International Journal of Pharmaceutics (v.241, #1)
Biochemical and biophysical characteristics of lipoplexes pertinent to solid tumour gene therapy by Crispin R Dass (1-25).
Cationic liposomes have become the reagent of choice for transfer of nucleic acids such as plasmids and oligodeoxynucleotides to cells in culture and in vivo. Whilst these reagents have several advantages over other forms of nucleic acid transfer methods, toxicity remains a significant problem, especially in vivo. Recent studies have also highlighted the immunostimulatory nature of these cationic vesicles when complexed to plasmid DNA, a phenomenon that may be harnessed for efficacious usage against tumours. Current research in this dynamic technological field is aimed at the development of cationic lipids that have negligible toxic effects and enhanced transfection capabilities.
Keywords: Cationic liposome; Lipoplex; Gene therapy; Cancer; Nucleic acid;
In vitro evaluation of nimodipine permeation through human epidermis using response surface methodology by S.A Giannakou; P.P Dallas; D.M Rekkas; N.H Choulis (27-34).
An optimization technique (response surface method) was used in order to investigate the effect of the combination of two enhancers, namely caprylic acid and cineol on nimodipine's permeation through human cadaver epidermis. Using this quadratic model it was found that at 24 h the increase of the permeation of nimodipine it was mainly due to the effect of caprylic acid. On the contrary, it was shown that at 48 and 72 h the combination of the two enhancers contributed to the increase of the permeation. The greater Q gel/Q control values, at all time intervals (24, 48 and 72 h), were obtained when the concentration of cineol and caprylic acid range from 3.0 to 5.0% (v/v) and 8.0 to 9.5% (v/v), respectively.
Keywords: Nimodipine; Transdermal; Response surface methodology;
Effects of superporous hydrogels on paracellular drug permeability and cytotoxicity studies in Caco-2 cell monolayers by Farid A Dorkoosh; Dewi Setyaningsih; Gerrit Borchard; Morteza Rafiee-Tehrani; J.Coos Verhoef; Hans E Junginger (35-45).
The aim of this study was to evaluate the effect of superporous hydrogel (SPH) and SPH composite (SPHC) as permeation enhancers for peptide drug delivery on Caco-2 cell monolayers. Moreover, the cytotoxic effects of these polymers were also studied using trypan blue test, MTT assay and propidium iodide staining. Transepithelial electrical resistance (TEER) studies revealed that both SPH and SPHC polymers were able to decrease TEER values to about 40% of initial values, indicating the ability of these polymers to open tight junctions. Recovery studies of TEER showed that the effects of polymers on Caco-2 cell monolayers were reversible, indicating viability of the cells after incubation with polymers. Both polymers were able to enhance the transport of the hydrophilic marker 14C-mannitol up to 2.7 and 3.8-fold in comparison to the control group. The cumulative transport of fluorescein isothiocyanate labelled dextrans with a molecular weight of 4400 Da (FD4) and 19 600 Da (FD20) was enhanced by SPH and SPHC polymers by opening of tight junctions; however, this enhancement was inversely proportional to the molecular weight of marker compounds. Cytotoxicity studies confirmed that the transport enhancing properties of SPH and SPHC polymers were not caused by damage of the Caco-2 cell monolayers. The cells were able to exclude trypan blue as well as propidium iodide after incubation with SPH and SPHC polymers. MTT assay showed that the number of viable cells was higher than 95% after incubation with SPH and SPHC polymers. This indicates that the mitochondrial metabolic activities of the cells were preserved after application of the polymers.
Keywords: Superporous hydrogels (SPH); SPH composite; Caco-2 cells; Cytotoxicity; Paracellular drug transport;
In vitro and in vivo evaluation of Pluronic F127-based ocular delivery system for timolol maleate by A.H El-Kamel (47-55).
