Effect of adhesive matrix composition and terpinolene on indomethacin bioavailability in rats from transdermal therapeutic system.

Drug-in-adhesive matrix-type transdermal therapeutic systems for indomethacin (IND) were formulated and evaluated. Silicone and two types of polyacrylates were used as the bases of matrices. Terpinolene was used as a penetration enhancer. The physicochemical properties of matrices were determined. The bioavailability study of IND was performed in rats. The presence of IND in blood was demonstrated for each system. The calculated pharmacokinetics parameters for IND mainly depend on the solubility of IND in the adhesive layer. The positive influence of a penetration enhancer on IND bioavailability was observed only for one type of polyacrylate matrices.

Feasibility of the Ph.Eur. flow-through cell for dissolution testing of the compounded rectal suppositories containing indomethacin or sodium diclofenac.

Ph.Eur. and BP have introduced a dissolution apparatus for suppositories. Suitability of the apparatus for quality control of indomethacin or sodium diclofenac (100 mg) compounded suppositories was evaluated and the effect of the type of suppository base on dissolution profiles was studied. The fastest and most reproducible release profiles were observed for hydrophilic base (macrogols). More than 80% of the drug was released during 60 min, while after 350 min 18.5-50% of the total amount was released from lipophilic bases (Witepsol and Adeps solidus). The results demonstrate that slow and non-reproducible release occurs when the lipophilic suppository base does not melt. The feasibility of the test for the formulations, which do not melt during the procedure, is questionable.

pH-induced modifications to stratum corneum lipids investigated using thermal, spectroscopic, and chromatographic techniques.

The effects of nonphysiological pH on stratum corneum lipid content and structure have been studied. Human stratum corneum samples were soaked in solutions at pH 1, 2, 6, 11, or 12 for up to 24 h. After removal of the stratum corneum, the buffer solutions were analyzed for lipid composition using thin-layer chromatography analysis and the stratum corneum sheets were examined using differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR) spectroscopy. The results demonstrate that only buffers of pH 11 or higher affect the stratum corneum lipids. No large difference in the contents of ceramides and cholesterol extracted by buffers of varying pH was observed. In contrast, free fatty acid extraction was pH dependent; amounts removed by 24-h treatment with pH 11 or 12 buffers were comparable, and were similar to amounts extracted with a methanol-chloroform mixture for 15 min. No appreciable changes in DSC and FTIR spectra were detected between untreated stratum corneum and stratum corneum samples treated with buffers at pHs in the range 1-6. For tissue treated with pH 11 and 12, the position of the endothermal melting peak T2 shifted from 72 to 74 degrees C on the DSC thermograms. Small changes in the broadness of spectral peaks at 2855 cm(-1) [attributable to upsilon(CH(2)) stretching of stratum corneum lipids and 1655 cm(-1) upsilon(C=O) stretching amide I band] can be seen in the FTIR spectra from the treated stratum corneum samples, although no shifts in peak positions were observed. Intensity changes in peaks from extraneous lipids [upsilon(C=O) stretching mode at 1735 cm(-1)] were observed after buffer treatments. The changes provoked by the alkaline buffers are not dramatic and it may be concluded that the stratum corneum appears remarkably resilient to extended exposure in both highly acidic (pH 1) and highly alkaline (pH 12) environments.

The effect of cryoprotectants on the physical properties of large liposomes containing sodium diclofenac.

Large liposomes (1-10 microm) containing sodium diclofenac were prepared and lyophilized using lactose or mannitol (7.5% in respect to the lipid content) as cryoprotectants. The physical studies of liposomes were performed during 30 days of storage in a dry or resuspended form. Lyophilization of large liposomes and storage in the dry form at 5 degrees C increases their physical stability. Lactose is a cryoprotectant which does not influence changes of properties of liposomes regarding their size, encapsulation efficacy and release rate. Large liposomes lyophilized in the presence of mannitol tend to increase in size and encapsulation efficacy, but the lipid bilayers are stabilized and less permeable to the drug.

