Petteri Paronen

Interaction of liposomes with human skin in vitro — The influence of lipid composition and structure

Liposomes have been suggested as a vehicle for dermal and transdermal drug delivery, but the knowledge about the interaction between lipid vesicles and human skin is poor. Therefore, we visualized liposome penetration into the human skin by confocal laser scanning microscopy (CLSM) in vitro. Liposomes were prepared from phospholipids in different compositions and labeled with a fluorescent lipid bilayer marker, N-Rh-PE (L-alpha-phosphatidylethanolamine-N-lissamine rhodamine B sulfonyl). Fluorescently labelled liposomes were not able to penetrate into the granular layers of epidermis. However, the fluorescence from liposome compositions containing DOPE (dioleylphosphatidyl ethanolamine) was able to penetrate deeper into the stratum corneum than that from liposomes without DOPE. Pretreatment of skin with unlabeled liposomes containing DOPE or lyso-phosphatidyl choline (lyso-PC) enhanced the subsequent penetration of the fluorescent markers, N-Rh-PE and sulforhodamine B into the skin, suggesting possible enhancer activity, while most liposomes did not show such enhancement. Resonance energy transfer (RET) and calcein release assay between stratum corneum lipid liposomes (SCLLs) and the phospholipid vesicles suggested that the liposomes containing DOPE may fuse or mix with skin lipids in vitro and loosen the SCLL bilayers, respectively. Among the factors not affecting stratum corneum penetration were: negative charge, cholesterol inclusion and acyl chain length of the phospholipids. In conclusion, fusogenicity of the liposome composition appears to be a prerequisite for the skin penetration.

Prediction of the compression behaviour of powder mixtures by the Heckel equation

Abstract The compression behaviour of plastically flowing microcrystalline cellulose and pregelatinized corn starch and fragmenting α-lactose monohydrate and dicalcium phosphate dihydrate, and their binary mixtures was evaluated using the Heckel equation. Powders were compressed using an instrumented eccentric tablet press. The Heckel plots for both plastically flowing materials and their binary mixtures were linear in shape. In contrast, on the Heckel plots of the fragmenting materials and their mixtures, an obvious curvature was seen. The mean yield pressures were linearly proportional to the mixture composition of two plastically flowing materials. When mixed with a fragmenting material, a plastically flowing component had a greater effect on the compression behaviour of the mixture than a fragmenting mixture component had. This was explained by the more pronounced effect of plastic flow on volume reduction. When two fragmenting materials were compressed, the densification of their binary mixture was strongly influenced by the less compressible material with higher mean yield pressure. It was concluded that in the mixtures of two fragmenting materials the particles of the less compressible material constituted a firm structure, like a skeleton, which tended to dominate the compression behaviour of the binary mixtures. For binary mixtures of fragmenting materials the mean yield pressures were thus not linearly proportional to the mixture composition. Compression behaviour of powder mixtures seemed to be strongly dependent on the deformation properties of plain materials to be compressed. On the other hand, one mixture component may dominate the compression behaviour of the mixture, and the compressibility may change non-linearly with mixture composition. Therefore, caution is needed when the Heckel equation is applied for predicting compression behaviour of powder mixtures.

Effects of grinding and compression on crystal structure of anhydrous caffeine

Abstract The extent of the polymorphic transformation of anhydrous caffeine has been studied as a function of grinding time and compression pressure by using quantitative X-ray diffraction analysis. The measurements show that both grinding and compression induce the transformation from the metastable form I into the stable form II. The transformation can be observed even after 1 min grinding or by using a compression pressure of about 50 MPa in tableting. The degree of transformation is greater near the surface than in the middle part of the tablet.

Effect of powder inhaler design on drug deposition in the respiratory tract

Abstract Disodium cromoglycate particles were labelled with pure γ-radiator, 99m Tc, using the co-precipitation technique based on spray drying. Radioactive drug particles were mixed with lactose carrier and filled into hard gelatin capsules. Seven healthy volunteers inhaled drug doses using Spinhaler I.S.F., Berotec, and Rotahaler dry powder devices. The fractional deposition of drug particles in the upper airways and lung region were monitored using a gamma camera. The fraction of the dose retained in the powder inhaler was the smallest for I.S.F. and especially for Berotec inhalers. These devices have narrower air channel constructions with a smaller wall surface area than the Spinhaler and Rotahaler devices. Thus the sticking of the drug particles onto the plastic walls was less probable for the first-mentioned devices. The drug particles from all the dry powder inhalers seemed to be more able to follow the inspired air stream without depositing in the upper airways than previously documented for pressurized metered dose aerosols. I.S.F. and Berotec inhalers with narrow air channels gave the greatest lung deposition of the inhaled drug particles. Thus the design of the dry powder inhaler was noticed to have a remarkable effect both on the emptying of the capsules as well as on the redispersion of the powder mixture.

