloxamer, Synperonic® F127 by an adsorption method. Solid dispersions (10 and 20% w/w) were prepared with untreated PB or PB previously modified with Synperonic® F127 (PBT) in molten F127. Dissolution tests of capsule formulations of PB, PBT and solid dispersion formulations, in pH 6.4 buffer at 37±0.5°C demonstrated that after 140 min, release of PB was 16.7%, but 71.4% from the solid dispersion, whereas from the PBT formulation 85.6% was released. The Synperonic® F127 content of PBT was only 0.05% of that in the solid dispersion formulation which suggests that it is the nature of the drug polymer contact rather than the amount of polymer which is more critical in influencing dissolution behaviour. Comparison of PBT and the 10% w/w solid dispersion of PBT in F127 showed similar amounts of drug in solution after 140 min. However there was a significantly higher release rate for PBT. Both formulation techniques offer significant improvements in drug release over untreated PB, and a combination of techniques changes the rate but not the extent of release in comparison with the surface modification technique alone.
Keywords: Surface modification; Solid dispersions; Poloxamer; Hydrophobic drugs, Dissolution;
Effect of contamination of pharmaceutical equipment on powder triboelectrification by J Eilbeck; G Rowley; P.A Carter; E.J Fletcher (7-11).
Triboelectrification of pharmaceutical powders may cause problems during processing and manufacture due to adhesion/cohesion effects. The aim of this work was to investigate the role of adhered particles and moisture as contact surface contaminants on the electrostatic charging of size fractionated lactose, following contact with a surface, i.e. stainless steel, typically used in pharmaceutical process and manufacturing operations. Replicated experimental runs without cleaning the contact surface showed a successive decrease in the net electronegative charge due to adhered lactose particles. Removal of these contaminating particles by different cleaning methods had a considerable effect on the charge after triboelectrification. The charge on the lactose samples was found to decrease when humidity in the cyclone apparatus was increased from 2 to 100% relative humidity. These results clearly demonstrate that moisture, particulate contamination and method of cleaning of processing equipment during pharmaceutical manufacturing operations may influence the electrostatic behaviour of powders.
Keywords: Triboelectrification; Electrostatic charge; Contamination; Lactose; Moisture;
Prodrug to probe solution HFA pMDI formulation and pulmonary esterase activity by P.C Seville; C Simons; G Taylor; P.A Dickinson (13-16).
A novel salbutamol prodrug was synthesised. Solubility in HFA-134a and susceptibility to rat lung homogenate, blood and plasma esterase enzymes were investigated. Whereas salbutamol had a very low solubility in HFA-134a, the prodrug was found to be miscible in all proportions. In lung homogenate, the prodrug hydrolysed with a half-life of 45 min, re-generating approximately 17% of expected salbutamol after 8 h incubation. The use of a solution pMDI for pulmonary delivery of the salbutamol prodrug is predicted to result in liberation of salbutamol in the lungs following in vivo hydrolysis by lung esterases.
Keywords: Salbutamol; Ester; Prodrug; Solution; Inhaler; Lung;
Microcalorimetry does not predict the cellular phagocytosis of latex microspheres by B.G Jones; M Gumbleton; I.W Kellaway; P.A Dickinson (17-23).
Current literature highlights the potential suitability of microcalorimetry for the investigation of cell–drug interactions. Previous work using bacteria or antigens derived from infectious organisms yielded conclusions that heat production is a quantitative means of measuring phagocytosis. In this study we evaluated the potential of flow-through microcalorimetry as a method of quantifying the phagocytosis of microsphere particulates. The technique avoids the need to incorporate radioactive or fluorescent markers into the particulate formulation, and would be widely applicable in biopharmaceutical research. Using the monocyte cell line Mono Mac 6 a power output of 9.00 μW per million cells was increased significantly on addition of zymosan, lipopolysaccaride (LPS) and phorbol myristate acetate but not following exposure to FITC labelled latex microspheres (LM). TNFα production increased on exposure to zymosan, LPS and LPS–phorbol myristate acetate, though not on exposure to LB. An assay was developed which allowed the quantification of internalised particulates in phagocytic cells using fluorescent activated cell sorting (FACS). In contrast to the microcalorimetric and TNFα data FACS revealed that 20% of the MM6 population phagocytosed a mean of 1.35 LM. Microcalorimetry and measurements of TNFα production are assays of cellular activation a phenomenon not necessarily associated with phagocytosis. FACS, however, serves as a specific and quantitative measure of phagocytosis. Microcalorimetry may not be a suitable technique for the quantitative assessment of the phagocytosis of drug delivery particulates.
