[Ointments. IV. Release and absorption of drug substances from ointment bases and the factors that influence the therapeutic effectiveness of ointments].
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A novel ointment base suitable for the treatment of bedsore at the recovery stage was developed by the use of hydroxypropyl methylcellulose (HM-HPMC) modified on the basis of the hydrophobicity. A considerable sustained release of drug (minocycline hydrochloride) formulated to the ointment (T50 of 170 min) was attained with a macrogol ointment (MO) mixed with the HM-HPMC and Carbopol (CP) of the formulating ratio of 3:7. It was also found that a change in the formulating ratio of HM-HPMC and CP lead to a change in the drug release rate. The water absorption property of the ointment base, required to absorb on exudative solution in applying to the bedsore treatment, was as high as that of an ointment base containing hydroxypropyl cellulose (HPC) and CP reported in our previous paper. We clinically evaluated the effectiveness of the bedsore treatment, in which different ointment bases were applied to patients at different stages of the bedsore. A total of 22 cases were divided into two categories for applying to the different treatments. One category comprised of 11 subjects was treated with a povidone-iodine sugargel, which was the conventional method in our hospital, while the other 11 subjects were treated by the use of the newly developed ointment bases in consideration for the different stages of the bedsore. In comparison of the clinical results with the healing index, we ascertained that the latter method was significantly more efficacious (p < 0.01-0.05) than the conventional one. The effectiveness was emphasized in treating the intractable bedsore classified into the grades IV and V. Therefore, we confirmed that the newly developed ointment base formulation is useful in treating bedsore at each stage.
On the basis of absolute DL50 values 6alpha,9-difluor-11beta-hydroxy-16alpha-methyl-21-valeryloxy-1,4-pregnadiene-3,20-dione (diflucortolone valerate, Nerisona) is virtually non-toxic after single oral administration (mouse greater than 4 g/kg, rat ca. 3.1 g/kg, dog greater than 1 g/kg). Given s.c. (LD50 mouse ca. 180 mg/kg, rat ca. 13 mg/kg) and i.p. (LD50 mouse ca. 450 mg/kg, rat ca. 98 mg/kg) it is highly active and therefore produces also toxic effects. The formulations Nerisona ointment, fatty ointment and cream have proven practically non-toxic in rats after single oral gavage (LD50 greater than 33 g/kg). The daily s.c. administration over 6 weeks revealed systemic glucocorticoid effects in rats at 0.0004 mg/kg and in dogs at 0.04 mg/kg. Similar effects were seen in dogs after daily dermal treatment for 13-14 weeks with Nerisona ointment at 100 mg/kg body weight. On the skin of rabbits and dogs there were no differences in the reaction at the application site between Nerisona ointment, fatty ointment and cream and the corresponding ointment, or cream bases by daily dermal administration for 28 days. However, the 13-14 week dermal study in dogs with Nerisona ointment revealed atrophy of the epidermis at the application site in several cases. The daily dermal application of Nerisona ointment during organogenetic phases of pregnancy caused embryotoxic effects in rats at 500 mg/kg and in rabbits at 50 mg/kg. All of these findings are discusses as well-known glucocorticosteroid effects.
BACKGROUND: Vehicle-controlled studies have demonstrated the efficacy and safety of tacrolimus ointment for patients with atopic dermatitis. OBJECTIVE: This study was undertaken to compare 0.03% and 0.1% tacrolimus ointment with 0.1% hydrocortisone-17-butyrate ointment, a midpotent to potent topical corticosteroid, in the treatment of adult patients with moderate-to-severe atopic dermatitis. METHODS: Patients applied ointment twice daily to all affected areas for 3 weeks in this multicenter, randomized, double-blind, parallel-group study. The primary endpoint was the modified eczema area and severity index (mEASI) mean area under the curve as a percentage of baseline. RESULTS: Five hundred seventy patients were randomized and received treatment. Discontinuations included 22 of 193 patients from the 0.03% tacrolimus group, 22 of 191 patients from the 0.1% tacrolimus group, and 17 of 186 patients from the hydrocortisone butyrate group. The median mEASI mean area under the curve as a percentage of baseline was 47.0%, 36.5%, and 36.1% for patients who received 0.03% tacrolimus, 0.1% tacrolimus, and 0.1% hydrocortisone butyrate, respectively. There was no statistically significant difference between 0.1% tacrolimus and 0.1% hydrocortisone butyrate; however, the lower improvement in mEASI for 0.03% tacrolimus was statistically significant when compared with 0.1% tacrolimus (P <.001) or hydrocortisone butyrate (P =.002). Skin burning and pruritus at the application site showed a higher incidence in the tacrolimus treatment groups than in the hydrocortisone butyrate group (P <.05). Laboratory parameters showed no treatment differences and no marked changes over time. CONCLUSIONS: The efficacy of 0.1% tacrolimus ointment was similar to that of 0.1% hydrocortisone butyrate ointment and was lower for 0.03% tacrolimus ointment. No serious safety concerns were identified.
