Juha Kiesvaara

Microemulsions for topical delivery of estradiol

Estradiol has been widely used for the treatment of hormonal insufficiencies. Due to its extensive first pass metabolism after oral administration, transdermal administration of estradiol in gels and emulsions has been used to improve its bioavailability, prolong activity and to optimize metabolic profile. The purpose of this study was to investigate microemulsions as delivery systems for estradiol. Various o/w microemulsions were used to deliver estradiol across human abdominal skin in vitro. Trasdermal flux of estradiol was determined using Franz-type diffusion cells and the samples were analyzed by high-performance liquid chromatography (HPLC). The permeation data showed that microemulsion formulations increased estradiol flux 200-700-fold over the control, but permeability coefficients were decreased by 5-18 times. The superior transdermal flux of estradiol was due to 1500-fold improvement in solubilization of estradiol by microemulsions. The results suggest that microemulsions are potential vehicles for improved topical delivery of estradiol.

Silica xerogel as an implantable carrier for controlled drug delivery : evaluation of drug distribution and tissue effects after implantation

The purpose of the present study was to examine controlled delivery of toremifene citrate from subcutaneously implanted silica xerogel carrier and to evaluate silica xerogel related tissue effects after implantation. Toremifene citrate was incorporated into hydrolyzed silica sol in a room temperature process. Toremifene citrate treated silica xerogel implants were tested both in vitro and in vivo using healthy mice. Silica xerogel with tritium-labelled toremifene was implanted subcutaneously in mice for 42 d. To determine the amount of tritiated toremifene remaining in the silica discs at the implantation site, the discs were excised periodically and radioactivity measured. The amount of tritiated toremifene in the implant after 42 d was still about 16% and the amount of silica xerogel about 25%. In a histopathological study silica xerogel did not show any tissue irritation at the site of the implantation. A fibrotic capsule was formed around the implant. No silica xerogel related histological changes in liver, kidney, lymph nodes and uterus were observed during the implantation period. The silica xerogel discs showed a sustained release of toremifene citrate over 42 d. Histologically, toremifene-related changes in the uterus were also detectable at all studied time points. These findings suggest that silica xerogel is a promising carrier material for implantable controlled drug delivery system.

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.

Silica xerogel carrier material for controlled release of toremifene citrate

Sol-gel processed silica xerogel was used as a carrier material for toremifene citrate in order to develop an implantable controlled release formulation which could be localised to a desired site providing targeted and long-lasting disease control and resulting in a reduced amount of drug needed. Toremifene citrate, an anti-estrogenic compound, was incorporated into silica xerogel matrixes during polycondensation of organic silicate, tetraethyl ortho silicate (TEOS). The effects of drug amount, drying temperature and polyethylene glycol (PEG) on the release rate of toremifene citrate and degradation of the silica xerogel matrixes were investigated. Addition of PEG (M(w) 4600/10000) decreased the specific surface area of the matrix and lowered the release rate of the drug. Reducing the amount of drug in the matrix also decreased the release rate of toremifene citrate. However, drying temperature did not affect the release rate of silica or toremifene citrate. The release profiles of toremifene citrate were according to zero order kinetics, suggesting that drug release was controlled by erosion of the silica xerogel matrix. These results suggest that the toremifene citrate release rate can be controlled to some extent by adding (PEG) or by varying the amount of drug in the silica xerogel matrix.

Liposome-skin interactions and their effects on the skin permeation of drugs

The aim of the study was to evaluate the interaction of phospholipid liposomes with skin and stratum corneum lipid liposomes (SCLLs). The influence of phospholipid liposomes on the skin permeability of model drugs was also studied. The transdermal flux of the drugs applied in various phospholipid containing formulations through human epidermis was studied in diffusion chambers. Liposomes in water solutions did not enhance the skin permeability of the drugs, but when ethanol (32% w/v) was present in the donor with EPC (egg yolk lecithin), permeabilities of some model drugs were substantially increased. Confocal microscopy studies revealed that EPC do not penetrate into the skin from water solutions, while from ethanol solutions, EPC penetrates deeply into the stratum corneum. Also, resonance energy transfer between different liposome compositions and the release of calcein from SCLLs showed that interactions between phospholipid liposomes and SCLLs increased with increasing ethanol concentration in the liposome solutions.

Nanosuspensions of poorly soluble drugs: Preparation and development by wet milling

Nanosizing techniques are important tools for improving the bioavailability of water insoluble drugs. Here, a rapid wet milling method was employed to prepare nanosuspensions: 4 types of stabilizers at 4 different concentrations were tested on 2 structurally different drug compounds: indomethacin and itraconazole. Photon correlation spectroscopy (PCS) results showed that the finest nanosuspensions were obtained when 80 wt% (to drug amount) pluronic F68 was the stabilizer for indomethacin and 60 wt% pluronic F127 for itraconazole. Compared to physical mixtures, dissolution rates of the nanosuspensions showed significant increases. The morphology of nanoparticles was observed by transmission electron microscopy (TEM). Crystalline state of the drugs before and after milling was confirmed using differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). The physical and chemical stabilities of the nanosuspensions after storage for 2 months at room temperature and at 4°C were investigated using PCS, TEM and HPLC. No obvious changes in particle size and morphology and no chemical degradation of the drug ingredients were seen.

