Thermal behavior of food preservative sorbic acid and its derivates.

Sorbic acid and its potassium and calcium salts used as food preservatives and sorbic chloride were submitted to thermal analysis in order to characterize their thermal behavior on heating and cooling processes, using TG/DTG/DTA, TG-MS, DSC, hot stage microscopy and DRX analysis. Sorbic acid melted and decomposed under dynamic heating. Under isothermal it sublimated without decomposition before melting (T < 134 °C). The potassium salt presented a solid-solid phase transition before decomposition. Both potassium and calcium salts decomposed in temperatures higher than the acid without melting, producing the respective carbonates and oxides as final residues. Sorbic chloride evaporate without condensation, on dynamic heating.

Unique laser coding technology to fight falsified medicines.

Based on WHO statistics, counterfeit medicines represent 10% of the global drug trade. According to Directive 2011/62/EU as regards the prevention of falsified medicines from entering into the legal supply chain, a unique identification should be put on each box of drugs to be able to track and trace them. The objective of this study is to develop a technology to mark an individual traceability code directly on the surface of the tablet. By using this technique, anyone with a camera-enabled phone and a suitable application installed should be able to authenticate these drugs. By marking the medicine's surface, patients could be protected from fake drugs. The aim of the present work was to study how different types of lasers affect the film coating of the tablet during the laser marking intervention. To sum up, the present findings may contribute to efficient and reliable laser marking solutions in the unique identification procedure. Based on our measurement results, it can be stated that the excimer UV laser is clearly the most suitable marking instrument for anti-counterfeiting coding on solid coated tablet form as this caused the least amount of chemical degradation of the polymer film.

[Formulation and special investigations of innovative intraoral solid dosage forms.] / Not available.

During our work, we summarized the types of solid dosage forms which were in the focus of attention in the last years because of their innovative pharmaceutical technology solution and simple use. The biopharmaceutics of solid dosage forms for intraoral use and the advantages of the use of these dosages forms were presented in general. However, these dosage forms cannot always be prepared with conventional pharmaceutical processes, therefore the special pharmaceutical solutions which can be applied for their preparation were presented. In addition to testing the European Pharmacopoeia dosage forms, the special tests which can be applied for the characterization of innovative solid dosage forms were highlighted.

Metolose-PEG interaction as seen by positron annihilation spectroscopy.

The plasticizing effects of poly(ethylene glycol) (PEG 400) on methylcellulose (Metolose) cast films were studied by conventional physicochemical methods and positron annihilation spectroscopy. The PEG concentrations relative to the total polymer content were varied within the range 0-75% (w/w). At low concentrations (below 33.3%, w/w), the plasticizer was found to build in into the methylcellulose structure. On the other hand, at higher concentrations (above 50%, w/w), it formed small separate phases in the films. Positron annihilation spectroscopy (PALS) was applied to track the Metolose-PEG interaction. Controlled ageing of Metolose-PEG films at room temperature and at 75% RH revealed a significant difference between the ageing processes of the monophase and those of the separate phase films. The ageing involves two steps in both cases: a fast and a slow one. The PALS measurements demonstrated that the slow process is hindered in the phase-separated samples.

Preformulation experiences and in vitro model studies with spironolactone-containing suppositories.

The optimal suppository base for the formulation of rectal suppositories containing diuretic spironolactone was selected experimentally. Model studies were carried out about the effect of solubility-increasing additives on the release of the drug from the suppositories. During the in vitro examinations acceptor phases of different pH values were used, and both diffusion time and the number of samplings were changed. Among the lipophilic and hydrophilic suppository bases studied the hydrophilic Macrogolum 1540 was found to be optimal. The release and diffusion of spironolactone was the most favourable from these suppositories. During storage these suppositories remained stable and the values of release did not decrease significantly (p < 0.05).

[Comparison of in vitro model examinaitons with respect to drug release from suppositories]. / In vitro vizsgálati modellek eredményeinek összehasonlítása a kúpok hatóanyagleadása szempontjából.

