Development of gel-forming lyophilized formulation with recombinant human thrombin.

The objective of this work was development and evaluation of gel-forming lyophilized formulation with recombinant human thrombin for topical administration. The influence of pH, ionic strength and buffer type on protein stability was evaluated as part of the pre-formulation screening studies. Results indicated an optimal pH from 6.0 to 7.0 and increased stability with increasing content of sodium chloride. The tested buffer types had no significant effect on thrombin stability. For further development, thermosensitive Pluronic® F-127 was employed as a bulking and gelling agent. Physical and mechanical characterization and viscosity measurement confirmed the gel-forming properties of the formulation at the application temperature of 32 °C. Several techniques (addition of well-soluble polyols, different freezing protocols and reconstitution under vacuum) were tested to decrease the reconstitution time. The obtained results revealed that a vacuum in the vial headspace is crucial for acceptable reconstitution. The freeze drying process has no negative impact on recombinant thrombin stability, and this was confirmed by reverse-phase-HPLC, activity assay and optical density measurements.

In vitro liberation of indomethacin from chitosan gels containing microemulsion in different dissolution mediums.

The objective of this research is to outline the liberation of indomethacin from different chitosan gels containing O/W microemulsion. The influence of surfactant, sodium lauryl sulfate, in two concentrations (0.5% and 0.75%, w/w) was determined in dissolution medium on the release of indomethacin, which was used as poor water-soluble model drug. Chitosan gels were prepared in four different concentrations of chitosan-1%, 1.5%, 2%, and 3% (w/w). Microemulsion enhanced the liberation of the indomethacin from chitosan gels into all dissolution mediums. Adding the surfactant into phosphate-buffered saline decreased the amount of liberated indomethacin from microemulsion, gel mixture, but increased the drug liberation from pure chitosan gels. It was detected that with the increased concentration of chitosan in the samples, the amount of indomethacin liberated (p < 0.05) also increased. A conclusion was drawn that the liberation of indomethacin from chitosan gels was influenced by increased pH of the samples. The high viscosity induced a higher release of indomethacin from 3% (w/w) chitosan hydrogel at pH 5.8 as compared with 3% (w/w) chitosan hydrogel at pH 3.8. The highest percentage of released indomethacin was determined when a mixture of microemulsion gel with higher chitosan content was used.

Comparative study between synthetic and phospholipids of natural origin: effect of phospholipid selection on the behavior of a topical liposomal dosage form incorporating terbinafine.

Selection of excipients used is a critical step in the design of a pharmaceutical dosage form as it affects its behavior upon application, as during storage. The purpose of the present study is to evaluate and compare the behavior of six liposomal formulations intended for topical application composed of two widely used phospholipids 1,2-diacyl-sn-glycero-3-phosphocholine and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine with and without incorporation of cholesterol. Liposomal hydrogels made of hydroxyethylcellulose 3% and incorporating the anti-fungal agent terbinafine hydrochloride (E)-N-(6,6-dimethyl-2-hepten-4-inyl)-N-methyl-1-naphthalene-methanamine (-hydrochloride) were prepared, their viscosity was measured and in vitro drug release was studied. Moreover, physical stability and drug retention during storage at two different temperatures (2-8 °C and RT) were examined over time. The results showed differences in the behavior between the two phospholipids while incorporation of cholesterol at the studied concentrations was found to be of minor importance. Drug release was found to be favorable from 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) liposomal hydrogels and drug retention was found to be higher at lower storage temperature for all batches. Original physicochemical properties of all batches were found to be retained at least for a week.

Preparation of liposomal nanoparticles incorporating terbinafine in vitro drug release studies.

Terbinafine hydrochloride (TBH) (E)-N-(6,6-dimethyl-2-hepten-4-inyl)-N-methyl-1-naphthaline-methanamine(-hydrochloride) is an effective antifungal agent already existing on the market in the form of topical formulations. The present study deals with the preparation and physicochemical characterization (size, polydispersity, zeta-potential) of 1,2-Diacyl-sn-glycero-3-phosphocholine (EggPC) incorporating TBH in two different dispersion media (tris-buffered saline (TBS) of pH 7.4 or in phosphate buffer solution (PS) of pH 5.5) in order to investigate how pH of dispersion media affects the incorporation efficiency of TBH into liposomes. There were further prepared three Carbopol 934 hydrogels of different concentrations (0.5, 1 and 2%) and their viscosity was measured and evaluated. Moreover, the in vitro drug release from three liposomal gels was studied, in order to investigate the ability of liposomes to act as carriers for TBH in a gel. All formulations were found to retain their original physicochemical properties at least for three weeks. These early studies on the release kinetics from liposomal gel show that Korsmeyer-Peppas model could be the best fitted model concerning the TBH release profile and could be supported biophysically from extended Derjaguin-Landau-Verwey-Overbeek (DLVO) theory.

Permeation of indomethacin from semisolid preparations through various semipermeable membranes.