Mometasone furoate (Elocon) is a newly formulated and unique medium-potency synthetic 17-heterocyclic corticosteroid. The efficacy and safety of the ointment and cream formulations (0.1 percent) of the corticosteroid, administered once daily, were compared with those of the ointment and cream formulations of fluocinolone acetonide 0.025 percent administered three times daily and triamcinolone acetonide 0.1 percent administered twice daily in four multicenter clinical studies. They were conducted involving psoriasis patients with chronic and moderate to severe disease. Evaluation of change in disease sign scores indicated that mometasone ointment, applied once daily, was significantly more effective (P less than 0.01) than fluocinolone ointment, applied three times daily, and triamcinolone ointment, applied twice daily. The cream formulation of mometasone was significantly more effective (p less than 0.001) than fluocinolone cream, applied three times daily, and equivalent to triamcinolone cream, applied twice daily. The incidence of local adverse experiences following treatment with the ointment or cream formulations of mometasone was minimal. Mometasone ointment and cream provide a highly effective once-a-day treatment for moderate to severe psoriasis with minimal risk of side effects.
A multicentre, between-patient, comparative trial was carried out by nine dermatologists in the Federal Republic of Germany to compare the efficacy and tolerability of 0.05 halometasone ointment with those of an ointment, containing 0.25% fluocortolone + 0.25% fluocortolone caproate, in patients with psoriasis vulgaris. The evaluable trial population consisted of 182 patients, 115 males and sixty-seven females. Halometasone ointment yielded a higher success rate ('good' to 'very good' results), namely 56.4% than that obtained with the comparative ointment (45.4%). Halometasone ointment also produced a higher cure rate, namely 26.6%, than that reported with the comparative preparation (19.3%). An improvement of one score over the pre-treatment clinical status of the psoriatic lesions reported at the Day 10 visit was significantly higher (p = 0.04), namely 48.9%, with halometasone ointment than that with the comparative preparation (35.2%). The percentages of patients obtaining an early cure, i.e. in less than 30 days, and onset of action were practically identical in both treatment groups. No adverse effects were reported in any of the ninety-four patients treated with halometasone ointment, while unwanted reactions were observed in three of the eighty-eight patients treated with the comparative preparation.
In a double-blind, parallel-group, multicenter comparative trial on 104 evaluable patients with severe, localized plaque psoriasis, 0.05% halobetasol propionate ointment demonstrated an 88.7% success rate assessed as "healed" or "marked improvement" compared with 78.5% for 0.05% betamethasone dipropionate ointment. Healing was observed within 24 days of the start of treatment in 40% and 25% of the patients who received halobetasol propionate and betamethasone dipropionate ointments, respectively. After 4 weeks' treatment, tolerability of both ointments was good. Neither skin atrophy nor systemic adverse effects were observed. Patient acceptance of halobetasol propionate ointment, based on cosmetic acceptability and ease of application, was significantly better (p = 0.02) than that of betamethasone dipropionate ointment.