Dodecyl N,N-dimethylamino acetate and azone enhance drug penetration across human, snake, and rabbit skin

The effectiveness of the penetration enhancers, dodecyl N, N-dimethylamino acetate (DDAA) and Azone, on pretreated human epidermis for the permeation of model drugs, indomethacin, 5-fluorouracil, and propranolol-HCl, was studied in in vitro diffusion cells. Snakeskin (Elaphe obsoleta) and rabbit pinna skin were compared as possible models for human skin. The drug concentrations were analyzed by HPLC. With all skins and all model drugs, DDAA increased drug permeability at least as well as Azone, and in most cases it was a more effective permeation enhancer. The relative permeation improvements in human skin, snakeskin, and rabbit skin were 10- to 20-, 5- to 50-, and 20- to 120-fold, respectively. Tritiated water served as an indicator of skin condition. Its penetration in the skin samples was independent of the drugs used, and both penetration enhancers significantly increased the flux of tritiated water through all skins. Thus, DDAA and Azone significantly increased the permeation of lipophilic and hydrophilic model compounds. Rabbit pinna skin was a poor model for human skin in vitro, while snakeskin was much closer to human skin in terms of transdermal permeability. In most cases drug permeability decreased in the order rabbit ≫ human > or < snake.

Starch Acetates—Multifunctional Direct Compression Excipients

Native starch grains contain polymers consisting in varying ratios of linear amylose and branched amylopectin, which are composed of glucose monomers. Glucose monomers are linked to each other mainly by a-1,4 glucosidic bonds. A glucose monomer contains three hydroxyl groups, which can be, in the present case, acetylated. Native starch grains are insoluble in water, but they are hydroscopic materials which swell in the presence of water. Starches from various natural origins and their common derivates are well-known, safe, and have been extensively investigated in tablet formulations for various purposes. Native starches are used as disintegrants, diluents, and wet binders. However, their poor flow and high lubricant sensitivity make them less favoured in direct compression. Different chemical, mechanical, and physical modifications of native starches have been used to improve both their direct compression and controlled release properties (1– 5). Although, various starches and their derivatives have been studied extensively, there is still much to examine about their mechanical properties as compacts. Furthermore, starchbased formulations are usually multicomponent formulations which increase the risks of incompatibility. In the present study, novel direct compression excipients are introduced as starch acetates (6). The preparation of these acetates was accomplished, and their chemical properties were evaluated. The effects of substitution on the starch acetates were investigated according to physical and tablet properties. The resulting starch acetates were compared to commercially available direct compression excipients.

Enhanced film-forming properties for ethyl cellulose and starch acetate using n-alkenyl succinic anhydrides as novel plasticizers

PURPOSE The aim of this study was to investigate the ability of n-alkenyl succinic anhydrides (n-ASAs) to improve the film-forming characteristics of a novel coating polymer, potato starch acetate degree of substitution 2.8 (SA). n-ASAs were also applied to improve the otherwise brittle properties of ethyl cellulose (EC) aqueous dispersion (Aquacoat) and EC solvent-based films. METHODS The effectiveness of two n-ASAs, 2-octenyl succinic anhydride (OSA) and 2-dodecen-1-ylsuccinic anhydride were evaluated as plasticizers. Mechanical properties, both water vapor and drug permeabilities, and glass transition temperatures of the cast free films were measured. Triethyl citrate and dibutyl sebacate were used as reference plasticizers. RESULTS The long hydrocarbon chain of n-ASA, with its accessible carbonyl groups, enabled a strong plasticization effect on the tested polymers. Due to the excellent mechanical properties (i.e., a tough film structure with considerable flexibility) and low permeability of the plasticized films, n-ASAs, and especially OSA proved to be an ideal plasticizer particularly for EC based coatings. Also, the EC aqueous dispersion plasticized with n-ASAs resulted in a markedly enhanced coalescence of the colloidal polymer particles, even at low drying temperatures. CONCLUSIONS In applications where a coating with high flexibility is required, n-ASAs can be used as plasticizers at moderately high concentrations (up to 60-70%, w/w) without losing the high tensile strength, excellent toughness and low permeability of EC and SA films.