The purpose of this study was to develop Pluronic F127 (PF127) based formulations of timolol maleate (TM) aimed at enhancing its ocular bioavailability. The effect of isotonicity agents and PF127 concentrations on the rheological properties of the prepared formulations was examined. In an attempt to reduce the concentration of PF127 without compromising the in situ gelling capabilities, various viscosity enhancing agents were added to PF127 solution containing 0.5% TM. The viscosity and the ability of PF127 gels to deliver TM, in vitro, in absence and presence of various viscosity enhancing agents were also evaluated. At the used concentration, some of the examined isotonicity agents had effect on the viscosity of TM gel. However, the viscosity of gel increased as the PF127 concentrations increased. The viscosity of formulations containing thickening agents was in the order of PF–MC 3%>PF–HPMC 2%>PF–CMC 2.5%>PF127 15%. The slowest drug release was obtained from 15% PF127 formulations containing 3% methylcellulose. In vivo study showed that the ocular bioavailability of TM, measured in albino rabbits, increased by 2.5 and 2.4 fold for 25% PF127 gel formulation and 15% PF127 containing 3% methylcellulose, respectively, compared with 0.5% TM aqueous solution.
Keywords: Pluronic F127; Timolol maleate; Rheological behavior; Additives; Ocular bioavailability;
Plasma protein binding, lipoprotein distribution and uptake of free and lipid-associated BCL-2 antisense oligodeoxynucleotides (G3139) in human melanoma cells by Ellen K Wasan; Dawn Waterhouse; Olena Sivak; Marcel B Bally; Richard J Klasa; Kishor M Wasan (57-64).
The objectives of this study were to determine the protein binding and lipoprotein distribution of G3139 and G3139 lipoplexes following incubation in human plasma, assess complement activation of, and the effect of pre-incubation of G3139 and G3139 lipoplexes in human plasma on in vitro cellular uptake of G3139. Effect of concentration and time on incorporation of free and lipid associated (lipoplexes) [3H]Bcl-2 AO (25–600 ng/ml) into normolipidemic human plasma lipoproteins was determined by density gradient ultracentrifugation after incubation at 37 °C for 5, 30, 60 and 120 min. Protein binding in the lipoprotein deficient fractions (LPDP) was determined by equilibrium dialysis. Complement interaction was determined by ELISA after exposure of human plasma to AO+/− liposomes prepared in serial dilution. In vitro uptake of G3139 and G3139 lipoplexes into human melanoma cells was assessed qualitatively by fluorescence microscopy after 4-h exposure to G3139 (free or as lipoplexes) with or without pre-incubation of G3139 in normal human plasma. Analysis of Bcl-2 AO-lipoprotein interaction over time and concentration indicated no significant movement of the compound within the different lipoprotein and LPDP fractions. Majority of drug was recovered within LPDP fraction, and more than 85% of drug recovered within LPDP fraction was protein bound. No significant activation of complement was noted for either free AO or lipoplexes. Pre-incubation of free AO or AO-lipoplexes in human plasma resulted in a greater cellular uptake of AO-lipoplexes compared with plasma free controls. These findings suggest that the majority of [3H]Bcl-2 AO is plasma protein bound with little lipoprotein association and no significant movement between different lipoprotein and LPDP fractions. Plasma protein binding other than lipoprotein binding may be responsible for the difference in cellular uptake of free AO vs. cationic lipoplexes.
Keywords: Bcl-2; Antisense therapy; Phosphorothioate oligodeoxynucleotides; Lipoplexes; Plasma proteins; Lipoproteins; Human complement proteins; Human melanoma cells;
Failure of stability prediction for minodronic acid injectable by accelerated stability testing by Katsutoshi Nakamura; Shigeharu Yokohama; Takashi Sonobe (65-71).
A liquid formulation containing 0.5 mg/ml minodronic acid, 40 mM, pH 4.5, citrate, and sodium chloride added to adjust the osmolarity of the final formulation was stored in flint glass ampoules at 25, 40, 50, and 60 °C. At specified times, the drug potency and pH, and the tendency to generate particulate matter, were measured. Test samples stored at 40 °C for 6 months or at 50 and 60 °C for 3 months were stable with no potency loss and no particulate increase. However, despite the satisfactory stability at high temperatures, the amount of particulate matter increased when the formulation was stored at 25 °C. Scanning electron microscopy-energy dispersive X-ray analysis of the particulate matter revealed that it contains aluminum and phosphorus, the latter thought to be derived from minodronic acid. In contrast, the number of the particulate matter did not increase, when the formulation was stored in either plastic containers or in SiO2-treated glass ampoules. The spike of minodronic acid solution with aluminum ions led to the particulate generation. These results demonstrate that the particulate matter is a complex of minodronic acid molecules and aluminum ions, which apparently leached from the glass of regular ampoules. Since the particulate generation could not be observed at higher temperatures, it was suggested that the complex formation was exothermic and accelerated testing did not predict the stability in terms of particulate generation.