Keywords: Phagocytosis; Microcalorimetry; FACS; Cellular activation;
Characterisation of fatty acid multilayers using a TSM biosensor by Matthew Reason; Geoff Smith; Roger Latham; Paul Teesdale-Spittle; Justine Ramsden; Brian Henry (25-28).
Thickness shear mode (TSM) biosensors have many potential applications within the pharmaceutical sciences as a means of measuring mass changes in the nanogram range, film thickness, viscosity and shear moduli. This study addresses the possible use of the TSM sensor as a biosensor for measuring drug partition coefficients. In order to realise this potential, some fundamental understanding is required of the behaviour of lipid films on the sensor. The present study characterises the behaviour of fatty acid multilayers as a suitable model chemical system. Frequency shifts and impedance spectra are presented for multilayers of three fatty acid films coated on to the sensor using a Langmuir-Blodgett trough. The results indicate that the frequency shift is non-linear at lower numbers of fatty acid layers but the response is Sauerbrey-like at higher numbers of layers. Also at high numbers of layers, changes in the impedance spectra indicate viscoelastic behaviour in thicker membranes. An inverse relationship is observed between chain length and frequency shift, which is attributed to variations in the topography of the sensor surface. This work demonstrates the importance of fully characterising the physical behaviour of the lipid multilayers prior to using these systems for the measurement of drug partition coefficients.
Keywords: Thickness shear mode sensors; Biosensor; Fatty acid; Partition coefficient;
In vitro peptide release from liquid crystalline buccal delivery systems by Jaehwi Lee; Ian W Kellaway (29-33).
Swelling and [d-Ala2, d-Leu5]enkephalin (DADLE) release from the lamellar and cubic liquid crystalline phases of glyceryl monooleate (GMO) were studied using two in vitro methods, a total immersion method and a Franz cell method. The swelling of the lamellar phase and glyceryl monooleate (0% w/w water content) and DADLE release from the liquid crystalline phases were temperature dependent. The swelling ratio was greater at 20°C than 37°C while DADLE release increased at 37°C compared to 20°C for both the lamellar and cubic phases. The water uptake increased dramatically with decreasing initial water content of the liquid crystalline phases. However, DADLE release increased with increasing initial water content, which corresponded to increased viscosity. The swelling and DADLE release profiles obtained using a Franz cell method with a moist nylon membrane to mimic buccal drug release conditions were slower than the total immersion method. These results show that the swelling and DADLE release strongly depended on temperature, the initial water content of the liquid crystalline matrix and the methodology employed for determining the swelling and DADLE release.
Keywords: Buccal; Liquid crystalline phase; Glyceryl monooleate; Swelling; In vitro release;
Buccal permeation of [d-Ala2, d-Leu5]enkephalin from liquid crystalline phases of glyceryl monooleate by Jaehwi Lee; Ian W Kellaway (35-38).
The ex vivo buccal permeability of a [d-Ala2, d-Leu5]enkephalin (DADLE) and glyceryl monooleate (GMO) was examined from the cubic and lamellar liquid crystalline phases of GMO and aqueous phosphate-buffered saline (pH 7.4, PBS) solution across excised porcine buccal mucosa mounted in a Franz cell. GMO was released in vitro from the liquid crystalline phases indicating the erosion of the liquid crystal matrices. GMO released from the liquid crystalline matrices permeated the porcine buccal mucosa with fluxes of 0.10±0.03 and 0.07±0.00%/cm2 per h for the cubic and lamellar phases, respectively. The flux of DADLE (1.21±0.32 and 1.15±0.11%/cm2 per h for the cubic and lamellar phases, respectively) from the liquid crystalline phases was significantly enhanced by the GMO compared with PBS solution (0.43±0.08%/cm2 per h) during the initial permeation phase (t<3 h). Our results suggest that the cubic and lamellar liquid crystalline phases can be considered as promising buccal drug carriers for peptide drugs as well as acting as permeation enhancers.
Keywords: Buccal permeation; Peptide and protein; Liquid crystalline phase; Glyceryl monooleate; Permeability enhancement of peptide;
Pharmaceutical applications for molecularly imprinted polymers by C.J Allender; C Richardson; B Woodhouse; C.M Heard; K.R Brain (39-43).
Molecular imprinting is a means of introducing sites of specific molecular arrangement into an otherwise uniform polymeric matrix. This is achieved by formation of a pre-polymerisation complex between complementary monomers and the template molecule. Subsequent polymerisation in the presence of a crosslinker, in a porogenic environment, results in the production of a macroporous polymer capable of specific molecular recognition. This paper considers potential roles for molecularly imprinted polymers within a pharmaceutical remit. Applications including controlled release, drug monitoring devices and biological receptor mimetics are discussed. Histamine and ephedrine molecularly imprinted polymers (MIPs) were studied as potential biological receptor mimics whilst a propranolol MIP was investigated for its use as a rate attenuating selective excipient in a transdermal controlled release device. Preliminary studies concerning the preparation of a theophylline selective transcutaneous monitoring device, using a theophylline MIP, are also described.
