Jacqueline Plaizier-Vercammen

Evaluation of Xanthan Cum as a Hydrophilic Matrix for Controlled-Release Dosage form Preparations

AbstractXanthan gum was evaluated as hydrophilic matrix for controlled release preparations. Different parameters were considered: direct and wet granulation, gum concentration, effect of addition of binders, pH, ionic strength, rotation speed and surfactant. Suitable controlled release profile could be obtained. Practically no influence of the parameters studied was noted, with the exception of gum concentration, the rotation speed and presence of ion in the dissolution medium. The release rate profiles were evaluated by different kinetic equations: Zero order, First order, Higuchi equation and RRSBW equation and the data statistically analyzed with F-Ratio. Without binder, in aqueous medium, zero order kinetics were found from the origin of the release rate profile. With binder and dissolution media with electrolytes or buffer solutions, generally zero order kinetics were also found after an initial period of about half an hour. The release kinetics were independent of the method of preparation and comp...

Quality control of active ingredients in artemisinin-derivative antimalarials within Kenya and DR Congo

Objectives  Artemisinin‐derivative drugs are widely used to treat Plasmodium falciparum malaria and very few studies have investigated the quality of these medicines in Africa. We analysed the active ingredient contents of artemisinin‐derivative drugs marketed in Kenya and DR Congo.

Preparation of β-artemether liposomes, their HPLC–UV evaluation and relevance for clearing recrudescent parasitaemia in Plasmodium chabaudi malaria-infected mice

Egg phosphatidylcholine-cholesterol liposome formulations containing the antimalarial drug beta-artemether have been prepared and analyzed for their encapsulating capacity, chemical stability, leakage, in vitro release and their therapeutic efficiency against Plasmodium chabaudi infection. A HPLC-UV analysis of beta-artemether liposomes without derivatisation was achieved. A good linearity of y=4437.7 x+469.01 (R(2)=0.9999) with a detection limit of 2 microg ml(-1) was reached. Prior to this, liposomal formulations composed of different molar ratios of EPC-CHOL were prepared to select beta-artemether crystal-free liposome preparations. The formulation corresponding to 4:3 and a total concentration of 300 mg lipids ml(-1) buffer (pH 7.2), which could incorporate as much as 1.5 mg beta-artemether was selected for therapy. A trapping efficiency of nearly 100% was reached, the drug being located in the lipid bilayers. A dialysis test demonstrated that the drug could be reversibly released from the liposomes, reaching equilibrium within 24 h. After 3 months storage at 4 degrees C, no leakage of beta-artemether had occurred indicating a high stability of the liposomes. These liposomes were used to treat mice infected with the virulent rodent malaria parasite Plasmodium chabaudi chabaudi, with a 100% cure by clearing the recrudescent parasitaemia.

Investigation on the photostability of a tretinoin lotion and stabilization with additives

Tretinoin, a drug that is used in topical preparations for the treatment of acne vulgaris, is known to be very susceptible to degradation under daylight. The objective of this work was to investigate the degradation of a tretinoin lotion placed in front of a xenon lamp. Analysis was performed with HPLC. The tretinoin lotion was degraded to about 20% of its initial concentration within 30 min. Incorporation of tretinoin in beta-cyclodextrin or in some surfactants (Brij(R)s) did not have any effect on the photodegradation of tretinoin. Neither could a UV-B sunscreen retard the photodegradation of tretinoin while a UV-A sunscreen had very little effect. Irradiation with selected wavelengths revealed that 420 nm seemed to be the most harmful wavelength for the degradation of tretinoin and not the wavelength of maximum absorption (350 nm) as expected. Then the addition of the yellow colourants chrysoin and fast yellow, absorbing in the region of 420 nm, was tested. These colourants did indeed retard the photo-degradation of tretinoin more or less depending on the concentration of the dye. Finally we only had to select a concentration that was still effective but that did not colour the skin.

Liposomes with tretinoin: a physical and chemical evaluation.

The comedolytic activity of tretinoin, incorporated in liposomes, is five to ten times higher compared to the conventional preparations and also the local tolerability is much better. This implies the big interest of a study on tretinoin in liposomes. First, the encapsulation capacity of tretinoin in the liposomes was determined. Therefore, a series of liposomes was prepared with different concentrations of tretinoin (1-6 mg/ml buffer) and lipids (100-300 mg/ml buffer) (egg phosphatidyl choline/cholesterol) with buffers pH=5 and 7. These series of liposomes were evaluated microscopically on the presence of tretinoin crystals outside the liposomes. The highest incorporation capacity was obtained using 2 mg of tretinoin and 300 mg of lipids per milliliter of buffer pH=5. The chemical stability of tretinoin in the liposomes, evaluated during 1 year, revealed no remarkable loss in tretinoin content, even when stored at 25 degrees C. The photo-degradation of tretinoin in the liposomes was about two times slower than in castor oil, but tretinoin degraded to approximately 25% of its initial content. The chemical evaluation of the lipid fraction showed no oxidative degradation of the polyunsaturated fatty acids in EPC because the determined concentration of conjugated dienes and hydroperoxides, two oxidative degradation products, was <1%, which is negligible. Finally, the in-vitro release of tretinoin from the liposomes, evaluated with a dialysis technique, was very low, but this is not a problem for topical use.

Validation of an HPLC method on short columns to assay ketoconazole and formaldehyde in shampoo.

