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Topical medications, such as ointments, creams, and lotions, are frequently used for dermatological treatments. In clinical situations, improper use of topical medications might often be observed. First of all, changes to topical generic medication from an innovator might induce a change in release of the main compound and thus clinical efficacy. Next, there are some precautions during the preparation of an admixture of a topical medication. For example, no differences in the vasoconstriction response were observed with small degrees (16 times) of dilution in a steroid ointment. Another important consideration is the combination effect of a change to a generic medication from an innovator with preparation of the admixture. From a pharmacist’s perspective, three precautions that should be considered when applying topical medications are considered here.

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We surveyed sheets prescribed by dermatologists in our hospital during a 6-month period to investigate the stability of the admixture of commercially available ointments and/or creams. The total prescribed sheets numbered 21, 626, with 690 admixtures being found in 676 sheets. Seventy-two percent of these admixtures were combined corticosteroid preparations with white petrolatum or urea creams. Seven kinds of well-prescribed admixtures were presumed to develop some combinational problems. These admixtures were then prepared in our department, and the rate of air inclusion into the admixtures by mixing process was measured. The quantities of the water phase separated by centrifugation employed as an indice of the destruction of emulsion after mixing were measured, with a high value being obtained with the combination of corticosteroid ointments and o/w-type urea creams (ranging 10-30%). From the visual change noted by a naked eye supplemented with microscopic examinations, the emulsion in these admixtures was found to have already been destroyed after mixing. In contrast, the admixtures utilizing corticosteroid ointments and w/o-type urea creams were physically stable for a month. We also discussed on prescriptions made by many physicians. Consequently, it is strongly hoped that the information described in the package inserts and the naming of the products will be improved in relative to their physico-chemical properties.
We examined the stability and release profiles of dexamethasone dipropionate (DDP) from admixtures by using an innovator ointment (Methaderm [IM]), two generic ointments (Promethasone [GP] and Mainvate [GM]), and a heparinoid ointment. The admixtures were prepared using a spatula and an ointment slab and were stored at room temperature. Microscopic and Fourier transform-Raman spectrometric analyses showed that crystallization of DDP in admixtures of IM after 1 week of storage occured. And DDP crystals in all admixtures of GP and GM were observed. DDP was not decomposed in the admixtures after storage. Cumulative DDP permeation across a silicone membrane in a 1-week storage sample of the IM system decreased with DDP crystallization and reached a plateau after 2 weeks. In the GP and GM systems, DDP permeation decreased after 1 week of storage and increased again after 2 and 4 weeks. Each admixture was separated into 3 phases (liquid, lower, and upper solid phases) by ultracentrifugation to determine the apparent solubility of DDP. The DDP contents in the upper solid phase of the IM admixtures at 1, 2, and 4 weeks were lower than that in the 0-week sample. No significant differences were observed in the DDP content between the liquid phases throughout the storage period. Therefore, the amount of DDP dissolved in the upper solid phase may influence DDP release from the IM admixtures. The GP and GM systems showed no significant differences in the apparent DDP solubility. These results indicate that the dispersion state of DDP in the tested admixtures may be altered with storage.
Semisolid creams and ointments containing 0.05% w/w clobetasol 17-propionate (CP) as active ingredient are categorized as super-potent topical dermatological corticosteroids. The objective of the study was to evaluate the content and transdermal delivery of CP from eleven commercial dosage forms, including three ointments and eight creams. It was found that the CP content of the ointments ranged from 77.5 to 96.1% of the labeled amount, and that of the creams ranged from 84.0 to 105.6%. In vitro transdermal flux of CP through nude mouse skin ranged from 0.156 to 0.270 µg/cm 2 /h for ointments, and 0.100 to 0.521 µg/cm 2 /h for creams. Total amount of CP penetrated in 8 h ranged from 1.03 to 1.75 µg for ointments, and 0.67 to 2.95 µg for creams. Lag time to reach steady-state of delivery ranged from 1.48 to 1.63 h for ointments, and 1.53 to 3.19 h for creams. In comparison with the brand name products, transdermal flux of CP from the generic ointments was 57.7% and 83.5% of Dermovate ointment, and that from the generic creams ranged from 19.2 to 94.8% of Dermovate cream. The results demonstrated that commercial 0.05% CP creams and ointments were highly variable in the transdermal delivery of CP, which may influence their bioavailability and clinical efficacy.