Phospholipids affect stratum corneum lipid bilayer fluidity and drug partitioning into the bilayers

Phospholipids, e.g. fluid-state EPC (l-alpha-phosphatidylcholine from egg yolk), may diffuse into the stratum corneum and enhance dermal and transdermal drug penetration, while many other phospholipids, e.g. gel-state DSPC (distearoylphosphatidyl choline), are not able to do this. These effects are suggested to be due to the interactions between the phospholipids and the skin lipid bilayers, and so an in vitro method was developed to evaluate the influence of phospholipids on the distribution of drugs to stratum corneum lipids. The distribution coefficients of estradiol, progesterone and propranolol between stratum corneum lipid liposomes (SCLLs) without phospholipids or with EPC, DSPC, SPC (l-alpha-phosphatidylcholine from soybean) or DOPE (dioleylphosphatidyl ethanolamine), and pH 7.4 buffer were determined. Fluid-state phospholipids in SCLLs increased the partitioning of drugs into SCLLs, while gel-state lipid, DSPC, did not. The increased distribution of drugs into the SCLLs was at least partially due to the increased fluidity of SCLL bilayers by phospholipids, which was shown using steady-state fluorescence anisotropy. This in vitro method enables screening of the effects of phospholipids and other permeation enhancers on stratum corneum bilayer fluidity and drug partitioning.

In vitro evaluation of sol–gel processed spray dried silica gel microspheres as carrier in controlled drug delivery

The objective of this study was to evaluate sol-gel-derived spray dried silica gel microspheres as carrier material for dexmedetomidine HCl and toremifene citrate. The drug was dissolved in sol-gel processed silica sol before spray drying with Büchi laboratory scale equipment. Microspheres with a low specific surface area were spherical by shape with a smooth surface without pores on the external surface. The particle size distribution was quite narrow. The in vitro release of toremifene citrate and dexmedetomidine HCl showed a dose-dependent burst followed by a slower release phase, that was proportional to the drug concentration in the concentration range between 3.9 and 15.4 wt.%. The release period for toremifene citrate was approximately 10 days and for dexmedetomidine HCl between 7 and 50 days depending on drug concentration. Spray drying is a promising way to produce spherical silica gel particles with a narrow particle size range for controlled delivery of toremifene citrate and dexmedetomidine HCl.

Sol‐gel‐processed sintered silica xerogel as a carrier in controlled drug delivery

Sol-gel-processed sintered silica xerogel was studied as a controllable, dissolvable, implantable material. The erosion of the matrix and the release of the preadsorbed drug toremifene citrate was investigated both in vitro and in vivo using mice. In an in vitro dissolution study, 50 to 60% of the drug was released after 24 h, according to the square root of time kinetics, and the weight loss of the silica was 24 wt %. Silica xerogel with tritium-labeled toremifene was implanted subcutaneously in mice for 56 days. To determine the amount of tritiated drug remaining in the silica disks at the implantation site, the disks were excised periodically and the radioactivity measured. About 40% of the radioactivity was released during the first 4 days and all of it within 28 days. Radioactivity also was measured in the liver, lungs, kidneys, uterus, and blood. The radioactivity reached a maximum level after 4 days in the liver, kidneys, and lungs and slowly decreased until all of the drug had been released from the matrix after 28 days. After release of the drug (28 days) the amount of remaining silica xerogel implant was 45 wt %, and at the end of the study (56 days) it was 24 wt %. In the histopathological study, sintered silica xerogel did not show any tissue toxicity at the site of the implantation, in the liver, or in the kidneys. It was concluded that sintered silica xerogel is a biocompatible and controllably resorbable material and therefore is a promising matrix for use in the sustained delivery of drugs.

In vitro release of dexmedetomidine from silica xerogel monoliths: effect of sol-gel synthesis parameters

Dexmedetomidine, an alpha 2-agonist, was incorporated as a hydrochloride salt into silica xerogel in order to evaluate the effect of sol-gel synthesis parameters: pH of the sol, water/alkoxide molar ratio, drug concentration and size of the device on the drug release rate and degradation rate of the matrix. This study showed that diffusion controlled the release of dexmedetomidine from silica xerogel prepared between pH 1 and pH 5. The drug release was, however, slowest near the zero charge of silica xerogel (pH 2-3). The burst of dexmedetomidine, a lipophilic, but in the form of hydrochloride salt water-soluble drug, was increased from the matrix prepared either below or above the isoelectric point. It follows that the optimum pH for preparing a drug delivery device for dexmedetomidine, is near the zero charge of silica xerogel, where the degradation of the matrix was also slowest. In addition to processing pH, the release rate of drugs can be controlled by changing the water/alkoxide molar ratio of the sol.