病棟配置された処置用の

やクリーム剤に対して，これまでに管理方法や微生物汚染の実態を複数施設で調査した報告はない．そこで本研究では，長崎県病院薬剤師会感染制御ワーキンググループの会員施設で協力が得られた3施設を対象に，病棟配置された処置用のやクリーム剤の衛生管理に関する聞き取り調査および微生物汚染の実態調査を行った．さらに，病棟配置された処置用のやクリーム剤の開封後の使用期限について検討する目的で，基剤の異なる代表的なやクリーム剤に手指の常在微生物を塗布する評価法を用いて，微生物汚染までの期間を調査した．その結果，3施設いずれにおいてもやクリーム剤の衛生管理マニュアルは整備されていなかった．また，微生物汚染の実態調査では，3施設のやクリーム剤128個全てで微生物汚染は認められなかった．さらに，実験による評価では，基剤の違いや防腐剤の有無に関わらず，6か月間にわたりやクリーム剤で微生物汚染は認められなかった．よって，処置用のやクリーム剤は直接素手で採取しないなどの衛生管理に注意を払えば，開封後6か月間まで使用可能であることが示唆された．

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Topical retinoids are very important in acne treatments. Clinical experience has shown that adapalene, a new topical retinoid, has a superior cutaneous safety profile. In the guidelines of care for acne vulgaris management of our country, the combinations with adapalene gel and topical antibiotics (e.g., clindamycin nadifloxacin) are an effective acne treatment, and these combination treatments are ranked as a recommendation A. For the purpose of improvement of compliance, the mixing of ointments and/or creams is common practice. However, many of the admixtures of ointments and/or creams may lack pharmaceutical stability.

To assess the pharmaceutical stability of these mixtures after mixing, we attempted to investigate the change in the appearance and contents of adapalene, clindamycin and nadifloxacin in admixtures. As a result, no lowering of the content of adapalene was noted in any admixtute. After admixtures of adapalene and clindamycin or nadifloxacin, the contents of clindamycin or nadifloxacin were constant.

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The linear slope obtained from plotting the cumulative amount of drug released against the square root of time (Q-√t plot) has generally been used as an index of in vitro drug release from topical semisolid dosage forms. This parameter is also designated as an index for in vitro drug release in SUPAC-SS. An in vitro drug release test was performed with liquid droplet dispersed ointments consisting of white petrolatum (Vaseline), liquid paraffin, N-methylpyrrolidone (NMP, local phase), and mometasone furoate (MF) as a drug. The linearity of the Q-√t plot was not realized when the NMP concentration was incorporated more than 8%: An initial burst release of MF was observed, depending on the amount of NMP incorporated, followed by a straight line. This is because NMP has relatively high compatibility to the continuous phase of the white petrolatum base by which the effective drug concentration in the continuous phase increases. For practical purposes to verify the equivalence of two formulations, the in vitro release profiles could be simply compared statistically. When the test is used for comparison of the efficacy of formulations, the Q_t (the cumulative amount of drug released for time t) seems to be a suitable index that displays good correlation with in vivo responses.

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To demonstrate the usefulness of an in vitro drug release test from ointments as a simple screening method, the correlation between the in vitro drug release and the percutaneous absorption of the drug on rats and vasoconstrictor response in human volunteers was investigated. The in vitro drug release test was performed by using a Franz-type diffusion cell, and the amount of drug released at 60 min (Q₆₀) was employed for an index of the in vitro drug release test. The amount of drug in the rat skin at 24 h after application was employed for an index of in vivo percutaneous absorption test. Good correlation was observed between Q₆₀ and the amount of drug in the skin. Furthermore, the correlation between the in vitro drug release test and the vasoconstrictor response was also investigated. Good correlation was observed between Q₆₀ and the vasoconstrictor score. The results demonstrated the usefulness of an in vitro drug release test in predicting the efficacy of ointments. Moreover, good correlation was observed between drug concentration in the bleeding liquid and Q₆₀, or drug in the skin. Therefore, it is most likely that drug concentration in the bleeding liquid is an important parameter of percutaneous absorption.

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The dilution or mixing of commercially available corticosteroid formulations is a common practice in our country. We therefore evaluated the pharmaceutical stability and clinical effects of such admixtures.
The quantities of the aqueuos phase separated by centrifugation employed as an index of the destructution of an emulsion after mixing were measured, with a high value being obtained with the admixtures of corticosteroid ointments and o/w-type moisuturizing creams. In contrast, the admixtures utilizing w/o-type creams were found to be physically stable for a month.
To evaluate the preservative efficacy, we attempted to investigate the microbial contamination of these admixtures with Antebete^® ointment. For all aqueous phases separated by centrifugation stored and at room either temperature or in a refrigerator for one week, and each mixture was touched by a human finger twice a day. As a result, it was impossible to prevent microbial contamination in these admixtures.
The permeability of corticosteroids using hairless mice skin in the admixture of Lidomex^® ointment, Antebete^® ointment, and Myser^® ointment and moisturizing creams through the skin was 5-, 2-, 3-fold greater, respectively, than that from each corticosteroid ointment alone. The extent of the stability of the emulsion after mixing was related to the permeability.
The vasoconstrictor activity of humans in the admixture of Lidomex^® ointment and moisturizing creams, urea or heparinoid, was about 2 fold greater than that from the corticosteroid ointments alone, and this difference was significant.
When the concentration of corticosteroid was reduced by half using an admixture of corticosteroid ointment with vaseline or moisturizing creams, no difference was observed in the systemic side effects between the corticosteroid ointment alone and the admixtures.