Keywords: Molecularly imprinted polymer; Biomimetic; Molecular recognition;
Preparation and characterization of Furosemide-Eudragit controlled release systems by Juan M Aceves; R Cruz; E Hernandez (45-53).
Solid dispersions and physical mixtures were prepared and characterized by X-ray diffraction, infrared spectroscopy, electronic microscopy and dissolution rate studies. The characterization with X-ray diffraction showed a transition from the crystalline to the amorphous phase. A new phase near 50% Furosemide concentration with both types of carriers was present. From infrared spectroscopy strong interactions between amine and carbonyl groups from both the Furosemide and the polymers were found. Electronic microscopy analysis showed that the Furosemide changed its crystalline habit from needle to a new spherical phase, with diameter near to 1 μm. Solid dispersions were prepared in order to modify the system characteristics. The Furosemide dissolution rate was determined in order to follow the behavioural changes of the system. Scanning electron microscopy showed the presence of micro spheres within the polymeric matrix, and the channels formed due to the Furosemide dissolution inside the Eudragit: this fact modified the release pattern of the Furosemide system.
Keywords: Furosemide solid dispersions; Infrared spectroscopy; X-ray diffraction patterns; Crystals; Dissolution rate; Eudragit;
In vitro percutaneous penetration of topically applied capsaicin in relation to in vivo sensation responses by B.M Magnusson; L.-O.D Koskinen (55-62).
Capsaicin, the primary pungent element in several spices, elicits a variety of physiological effects which are due to neurogenic responses. The aim of the study was to explore the in vivo sensation responses of capsaicin and to compare the results with the in vitro percutaneous absorption of the substance. The overall objectives were to determining an in vitro–in vivo correlation for capsaicin. Capsaicin was applied in a chamber on the volar forearm of twelve volunteers and in a flow-through diffusion chamber on excised human epidermal membranes. Topical administration of capsaicin produced a complex cutaneous sensation that changed in intensity and quality as a function of time and was characterized by sting, prick, burn and pain. Percutaneous steady-state penetrations of capsaicin with a receptor fluid consisting either of 4% bovine serum albumin in phosphate buffered saline or 50% ethanol in water were 28.2±2.7 and 29.6±2.9 μg/cm2 per h, respectively. The corresponding cumulative penetrated amounts of capsaicin after 30 min were 14.7±1.7 and 19.2±2.1 μg/cm2, respectively. The present investigation indicates that there is a good correlation between in vivo physiological responses and in vitro percutaneous penetration of topically applied capsaicin.
Keywords: Capsaicin; Transdermal delivery; Sensation responses; Diffusion chamber;
Does the site of intestinal delivery of oleic acid alter the ileal brake response? by Clair L Dobson; Stanley S Davis; Sushil Chauhan; Robert A Sparrow; Ian R Wilding (63-70).
Previous work has demonstrated that high doses of oleic acid can activate the ileal brake but the importance of site of delivery has yet to be investigated. The objective of this study was to use modified release capsules to release oleic acid in different regions of the intestine. When tested by in vitro dissolution in pH 6.8 phosphate buffer, one batch released the contents almost immediately, another after around 30 min and the last batch after around 60–70 min. The effect of oleic acid release site on the ileal brake was assessed by the measurement of transit time of radiolabelled non disintegrating tablets by γ scintigraphy. The results demonstrated that the transit of tablets could be slowed down by oleic acid and therefore it appears the ileal brake can be activated along the entirety of the small intestine.
Keywords: Ileal brake; Oleic acid; Tablets; Gastrointestinal transit; Scintigraphy;
Interaction of p-hydroxybenzoic esters with beta-cyclodextrin by L.W. Chan; T.R.R. Kurup; A. Muthaiah; J.C. Thenmozhiyal (71-79).
In the present investigation, the complex formation of beta-cyclodextrin (βCD) with p-hydroxybenzoic esters (parabens) was studied by mixing βCD with methyl, ethyl, propyl and butyl parabens, respectively, in aqueous solutions and subjecting the resultant mixtures individually to the following processes: occasional shaking for 24 h at 25°C, continuous shaking using shaker bath for 24 h at 25°C, intermittent ultrasonification for 90 min at 25°C, autoclaving at 115°C for 30 min and freeze-drying followed by reconstitution with distilled water. The degrees of interaction between βCD and the parabens subjected to the various processes were evaluated, using the membrane dialysis method. The difference in the method of processing did not affect the degree of interaction significantly. However, the degree of interaction was found to increase proportionally with the concentration of βCD. The alkyl group of the parabens was also found to affect the extent of interaction. Compared to methyl paraben, the degree of interaction of ethyl paraben was observed to be lower. Interestingly, further increase in the size of the alkyl group significantly enhanced the extent of interaction. Studies using 1H-NMR showed that the extent of interaction depended on how well the parabens could fit into the βCD cavity.
