International Journal of Pharmaceutics (v.236, #1-2)

The absorption of drugs into the nail unit, following topical application to the nail plate, is highly desirable to treat nail disorders, such as onychomycosis (fungal infections of the nail). Nail permeability is however quite low and limits topical therapy to early/mild disease states. In this paper, the recent research into ungual drug delivery is reviewed. The nail unit and the two most common diseases affecting the nail—onychomycosis and nail psoriasis—are briefly described to set the scene and to give an overview of the nature and scope of the problem. The factors, which affect drug uptake and permeation through the nail plate such as solute molecular size, hydrophilicity/hydrophobicity, charge, and the nature of the vehicle, are then discussed, followed by ways of enhancing drug transport into and through the nail plate. Finally, drug-containing nail lacquers which, like cosmetic varnish, are brushed onto the nail plates to form a film, and from which drug is released and penetrates into the nail, are reviewed.
Keywords: Ungual drug delivery; Nail; Nail lacquers; Topical application;

Evaluation of Pulsincap™ to provide regional delivery of dofetilide to the human GI tract by Howard N.E Stevens; Clive G Wilson; Peter G Welling; Massoud Bakhshaee; Julie S Binns; Alan C Perkins; Malcolm Frier; Elaine P Blackshaw; Margaret W Frame; Don J Nichols; Michael J Humphrey; Steve R Wicks (27-34).
Pulsincap™ formulations designed to deliver a dose of drug following a 5-h delay were prepared to evaluate the capability of the formulation to deliver dofetilide to the lower gastrointestinal (GI) tract. By the expected 5-h release time, the preparations were well dispersed throughout the GI tract, from stomach to colon. Plasma analysis permitted drug absorption to be determined as a function of GI tract site of release. Dofetilide is a well-absorbed drug, but showed a reduction in observed bioavailability when delivered from the Pulsincap™ formulations, particularly at more distal GI tract sites. Dispersion of the drug from the soluble excipient used in this prototype formulation relies on a passive diffusion mechanism and the relevance of this factor to the reduced extent and consistency of absorption from the colon is discussed. In these studies the effects of the degree of dispersion versus the site of dispersion could not be ascertained; nevertheless the scintigraphic analysis demonstrated good in vitro–in vivo correlation for time of release from Pulsincap™ preparations. The combination of scintigraphic and pharmacokinetic analysis permits identification of the site of drug release from the dosage form and pharmacokinetic parameters to be studied in man in a non-invasive manner.
Keywords: Pulsatile release; Site-release; Gamma scintigraphy; Pharmacokinetics; Dofetilide; Pulsincap™;

The effects of ethanol on the simultaneous transport and metabolism of methyl p-hydroxybenzoate (HBM) were investigated in the skin of Yucatan micropig in vitro. It was found that transesterification occurred in the permeation studies involving ethanol. This was confirmed by monitoring the flux of ethyl p-hydroxybenzoate (HBE) into the receptor phase, as well as by monitoring the fluxes of HBM and p-hydroxybenzoic acid (HBA). The apparent flux of total HBM was decreased. The solubility of HBM increased with ethanol concentration, thus, the activity of HBM in ethanol solution became low because we used 10 mM HBM solution for permeation studies. The enhancement factor (E) was calculated to correct the activity. E increased with increasing the flux of ethanol, thus, ethanol may function as an enhancer of HBM transport. The hydrolysis of HBM to HBA was inhibited, whereas transesterification of HBM to HBE was induced at all concentrations of ethanol used (10–40%). The formation of HBE occurred much more readily than that of HBA at all concentrations of ethanol used.
Keywords: Skin metabolism; Skin permeation; Methyl p-hydroxybenzoate; Ethanol; Transesterification; Yucatan micropig skin;