Dehydration of theophylline monohydrate : a two step process

The physicochemical properties of theophylline monohydrate and anhydrous polymorphic form II were evaluated using crystallographic, calorimetric and computational methods. The heats of solution of theophylline monohydrate and its anhydrous form were 28.6 and 19.4 kJ/mol, respectively, and the heat of hydration of theophylline anhydrous was 12.2 kJ/mol, as determined by solution calorimetry. Dehydration of theophylline monohydrate was studied by DSC. Under closed, hermetic conditions, the heat of dehydration, 10.7 kJ/mol, was almost equal to the heat of hydration. Under open conditions, the measured heat of dehydration was 47.3 kJ/mol. The dehydration phenomenon was examined also by molecular modelling and the computed heat changes were equal to those determined experimentally. The obtained experimental and theoretical results indicated that the monohydrate-anhydrate transition of theophylline is energetically reversible. Under closed conditions and in the aqueous media, the reversible monohydrate-anhydrate transition comprised only the dehydration or hydration step and the heat of transitions were considerably lower than under open conditions. Under open conditions, the dehydration of theophylline monohydrate proceeds in two steps even though the steps are overlapping. The first step is dehydration and the second is evaporation of the loosened crystal water.

Lactose modifications enhance its drug performance in the novel multiple dose Taifun DPI.

Drug-carrier particle interactions greatly affect the detachment of drug from the carrier in inhalation powders. In this study, a novel multiple dose, reservoir-based Taifun was used as a dry powder inhaler, and the effects of carrier physical properties were evaluated on the pulmonary deposition of budesonide, along with physical stability of the inhalation powder. In this study, untreated commercial preparation of alpha-lactose monohydrate, highly amorphous spray dried lactose, crystallized spray dried lactose, Flowlac-100 and Flowlac-100 mixed with crystalline micronized lactose were used as carriers. Dry powder formulations were prepared by the suspension method, where the budesonide-carrier ratio was 1:15.1 (w/w). Carriers and formulations were initially characterized, and again after 1 months storage at 40 degrees C/75% RH. The physical properties of the carriers strongly affected the pulmonary deposition of budesonide and the physical stability of the inhalation powder. Initially, amorphous contents of the carriers were 0-64%, but spontaneous crystallisation of the amorphous lactose occurred during storage and, thus all carriers were 100% crystalline after storage. When compared to an untreated alpha-lactose monohydrate, the highly amorphous spray dried lactose and Flowlac-100 did not improve aerosol performance of the inhalation powder. When crystalline spray dried lactose was used as a carrier, the highest RF% values were achieved, and RF % values did not alter during storage but the emitted budesonide dose was lower than the theoretical dose. When Flowlac-100 mixed with crystalline micronized lactose was used as a carrier, the emitted budesonide dose was close to the theoretical dose, and high RF % values were achieved but these changed during storage.

Predicting Plasticization Efficiency from Three-Dimensional Molecular Structure of a Polymer Plasticizer

AbstractPurpose. In polymeric coatings, plasticizers are used to improve the film-forming characteristic of the polymers. In this study, a computerized method (VolSurf with GRID) was used as a novel tool for the prediction plasticization efficiency (β) of test compounds, and for determining the critical molecular properties needed for polymer plasticization. Methods. The film-former, starch acetate DS 2.8 (SA), was plasticized with each of 24 tested compounds. A decrease in glass transition temperature of the plasticized free films (determined by differential scanning calorimeter (DSC)) was used as an indicator for β. Partial least squares discriminant analysis was used to correlate the experimental data with the theoretical molecular properties of the plasticizers. Results. A good correlation (r2 = 0.77, q2 = 0.58) between the molecular modeling results and the experimental data demonstrated that β can be predicted from the three-dimensional molecular structure of a compound. Favorable structural properties identified for the potent SA plasticizer were strong hydrogen bonding capacity and a definitive hydrophobic region on the molecule. Conclusions. The VolSurf method is a valuable tool for predicting the plasticization efficiency of a compound. The correlation between experimental and calculated glass transition temperature values verifies that physicochemical properties are primary factors influencing plasticization efficiency of a compound.