Keywords: Minodronic acid; Parenteral formulation; Stability; Particulate matter; Complex; Aluminum ion;
Comparison of the mechanical properties of the crystalline and amorphous forms of a drug substance by Bruno C Hancock; Glenn T Carlson; Dauda D Ladipo; Beth A Langdon; Matthew P Mullarney (73-85).
Purpose: To better understand the influence of long-range molecular order on the processing characteristics of an active pharmaceutical ingredient (API). Methods: Crystalline and amorphous samples of a model drug substance were isolated and their “true” density, crystallinity, melting point, glass transition temperature, particle size distribution, and powder flow characteristics determined. Compacts of a standard porosity were manufactured from each form and their dynamic indentation hardness, quasi-static indentation hardness, tensile strength and “compromised tensile strength” determined. X-ray powder diffraction was used to confirm that no changes were induced by compact formation or testing. Results: The crystalline and amorphous forms of the drug substance had relatively high melting and glass transition temperatures (approximately 271 and 142 °C, respectively) and were physically and chemically stable under the conditions of the testing laboratory. Consistent with this there was no evidence of crystallinity in the amorphous samples or vice versa before, during or after testing. The two API lots were effectively equivalent in their particulate properties (e.g. particle size distribution), although differences in their particle morphologies were observed which influenced powder flow behavior. The compacts of the bulk drug samples exhibited moderate ductility, elasticity, and strength, and high brittleness, in keeping with many other drug substance samples. A significantly greater compression stress was required to form the compacts of the crystalline material, and these sample materials were more ductile, less brittle and less elastic than those made from the amorphous API. There were no major differences in the tensile strength or the viscoelasticity of the compacts made from the crystalline and amorphous samples. Conclusions: The mechanical properties of compacted amorphous and crystalline samples of a drug substance have been measured and the contributions due to the molecular ordering of the crystalline form proposed. Small but significant differences in the mechanical properties were noted which could potentially affect the processing performance of API.
Keywords: Amorphous; Crystal; Mechanical;
Development of level A, B and C in vitro–in vivo correlations for modified-release levosimendan capsules by H. Kortejärvi; J. Mikkola; M. Bäckman; S. Antila; M. Marvola (87-95).
The aim of this study was to investigate the possibility of developing different levels of correlation between in vitro release and in vivo absorption rate for four modified-release levosimendan capsule formulations. Differences and similarities in the in vitro dissolution curves were compared with pharmacokinetic parameters describing absorption rate. Formulations F, G, H and I differed in the amounts of the delaying excipients alginic acid and HPMC. In vitro release rate was studied by the USP basket method using the following conditions: pH 5.8 or 7.4 and a rotation speed of 50 or 100 rpm. In vivo bioavailability was tested in nine healthy male volunteers and the fractions absorbed were calculated by the Wagner–Nelson method. Dissolution conditions pH 5.8 and a rotation speed of 100 rpm predicted best the similarities and differences in absorption rates among different formulations, and levels C and B correlation coefficients were 0.85 and 0.97, respectively. For formulation H level A correlation (r=0.997) was found when in vitro lag time was 0.2 h and time scale factor 1.9. This study indicated that dissolution tests developed can be used as a surrogate for human bioequivalence studies, for development processes of final commercial products, to ensure batch to batch bioequivalence and in the future in possible scale-up and post approval change cases for modified-release levosimendan formulation H.
Keywords: Modified-release; Levosimendan; In vitro–in vivo correlation; Wagner–Nelson; Weibull;
The effect of ethanol on acrylic bone cement by A Bettencourt; A Calado; J Amaral; F.M Vale; J.M.T Rico; J Monteiro; M.F Montemor; M.G.S Ferreira; M Castro (97-102).
