Anti-Inflammatory Effect of Diclofenac-Sodium Ointment (Cream) in Topical Application
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ANTI-INFLAMMATORY EFFECT OF DICLOFENAC-SODIUM OINTMENT (CREAM) IN TOPICAL APPLICATION Kohei KYUKI, Tomohisa SHIBUYA, Kaito TSURUMI and Hajime FUJIMURA Department of Pharmacology, Gifu University School of Medicine, 40 Tsukasamachi, Gifu 500, Japan Accepted September 16, 1982 Abstract-This study was performed to develop a topical ointment of diclofenac-Na which has a potent anti-inflammatory activity by oral administration. At first, research was carried out on the ointment base which influences the external anti-inflammatory effect of the drug. Ointments of diclofenac-Na were prepared with three kinds of bases: lipophilic, emulsion (cream) and gel bases; and their anti-inflammatory effects were compared. The cream was found to have the most potent effect. Therefore, in the next experiment, an optimum concentration of diclofenac-Na in cream was determined comparing the anti-inflammatory effect among the cream preparations containing 0.5, 0.75, 1.0 and 1.5% of the drug. Obvious effects were observed with the cream containing 1.0% and 1.5% of the drug concentration, and there was no significant difference in the anti-inflammatory activities of these two concentrations. Based on these results, the cream preparation containing 1.0% of diclofenac-Na (DF cream) was adopted as the external ointment of the drug. The anti-inflammatory effect of this cream was compared with that of existing anti-inflammatory ointments, i.e., indomethacin gel (IM gel), bufexamac cream (BM cream) and mobilat ointment (ML ointment). DF cream produced obvious inhibition on increased vascular permeability and on acute edema and remarkable suppression of ultraviolet erythema. These activities of DF cream were similar to those of I M gel and more potent than those of BM cream and M L ointment. The inhibitory effect of DF cream on the proliferation of granulation tissue was almost equal to that of ML ointment and more distinguishable than that of IM gel and BM cream. In adjuvant arthritis, DF cream reduced the swelling ramarkably in the treated paw and slightly in the untreated paw. The anti-adjuvant activity of DF cream was equal to that of IM gel and more potent than that of BM cream and ML ointment. In pain to pressure stimulation, an analgesic effect was observed in the early stage of DF cream application, and its activity was slightly stronger than that of the other ointments. These results show that DF cream has an obvious anti-inflammatory effect as an external preparation, and the activity is comparable or superior to that of similar existing anti-inflammatory ointments. This cream may be considered as useful in the clinical field as a topical anti-inflammatory preparation. Various non-steroidal anti-inflammatory reactions. The efforts include development of drugs (NSAID) have been used clinically, new compounds and also preparational but use of these drugs is sometimes restricted improvement of existing drugs, i.e., change in due to side effects. Particularly, gastro the administration route to suppository, ar intestinal disorder is inevitable. Many efforts rangement in drug design such as a slow have been made to avoid these adverse release agent (1), and device of prodrug (2). Topical application is also included, though of DF cream the bioavailability of an external preparation DF creams which contained 0.5, 0.75, 1.0 had not been studied satisfactorily. Appli and 1.5% of diclofenac-Na were examined to cation of the drug on the diseased site or the establish the optimum concentration of the neighboring part is reasonable since drugs drug in the cream preparation. All the samples produce effects after they reach the affected used in the sections 1 and 2 were prepared by site. However, only steroids have been used as and offered to us by C I BA-G EI BY (Japan) the topical anti-inflammatory agent because Ltd. the actions of NSAI D are relatively mild, and 3. Existing NSAID ointments for comparative moreover, it has been thought that topical drugs application of NSAID scarcely influenced the The following materials available on the muscle or joint due to bad absorption from market were used as comparative drugs. 1) the normal skin. On the other hand, it has been Bufexamac cream (BM cream: Anderm revealed from a number of recent studies that cream, 5% bufexamac cream using emulsion NSAID are absorbed rather well from normal base o/w type, Lederle Japan). 2) Indo skin (3) and diffuse into subcutaneous soft methacin gel ointment (IM gel: Inteban tissue under the topically applied site (4). ointment, 1 % indomethacin gel using car Thus, it became desirable to use NSAID in boxyvinyl polymer base, Sumitomo Chemical topical preparation as well as in systemic Industry). 