9 lipophilic suppository bases with different physical-chemical parameters were examined. Buspiron-hydrochloride, an anxiolytic drug with good water-solubility was used--partly as a model--as a pharmacon, in a concentration of 10.0 mg/2.00 g. The rate and extent of in vitro drug release was monitored with static and dynamic methods. Kidney-dialysing membranes with various surfaces were used. The quantitative measurements were carried out spectrophotometrically and the amount of the diffused drug was determined at lambda = 298 nm. The mean values were calculated from 5 parallel measurements each time. The percentage values of in vitro relative availability revealed that the results of the two static diffusion studies did not differ significantly (p < 0.05) and were almost independent of the size of the membrane surface. The results of the dynamic diffusion method were well-reproducible but were vehicle-dependent. The process of release was characterized by the mathematical transformation of the release curves, while the correlation coefficients described the closeness of the relation. Two German vehicles, namely Witepsol H 15 with a medium hydroxyl value and Massa Estarinum 299, and a French vehicle, Suppocire AS2X were found to be excellent for the formulation of suppositories containing Buspiron-hydrochloride.

Bioavailability of acetaminophen containing suppositories in rats.

An attempt was made to optimize the rectal delivery of acetaminophen (paracetamol). One of the aims was to determine which of the various lipophilic and hydrophilic suppository bases proved to be the best with respect to in vitro drug liberation. Among several experimental vehicles the Witepsol H 15 base with 10 of Miglyol 812 and the Macrogolum 1540 with 5% of Span 20 proved to be excellent. Furthermore, a well-known pharmacological effect of the paracetamol containing suppositories was evaluated in vivo in rats. The antipyretic response to the drug depends on the vehicle administered, showing an excellent correlation between in vitro and in vivo results.

[Experiences with the rectal use of a chemotherapeutic agent. 1. In vitro biopharmaceutical examinations; selection of the optimal vehicle]. / Kemoterápiás szer rektális alkalmazásának tapasztalatai. 1. Rész. In vitro biofarmáciai vizsgálatok; optimális vehikulum kiválasztása.

The factors influencing in vitro liberation (Part 1) and in vivo absorption (Part 2) from trimethoprim-containing rectal suppositories and the authors' results related to them are reported in this two-part publication. Special emphasis was laid on selecting the optimal suppository base which is harmless physiologically yet not indifferent pharmacologically. From among the 24 compositions studied, a lipophilic mixture containing a surface active additive (Witepsol W 35) and a hydrophilic (Macrogolum) mixture were found to be the best in all respects. Liberation from the trimethoprim-containing rectal suppositories was measured with in vitro dynamic diffusion and spectrophotometrically. A power relation was found to exist between the quantity of the released pharmacon and the diffusion time, and a significant negative exponential relation was observed between the doses and their respective in vitro availability values.

[Experiences with the rectal use of chemotherapeutic agents. 2. Pharmacokinetic examinations with animals]. / Kemoterápiás szer rektális alkalmazásanak tapasztalatai. 2. Rész. Allatkísérletes farmakokinetikai vizsgálatok.

The aim of the investigations was to optimise vehicle for trimethoprim (TMP) suppositories ready for clinical trials. The rectal absorption of TMP was studied in anaesthetized rats. The drug liberation properties of the five mixed vehicles with promising in vitro results (Part 1.) were studied. The course of the blood level curves was monitored with serial sampling. The TMP concentration of blood was determined by bioassay. Individual bases were compared with the use of the pharmacokinetic parameters derived from the analysis of the obtained blood level curves, with special respect to biological availability (BA). The extent of bioavailability is influenced considerably by the hydro-, lipo- or lipohydrophilic property of the vehicle. TMP, if incorporated in the proper vehicle, is absorbed well. With three vehicles the extent of absorption exceeded the absorption seen with oral administration on the same model (BA = 38.8%). The best results were achieved with the lipophilic base Witepsol W 35 containing 10% of Polysorbate 20 and 10% of Polysorbate 61 (BA = 63.8%) and with Witepsol W 35 containing 10% of Polysorbate 60 (BA = 64.9%). The hydrophilic Macrogol 1540 vehicle containing 5% of Macrogol 400 had only slightly worse results (BA = 52.9%). In the case of the lipohydrophilic Witepsol W 35 vehicle with 10% of Polysorbate 20 and 10% of Polysorbate 61 content a significant negative exponential relation was found between the administered doses and their respective bioavailability values, this tendency had been observed during the in vitro examinations, too. No such relation was found in the case of the lipophilic Witepsol W 35 vehicle containing 10% of Miglyol 812.