Studies on the development of oral colon targeted drug delivery systems for metronidazole in the treatment of amoebiasis by Y.S.R. Krishnaiah; P.R. Bhaskar Reddy; V. Satyanarayana; R.S. Karthikeyan (43-55).
The aim of the present study is to develop colon targeted drug delivery sytems for metronidazole using guar gum as a carrier. Matrix, multilayer and compression coated tablets of metronidazole containing various proportions of guar gum were prepared. All the formulations were evaluated for the hardness, drug content uniformity, and were subjected to in vitro drug release studies. The amount of metronidazole released from tablets at different time intervals was estimated by high performance liquid chromatography method. Matrix tablets and multilayer tablets of metronidazole released 43–52% and 25–44% of the metronidazole, respectively, in the physiological environment of stomach and small intestine depending on the proportion of guar gum used in the formulation. Both the formulations failed to control the drug release within 5 h of the disolution study in the physiological environment of stomach and small intestine. The compression coated formulations released less than 1% of metronidazole in the physiological environment of stomach and small intestine. When the dissolution study was continued in simulated colonic fluids, the compression coated tablet with 275 mg of guar gum coat released another 61% of metronidazole after degradation by colonic bacteria at the end of 24 h of the dissolution study. The compression coated tablets with 350 and 435 mg of guar gum coat released about 45 and 20% of metronidazole, respectively, in simulated colonic fluids indicating the susceptibility of the guar gum formulations to the rat caecal contents. The results of the study show that compression coated metronidazole tablets with either 275 or 350 mg of guar gum coat is most likely to provide targeting of metronidazole for local action in the colon owing to its minimal release of the drug in the first 5 h. The metronidazole compression coated tablets showed no change either in physical appearance, drug content or in dissolution pattern after storage at 40 °C/75% RH for 6 months.
Keywords: Guar gum; Metronidazole; Colon targeting; In vitro dissolution; Compression coating;

The effects of vehicles and penetration enhancers on the in vitro permeation of tenoxicam from saturated solutions through dorsal hairless mouse skin were investigated. Various types of vehicles, including ester-, alcohol-, and ether-types and their mixtures, were used as vehicles, and then a series of fatty acids and amines were employed as enhancers, respectively. Even though the fluxes of tenoxicam from saturated pure vehicles were generally low (0.1–1.1 μg/cm2 per h), the skin permeability of tenoxicam was significantly increased by the combination of diethylene glycol monoethyl ether (DGME) and propylene glycol monolaurate (PGML) or propylene glycol monocaprylate (PGMC); the highest fluxes were achieved at 40% of DGME in both of the two cosolvents. The marked synergistic enhancement was also obtained by using propylene glycol (PG)–oleyl alcohol (OAl) cosolvent. The greatest flux was attained by the addition of unsaturated fatty acids at 3% concentration to PG. But saturated fatty acids failed to show a significant enhancing effect. The enhancement factors with the addition of oleic acid (OA) or linoleic acid (LOA) to PG were 348 and 238, respectively. Tromethamine (TM) showed an enhancing effect by the increased solubility; however, triethanolamine (TEA) did not show a significant enhancing effect. Rather, it decreased the fluxes of tenoxicam when added to PG with fatty acids. The above results indicate that the combinations of lipophilic vehicles like OA, LOA or OAl and hydrophilic vehicles like PG can be used for enhancing the skin permeation of tenoxicam.
Keywords: Percutaneous absorption; Tenoxicam; Penetration enhancers; Fatty acids; Amines;

The inhibition of phagocytosis of respirable microspheres by alveolar and peritoneal macrophages by B.G Jones; P.A Dickinson; M Gumbleton; I.W Kellaway (65-79).
Respirable poly(lactic co-glycolic acid) (PLGA) microspheres (2–3 μm diameter), were fabricated as a model drug delivery system whose uptake by macrophages could be quantified by fluorescent activated cell sorting. The microspheres exhibited minimal release of the entrapped flourophore (rhodamine B) and thus avoided possible fluid phase uptake of the flourophore. Externally bound microspheres were removed from the cell membrane by acid washing. The fluorescent intensity associated with the cells arose, therefore, from the internalised microspheres. NR8383 continuous culture alveolar macrophages were verified against primary cultures as a good model of alveolar phagocytosis. Peritoneal macrophages were also isolated and systemic and alveolar phagocytosis compared. Poloxamer 338 adsorbed at the microsphere surface did not reduce phagocytosis by NR8383 macrophages. It did, however, reduce the number of microspheres contained in primary alveolar macrophages but did not reduce the percentage of phagocytic cells. Poloxamer coatings did not reduce phagocytosis by peritoneal macrophages once the ratio of five microspheres per cell was exceeded. Dipalmitoylphosphatidylcholine (DPPC), the major component of lung surfactant, was added to cultures to model the alveolar environment where it was observed to reduce phagocytosis. In light of this finding, microspheres were coated in DPPC, which reduced their uptake by all cell types at all microsphere to cell ratios.
Keywords: Alveolar macrophages; Peritoneal macrophages; Phagocytosis inhibition; PLGA microspheres; DPPC; Poloxamer 338;