AIMS: The main objective of this explorative study was to evaluate if tacrolimus ointment could be safer than corticosteroid ointment, with special reference to the intraocular pressure in the treatment of eyelid eczema in patients with atopic keratoconjunctivitis (AKC). Secondary aims were to compare the effects of the treatments on eyelid eczema and their potential impact on ocular surface inflammation. METHODS: Tacrolimus 0.1% ointment and clobetasone butyrate 0.05% ointment were compared in a double-masked explorative crossover study. In total, 25 AKC patients were included. Each ointment was applied twice daily for 3 weeks, with 2 weeks of washout before, between, and after treatments. Efficacy was determined by eye examination and the patients' own symptom scoring. Cytology and cytokine measurements were performed on tear samples. Safety parameters were intraocular pressure, presence of bacteria and fungi, and the patients' reports of adverse events. The validity of the crossover design was explored with analysis of variance, and the effect of each medication was calculated with paired t-test and Wilcoxon paired test. RESULTS: A total of 20 patients completed the study. Both treatments were effective in reducing signs and symptoms of eyelid eczema, with a near superior benefit for tacrolimus in terms of eczema (total skin score) signs (P=0.05). No serious adverse events occurred and interestingly, intraocular pressure was not evidently affected by either treatment. CONCLUSION: Tacrolimus 0.1% ointment is a promising alternative therapy for eyelid eczema in AKC patients. Long-term studies are needed to further determine the value of tacrolimus in this patient group.
Atopic dermatitis (AD) is thought to be induced by a complex of various allergic reactions and T cells are implicated in its etiology. Since tacrolimus strongly inhibits T cell activation, tacrolimus ointment has been developed as a novel drug for AD throughout the world. Tacrolimus inhibits mast cell and eosinophil activation and antigen presenting activity of Langerhans cells in vitro. In the in vivo experimental animal models of AD, such as contact and spontaneous dermatitis in mice and repeated hapten treated skin inflammation in rats, tacrolimus ointment showed inhibitory activity. In clinical studies with AD patients in Japan, USA and Europe, tacrolimus ointment showed a marked effect. In comparative studies in Japan, it showed the same efficacy as a strong class steroid ointment on eczema at the trunk and extremities and superior efficacy at the face and neck compared to a medium class steroid. The most prominent adverse event is experienced at the local application site with reactions such as a burning sensation and erythema. Systemic side effects were rarely observed. While there is a possibility of skin infections when using tacrolimus, skin atrophy, even after long term treatment, was not observed. Thus tacrolimus ointment could be an efficient alternative to steroid ointment for AD.
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Topical corticosteroids and keratolytics are both used widely in the management of patients with psoriasis. A combination of the two types of agents may provide enhanced relief. The purpose of this study was to compare the efficacy and safety of the combination ointment mometasone furoate 0.1% plus salicylic acid 5% with that of mometasone furoate 0.1% ointment in the treatment of moderate-to-severe psoriasis vulgaris. A total of 408 patients were enrolled in this controlled, randomized, double-masked, parallel-group, multicenter comparison. Patients applied either mometasone furoate-salicylic acid ointment or mometasone furoate ointment alone to target lesions twice daily for 21 days. Severity of erythema, induration, and scaling were scored at baseline and at days 4, 8, 15, and 22. An evaluation of overall change in disease status of all treated lesions was performed at each follow-up visit. Adverse events were also monitored and scored, including signs of skin atrophy. Beginning on day 8, the combination of mometasone furoate-salicylic acid was significantly more effective than mometasone furoate alone, as indicated by the mean percentage of improvement in total disease scores, mean total disease sign scores, and the individual score for scaling. Similarly, the combination was more effective beginning on day 15, as indicated by the global evaluation of overall clinical response and individual scores for erythema and induration. Both treatments were well tolerated. Mometasone furoate-salicylic acid ointment provides more effective treatment of moderate-to-severe psoriasis than does mometasone furoate ointment alone and is safe and well tolerated.
In a double-blind, parallel-group, multicenter, comparative trial in 120 evaluable patients with chronic, localized atopic dermatitis or lichen simplex chronicus, the success rate (described as "healed" and "marked improvement") was 91.5% in patients treated with halobetasol propionate ointment and 83.6% in those in the diflucortolone valerate treatment group. Of patients treated with halobetasol propionate ointment, 40.7% reported healing within 17 days, whereas of those in the diflucortolone valerate treatment group, 32.8% reported healing within that time. Early onset of therapeutic effect, that is, within 3 days of the start of treatment, was reported in a higher percentage of patients treated with halobetasol propionate ointment than in those treated with diflucortolone valerate ointment (70% versus 59%). Adverse effects at the site of application were less frequently reported in patients belonging to the halobetasol propionate treatment group than in those treated with diflucortolone valerate ointment (3% versus 8%).