Prosthesis loosening is a major problem associated with the use of poly(methyl methacrylate) (PMMA) bone cement that may be related to a peri-implant vacuolisation commonly observed at bone–cement interface. Methyl methacrylate (MMA) monomer may be one of the cement components partly responsible for the mentioned vacuolisation due to a cytotoxic effect associated to this compound. Alcoholism has been related to bone necrosis in predisposed individuals. Furthermore, ethanol has been shown to clean material with adherent cement debris during cleaning procedure in laboratory. Consequently, we have decided to study whether ethanol will also be related to an increased liberation of MMA from the polymer matrix. ‘In vitro’ release studies using PMMA plates were conducted to access the role of ethanol on the liberation of the monomer. Contact angle measurements and surface tension estimation were also carried out in order to find a possible effect of ethanol on surface cement properties. Results suggest that ethanol, even in small quantities, enhances the leaching of the monomer from the polymer matrix, but does not considerably change the wettability properties of the cement surface.
Keywords: Poly(methyl methacrylate); Methyl methacrylate; Bone cement; Ethanol; Release model; Surface tension;
Stabilization of amorphous indomethacin by co-grinding in a ternary mixture by Tomoyuki Watanabe; Ikumasa Ohno; Naoki Wakiyama; Akira Kusai; Mamoru Senna (103-111).
Mechanochemical amorphization of indomethacin (IM) was substantially enhanced by grinding with SiO2, talc and a Mg(OH)2–SiO2 mixture. The rates of the mechanochemical amorphization were in the order of Mg(OH)2–SiO2 mixture>talc>SiO2. Amorphous state stability of IM compounded with the carrier was examined by crystallization behavior under the condition of 30 °C and 11% relative humidity. Superiority of the binary mixture as a carrier was explained in terms of the mechanically induced strong acidic sites of the carrier.
Keywords: Co-grinding; Indomethacin; Mechanochemical; Crystallization; Acidic site;
Evaluation of a new controlled-drug delivery concept based on the use of thermoresponsive polymers by Frederic Eeckman; André J Moës; Karim Amighi (113-125).
The purpose of this work is to develop a new delivery concept making a thermosensitive polymer based on poly(N-isopropylacrylamide) (PNIPAAm) useful as a time-controlled drug release device, without any temperature changes of the dissolution medium. It was previously found that some salts induce a decrease of the polymer lower critical solution temperature (LCST). Use is here made of that property to show that salt concentration variations can be used as a substitute for temperature changes to make the polymer coating of compression-coated tablets soluble or insoluble, consequently creating a possible new concept of drug delivery control from delivery systems containing thermoresponsive polymers. The obtained results show the influence of the type and amount of salts incorporated into compression-coated tablets on the release lag time of a model drug.
Keywords: Poly(N-isopropylacrylamide); Thermoresponsive polymers; Salts; Controlled-drug delivery; Compression-coated tablets;
Buccal transport of flecainide and sotalol: effect of a bile salt and ionization state by V.H.M Deneer; G.B Drese; P.E.H Roemelé; J.C Verhoef; L Lie-A-Huen; J.H Kingma; J.R.B.J Brouwers; H.E Junginger (127-134).
Patients with infrequent attacks of supraventricular arrhythmia may benefit from self administration of antiarrhythmic drugs on an ‘as required’ basis. The oral cavity is easily accessible and the potential for rapid absorption exists. The effects of ionization state and sodium glycocholate on the ex vivo transport of sotalol and flecainide across porcine buccal mucosa were studied. The permeated amounts at 3 h (Q) and fluxes (J) of sotalol in an aqueous solution at pH 7.4 and 9.0 were similar. At pH 7.4, in contrast to pH 9.0, the addition of 1.0% (w/v) sodium glycocholate decreased Q and J four and five fold. Flecainide base in propylene glycol resulted in a nine and 12 fold higher Q and J as compared with an aqueous solution of flecainide acetate at pH 5.8. The presence of sodium glycocholate reduced the transport rate of the flecainide base. However, Q and J were increased 110 and 75 fold by adding 1.0% (w/v) sodium glycocholate to a solution of flecainide acetate at pH 5.8. Sodium glycocholate seems to be an effective penetration enhancer for the buccal absorption of the more polar ionized form of flecainide in an aqueous solution. Sodium glycocholate does not seem to improve the transport of sotalol.
Keywords: Ex vivo buccal absorption model; Porcine buccal mucosa; Penetration enhancer; Sodium glycocholate; Sotalol; Flecainide;
Mucoadhesion on pig vesical mucosa: influence of polycarbophil/calcium interactions by M Kerec; M Bogataj; B Mugerle; M Gašperlin; A Mrhar (135-143).