Keywords: Beta-cyclodextrin; Parabens; Interaction;
Prediction of suitable amount of water addition for wet granulation by Akio Miwa; Toshio Yajima; Shigeru Itai (81-92).
The purpose of this study was to predict the amounts of water addition suitable for pharmaceutical formulations in wet granulation, using a high-speed mixer or a fluidized bed granulator, before granulation trials. In order to determine the suitable amount of water addition, each excipient was first subjected to kneading with water in a mortar and a refractive near-infrared moisture sensor (IR sensor) measured the amount of water at the powder surface. Further by analysis the plot (output value of the IR sensor vs. amount of added water) for each excipient, the amount of water addition for granulation was determined for it. As a second step, two model formulations were designed and suitable amounts of water for granulation were predicted by summation of the obtained excipient values. The predicted value was compared with the experimental value for high-speed mixer granulation. The predicted and experimental amounts of water addition corresponded for the two model formulations, suggesting that the above method is useful for estimating suitable amounts of addition of water for formulations before granulation trials.
Keywords: Infrared sensor; Wet granulation; Water; Suitable amount; Prediction; Excipient;
Characterization of proteolytic activities of pulmonary alveolar epithelium by Xiaodong Yang; Joseph K.A Ma; Carl J Malanga; Yon Rojanasakul (93-101).
Pulmonary alveolar type I epithelial cell and its progenitor, type II cell, present major transport and enzyme barriers for systemic delivery of pulmonary administered peptide drugs. The present study investigates the effect of cellular differentiation of type II to type I cells on their proteolytic activities, and evaluates the suitability of a continuous lung cell line, A549, for drug transport and degradation studies. High performance liquid chromatography was used to assess the degradation kinetics of two model peptide substrates, luteinizing hormone releasing hormone (LHRH) and [d-Ala6]-LHRH, and their metabolites in lung cell preparations. Isolated primary type II cells when grown in culture developed tight monolayers and exhibited morphologic characteristics of type I cells, as determined by transepithelial electrical resistance measurements and electron microscopy. The transformed type I-like cells exhibited a >10-fold decrease in proteolytic activities for LHRH, as compared to type II cells. The continuous lung cell line A549 formed leaky monolayers and exhibited similar enzyme activities to the primary type II cells. The responsible enzymes for degradation of LHRH in type II and A549 cells were angiotensin converting enzyme (ACE), EP24.11, and EP24.15. In contrast, no EP24.15 or ACE activity was observed in type I-like pneumocytes and only a weak EP24.11 activity was detected. In all cell types, the degradation rate of [d-Ala6]-LHRH was about 3–8 times lower than that of LHRH. This peptide analog was resistant to degradation by EP24.15 and EP24.11, but was susceptible to ACE-mediated cleavage.
Keywords: Peptide degradation; Lung; Enzyme activity; LHRH; A549; Epithelial cells;
Ethyl formate — alternative dispersed solvent useful in preparing PLGA microspheres by Hongkee Sah (103-113).
In an effort to substitute methylene chloride with a less toxic solvent, this study was aimed at developing new ethyl formate-based emulsion processes to fabricate poly-d,l-lactide-co-glycolide (PLGA) microspheres. To do so, a polymeric dispersed phase was emulsified in a 1% polyvinyl alcohol aqueous solution at an ethyl formate to aqueous volume ratio of 8:20. Microsphere hardening was then achieved by solvent evaporation and quenching techniques. The average encapsulation efficiency of a model drug progesterone amounted to 95.2±2.7%. When the tendency of ethyl formate and methylene chloride to evaporate to air was compared, the evaporation rate of ethyl formate was 2.1 times faster than that of methylene chloride. The ease with which ethyl formate evaporated to air was beneficial in shortening the microsphere hardening step. For the solvent quenching process, only 80 ml of additional water was required to extract ethyl formate to the aqueous phase, due to its considerable water miscibility. In particular, the timing of ethyl formate quenching affected to a great extent dynamic processes of the breakup of elementary microdroplets into smaller ones. Therefore, variations in quenching time affected microsphere characteristics such as the degree of solvation, size distribution, and tendency to aggregate on drying. The results of this study showed that PLGA microspheres were successfully prepared using the new ethyl formate-based processes.
Keywords: Ethyl formate; Microencapsulation; Poly(lactide-co-glycolide); Microspheres;
Carrier-mediated transport of valproic acid in BeWo cells, a human trophoblast cell line by Naoki Utoguchi; Kenneth L Audus (115-124).