OBJECTIVE: The aim of this study was to evaluate and compare the permeation of model drug indomethacin (IND) from various types of gels through several semipermeable membranes. METHODS: Permeation of IND from gels based on carbomer (CA), hydroxyethylcellulose (HEC), and polyacrylamid/laureth-7/isoparaffin was performed via diffusion cell method through membranes: shed snake skin, full thickness chicken skin, mucosa of pork small intestine, and cellophane. RESULTS: The least permeation of IND was observed in the case of shed snake skin and full thickness chicken skin. It did not exceed 5.4% of original amount in the preparation after 3 h of measurement regardless the type of gel. In the case of mucosa of pork small intestine and cellophane the permeated amount of IND ranged from 9.4 to 55.4% depending on the type of gelling agent used. There was also quite a significant influence of a gelling agent on the permeation of IND observed. The permeation of IND was highest from CA gel, where it ranged from 0.6 to 52.2% of original amount in the preparation depending on the type of membrane used. Gelling agent inhibiting the permeation the most was HEC, where the permeated amount of IND did not exceed 12.3% regardless the type of membrane used. CONCLUSIONS: In general the permeated amount of IND through biological membranes containing stratum corneum represented just a small part of the amount in original preparation. Gelling agent has significant effect on the extent and rate of permeation.

[Influence of membranes on alaptide permeation from hydrogels]. / Vplyv membrán na permeáciu alaptidu z hydrogélov.

The paper evaluates the liberation of alaptide from gels through various types of permeable membranes. The gels were prepared on the basis of three different polymers (3% chitosan; 2.5% hydroxypropyl cellulose; 3% hydroxyethyl cellulose) in different concentrations with additions of humectants (5 %; 15% propylene glycol and 10% glycerol) and the preserving agent, 0.3% Sepicide HBR with 1% alaptide, and finally without the drug. The permeation of the drug from gels into the acceptor solution was evaluated with the use of the following membranes: the hydrophilic membrane from Chemosvit, the chicken skin, the stripped snakeskin, and the wall of the small intestine. The measurements showed that the highest percentage of the drug penetrated through the small intestine, a smaller percentage through the chicken skin, and the smallest amount through the snakeskin. Rheological properties of the prepared hydrogels were evaluated as well. The pseudoplastic flow was only confirmed for the hydrogel prepared on the basis of hydroxypropyl cellulose. An utterly opposite situation was with the hydrogels prepared on the basis of chitosan and hydroxyethyl cellulose. They showed a significant thixotropic character and the degree of thixotropy increased with time. Based on the results of the pH measurement, the samples prepared on the basis of chitosan and hydroxypropyl cellulose have been shown to be inconvenient because they reached a lower pH and had a potential of causing skin irritation. The hydroxyethyl cellulose hydrogel matched the physiological values of skin pH even after 14 days since its preparation.

[Study of local anaesthetics--Part 194. Evaluation of carbopol hydrogels with lidocaine]. / Stúdium lokálnych anestetík--6ast' 194. Hodnotenie karbopolových hydrogélov s lidokaínom.

The objective of this article is to describe the formulation and evaluation of dermal semisolid drugs--carbopol hydrogels containing the solution of Bukofit, zinc chloride and the local anaesthetic lidocaine. The hydrogels were evaluated after 2, 7, 14 and 28 days after their preparation and stored at the temperature of 5 degrees C +/- 0.2 degrees C. All prepared hydrogels were found to be stable with respect to pH values and rheological parameters. It follows from the found rheological parameters and flow curves that all evaluated hydrogels belong to non-Newtonian thixotropic systems. The extensometric analyses revealed increased deformation values, indicating that the gels can be easily spread out over the mucous membrane which results in the increased ability of the drug to diffuse into it. Based on the results obtained, it can be concluded that the prepared hydrogels have appropriate technological parameters and therefore in the future they may become potential drugs for the treatment of various inflammations in the oral cavity.

Alternative and generalized approach to in vitro-in vivo correlation.

Evaluation of in vitro-in vivo correlation (IVIVC) plays important role in securing therapeutic effect if a dosage form undergoes technological modifications. Similarity (closeness) of dissolution profiles of the original and modified dosage forms has been traditionally considered to be sufficient for similar in vivo responses. This may be true if the IVIVC model (dependence between the dissolution and corresponding absorption profiles) is given by a linear straight line with the unit slope. The paper presents an alternative and generalized approach to IVIVC evaluation. Influences of pre-systemic processes (disintegration, dissolution, absorption) on the system response (concentration time profile C(t), bioavailability BD and other) are analyzed and evaluated. Both the magnitude and sign of IVIVC are then derived from the magnitudes and signs of these influences. The underlining idea is that pre-systemic processes do not correlate with the system response, (e.g., plasmatic concentration) if small modifications of the former do not induce significant changes of the later. If this is so, the therapeutic effects of the modified and original dosage forms may be considered equal or at least similar. In this way the problem of IVIVC is not only exactly mathematically founded but modifications of pre-systemic processes are directly projected to the system output-- the time profile of plasmatic concentration. Moreover, the approach is applicable to virtually any dosage form. Its feasibility was validated in vivo.