The crystallization of drug in a matrix may significantly affect the efficacy and quality of the transdermal drug delivery system. Therefore, the control of drug crystallization is of particular interest in the development of efficient transdermal delivery systems. In this study, we investigated the effects of various additives on the crystallization of ketoprofen in polyisobutylene (PIB) adhesive matrix. The effects of various additives on the permeation of ketoprofen from PIB matrix across hairless mouse skin were also examined. Poly(vinyl pyrrolidone) (PVP) K-30 was found to be the most effective crystallization inhibitor. Also, Poloxamer, Tween 80 and Labrasol significantly inhibited the crystallization of ketoprofen in a PIB matrix. In case of Tween 80, Labrasol, and PVP K-30, the flux of ketoprofen decreased as the loading content of the additives increased. However, the addition of Tween 80, Labrasol, or PVP K-30 significantly reduced the decrease in the flux of ketoprofen within the PIB matrix during a storage time of 3 weeks.
Keywords: Crystallization; Ketoprofen; Poly(vinyl pyrrolidone); Polyisobutylene;

An in vitro model for investigating the gastric mucosal retention of 14C-labelled poly(acrylic acid) dispersions by Robert G Riley; John D Smart; John Tsibouklis; Simon A Young; Frank Hampson; Alf Davis; Grant Kelly; Peter W Dettmar; William R Wilber (87-96).
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.
Keywords: Mucoadhesion; Bioadhesion; Poly(acrylic acid)s; Gastric mucosa;

Altered immune response to liposomal allergens of Aspergillus fumigatus in mice by Shailly Nigam; P.C Ghosh; P.Usha Sarma (97-109).
Aspergillus fumigatus has been implicated as the major pathogenic fungus causing Aspergillus-mediated disorders. It secretes complex glycoprotein antigens and allergens, which induce type I and type III mediated hypersensitivity reactions. The immune response to these allergens/antigens in allergic disorders is characterized by elevated levels of specific IgE, Th2 cytokines and eosinophilia. In the current study, the ability of negatively charged liposomes entrapped with glycoprotein antigens and allergens of A. fumigatus to modulate the immune response was studied. Immune response in mice was evaluated with both free and liposomal formulations. Liposome entrapped glycoprotein antigens/allergens of A. fumigatus elicited a Th1 type response with increased levels of TNF-α (5.5-folds), IFN-γ (four-folds), specific IgG (three-folds) and IgG2a (2.4-folds), low titers of specific IgG1 (2.2-folds decrease) and IgE (three-folds decrease), and decreased peripheral eosinophilia by four-folds in comparison to mice receiving free glycoprotein allergens/antigens of A. fumigatus. Histopathological examination of lung tissue sections clearly indicated reduced eosinophil infiltration in mice immunized with liposomal formulations. These results suggest potential of liposomal formulations for A. fumigatus allergens/antigens for exploration in immunotherapy.
Keywords: Cytokines; Eosinophils; Glycoprotein antigens/allergens; Immune response; Liposomes;

Solid-state characterization of nifedipine solid dispersions by Sudha R. Vippagunta; Karin A. Maul; Siva Tallavajhala; David J.W. Grant (111-123).
The purpose of this study is to characterize the nature and solid-state properties of a solid dispersion system of nifedipine (33.3% w/w) in a polymer matrix consisting of Pluronic F68 (33.3% w/w) and Gelucire 50/13 (33.3% w/w). The nature of nifedipine dispersed in the matrix was studied by powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC) and diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS). The rate and extent of water uptake of the solid dispersion were determined by weight gain. The dissolution rate of nifedipine solid dispersion was determined using Apparatus 2 of USP XXIII (1995). Quantitative PXRD showed that the saturation solubility of nifedipine in the polymer matrix is 2.1–3.0% w/w and indicated an excess of crystalline nifedipine in the solid dispersion. The maximum water uptake by the solid dispersion exposed to 75% RH at 45 °C was 3.3 times higher than for the dispersion exposed to 65% RH at 25 °C. Over 8 weeks, PXRD and DRIFTS of the nifedipine matrix stored at 25 or 4 °C were unchanged, showing constancy of crystallinity and intermolecular interactions. For a given mass of nifedipine (20 mg) and for a given particle size of nifedipine (<850 μm), the initial release rate of nifedipine from the solid dispersion was faster (46.2% of the nifedipine dissolved in 20 min) than that of the pure drug (1.2% of the nifedipine dissolved in 20 min). The results indicate that the nifedipine solid dispersion is physically stable over 8 weeks. Nifedipine is released faster from the solid dispersion than from the pure crystalline drug of the same particle size.
Keywords: Solid dispersion; Nifedipine; Pluronic F68; Gelucire 50/13; Solubility; Dissolution rate;