Experiences with the rectal use of trimethoprim.

The possibility of rectal use of trimethoprim was studied. The in-vitro liberation of the drug from 24 different suppository bases was examined and the results used to select bases for in-vivo examination. The in-vitro liberation from the suppositories containing 50-200 mg trimethoprim was studied by the method of dynamic diffusion, and the released drug content was measured spectrophotometrically. The in-vivo examinations were performed in anaesthetized rats. The concentration of trimethoprim in blood was determined by bioassay. The absorption of the drug in the form of oral suspension, rectal solution and suppository was also studied. The pharmacokinetic parameters obtained after blood-level curve fitting were compared by use of the MedUSA 1.6 program. The best in-vivo results were achieved with the lipohydrophilic Witepsol W 35 vehicle containing 10% polysorbate 20 and 10% polysorbate 61 (bioavailability = 63.8%) and with Witepsol W 35 containing 10% polysorbate 60 (bioavailability = 63.8%). The results for hydrophilic Macrogol 1540 vehicle containing 5% of Macrogol 400 were only slightly worse (bioavailability = 52.9%). In the case of the lipohydrophilic Witepsol W 35 vehicle with 10% polysorbate 20 and 10% polysorbate 61 content a significant negative exponential relationship was found between the administered doses and their respective bioavailability values; this tendency was also observed during in-vitro examinations. When incorporated in the appropriate vehicle trimethoprim was absorbed well. With three vehicles the extent of absorption exceeded that for oral administration on the same model (bioavailability = 38.8%). Trimethoprim rectal suppositories, which are formulated with the vehicles having the best in-vitro and in-vivo results, are suitable for clinical pharmacological investigation.

[Formulation and in vitro examination of furosemide-containing suppositories and preliminary experiences of their clinical use]. / Furosemid-tartalmú kúpok elóállítása, in vitro vizsgálata és a preklinikai alkalmazás tapasztalatai.

Rectal suppositories containing Furosemide (4-Chloro-N-furfuryl-5-sulfamoylanthranilic acid) and Furosemide Sodium were formulated with various suppository bases. The in vitro drug release of Massa Estarinum 299 proved to be the best from among the vehicles having various physical-chemical properties. The diuretic effect of the two suppositories was compared in a prospective, cross-over clinical trial including 8 patients. Both preparations have induced and increase of urine flow, which was comparable to the diuretic effect of the tablet. Thus the possibility of rectal use has been added to the modalities of therapeutic Furosemide administration.

Formulation and in vitro examination of furosemide containing suppositories and preliminary experiences of their clinical use.

Rectal suppositories containing furosemide (4-chloro-N-furfuryl-5-sulfamoylanthranilic acid) and furosemide sodium were formulated with various suppository bases. The in vitro drug release of Massa Estarinum 299 proved to be the best from the vehicle having various physical-chemical properties. The diuretic effect of the two suppositories was compared in a prospective, crossover clinical trial including 8 patients. Both preparations have induced an increase of urine flow, which was comparable to the diuretic effect of the tablet.

[Production technology and in vitro study of rectal suppositories containing chloroquine phosphate]. / Klorokinium-foszfát tartalmú végbélkúpok gyártástechnológiája és in vitro vizsgálata.

Chloroquine-phosphate was suspended in various lipophilic and hydrophilic suppository bases in an amount of 250 mg/2.0 g. The authors studied the solidity and the disintegration time of the suppositories as well as the in vitro drug liberation with a membrane diffusion method. The effect of the storage time and the storage circumstances on the stability of the suppositories was observed. Tropics-resistance studies were also carried out at a temperature of 45 degrees C and at a relative humidity content of 75%, thus these suppositories may be used for the treatment of malaria. The Witepsol H 15 base was found to be the best in all respect for use in countries with a continental climate. Finally a function relationship was found between the concentration of the pharmacon and the diffusion time with linear regression analysis.

