International Journal of Pharmaceutics (v.305, #1-2)

Historical perspectives by A.T. Florence (1).

Skin permeation: The years of enlightenment by Jonathan Hadgraft; Majella E. Lane (2-12).
Considerable advances in our understanding of the mechanisms by which drugs permeate the skin barrier have been made over the past 60 years. The key publications, which have influenced the field of skin permeation research are highlighted in the present review. The methodologies commonly employed for estimation of skin permeability are discussed as are the mechanisms proposed for skin permeation. The principal findings from the commonly employed in vitro and in vivo models are considered as well as the applications of enhancers and surfactants for optimization of skin delivery. As these studies presaged the emergence of transdermal drug delivery research in the 1970s, early approaches to model and predict dermal and transdermal absorption are also outlined. The published work on skin permeability in this period embodies the fundamental literature sources for consultation by scientists new to and currently engaged in transdermal drug delivery.
Keywords: Skin absorption; Topical formulation; Enhancers;

Evaluation of the taste and smell of bottled nutritive drinks by Masumi Kataoka; Koichi Yoshida; Yohko Miyanaga; Eriko Tsuji; Emi Tokuyama; Takahiro Uchida (13-21).
The purpose of this study was to evaluate the palatability of 15 bottled nutritive drinks, all commercially available in the Japanese market, using data from artificial taste and odor sensors. In gustatory sensation tests, well-trained healthy volunteers were asked to score the drinks in terms of palatability and of the four basic tastes. The results suggest that overall palatability is positively correlated with sourness intensity and fruitiness (R  = 0.82 and 0.86, respectively) and negatively correlated with bitterness intensity and the tasting of medicinal plants (R  = −0.85 and −0.80, respectively).The sourness and bitterness intensity could be predicted by taste sensor and fruitiness could be predicted by odor sensor, respectively.By performing principal component analysis of the taste sensor data, the 15 drinks could be classified into four groups. The group classified as being predominantly sour had the highest palatability score, 3.8. By principal component analysis of odor sensor data, the drinks could also be classified into four groups and this time the group with a fruity flavor (smell) showed the highest palatability score, 3.4. In the combined analysis of both taste and odor data, products containing medicinal plants showed the lowest palatability. Finally, the combined usage of the taste and odor sensors gave rise to a three-group classification. Thus, not only the taste sensor but also the odor sensor may be useful in evaluating the palatability of bottled nutritive drinks.
Keywords: Taste sensor; Nose sensor; Sourness; Bitterness; Medicinal plant; Nutritive drinks;

The objective of this study was to evaluate the effect of two factors (ratio of Eudragit S100 and Eudragit L100 and the coating level) on indomethacin release from pellets in order to optimize coating formulations for colonic delivery. Coating formulations were designed based on the full factorial design. Two independent variables were the ratio of Eudragit S100:Eudragit L100 (1:4, 1:1 and 1:0) and the level of coating (10%, 15% and 20%, w/w), respectively. The evaluated responses were lag time prior to drug release at pH 6.8 (the time required for drug release up to 2%) and percent of drug release at pH 6.8 in 5 h. Polymers were coated onto the pellets containing 20% (w/w) indomethacin, using a fluidized bed coating apparatus. Dissolution test was carried out in media with different pH (1.2, 6.5, 6.8 and 7.2). The dissolution data revealed that the level of coating and the ratio of polymers are very important to achieve optimum formulation. Using responses and resulted statistical equations, optimum formulation consisted of Eudragit S100:L100 in 4:1 ratio and the level of coating (20%) was predicted. Practical results showed that the pellets prepared according to above formulation released no indomethacin at pH 1.2 (simulating stomach pH) and pH 6.5 (simulating proximal part of small intestine pH); drug release was slowly at pH 6.8 (simulating lower part of small intestine pH), but it was fast at pH 7.2 (simulating terminal ileum pH). The results of this study revealed that factorial design is a suitable tool for optimization of coating formulations to achieve colon delivery. It was shown that coating formulation consisted of Eudragit S100:Eudragit L100 in 4:1 ratio at 20% coating level has potential for colonic delivery of indomethacin loaded pellets. The optimized formulation produced dissolution profiles that were close to predicted values.
Keywords: Colonic delivery; Eudragit; Statistical optimization; Factorial design; Indomethacin;