The biochemical mechanisms mediating the rapid distribution of valproic acid across placenta are not precisely known. We have characterized valproic acid transport by the human trophoblast using the human choriocarcinoma cell line, BeWo. The uptake of [14C]valproic acid by BeWo cells was found to be saturable and blocked by pre-exposure to the metabolic inhibitors, sodium azide and 2,4-dinitrophenol. Valproic acid uptake by the BeWo cells was also inhibited by the protonophore, carbonylcyanide p-trifluoromethoxyphenylhydrazone, but not anion exchange inhibitor. Selected monocarboxylic acids inhibited the uptake of [14C]valproic acid by BeWo cells, whereas dicarboxylic acids did not alter the uptake process. Analysis of Lineweaver–Burk plots of valproic acid uptake in the presence of benzoic acid, a marker for the monocarboxylic acid transporter, revealed a competitive process for uptake. In transcellular transport experiments, the permeation of [14C]valproic acid from the apical-to-basal side of the monolayers was significantly greater than the permeation from basal-to-apical side. Additionally, the permeation of [14C]valproic acid from apical-to-basal side was inhibited by monocarboxylic acids and not dicarboxylic acids. The results provide biochemical evidence of a proton-dependent, saturable, and asymmetric transport system, presumed to be a monocarboxylic acid transporter, for valproic acid in a human trophoblast model.
Keywords: Valproic acid; Placenta; Trophoblast; BeWo; Monocarboxylic acid transporter;
Optimisation of floating matrix tablets and evaluation of their gastric residence time by Saša Baumgartner; Julijana Kristl; Franc Vrečer; Polona Vodopivec; Bojan Zorko (125-135).
The present investigation concerns the development of the floating matrix tablets, which after oral administration are designed to prolong the gastric residence time, increase the drug bioavailability and diminish the side effects of irritating drugs. The importance of the composition optimisation, the technological process development for the preparation of the floating tablets with a high dose of freely soluble drug and characterisation of those tablets (crushing force, floating properties in vitro and in vivo, drug release) was examined. Tablets containing hydroxypropyl methylcellulose (HPMC), drug and different additives were compressed. The investigation shows that tablet composition and mechanical strength have the greatest influence on the floating properties and drug release. With the incorporation of a gas-generating agent together with microcrystalline cellulose, besides optimum floating (floating lag time, 30 s; duration of floating, >8 h), the drug content was also increased. The drug release from those tablets was sufficiently sustained (more than 8 h) and non-Fickian transport of the drug from tablets was confirmed. Radiological evidence suggests that, that the formulated tablets did not adhere to the stomach mucus and that the mean gastric residence time was prolonged (>4 h).
Keywords: Tablet; Floating; Matrix; Non-Fickian diffusion; Gastric residence time;
An investigation into the release of cefuroxime axetil from taste-masked stearic acid microspheres. II. The effects of buffer composition on drug release by H Robson; D.Q.M Craig; D Deutsch (137-145).
The influence of buffer composition on the release of cefuroxime axetil from stearic acid microspheres has been investigated, with particular emphasis on establishing the relationship between buffer composition and release at a single pH value. Studies of drug dissolution and release from spheres in pH 7.0 citrate phosphate buffer (CPB), boric acid buffer (BAB), phosphate buffer mixed (PBM) and Sorensens modified phosphate buffer (SMPB) indicated marked differences in release profile from the spheres, with an approximate rank order of SMPB>CPB≈BAB>PBM. The role of added sodium was then investigated by examining the release profiles in SMPB and PBM to which sodium ions had been added. Increases in the sodium content from ≈0.11 to 0.2 M were found to decrease the release rate for the SMPB, while increases from 0.007 to 1.0 M sodium in PBM resulted in a maximum release being seen for the systems containing 0.05 M sodium. Studies on surface disintegration, using scanning electron microscopy (SEM) and sodium uptake using flame emission spectroscopy, indicated an interrelationship between medium composition, disintegration and release. The data are discussed in terms of the possible mechanisms associated with drug release from these spheres.
Keywords: Cefuroxime axetil; Flame emission spectroscopy; Microsphere; Stearic acid; Taste masking;
Anti-mucus polyclonal antibody production, purification and linkage to the surface of albumin microspheres by A.B. MacAdam; Z.B. Shafi; C. Marriott; G.P. Martin; S.L. James (147-158).