Formulation and in vitro study of antibacterial vaginal suppositories.

Vaginal suppositories frequently used in gynaecological therapy were studied. Several antibacterial pharmacons are used for the topical treatment of vaginitis of various origins. In view of the fact that the liberation of the given active substance and the subsequent therapeutic effect may be improved or inhibited by the vehicle, our aim was to find the optimal suppository base for vaginal suppositories containing sulfadimidine, chloramphenicol and gentamicin sulfate by means of in vitro experiments. On the basis of breaking hardness, disintegration time and spreading properties the French Suppocire NA product, and compositions of macrogols with lower molecular weight proved to be the best lipophilic and hydrophilic bases, respectively. Among the lipophilic bases the in vitro drug liberation of Suppocire NA was significantly better (P < 0.05) than the other lipophilic bases. This vehicle is recommended for the topical treatment of vaginitis, as these suppositories have the further advantage that they can easily be produced on a magistral, galenical or industrial scale as well.

Formulation of diazepam containing rectal suppositories and experiences of their biopharmaceutical study.

Methodology and the results of the in vitro membrane diffusion and in vivo bioavailability studies are presented. The results confirm a correlation between in vitro and in vivo findings. Hydrophilic macrogol-mixture with great molecular mass can be recommended as the optimal vehicle for formulation of diazepam suppositories.

[Acetaminophen-containing suppositories in vitro and in vivo]. / Paracetamol-tartalmú kúpok in vitro és in vivo vizsgálata.

Rectal suppositories with a paracetamol content of 300 mg were prepared and the optimal vehicle was searched for experimentally. 9 different kinds of lipophilic, lipohydrophilic and hydrophilic vehicles were used for this purpose. Research was focused on determining the factors influencing in vitro drug liberation. The suppository compositions which proved to be the best by the membrane diffusion method were tested by in vivo animal experiments with respect to their antipyretic effect. The in vitro and in vivo results were evaluated statistically and some of the suppository bases showed significant differences. In the authors' opinion the optimal vehicle for the preparation of paracetamol-containing suppositories is the Witepsol H 15 suppository base containing 10% Miglyol 812 (neutral oil).

[Formulation of diazepam suppositories, results of rheological and biopharmaceutical studies. 1. Rheological study of the used suppository bases]. / Diazepám-tartalmú végbélkúpok formulálása, reológiai és biofarmáciai vizsgálatának tapasztalatai. 1. Az alkalmazott kúpalapanyagok reológiai tanulmányozása.

The rheological properties of four lipophilic and three hydrophilic suppository bases were studied. The flow and viscosity curves, the initial, equilibrium and plastic viscosity as well as the Bingham's yield value of the systems were determined. It was found that the viscosity curves had two different parts in the examined shearing rate range: the part of greater rise described a definitive destruction of the system, while the part of smaller rise represented an equilibrium state. The values of the rheological parameters of the lipophilic and hydrophilic systems showed a definite difference, which was explained by the greater association of the hydrophilic bases.

[Formulation of diazepam suppositories, results of rheological and biopharmaceutical studies. 2. In vitro membrane diffusion and in vivo absorption results]. / Diazepám-tartalmú végbélkúpok formulálása, reológiai és biofarmáciai vizsgálatának tapasztalatai. 2. In vitro membrándiffúziós és in vivo felszívódási eredmények.

In the first part of the publication the rheological properties of the vehicles used for the production of suppositories were studied in order to determine the ideal parameters for formulation. In this part a detailed methodology and the results of the in vitro membrane diffusion and in vivo bioavailability studies, are presented. The results confirm a general correlation between the in vitro and the in vivo findings. It seems that hydrophilic macrogol-mixture with great molecular mass can be recommended as the optimal vehicle for formulation of diazepam suppositories.