Menthol facilitates the skin analgesic effect of tetracaine gel by Yi Liu; Xun Ye; Xuemei Feng; Guanhuai Zhou; Zhengxing Rong; Chao Fang; Hongzhuan Chen (31-36).
The aim of this study is to observe the effect of menthol on the percutaneous penetration and skin analgesic action of tetracaine gel (T-gel). Anesthetic gels containing 4% tetracaine in carbomer vehicle with and without menthol were prepared. The menthol penetration-enhanced gel conferred significantly higher diffusion of tetracaine across full-thickness mouse skin than non-penetration-enhanced gel, in a dose-dependent manner. The inter-cellular spaces of the stratum corneum in skin treated with menthol penetration-enhanced gel became extended as compared with those in non-penetration-enhanced gel. This may suggest that menthol's action was related to the changes of the epidermis ultra structures. An enlarged inter-cellular space, per se, would allow a better passage to tetracaine. To determine the efficacy of menthol penetration-enhanced tetracaine gel in the management of pain, a double-blind, placebo-controlled, randomized controlled trial (RCT) design was used. The mean verbal pain scores (VPS) were significantly lower in volunteers treated with penetration-enhanced tetracaine gel than those in volunteers receiving non-penetration-enhanced tetracaine gel or placebo. Menthol improved the analgesic efficacy of the tetracaine 4% gel in part through enhanced percutaneous permeation.
Keywords: Menthol; Tetracaine gel; Percutaneous permeation;

Inhibition of a solid phase reaction among excipients that accelerates drug release from a solid dispersion with aging by Masayasu Mizuno; Yutaka Hirakura; Ikuro Yamane; Hideo Miyanishi; Shoji Yokota; Munetaka Hattori; Atsushi Kajiyama (37-51).
Hydrophobic drug substances can be formulated as a solid dispersion or solution using macromolecular matrices with high glass transition temperatures to attain satisfactory dissolution. However, very few marketed products have previously relied on solid dispersion technology due to physical and chemical instability problems, and processing difficulties. In the present study, a modified release product of a therapeutic drug for hypertension, Barnidipine hydrochloride, was developed. The drug product consisted of solid dispersion based on a matrix of carboxymethylethylcellulose (CMEC), which was produced using the spray-coating method. An enteric coat layer was sprayed on the surface of the solid dispersion to control drug release. Interestingly, the release rate accelerated as the drug product aged, while there were no indications of deceleration of the release rate which was due to crystallization of the drug substance. To prevent changes in the dissolution kinetics during storage periods, a variety of processing conditions were tried. It was found that not only use of non-aqueous solvents but also a reduction in coating temperatures consistently resulted in stable solid dispersions. The molecular bases of dissolution of the drug substance from those matrices were investigated. The molecular weight of CMEC was found to be a dominant factor that determined dissolution kinetics, which followed zero-order release, suggesting an involvement of an osmotic pumping mechanism. While dissolution was faster using a higher molecular weight CMEC, the molecular weight of CMEC in the drug product slowly increased with aging (solid phase reaction) depending on the processing conditions, causing the time-induced elevation of dissolution. While no crystalline components were found in the solid dispersion, the amorphous structure maintained a degree of non-equilibrium by nature. Plasticization by water in the coating solution relaxed the amorphous system and facilitated phase separation of the drug substance and CMEC upon production. The solid phase reaction advanced differentially in the solid dispersion depending on the degree of phase separation set initially. The use of non-aqueous solvents and/or a decrease in the coating temperatures inhibited the occurrence of phase separation upon production, thereby preventing the formation of CMEC-rich phases where the solid phase reaction occurred during storage.
Keywords: Solid dispersion; Phase separation; Dissolution; Solid phase reaction; CMEC; Aging;