Solubilizing potential of submicron emulsions and aqueous dispersions of lecithin.

Aqueous lecithin dispersions (WLD, water-lecithin-dispersion) were obtained by dispersing egg lecithin (1.2 or 2.4% w/w) in an isotonic mixture of glycerol and water. The solubilization potential of the pure phospholipid structures was investigated and compared with that of submicron emulsions containing the same amounts of lecithin and 10 or 20% (w/w) of soya-bean oil. The increase in solubility of the investigated lipophilic drugs in WLD was proportional to the lecithin concentration. Concentration of lecithin in the emulsion was the main factor determining solubility of drugs moderately lipophilic (logP below 2.5), while for more lipophilic compounds the presence of oil was a determinant and for such drugs solubility in submicron emulsion was better than in WLD. WLD obtained in a simple technological process may be considered as a carrier particularly for highly lipophilic drugs: solubility of estradiol in this system was 100-fold higher than in water.

Physicochemical screening of antimicrobial agents as potential preservatives for submicron emulsions.

Antimicrobial agents should be added to lecithin-stabilized submicron emulsions when these preparations are non-sterile products or when packed in multidose containers. Eleven antimicrobials were introduced to a standard submicron emulsion. The emulsions were adjusted to pH 5.0 or 8.2 prior aseptic filtration or thermal sterilization, respectively. The physicochemical stability of the preparations was observed during storage for 2 years at room temperature. Parabens showed the best compatibility but satisfying stability was also observed in emulsions containing phenylethanol, m-cresol and benzalkonium chloride. Partitioning studies revealed poor correlation between aqueous solubility and content of the preservatives in the aqueous phase of the emulsion. Only 1.2% of the total content of benzalkonium chloride was found in this phase and incorporation of this compound into different microscopic structures of the emulsion is proposed as a reason for such effect. Preliminary studies on the efficacy of antimicrobial preservation was performed for emulsions containing parabens, benzalkonium chloride or chlorocresol and the negative results bring conclusion that higher concentration of antimicrobials or their combination may be required for efficient preservation of submicron emulsions.

[Liposomes--therapeutic progress and technological problems]. / Liposomy--postep terapeutyczny i problemy technologiczne.

Liposomes represent globular vesicles composed of an aqueous core and one or several phospholipid bilayers. They can encapsulate hydrophilic or lipophilic drugs used in therapy and diagnostic imaging. Liposomes provide protection of the active substances, sustained or controlled release and also targeted delivery of drugs to specific cells, tissues, organs. Easy oxydation of phosphatidylcholin (lecithin)--the main membrane component--is the limitation of the introduction of liposomes to the medicinal practice in a broader scale. Unsatisfying chemical stability of lecithin has an unfavourable influence on drug and liposome stability. Liposomes decompose during storage and leakage of the encapsulated drug occurs. A review of advantages of application of liposomes in medicine and methods of increasing their stability was presented.

Pharmacokinetics of verapamil and its metabolite norverapamil from a buccal drug formulation.

Pharmacokinetics of verapamil and its metabolite norverapamil, from buccal drug formulation administered in a dose 20 mg in relation to conventional tablets of verapamil 40 mg, used in medical practice, was determined. Buccal formulation has previously been designed as an alternative form of dosing verapamil. Bioavailability was determined by a crossover method in 12 healthy volunteers. Drug concentration in plasma was determined by means of HPLC with a fluorescence detector. For buccal formulation the average values of C(max) and AUC(0-24 h) for verapamil were much higher than for the reference Staveran tablets and amounted to 51.28 and 320.23 ng/ml h, respectively. However, for norverapamil the corresponding values for buccal formulation were much lower than for a conventional tablet. It has been demonstrated that the proposed buccal verapamil dosing ensures different metabolism of the drug as compared to tablets. Better parameters of bioavailability of verapamil from buccal formulation of twice a smaller dose than that in the tablet, prove that this new drug might be form more effective clinically than the conventional one.