An HPLC method to determine simultaneously ketoconazole and formaldehyde in an anti-dandruff shampoo, originally developed on a long column, was transferred to two short columns with similar stationary phase properties, but with a length of at the most 30% of the initial one. Using the conventional column as reference, the fast HPLC methods on the short columns were validated. The validation characteristics consisted of selectivity, linearity range, precision (repeatability and time-different intermediate precision), bias and robustness. For the ketoconazole assay, linearity for peak area was found in the concentration range up to 0.20 mg/ml. For formaldehyde, two calibration ranges (0-10 x 10(-5) and 0-10 x 10(-4)%) were linear, both for peak area and height. The assays for both ketoconazole and formaldehyde in these ranges showed no bias and an acceptable precision, although the precision found with the short columns was slightly worse than with the long one. The robustness tests were performed applying a Plackett-Burman design. For the ketoconazole assay, 6 factors were examined in a 12 experiments design and for formaldehyde, 11 factors in 16 experiments. The methods were found to be robust. Despite the somewhat less good precision the transfer seems to be successful and the obtained assays on the short columns are applicable for fast routine analysis.

Chemical stability of tretinoin in dermatological preparations

Tretinoin is commonly used in dermatological preparations, for example in the treatment of acne vulgaris. Tretinoin or all trans retinoic acid is easily oxidizable, thermally unstable and it isomerizes fast when exposed to radiation. In this investigation, the chemical stability of tretinoin was studied in different dermatological preparations. For this purpose, accelerated stability analysis was carried out and also the influence of daylight was investigated. To analyze the dermatological preparations, a HPLC method on a reverse-phase column seemed to be the most suitable one and also the sample preparation for this method was relatively simple. The decomposition of tretinoin in preparations which were exposed to radiation was very fast. A 10% decomposition was noted between less than 1 h and 181 h, depending on the formulation of the preparation. The tretinoin stability was also influenced by temperature, depending on the ingredients of the dermatological preparations. The adjuvant Brij 35 S, used as solubilizing agent, had a very bad influence on the chemical stability of tretinoin.

Simultaneous determination of ketoconazole and formaldehyde in a shampoo: liquid chromatography method development and validation

Ketoconazole is an antifungal agent, which is the active ingredient in a shampoo primarily used for the treatment of seborrhatic dermatitis (anti-dandruff shampoo). The shampoo also contains imidazolidinylurea as a formaldehyde releasing preservative. The aim of this study was to develop a HPLC system that allows the determination of both ketoconazole and formaldehyde. The finally selected isocratic system consisted of an Interchrom Nucleosil (250 X 4.6 mm, 5 microm) C8 column and a mobile phase containing acetonitrile-phosphate buffer 0.025 M, pH 4.0, 45/55 (v/v). Ketoconazole could immediately be determined at 250 nm after injection of diluted shampoo. Formaldehyde was measured at 345 nm after derivatisation with a 2,4-dinitrophenylhydrazine solution. At the selected conditions, the other excipients of the shampoo did not interfere in the assays for both substances. Method validation was performed on both assays. Different selectivity towards ketoconazole and formaldehyde was observed when applying other C8 columns. This fact, however, did not affect the assays of both substances.

Differential sensitivity of erythrocytic stages of the rodent malaria parasite Plasmodium chabaudi chabaudi to dioncophylline B, a highly active naphthylisoquinoline alkaloid

Abstract Four-week-old OF1 mice, infected with synchronized Plasmodium chabaudi chabaudi blood forms, were intraperitoneally injected with the naphthylisoquinoline alkaloid dioncophylline B (10 mg kg−1 day−1) at three consecutive days. The respective groups were treated when rings, trophozoites, and schizonts were predominant. Microscopical observations of thin blood smears were made every two hours after the start of the experiment. A clear dependency of the effectiveness of dioncophylline B treatments on the timing of drug administration was demonstrated. Based upon the evolution of total parasitaemia and the survival rates, it was concluded that ring stages are insensitive to dioncophylline B, while the drug is highly effective when given at the trophozoite stage and partially effective when given at the schizont stage. Dioncophylline B seems to act by inhibiting the haemozoin degradation, as indicated by pigment clumping, and by impairing the segmentation of schizonts.

Preparation and in-vitro release rate of fentanyl-cyclodextrin complexes for prolonged action in epidural analgesia.

Fentanyl was complexed with cyclodextrin derivatives with the intention to obtain parenteral solutions able to provide prolonged analgesia following epidural administration. Three cylodextrins (CDs) suitable for parenteral use were used: hydroxypropyl-beta-cyclodextrin (HP-beta-CD), sulfobutylether-beta-cyclodextrin (SBE-7-beta-CD), and maltosyl-beta-cyclodextrin (malt-beta-CD). Analysis of fentanyl was done with HPLC-UV. The inclusion capacity of HP-beta-CD was determined from phase-solubility diagrams at pH 6.5, 7.2 and 8.0, and those of SBE-7-beta-CD and of malt-beta-CD at pH 8.0. Solubility of fentanyl increased linearly (i) as a function of the CD concentration, and (ii) with decreasing pH. Complexation was highest with HP-beta-CD and malt-beta-CD, much higher than with SBE-7-beta-CD, with stability constants at pH 8.0 of 801, 729 and 1309 M(-1), respectively. The CD concentration was calculated to obtain a fentanyl-CD formulation, with the desired amount free fentanyl as loading dose in solution and the rest complexed with CD, as reservoir for prolonged action. A suitable membrane and a release-rate apparatus were selected for in-vitro release-rate studies. Best results were obtained with Spectrapor membranes and a home-made release-rate apparatus. Release rate was evaluated in static and dynamic conditions. For both modes, the release rate of fentanyl decreased as a function of CD concentration, due to complex formation of fentanyl, which suggests the possibility to provide prolonged pharmacodynamic effects in vivo.