Drug release from complexes with a series of poly(carboxyalkyl methacrylates), a new class of weak polyelectrolytes by Jose M. Cornejo-Bravo; Maria E. Flores-Guillen; Eder Lugo-Medina; Angel Licea-Claverie (52-60).
Carboxyalkyl methacrylates, a new class of non-cross-linked, hydrophobic weak polyelectrolytes, were synthesized, and then bound to cationic drugs (propranolol·HCl, diltiazem·HCl and verapamil·HCl) to form water-insoluble complexes that release the bound drug only in ionic media (pH 7.4). Compressed tablets were prepared from these cation exchange polyelectrolytes. Release profiles followed zero order kinetics (n  > 0.90; n is the release exponent). As the hydrophobicity of the polyelectrolytes increased, the rate of release decreased and deviated from linearity (n  = 0.7). Both the ionic strength of the medium as well as the solubility of the drug affected the rate of release. In acidic media (pH 1.2) a burst of drug was released but the release was halted by a layer of non-ionized polymer precipitated on the surface of the tablets. The results indicate that it is possible to “tailor-make” the release kinetics by using a polyelectrolyte from the series with the suitable hydrophobicity.
Keywords: Polyelectrolyte; Hydrophobic; Sustained drug release; Methacrylates; Ion exchange;

The design of the novel O/W microemulsion formulation, which enhances the oral bioavailability by raising the solubility of poorly water soluble compounds was examined. Using medium chain fatty acid triglyceride (MCT), diglyceryl monooleate (DGMO-C), polyoxyethylene hydrogenated castor oil 40 (HCO-40), ethanol and PBS (pH 6.8) as an oil phase, a lipophilic surfactant, a hydrophilic surfactant, a solubilizer and an aqueous phase, at the mixture ratio of 5%/1%/9%/5%/80% (w/w), respectively, the O/W microemulsion with an average particle diameter of 20 nm or less was prepared. Moreover, for nine kinds of poorly water soluble compounds, such as Ibuprofen, Ketoprofen, Tamoxifen, Testosterone, Tolbutamide and other new compounds, the solubility to water was increased from 60 to 20,000 times by this O/W microemulsion formulation. The AUCs in plasma concentration of Ibuprofen and a new compound, ER-1039, following single oral administration of these compounds as the O/W microemulsion to fasted rats were equivalent to that of solution administration or increased by nine and two times that of suspension administration, respectively. Accordingly, this novel O/W microemulsion is a useful formulation, which enhances the oral bioavailability by raising the solubility of poorly water soluble compounds.
Keywords: O/W microemulsion; Poorly water soluble compounds; Solubility; Gastrointestinal absorption; Enhancing effect; Rat;

Synthesis, physicochemical properties and antiviral activities of ester prodrugs of ganciclovir by Kunal Patel; Shrija Trivedi; Shuanghui Luo; Xiaodong Zhu; Dhananjay Pal; Earl R. Kern; Ashim K. Mitra (75-89).
The purpose of this study was to synthesize a series of diester prodrugs of ganciclovir (GCV), for improving ocular and oral bioavailability and therapeutic activity. Solubility, log  P, pH stability profile, in vitro antiviral activity, cytotoxicity, inhibition profile and ocular tissue hydrolysis of the GCV prodrugs were measured. Val–Val–GCV and Val–Gly–GCV diesters were found to exhibit greater aqueous stability compared to Val–GCV and Gly–Val–GCV while ocular tissue hydrolysis demonstrated Val–Gly–GCV and Gly–Val–GCV to be more stable. Val–Val–GCV and Val–GCV diesters were the most lipophilic compounds and were predicted to possess a partition coefficient 295- and 12-fold greater than that of GCV, respectively. All the prodrugs possess much higher aqueous solubility than the parent drug GCV. Ex vivo uptake in the rabbit eye indicates that the prodrugs have high uptake potential. The prodrugs showed no increase in cytotoxicity compared to GCV, instead there was a marked increase in their potency against human cytomegalovirus (HCMV) as well as HSV-1 and HSV-2. This should allow therapeutic response to be seen at a lower concentration that can be achieved more easily, than the drugs currently being used. In conclusion, the diester GCV prodrugs demonstrated excellent chemical stability, high aqueous solubility and markedly enhanced antiviral potency against the herpes viruses without any increase in cytotoxicity.
Keywords: Ganciclovir; Peptide; Diester; Prodrug; Esterification; Antiviral activity;