This aim of this study was to develop a microparticulate based oral drug delivery system, which could prolong gut transit time by binding via specific interactions to the gut mucus layer. Porcine gastric mucus was semi-purified and used as an antigen to raise a polyclonal antiserum in rabbits. The immunoglobulin fraction of this serum was isolated, purified and tested for homogeneity and cross reactivity. High cross-reactivity was displayed when the antiserum was challenged against types of mucus other than that used as an antigen, but no significant cross-reactivity occurred when challenged against some other common macromolecules. The antibody fraction of this serum was covalently linked to three types of albumin microspheres (MS) using 1-ethyl-3(3-dimethyl aminopropyl) carbodiimide. The MS employed had either a hydrophobic, a hydrophilic or a carboxymethylated surface, and were prepared and characterised as described earlier (MacAdam, A.B., Shafi, Z.B., Martin, G.P. and James, S.L. 1997. Preparation of hydrophobic and hydrophilic MS and determination of surface carboxylic acid and amino residues. Int. J. Pharm. 151, 47–55). Binding of these MS to both radioiodinated mucin in suspension and to isolated gut segments was measured. Hydrophilic and carboxymethylated MS with surface-associated antibody bound significantly more mucin from a suspension than did uncoated controls. Similarly, anti-mucus antibody-coated hydrophilic and carboxymethylated MS bound more strongly to an isolated gut segment than did uncoated controls or controls coated in an antibody specific for albumin. These results suggest anti-mucus antibody coated albumin MS may be a useful model to act as comparators in studies aimed at developing drug delivery systems with delayed gastrointestinal transit.
Keywords: Polyclonal antibodies; Bovine serum albumin; Albumin microspheres; Ligand binding; Antibody production; Antibody isolation; 35S anti-rabbit IgG; Antibody linkage; ELISA; PAGE; Carboxymethylated MS; Bioadhesion; Mucoadhesive strength; Radio-iodinated mucus; Perfusion of rat jejunum segments; Carboxymethylated mucus;
Artefact formation in the determination of residual solvents according to a method of the European Pharmacopeia by C.R Lee; C Nguyen van Dau; A.M Krstulović (159-169).
Method 2 of the procedure for the identification and assay of residual solvents, of the European Pharmacopeia 3rd edition 1999 addendum, leads to artefactual formation of N-chlorodimethylamine when the hydrochlorides of basic compounds are examined. This is due to degradation of the dissolution solvent N,N-dimethylformamide under the prescribed conditions. N-Chlorodimethylamine has been detected during analysis of several hydrochloride salts of nitrogen bases including drug substances. Artefact formation did not occur consistently with all the compounds examined, but with diltiazem hydrochloride it was observed in the majority of experiments. The discovery that the alkylating reagent N,N-dimethylaminoethyl chloride (DMC) used in the synthesis of diltiazem gives apparently high yields of N-chlorodimethylamine was cause for concern. However, it has been confirmed that production batches of diltiazem hydrochloride contain <1 ppm of this synthetic intermediate. The formation of N-chlorodimethylamine in the presence of the drug substance is probably due to a reaction between dimethylformamide and HCl, that would be released as a result of hydrolysis by residual water of the O-acetyl function of diltiazem. In view of these findings, the compendial general method should be reviewed. It may be necessary to adopt a different approach to the drafting of methods for volatile impurities, since most of the operating conditions are in practice specific to the substance being examined.
Keywords: Diltiazem; GC-headspace analysis; Pharmacopeial method;
In vitro permeation through porcine buccal mucosa of Salvia desoleana Atzei & Picci essential oil from topical formulations by G.C. Ceschel; P. Maffei; M.D.L. Moretti; S. Demontis; A.T. Peana (171-177).
In the light of recent studies, which have shown that the essential oil derived from some Lamiaceae species has appreciable anti-inflammatory activity, moderate anti-microbial action and the ability to inhibit induced hyperalgesia, an assessment of the diffusion and permeation of Salvia desoleana Atzei & Picci (S. desoleana) essential oil through porcine buccal mucosa was considered useful for a possible application in the stomatological field. Topical formulations (microemulsions, hydrogels and microemulsion–hydrogels) were prepared for application to the buccal mucosa. The mucosa permeation of the oil from the formulations was evaluated using Franz cells, with porcine buccal mucosa as septum between the formulations (donor compartment) and the receptor phase chambers. The study also aimed at optimising the permeability of the S. desoleana essential oil by means of an enhancer, the diethylene glycol monoethyl ether Transcutol®. The diffusion of the oil through the membrane was determined by evaluating the amount of essential oil components present in the receiving solution, the flux and the permeation coefficient (at the steady state) in the different formulations at set intervals. Qualitative and quantitative determinations were done by gas chromatographic analysis. All the formulations allow a high permeability coefficient in comparison with the pure essential oil. In particular, the components with a terpenic structure (β-pinene, cineole, α-terpineol and linalool) have the highest capacity to pass through the porcine buccal mucosa when compared to the other components (linalyl acetate and α-terpinil acetate). Moreover, the enhancer, diethylene glycol monoethyl ether largely increases the permeation of the essential oil components in relation to the concentration.