3) Mobilat ointment (ML oint ones, and ointments of some NSAID are on ment: Ointment containing 1.0% adrenal the market already. These situations stimu extract, 0.2% anti-thrombin heparin-like sub lated us to plan the development of a topical stance and 2.0% salicylic acid and using preparation for diclofenac-Na which pro hydrophilic base, Maruho Co., Ltd.). duces an excellent anti-inflammatory effect 4. Animals in systemic use. Basic investigations were Experiments were carried out in dd-strain made regarding the ointment base and mice, Wistar or Sprague-Dawley rats and optimun concentration, and 1 % diclofenac Hartley white guinea pigs. These animals Na cream was selected as the topical pre were fed and kept under controlled con paration. The anti-inflammatory effect of this ditions in an air-conditioned room (22±2°C) preparation was compared with that of after purchase from Kitayama Labes Co., Ltd; some existing NSAID ointments. and only healthy animals were used for the study. Body weight, sex and the numbers of Materials and Methods the used animals are described in the methods Materials section which follows. 1. Screening of the base for external diclo Methods fenac-Na ointment 1. Inhibition of increased vascular perme To select the most suitable base for the ability external ointment, the following three samples Each group consisted of 8 male Wistar rats were tested: 1) 1 % diclofenac-Na ointment weighing about 140 g. On these animals, using a lipophilic base (DF ointment in the three points were marked on the median line following description). 2) 1 % diclofenac-Na of the depilated dorsal skin, where 50 mg of ointment using an emulsion base (o/w type) the test ointment was rubbed carefully for 1 (DF cream). 3) 1% diclofenac-Na ointment min on a circular area with a 2 cm diameter using carboxyvinyl polymer (DF gel). with each point. The ointment was applied 2. Screening of the optimum concentration twice, 1 and 2 hr before a phlogogenic substance was given. As a phlogogenic was measured hourly for 5 hr. The edema rate substance, histamine (100 /eg/0.1 ml/site) was calculated from the initial volume. was intracutaneously injected at the center 3) Inhibition of croton oil-induced edema of the ointment-applied site. Immediately in the ear (5): Each group consisted of 10 after the injection, 2% pontamine sky blue male mice weighing about 23 g. Twenty mg solution was intraveneously injected in a of the test ointment was rubbed on the back volume of 0.2 ml/100 g. After 20 min, the rats of the right ear 30 min after 30 td of 4% were sacrificed, and the skin was stripped off. croton oil ether solution was dropped on the The blue-stained phlogogen-injected site was surface of that ear. The mice were sacrificed traced from the inner site for measurement of 4 hr after the dropping of croton oil, and the the area using planimeter. bilateral ears were cut off. Central part of the 2. Inhibition of edema ear was punched out using a puncher with a 1) Inhibition of carrageenin-induced skin 9 mm diameter and weighted. The edema rate edema (Punch method): Each group con of the right ear was calculated in comparison sisted of 7 male Wistar rats weighing about with the weight of the untreated left ear. 140 g. The animals were depilated of the 3. Inhibition of ultraviolet erythema dorsal hair, where two points were marked Each group consisted of 5 male guinea pigs symmetrically on both sides of the median weighing 300-350 g. The animals were line. On the two points of one side, 50 mg depilated of the dorso-lateral hair; and 24 hr of the test ointment was carefully rubbed for later, an adhesive plaster with two small 1 min at 1 and 2 hr before intracutaneous holes was placed on the depilated flank injection of carrageenin (1%, 0.1 ml/site). where ultraviolet irradiation was applied for On the two points of the other side, only 40 sec from a distance of 20 cm (High physiological saline solution (0.1 ml/site) pressure mercury lamp by Wako Electric was injected without pretreatment. After Physicochemical Industry). Immediately after 2 hr, the rats were sacrificed, and the skin UV-application, 100 mg of the test ointment was stripped off. A 16 mm circle of skin from was rubbed carefully on the UV-applied site the injected site was removed using a for 1 min. The effect was evaluated by hourly puncher for leather, and the weight of the macroscopic observations for 5 hr and punched-skin was measured. The ratio of graded as follows: Score 3=a full circle of weight gain at the phlogogen-injected site definite redness of any intensity, score 2=an to the saline-treated site (edema rate) was area of erythema not clearly defined as a calculated. circle, score 1 =an erythema barely observed 2) Inhibition of carrageenin-induced paw and score 0=no evident erythema.