Mechanisms of action of novel skin penetration enhancers: Phospholipid versus skin lipid liposomes by Gamal M.M. El Maghraby; Michael Campbell; Barrie C. Finnin (90-104).
Employing thermal analysis, we investigated the mechanism of action of novel enhancers and probed phospholipid (PL) versus stratum corneum lipid (SCL) liposomes as model membranes. The enhancers included octyl salicylate (OS), padimate O (PADO) and 2-(1-nonyl)-1,3-dioxolane (ND). The negative controls were the empty liposomes. Positive controls employed dimethylsulfoxide (DMSO) and Azone™ (AZ). For PL liposomes, DMSO sharpened the transitions. AZ abolished the pre-transition, broadened the main transition and linearly reduced its transition temperature (T m). OS or PADO reduced T m and size of pre-transition, broadened the main transition and decreased its T m (non-linearly). ND abolished the pre-transition but increased T m of the main endotherm, suggesting retardation rather than enhancement. The results of SCL correlated with PL liposomes except for ND. In SCL liposomes, ND reduced T m and broadened the peaks indicating lipid disruption, which indicated its enhancing effects. In conclusion, OS, PADO and ND can enhance drugs by disrupting intercellular lipid domain but they differ from AZ in terms of the relationship between efficacy and concentration. Although PL liposomes are simple model membranes with sharp transitions which give detailed information about the effects of enhancers, they can provide misleading results. Simultaneous use of other models like SCL liposomes is recommended.
Keywords: Skin penetration enhancers; Mechanisms; Model membranes; Stratum corneum lipid liposomes; High sensitivity differential scanning calorimetry;

Porcine vaginal mucosa as an in vitro permeability model for human vaginal mucosa by Armorél D. van Eyk; Pieter van der Bijl (105-111).
The availability of human tissue for experimental purposes is often problematical and use is thus made of animal tissue as models of the human tissue. In this study, porcine vaginal mucosa was used as an in vitro permeability model for human vaginal mucosa using tritium-labelled permeants (17β-estradiol, r-arecoline, vasopressin, oxytocin and water). Fresh porcine and human vaginal tissues were frozen in liquid nitrogen and stored at −85 °C. In vitro permeability studies were performed using a flow-through diffusion apparatus (24 h, 20 °C, 1.5 ml/h). The mean steady state flux values for water, r-arecoline and vasopressin were approximately 4, 12 and 5% lower, while those for 17β-estradiol and oxytocin were approximately 17 and 53% higher, through porcine vaginal mucosa as compared to human vaginal mucosa, respectively. Using a F-test (comparing whole curves), statistically significant differences in the diffusion of 17β-estradiol, r-arecoline and oxytocin were indicated when comparing human and porcine vaginal mucosa. Generally, porcine vaginal mucosa seems a good in vitro permeability model for human vaginal mucosa. However, permeability of these two mucosa towards all permeants tested does not always correspond closely. These differences must always be considered when using porcine tissue as an in vitro permeability model for human vaginal mucosa.
Keywords: Human; Mucosa; Permeability; Porcine; Vaginal;

The influence of a low-frequency massage device on transdermal absorption of sodium benzoate, ketoprofen and diclofenac sodium was investigated in rats. Electrode pads spread with a hydroxypropyl cellulose gel containing the drug model were placed on excised skin in vitro. The transdermal permeation studies were carried out in the treatment group with the pulse applied through electrode pads spread with the gel, the pretreatment group with the gel applied after the application of the pulse and in the control group in which the gel was applied without the pulse. In vivo, transdermal absorption of ketoprofen was examined in the same groups used for the in vitro study. The pharmacokinetics of ketoprofen in plasma after intravenous injection was also studied. The treatment group showed higher cumulative permeated amounts of the drug models than the control in vitro. However, the enhancing effect was not observed in the pretreatment group. In vivo, the plasma ketoprofen level increased temporarily after the pulse was applied and then increased gradually as compared with the control. Since the distribution of ketoprofen from the central to the peripheral compartment was enhanced by the pulse in the injection study, enhancement of the biodistribution of ketoprofen by the low-frequency pulse was suggested.
Keywords: Low-frequency pulse; Low-frequency massage device; Skin permeation; Transdermal absorption; Enhancing effect;

The present study aims to investigate the effect of naringin, a flavonoid, on the pharmacokinetics of diltiazem and its active metabolite, desacetyldiltiazem, in rats. Pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined in rats following an oral administration of diltiazem (15 mg kg−1) to rats in the presence and absence of naringin (5 and 15 mg kg−1). Compared to the control given diltiazem alone, the C max and AUC of diltiazem increased by twofolds in rats pretreated with naringin, while there was no significant change in T max and terminal plasma half-life (T 1/2) of diltiazem. Consequently, absolute and relative bioavailability values of diltiazem in the presence of naringin were significantly higher (p  < 0.05) than those from the control group. Metabolite–parent AUC ratio in the presence of naringin decreased by 30% compared to the control group, implying that naringin could be effective to inhibit the metabolism of diltiazem. In conclusion, the concomitant use of naringin significantly enhanced the oral exposure of diltiazem in rats.
Keywords: Diltiazem; Desacetyldiltiazem; Pharmacokinetics; Naringin; Rat;