Keywords: Salvia desoleana Atzei & Picci essential oil; Buccal mucosa permeation; Enhancer effect; Diethylene glycol monoethyl ether; Transcutol®;
Diclofenac sodium incorporated PLGA (50:50) microspheres: formulation considerations and in vitro/in vivo evaluation by M Tunçay; S Çaliş; H.S Kaş; M.T Ercan; İ Peksoy; A.A Hincal (179-188).
Recently, considerable interest has been focused on the use of biodegradable polymers for specialized applications such as controlled release of drug formulations; meanwhile, microsphere drug-delivery systems using various kinds of biodegradable polymers have been studied extensively during the past two decades. Poly (lactide-co-glycolide) (PLGA) polymers have been proven to be excellent drug carriers for microparticulate systems due to their advantages, e.g. biocompatibility and regulatory approval. The administration of nonsteroidal anti-inflammatory drugs (NSAIDs) into the intra-articular cavity in patients with chronic inflammatory disease is complicated due to the short duration of effect. In the present study, controlled-release parenteral formulations of diclofenac sodium (DS), a commonly used NSAID, were prepared for intra-articular administration, and evaluated in vitro for particle size, yield, drug loading, surface morphology and release characteristics. For in vivo studies, Technetium-99m labelled polyclonal human immunogammaglobulin (99m Tc-HIG) was used as the radiopharmaceutical to demonstrate arthritic lesions by gamma scintigraphy. Evaluation of arthritic lesions post-therapy in rabbits showed no significant difference in the group treated with PLGA (50:50) (mw 34 000) DS microspheres compared to control groups.
Keywords: Poly (lactide-co-glycolic acid) microspheres; Diclofenac sodium; Solvent-evaporation method; Experimental arthritis; Scintigraphic imaging;
Unexpected skin barrier influence from nonionic emulsifiers by Ebba Bárány; Magnus Lindberg; Marie Lodén (189-195).
Skin disorders are often treated with creams containing various active substances. The creams also contain emulsifiers, which are surface-active ingredients used to stabilize the emulsion. Emulsifiers are potential irritants and in the present study the influence of stearic acid, glyceryl stearate, PEG-2, -9, -40, and -100 stearate, steareth-2, -10 and -21 on normal as well as on irritated skin have been evaluated with non-invasive measurements. Test emulsions were created by incorporating 5% emulsifiers in a water/mineral oil mixture (50:50). The emulsions and their vehicle were then applied to normal skin for 48 h and to sodium lauryl sulfate (SLS) damaged skin for 17 h in aluminum chambers. Twenty-four hours after removal of the chambers the test sites were evaluated for degree of irritation. In normal skin, the emulsifiers induced significant differences in TEWL but not in skin blood flow. Five of the emulsifiers increased TEWL. In SLS-damaged skin an aggravation of the irritation was expected. However, no differences regarding skin blood flow was noted from the emulsifiers. Furthermore, three emulsifiers unexpectedly decreased TEWL. These results highlight the possibility of absorption of these emulsifiers into the lipid bilayer, which increase TEWL in normal skin and decrease TEWL in damaged skin.
Keywords: Surface-active agents; Nonionic emulsifiers; Normal skin; Surfactant-irritated skin; Barrier function.;
Nasal absorption of (S)-UH-301 and its transport into the cerebrospinal fluid of rats by Maria Dahlin; Erik Björk (197-205).
Targeting the brain via nasal administration of drugs has been studied frequently over the last few years. In this study, the serotonin-1a receptor antagonist (S)-5-fluoro-8-hydroxy-2-(dipropyl-amino) tetralin ((S)-UH-301) hydrochloride was used as a model substance. The systemic absorption and transport of (S)-UH-301 into male Sprague–Dawley rat cerebrospinal fluid (CSF) were investigated after nasal and intravenous administration. Blood and CSF samples were obtained at regular time intervals from the arteria carotis and by cisternal puncture, respectively, after administration to both nostrils (total 12 μmol/kg) or into the vena jugularis (6 μmol/kg). The concentrations of (S)-UH-301 in plasma and CSF were measured by HPLC with electrochemical detection. The maximum plasma concentration of intranasal (S)-UH-301 occurred in about 7 min and the absolute bioavailability seemed to be complete (F=1.2±0.4). Initially, no increased concentrations of (S)-UH-301 were seen in CSF after nasal compared to intravenous administration i.e. it appeared that no direct transport of (S)-UH-301 from the nasal cavity, along the olfactory neurons and into the CSF occurred. However, a prolonged duration of the concentration was seen after nasal administration of (S)-UH-301 and after about 20 min the CSFna:CSFiv concentration ratio (corrected for different dosage) exceeded 1.
