Investigation on the photostability of tretinoin in creams.

In this investigation, the photodegradation of some tretinoin cream formulations was evaluated. Several oils were selected to prepare the cream formulations: olive oil, maize oil, castor oil, isopropyl myristate and Miglyol 812. A solubility study showed that tretinoin is best soluble in castor oil (0.60g/100ml), followed by isopropyl myristate, maize oil, Miglyol 812 and olive oil, respectively, 0.35, 0.30, 0.29 and 0.22g/100ml. The photostability of tretinoin in oils is comparable with the photostability of a tretinoin lotion (ethanol/propylene glycol 50/50), castor oil and olive oil giving slightly better results than the other oils. Investigation of the photodegradation of tretinoin in o/w creams, prepared with the same oils as mentioned above, revealed that tretinoin is far more stable in the cream formulations than in the respective oils, however it is not clear whether this is due to the formulation or due to a different irradiation technique. Tretinoin seemed to be most stable in the olive oil cream, followed by the castor oil cream. However microscopic investigation revealed the presence of tretinoin crystals in the olive oil cream, while the other creams were free of it. As a conclusion, one can say that the cream prepared with castor oil seems to be the most suitable one, in terms of solubility of tretinoin and in terms of photostability.

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.

Determination of hydroperoxides in liposomes by the modified IDF and the modified tiron methods.

Two new methods, the modified International Dairy Federation and the modified Tiron methods, were developed for the determination of hydroperoxides in liposomes. Interferences of alpha-tocoferol and egg-phosphatidylcholine (EPC) required a solid-phase extraction before the analysis to eliminate alpha-tocoferol and a fluid-fluid extraction based on the solvent triangle of Bligh and Dyer to separate EPC. The developed color, using thiocyanate and Tiron, respectively, as complex-formers for the generated ferri-ions, was measured spectrophotometrically. Both techniques showed good reproducibility and high sensitivity. Peroxide contents of 0.04 and 0.07% (g/g) in EPC samples were easily determined.

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.

Investigation of the chemical stability of an erythromycin-tretinoin lotion by the use of an optimization system.

A combination of 2% erythromycin and 0.05% tretinoin in an alcohol-isopropanol lotion was prepared. Two parameters were investigated for their influence on the stability of erythromycin and/or tretinoin, namely pH and the concentration of butylhydroxytoluene (BHT) as antioxidant. To investigate these two parameters, an optimization technique was used with two factors (pH and concentration of BHT) at two levels. Accelerated stability analysis was performed at 45 degrees C in the dark to exclude isomerization of tretinoin. To analyse erythromycin and tretinoin in the combination preparation, a TLC method, previously developed in the laboratory, was used. The degradation of erythromycin seemed to be much faster than the tretinoin degradation. Optimal stability is shown in the pH range of 8.2-8.6 for erythromycin and 7.2-8.2 for tretinoin while the concentration of BHT had no significant influence.

Densitometric thin layer chromatographic analysis of tretinoin and erythromycin in lotions for topical use in acne treatment.

A TLC-method was developed to analyse tretinoin and erythromycin in a lotion in the presence of several excipients. Erythromycin was separated on a silica gel plate and a mobile phase with dichloromethane, methanol and ammonia 25% (60:6:1 (v/v/v)), tretinoin on a C(18) RP plate with acetonitrile and water (50:25 (v/v)) as mobile phase, adding 1 ml acetic acid for the separation of the excipients and erythromycin. The derivatization for both was done with a dipping reagent, consisting of anisaldehyde, sulphuric acid and acetic acid (respectively 1, 2 and 10% (v/v/v)) and dissolved in chloroform/alcohol 94% v/v (60:30 (v/v)) for erythromycin and alcohol 94%/water (50:40 (v/v)) for tretinoin. These TLC-systems were quantitatively evaluated in terms of stability of the colour, precision, accuracy and calibration, proving the utility in the analysis of the lotion.

Investigation on the chemical stability of erythromycin in solutions using an optimization system.

Erythromycin, an antibiotic commonly used topically in the treatment of acne, is unstable in solution. The stability is influenced by the pH and by the presence of water. The influence of the pH on the stability of erythromycin was investigated even with the use of dimethyl isosorbide as co-solvent instead of water. The addition of zinc was attempted to ameliorate erythromycin stability as suggested in the literature. To investigate these three factors and their interactions, an optimization technique was carried out consisting of a 2(3) factorial analysis and a rotative central composite design. The erythromycin solutions were analysed with an HPLC method. The pH and the concentration of dimethyl isosorbide had a significant influence on the stability of erythromycin but the addition of zinc was not a significant factor. Moreover, there was a significant interaction between the pH and dimethyl isosorbide.