NMR characterization of paclitaxel/poly (styrene-isobutylene-styrene) formulations by Jian-Zhong Chen; Shrirang V. Ranade; Xiang-Qun Xie (129-144).
TAXUS™ is a coronary drug-eluting stent system utilizing a formulation consisting of cellular-target drug paclitaxel and poly (styrene-isobutylene-styrene) (SIBS). The present study investigates the interaction and interfacial dynamics of paclitaxel incorporated in a nano-polymeric matrix system. Solution and solid-state CP/MAS NMR experiments were designed to characterize the microstructure of heterogeneous drug–polymer mixtures in terms of its composition, molecular mobility, molecular order, paclitaxel–SIBS molecular interactions, and molecular mobility of the drug in the polymer matrix. The NMR spectra demonstrated unchanged chemical shifts between the neat and incorporated paclitaxel, and suggested that the level of the interactions between paclitaxel and SIBS is limited to non-bonding interactions or physical interactions between paclitaxel and SIBS when mixed in solution under NMR detection. Carbon spin-lattice relaxation time and proton spin-lattice relaxation time in the rotating frame offer further confirmation that the mobility of paclitaxel is increased in the paclitaxel–SIBS mixture. The results also indicate that a change occurs from crystalline packing to amorphous packing in paclitaxel due to its intermolecular interaction with SIBS. Our studies were used in understanding the detailed structure, morphology, and molecular motion of paclitaxel in the paclitaxel–SIBS system and to probe chemical and physical heterogeneity down to the nanometer scale.
Keywords: Paclitaxel; Poly (styrene-isobutylene-styrene) (SIBS); Solid-state NMR; Drug–polymer interactions;

Plasmid DNA (pDNA) is an important macromolecular therapeutic agent suitable for DNA-based therapies, such as non-viral gene therapy and DNA vaccination. Unmethylated CpG motifs abundant in bacterial DNA, but not in vertebrate DNA, are known to trigger an inflammatory response, which inhibits transgene expression, while modulating immunological consequences following vaccination. We studied cellular uptake and activation characteristics of naked pDNA and its cationic liposome complex in human macrophage-like cells. The present study has demonstrated that naked pDNA was recognized by human macrophage-like cells via specific mechanisms for polyanions. Moreover, it has shown that pDNA complexed with cationic liposomes activates human macrophage-like cells to induce the production of tumor necrosis factor-α (TNF-α) in a CpG motif-independent manner, while any types of naked DNA could not induce TNF-α production from these cells, regardless of the presence of CpG motifs in pDNA or oligonucleotide (ODN). These findings form an important basis for DNA-based therapies including gene therapy and DNA vaccination.
Keywords: Macrophages; Plasmid DNA; CpG motif; Cationic liposome; Tumor necrosis factor-α;

Dendrimers attract much attention as potential drug and gene carriers for intracellular delivery. From this point of view, it is crucial to extend our knowledge about their interactions with membranes.The influence of polyamidoamine (PAMAM) dendrimers on the thermotropic behavior of DPPC multilamellar vesicles and DMPC small unilamellar vesicles was examined by differential scanning calorimetry. We used three types of PAMAM dendrimers to determine how a dendrimer structure determines interactions with liposomes.We show that the strength of interactions depends on both the dendrimers’ structure and degree of hydrophobicity. A model for the interaction of each type of dendrimer with liposomes was proposed.
Keywords: Dendrimer; PAMAM; Liposome; Vesicle; Membrane; DSC; MLV; SUV;