HEPC-based liposomes trigger cytokine release from peripheral blood cells: effects of liposomal size, dose and lipid composition by Sayaka Yamamoto; Tatsuhiro Ishida; Akiko Inoue; Junko Mikami; Masahiro Muraguchi; Yasukazu Ohmoto; Hiroshi Kiwada (125-133).
The immune response caused by liposome stimulation was studied by assessing the level of several cytokines released from human peripheral blood cells. Liposome stimulation resulted in the release of IL-6, IL-10, IL-1β, TNF-α and IFN-γ. The size of the liposomes affected the degree of the cytokine releases with larger sized liposomes causing higher levels of cytokine induction. In addition, it appears that the lipid composition of liposomes had no effect on the degree of cytokine release. The release of cytokines occurred even in the absence of serum, suggesting that serum proteins did not contribute to liposome stimulation in peripheral blood cells. The release of cytokines induced by liposome stimulation was inhibited by the presence of either protein kinase-C (PKC) or protein tyrosine kinase (PTK) inhibitor, but not by the presence of an endocytosis inhibitor. This indicates that signal transduction via PKC or PTK is necessary, in order for human peripheral blood cells to release cytokines (IL-6, IL-10, IL-1β, TNF-α and IFN-γ) as the result of liposome stimulation. These quantitative data on the release of cytokines by liposomal stimulation provide useful information for the development of rational drug delivery systems and the safety of cytokine induction via the use of liposomes.
Keywords: Liposome; Cytokine; Human peripheral blood cell; Whole-blood induction; Immune system;

Dissolution testing of a poorly soluble compound using the flow-through cell dissolution apparatus by Shobha N Bhattachar; James A Wesley; Ann Fioritto; Peter J Martin; Suresh R Babu (135-143).
Dissolution of Pfizer Compound PD198306, a poorly soluble compound, was studied in 25 mM pH 9 sodium phosphate solution with 0.5% SLS using the flow-through cell dissolution apparatus. Unmicronized and micronized drug powders were tested. Several methods of loading the drug powder into the flow-through dissolution cells and their impact on dissolution were investigated. The influence of flow rate of the dissolution medium on the rate and extent of dissolution were studied. PD198306 has poor wettability even in the presence of 0.5% SLS. It was found that loading the drug powder into the dissolution cell in the form of a suspension provided the best dissolution profile in terms of the rate and extent of dissolution. The flow rate of 4 ml/min resulted in good particle size discrimination.
Keywords: Dissolution testing; Flow-through dissolution method; High throughput screening;

The aim of this study is to use texture analysis as a non-destructive test for hard gelatin capsules filled with liquid formulations to investigate mechanical changes upon storage. A suitable amount of water in the formulations is determined to obtain the best possible compatibility with the gelatin shell. This quantity of water to be added to a formulation is called the balanced amount of water (BAW). Texture profiling was conducted on capsules filled with hydrophilic polymer mixtures and with formulations based on amphiphilic masses with high HLB value. The first model mixture consisted of polyethylene glycol 400 and polyvinylpyrrolidone K17 with water and the second type consisted of caprylocaproyl macrogol glycerides (Labrasol®) with colloidal silica (Aerosil® 200) and water. The liquid-fill capsules were investigated by measuring changes on mass and stiffness after storage under confined conditions in aluminium foils. Capsule stiffness was investigated also as a parameter in a response surface analysis to identify the BAW. Polyvinylpyrrolidone did not show a great influence on the BAW in the range of 10–12% (w/w) for the first model mixture. Capsules with the less hydrophilic Labrasol® formulations, however, kept their initial stiffness after storage best with only half of that amount, i.e. 5–6% (w/w) of water in the compositions. From this study it can be concluded that texture profiling in the framework of an experimental design helps to find hydrophilic or amphiphilic formulations that are compatible with gelatin capsules. Short-term stability tests are meaningful if capsule embrittlement or softening is due to water equilibration or another migration process that takes place rapidly. Long-term stability tests will always be needed for a final statement of compatibility between a formulation and hard gelatin capsules.
Keywords: Texture analysis; Hard gelatin capsules; Liquid-fill; Compatibility testing; Experimental design; Optimisation;

Vedemecum for vitamin formulations by M.C Allwood (153).

Noticeboard (155-157).