Keywords: Nasal administration; 5-HT-1a receptor antagonist; Rat; Olfactory pathway; Cerebrospinal fluid (CSF); Brain targeting;
The interaction of human serum albumin and model membranes by Rita Galántai; Irén Bárdos-Nagy (207-218).
It is frequently observed that the interaction of human serum albumin (HSA) with different lipid membranes may affect molecular transport both in vivo and in vitro experiments. There was a lack of consensus however in the interpretation of results. Earlier studies on the serum albumin membrane association had different conclusions depending on the source of protein, the preparation and the composition of the membranes applied. In this work the change of heat capacity, a sensitive parameter of the interacting system, is compared for uni- and multilamellar liposomes (dimyristoyl-phosphatidylcoline/dimyristoyl-phosphatidylglycerol) at 0, 1×10−3, 8×10−3, 1.2×10−2 and 3.3×10−2 HSA–lipid ratios. The thermal properties of the sonicated and vortexed liposomes show remarkable differences. The presence of HSA in both types of liposomes also modified their thermal properties, providing clear evidence for protein–vesicle interaction, different in the uni- and multilamellar liposomes. In the case of unilamellar liposomes, two additional transitions were observed at lower temperature, independently of the HSA–lipid ratio, and the protein binding mode to smaller or larger sized liposomes was also distinguishable. The addition of HSA to the multilamellar liposomes resulted in an increase of the pretransition temperature only at the higher HSA–lipid ratio, but the main transition temperature was not affected.
Keywords: Liposome; Human serum albumin; Albumin–liposome interaction; Differential scanning calorimetry;
Silica xerogel carrier material for controlled release of toremifene citrate by Manja Ahola; Pirjo Kortesuo; Ilkka Kangasniemi; Juha Kiesvaara; Antti Yli-Urpo (219-227).
Sol-gel processed silica xerogel was used as a carrier material for toremifene citrate in order to develop an implantable controlled release formulation which could be localised to a desired site providing targeted and long-lasting disease control and resulting in a reduced amount of drug needed. Toremifene citrate, an anti-estrogenic compound, was incorporated into silica xerogel matrixes during polycondensation of organic silicate, tetraethyl ortho silicate (TEOS). The effects of drug amount, drying temperature and polyethylene glycol (PEG) on the release rate of toremifene citrate and degradation of the silica xerogel matrixes were investigated. Addition of PEG (M w 4600/10 000) decreased the specific surface area of the matrix and lowered the release rate of the drug. Reducing the amount of drug in the matrix also decreased the release rate of toremifene citrate. However, drying temperature did not affect the release rate of silica or toremifene citrate. The release profiles of toremifene citrate were according to zero order kinetics, suggesting that drug release was controlled by erosion of the silica xerogel matrix. These results suggest that the toremifene citrate release rate can be controlled to some extent by adding (PEG) or by varying the amount of drug in the silica xerogel matrix.
Keywords: Sol-gel; Silica xerogel; Controlled release; Polyethylene glycol; Toremifene citrate;
High molecular weight polyethylene oxides (PEOs) as an alternative to HPMC in controlled release dosage forms by L. Maggi; R. Bruni; U. Conte (229-238).
Keywords: Polyethylene oxides; Hydroxypropylmethylcellulose; Hydrophilic matrix; Three-layer system; Controlled release;
Preparation and characterisation of a new insoluble polymorphic form of glibenclamide by A Panagopoulou-Kaplani; S Malamataris (239-246).
A crystalline form of glibenclamide, with higher melting point (218°C) and lower solubility in simulated gastric and intestinal fluids, was arisen during an attempt to elucidate transitional phases by melting, cooling and reheating. The new form was obtained from the glassy state, by applying sublimation at 130–160°C and was characterised by differential scanning calorimetry (DSC), infrared (IR) spectroscopy, scanning electron microscopy (SEM), hot-stage microscopy (HSM), X-ray powder diffraction (XRD) and solubility studies. Formation of the new crystal form is considered as reason of reduction in dissolution and bioavailability of tablets.
Keywords: Glibenclamide; New crystal form; Equilibrium solubility; Sublimation;
Pharmaceutical Experimental Design (Drugs and the Pharmaceutical Sciences, Vol. 92), Edited by G.A. Lewis, D. Mathieu and R. Phan-Tan-Luu, 1st Edition, Marcel Dekker, New York, 1999. vi+498 pp., 23.5×15.5 cm., 1.9 lb., Hardcover, ISBN 0-8247-9860-0, Price $175.00 by Bhupinder Singh; Naveen Ahuja (247-248).