Characterization and release profiles of commercial dexamethasone dipropionate (DDP) from an innovator and 2 generic ointments (Methaderm (IM), Promethasone (GP), and Mainvate (GM)) and their admixtures with heparinoid ointment (Hirudoid Soft) were investigated. The admixtures were prepared using 2 mixing methods (slab or rotation/revolution mixer). Microscopic and FT-Raman spectrometric analyses revealed that the ointments, except for IM, contained DDP crystals. A silicone membrane was used for the evaluation of the DDP permeation. The permeated DDP amounts from GP and GM were lower than that from IM, indicating that DDP solubility in the ointment vehicle affected the release of DDP from the ointment. No significant differences were observed in DDP release between IM alone and its admixture prepared using a slab; however, DDP release from the admixture prepared using a rotation/revolution mixer was significantly lower than those from IM alone and its admixture by slab. In the GP system, DDP release from the admixtures by the 2 mixing methods was higher than that from GP alone, whereas no significant difference in DDP release between the 2 mixing methods was observed. No significant differences were observed between the GM and admixtures. The apparent solubility of DDP in the admixtures as determined by the ultracentrifugal separation method indicated that the DDP amount in the liquid phase of admixtures with GP was 6 times higher than that of admixtures with IM or GM. Therefore, the apparent solubility of DDP in the liquid phase in the GP system might influence the DDP release in admixtures.
Twenty percent of dermatologists have experienced a separation of water or deterioration of topical corticosteroids mixed with commercially available ointments and/or creams. However, few investigations of this deterioration of admixtures have been reported. To assess the effects of preservatives in preventing microbial contamination of these admixtures, we attempted to investigate the concentration of preservative agents in admixtures and the microbial contamination of these admixtures with a topical corticosteroid ointment (Antebate). The concentration of parabens was reduced by half using an admixture of corticosteroid ointment with four types of moisturizing creams, Urepearl, Pastaronsoft, Hirudoid, and Hirudoidsoft. After a further 3 months, no decrease in parabens was seen. No microbial contamination was found in any admixture stored at room temperature for 1 week and touched two times daily with a finger. The concentration and ratio of the parabens in the aqueous phase and oil phase were entirely different in the admixtures before being centrifuged. The aqueous phase of the admixtures of the oil/water (O/W)-type emulsions of Urepearl and Hirudoid was not found to have microbial contamination immediately after being centrifuged. All aqueous phases stored at room temperature or in a refrigerator for 1 week and touched with a finger twice daily exhibited microbial contamination. These experiments demonstrated that O/W-type emulsions, in which the water easily separates from the bases, should be thoroughly mixed to prevent microbial contamination.
The United States Food and Drug Administration recommends pilot dose duration-response and pivotal bioequivalence studies to be conducted using reflectance colorimetry for assessment of the in vivo bioequivalence of topical dermatologic corticosteroids. The major objectives of the present studies were to examine the applicability of the standardized pharmacodynamic modeling-based methodology to super-potent clobetasol 17-propionate (CP) in the Chinese population and to evaluate the bioequivalence of two generic ointments and four generic creams containing 0.05% (w/w) CP with respect to Dermovate formulations using such methodology. In the pilot dose duration-response study, although the E(max) model (where E(max) is the maximum fitted value of AUEC, which is the area under the baseline-corrected, untreated control-site-corrected a* scale data from 0 to 24 h after drug removal) did not provide acceptable model fits, E(max) parameter estimates of -38.97 +/- 3.62 and -41.89 +/- 11.28 a*-scale. h, and ED(50) (dose duration required to achieve 50% of the fitted E(max) value) estimates of 0.40 +/- 0.37 and 0.42 +/- 0.16 h were obtained for Dermovate ointment and cream, respectively, by population analyses. The estimates for the two formulations were not statistically different, so in vivo bioequivalence studies were conducted at an ED(50)dose duration of approximately 0.5 h for both Dermovate formulations. The results demonstrated that one generic ointment was bioequivalent to Dermovate, whereas the other was not. None of the generic creams were shown to be bioequivalent to Dermovate cream. The in vivo bioequivalence data from the vasoconstriction assay were linearly correlated with stratum corneum uptake of the drug at the same dose duration until the maximal vasoconstriction response was achieved. The studies illustrated the applicability of the standardized pharmacodynamic modeling-based methodology in detecting the product differences between a variety of generic 0.05% CP formulations and reference Dermovate formulations in Chinese skin.
Vasoconstriction activity test. Japan-Germany medical reports
  • M Kawashima
Admixture of ointments
  • T Ohishi
  • R Shinagawa
  • Y Harada
  • K Takebayashi
  • K Nasu