The influence of polycarbophil/calcium interactions on the mucoadhesive properties of polycarbophil has been examined. Polycarbophil dispersions and films with different concentrations of calcium or sodium ions were prepared and the following parameters were measured: detachment force on pig vesical mucosa, zeta potential, pH and viscosity. Polycarbophil detachment force decreased significantly in the presence of calcium but not sodium. Both ions decrease the pH of polycarbophil dispersions. On the other hand, altering the pH of hydrated polycarbophil films in the absence of added ions had an insignificant effect on detachment force. Both ions reduce the absolute values of polycarbophil zeta potential, calcium more efficiently than sodium. We could conclude that decreased mucoadhesion strength of polycarbophil in the presence of calcium is due to the chelation of polycarbophil carboxylic groups by calcium and crosslinking of polymer. The crosslinked polymer chains would be expected to be less flexible, and therefore, interpenetrate to a lesser extent with the glycosaminoglycans of mucus. Additionally, the interactions between functional groups of polycarbophil and mucus glycosaminoglycans are lowered due to the calcium, blocking the carboxylic groups. The mechanism of calcium influence on viscosity of polycarbophil dispersions appears to be different: repulsion between ionised carboxylic groups of polycarbophil prevails over the crosslinking of polycarbophil by calcium.
Keywords: Polycarbophil; Calcium binding; Mucoadhesion; pH; Zeta potential; Viscosity;
Development of hemoglobin aquasomes from spherical hydroxyapatite cores precipitated in the presence of half-generation poly(amidoamine) dendrimer by A.J Khopade; Surekha Khopade; N.K Jain (145-154).
Spherical hydroxyapatite cores were prepared by using carboxylic acid terminated half-generation poly(amidoamine) (PAMAM) dendrimer as templates or crystal modifiers. The hydroxyapatite cores were characterized by infrared spectroscopy (IR), X-ray diffraction (XRD) and transmission electron microscopy (TEM). The spherical core formation depended on phosphate saturation, pH of the simulated body fluid (SBF) and rate of crystal growth. Hydroxyapatite so formed was amorphous and a mixture of various calcium phosphates. Ca/P ratio determination which showed phosphate rich apatite formation. Hydroxyapatite ores were coated with a sugar layer followed by hemoglobin to obtain aquasomes. Aquasomes were characterized for size, hemoglobin loading, oxygen-binding characteristics and storage stability. The nanometric sized aquasome formulation could load approximately 13.7 mg hemoglobin per g of core and retained oxygen-affinity and cooperativity and stability for at least 30 days. Formulation efficacy was tested in albino rats and indicated its potential utility as blood-substitute.
Keywords: Dendrimer; Crystal modifiers; Hydroxyapatite; Self-precipitation; Aquasomes; Hemoglobin;
Rheological evaluation of thermosensitive and mucoadhesive vaginal gels in physiological conditions by Jung Yun Chang; Yu-Kyoung Oh; Han-gon Choi; Yang Bae Kim; Chong-Kook Kim (155-163).
The timely gelation and retention of in situ-gelling vaginal formulations would be fundamental to improve the efficacy of drugs. In this study, various rheological properties of clotrimazole gels were evaluated for predicting their performance in vagina. Two kinds of thermosensitive and mucoadhesive formulations were composed of poloxamer 407 (P407, 15%), polycarbophil (0.2%), and different amounts of P188 (15 vs. 20%). Both formulations were Newtonian at 20 °C but non-Newtonian at 37 °C. Although both liquid formulations gelled below the vaginal temperature, they differed in gelation time and viscoelastic properties in the presence of vaginal fluid simulant. At body temperature, the formulation with 20% of P188 gelled within 35 s but it took two times longer for the other one gelled. Upon dilution with simulated vaginal fluid, the formulation with 20% of P188 retained the rheology of a gel, but the other one lost the viscoelastic properties typical for a gel. Moreover, after dilution with simulated vaginal fluid, the elastic modulus was orders of magnitude higher in the formulations with 20% of P188 relative to the other one. These results indicate that the rheological evaluation at the physiologic conditions needs to be preceded to develop more effective in situ-gelling vaginal formulations.
Keywords: Rheology; Poloxamer; Thermosensitive gel; Clotrimazole; Vaginal formulation;
Bioavailability of a new ketoprofen formulation for once-daily oral administration by A. Roda; L. Sabatini; M. Mirasoli; M. Baraldini; E. Roda (165-172).