Solidified reverse micellar solutions (SRMS), i.e. mixtures of lecithin and triglycerides, offer high solubilisation capacities for different types of drugs in contrast to simple triglyceride systems [Friedrich, I., Müller-Goymann, C.C., 2003. Characterisation of SRMS and production development of SRMS-based nanosuspensions. Eur. J. Pharm. Biopharm. 56, 111–119]. Nanosuspensions based on SRMS were prepared by homogenisation close to the melting point of the SRMS matrix. In a first step the SRMS matrices of 1:1 (w/w) ratios of lecithin and triglycerides were loaded with 17β-estradiol-hemihydrate (EST), hydrocortisone (HC) or pilocarpine base (PB), respectively, and subsequently ground in liquid nitrogen to minimise drug diffusion later on. The powder was then dispersed in a polysorbate 80 solution using high pressure homogenisation. The drug loading capacities of the nanosuspensions were very high in the case of poorly water-soluble EST (99% of total 0.1%, w/w, EST) and HC (97% of total 0.5%, w/w, HC) but not sufficient with the more hydrophilic PB (37–40% of total 1.0%, w/w, PB). These findings suggest SRMS-based nanosuspensions to be promising aqueous drug carrier systems for poorly soluble drugs like EST and HC.Furthermore, in vitro drug permeation from the different drug-loaded nanosuspensions was performed across human cornea construct (HCC) as an organotypical cell culture model. PB permeation did not differ from the nanosuspension and an aqueous solution whereas the permeation coefficients of HC-loaded nanosuspensions were reduced in comparison to aqueous and oily solutions of HC. However, the permeated amount was higher from the nanosuspensions due to a much lower HC concentration in the solution than that in the nanosuspension (solution 0.02%, w/w, versus nanosuspension 0.5%, w/w). The high drug load of the nanoparticles provides prolonged HC release. Permeated amounts of EST were reduced in comparison to HC and only detectable with an ELISA technique.The EST release from nanosuspensions and different EST-loaded systems revealed a prolonged EST release from the nanoparticulate systems in contrast to a faster release of an oily solution of an equal EST concentration. With regard to an aqueous EST suspension of similar concentration which represents a depot system the release rate from the nanosuspensions revealed the same order of magnitude which points again to a prolonged release potential of the nanosuspensions.
Keywords: Nanosuspension; Solid lipid nanoparticles; Solidified reverse micellar solution; Drug delivery system; Drug release; Drug permeation;

Stability of latanoprost in an ophthalmic lipid emulsion using polyvinyl alcohol by Yusuke Sakai; Shin-Ichi Yasueda; Akira Ohtori (176-179).
Latanoprost in water is not stable against heat stress due to hydrolysis of the isopropyl ester in the latanoprost molecule. Therefore, the storage condition of latanoprost ophthalmic solution, Xalatan® brand, was in a low temperature (2–8 °C). We formulated a favorable ophthalmic lipid emulsion of latanoprost using polyvinyl alcohol as emulsifier which showed a good heat stability. The assays of the latanoprost ophthalmic lipid emulsions adjusted to pH 5.0, 6.0 and 7.0 were 100.4%, 100.7% and 99.2% after storage for 4 weeks at 60 °C, respectively. The possibility of room temperature storage for the latanoprost ophthalmic lipid emulsion was demonstrated.
Keywords: Latanoprost; Ophthalmic lipid emulsion; Polyvinyl alcohol; Stability;

Spray-freeze-dried liposomal ciprofloxacin powder for inhaled aerosol drug delivery by Lyle G. Sweeney; Zhaolin Wang; Raimar Loebenberg; Jonathan P. Wong; Carlos F. Lange; Warren H. Finlay (180-185).
Spray-freeze drying was utilized to manufacture a liposomal powder formulation containing ciprofloxacin as a model active component. The powder forms liposomally encapsulated ciprofloxacin when wetted. Aerosol properties of this formulation were assessed using a new passive inhaler, in which the powder was entrained at a flow rate of 60 l/min. A mass median aerodynamic diameter (MMAD) of 2.8 μm was achieved for this formulation. Using the experimental dispersion testing data, ciprofloxacin concentration in the airway surface liquid (ASL) was calculated using a Lagrangian deposition model. The reconstitution of the powder in various aqueous media gave drug encapsulation efficiencies as follows: 50% in water, 93.5% in isotonic saline, 80% in bovine mucin, 75% in porcine mucus and 73% in five-fold-diluted ex vivo human cystic fibrosis patient sputum.
Keywords: Aerosol; Ciprofloxacin; Liposomes; Powder; Spray-freeze drying;

Noticeboard (186-187).