A new sustained-release formulation (sustained release Ibifen®) that gradually releases ketoprofen within 24 h and ensures therapeutic plasma concentration for the entire period has been developed. It consists of tableted pH-dependent barrier film-coated ketoprofen granules and was administered at a single dose of 200 mg to 12 volunteers. Ketoprofen plasma profiles were compared with: (1) administration of Orudis retard® 200 capsule (200 mg); (2) two 12-h doses of prompt release Ibifen® capsules (100 mg). In vitro dissolution kinetics and ketoprofen plasma levels were measured by HPLC. Sustained release Ibifen® dissolution rate was constant for 10 h, whereas Orudis retard® 200 dissolution profile presented one higher slope (0–6 h) and a lower one (6–12 h). Both formulations showed a delayed kinetics with respect to prompt release Ibifen®. After sustained release Ibifen® administration, ketoprofen plasma peak, reached within 2 h, remained practically constant for at least 12 h (average 4 μg/ml), which is higher than therapeutic levels. Differently, Orudis retard® 200 produced a delayed, higher C max (5.91±0.66 vs. 4.51±0.65 μg/ml; P<0.01) and disappeared more quickly. In conclusion, sustained release Ibifen® can ensure therapeutic ketoprofen plasma levels for the entire 24 h period, avoiding plasma concentration spikes, with bioavailability similar to other ketoprofen preparations.
Keywords: Anti-inflammatory drug; Ketoprofen; Bioavailability; Sustained release formulations; Pharmacokinetics;
Influence of teardrop studs on rotating frictional base plate on spheroid quality in rotary spheronization by P.W.S Heng; C.V Liew; L Gu (173-184).
The effects of teardrop-shaped studs on the quality of rotary processed spheroids were investigated. The spheroids were produced under similar conditions using three rotating frictional base plates with teardrop studs of different height, volume, cross-sectional area and surface area. Spheroid properties were rated by size, size distribution, shape, friability and density. The amounts of lumps and fines produced, and the adhesion of material on the rotating frictional base plates was also looked into. The dimension of the teardrop studs on the rotating frictional base plate affected spheroid quality. The resultant shear forces and energy input during rotary spheronization differed depending on the different height, volume, cross-sectional area and surface area of studs. With the increase in height, volume, cross-sectional area and surface area of studs on the frictional base plate, the mass median diameter, e R and circularity of spheroids increased with corresponding decrease in span, lumps and fines. Although the frictional base plate with shortest studs had little adhesion, it may not supply enough shear force and energy input for the spheronization process, resulting in a less stable process. A balance between energy input and adhesion on the rotating frictional base plate was needed in order to optimize the production of spheroids by rotary processing.
Keywords: Rotary processor; Rotary processing; Teardrop studs; Frictional base plate; Spheroids;
In-vitro release of diclofenac diethylammonium from lipid-based formulations by Siamak Parsaee; Mohammad N Sarbolouki; Mohamad Parnianpour (185-190).
This article presents the preparation and topical performance of some new lipid-based formulations of diclofenac, namely (a) a diclofenac aqueous gel containing mixed micelles (sodium cholate:egg lecithin molar ratio 0.55); (b) diclofenac lotion that contains soya lecithin, ethanol and buffer; and (c) diclofenac lipogel containing egg lecithin, isopropyl myristate, propylene glycol and ethanol. Gel formulations were prepared using Carbomer 934. Release of diclofenac from all formulations was monitored via dialysis through Spectra/por membrane into phosphate buffer (0.2 M pH=7.4) using a Franz cell. Drug release profile and diffusion coefficients were compared with brand formulation (Geigy's Vlotaren Emulgel). Statistical analysis of data show that the diffusion coefficient of the drug from these formulations rank according to the following order: Diclofenac lotion (D=5.308×10−7 cm2/s) >lipogel (D=2.102×10−7 cm2/s) >Voltaren Emulgel (1.518×10−7 cm2/s) >aqueous gel mixed micelle (0.966×10−7 cm2/s). These results show that diclofenac lotion and lipogel maybe more suitable formulations than the conventional topical dosage form.
Keywords: Diclofenac; Topical; Lecithin; Release rate; Diffusion coefficient; Lipogel; Lipid-based;
INSTRUCTIONS TO AUTHORS (195-199).