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歯周疾患用の適用局所における為害作用を推測する目的で, これらのをヒト歯肉由来培養ケラチノサイトに作用させ, その細胞毒性をニュートラルレッド・アッセイ法で定量的に調べた。歯周ポケット注入用の細胞毒性は, ヒノポロン®≫テトラ・コーチゾン軟膏>ペリオクリン歯科用軟膏®≒テラ・コートリル®軟膏であり, ヒノポロンの細胞毒性は, テトラ・コーチゾン軟膏の約1,100倍, ペリオクリン歯科用軟膏やテラ・コートリル軟膏の少なくとも1,300倍強かった。また, 塗布用の細胞毒性は, デキサルチン軟膏口腔用)®>デスパコーワ®>テトラサイクリン・プレステロン歯科用軟膏®≒プレステロン®「歯科用軟膏」≒口腔用ケナログ®≒歯科用 (口腔用) アフタゾロン®であった。デキサルチン軟膏 (口腔用) およびデスパコーワの細胞毒性は, 他の塗布用より少なくとも3倍以上強かった。このように各種歯周疾患用のヒト歯肉由来培養ケラチノサイトに対する毒性がランク付けされ, その強弱が量的に比較できるようになった。これらの結果は, 歯肉に対してより為害作用の少ないの選択や適用方法を考慮したり, 新規製剤の毒性を評価する際, 役立つものと思われる。

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To ensure accurate application/dosing for patients, one fingertip unit press-out dispensing of ointments or creams is effective for knowing the exact quantity dispensed. Further, the press-out for a 1-yen diameter unit of topically applied liquid is also effective for accurate use with respect to quantity. To confirm the suitable topical usage for patients, we used multivariate analysis to investigate the relationship between the physicochemical properties of many commercial products (ointments, creams, and lotions) contained in tubes or bottles, and the exact quantity pressed out from these containers. We observed that not only the diameter of the tube opening but also the specific physicochemical properties of the products inside the tubes/bottles were closely related to the exact quantity pressed out. It is accordingly considered that for topical formulations, tube/bottle design based on the physicochemical properties of the contents is important for ensuring their accurate use.

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We investigated whether the component in cataplasm transmitted into hemorrhoid ointment in the combined storage of hemorrhoid ointment and non-steroidal anti-inflammatory drugs (NSAIDs) cataplasm. The NSAIDs cataplasm was used as a commercially available methyl salicylate (MS reishippu “TAIHO”, MS cataplasm) and indomethacin (Catlep^®, IMC cataplasm) cataplasm. In addition, the hemorrhoid ointment was in a polyethylene container with (Neriproct^® ointment, DFV-L ointment) or without aluminum laminate (Posterisan^® forte, HC ointment). As for the methyl salicylate, 5.68 mg / pieces in HC ointment were detected at 40 weeks of combined storage with MS cataplasm. The methyl salicylate concentration in DFV-L ointment was lower than that in HC ointment under the same conditions. On the other hand, no contamination of indomethacin in HC and DFV-L ointment was observed in the combined storage with IMC cataplasm. These results show that the methyl salicylate in cataplasm passed the polyethylene container, and provide significant information on the risk of contamination by the combined storage of cataplasm and hemorrhoid ointment.

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Incorporation of corticosteroids into the ointment bases and uniformity of homogenous ointments were microscopically observed. Of 32 commercial ointments, separating of steroid crystals was found in 18 products, not found in 5 products, and judgment was difficult in 9 products. It can be concluded that simple microscopic observations are considerably useful to pass judgment on pharmaceutical technology.

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We warmed and liquefied 24 kinds of steroid and non-steroid ointments dispensed in tubes used at our hospital, and then chilled the tubes to be rehardened in order to study basis homogeneity throughout the ointment. The results showed that distribusion of the basis stayed within acceptable ranges in 4 out of 19 of the steroid ointments and 2 out of 5 of the non-steroid ointments, but the remaining 18 ointments had problems with consistency, as the liquefied basis tended to pool at a specific part of the tube. We also conducted a number of studies on the ointment base with interesting results.

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日本人尋常性乾癬患者を対象に，カルシポトリオール/ベタメタゾンジプロピオン酸エステル（Cal/BDP）配合フォーム剤と Cal/BDP

の有効性と安全性を比較検討した。尋常性乾癬患者（182 例）を無作為に Cal/BDP フォーム剤群（87 例）と Cal/BDP 群（95 例）に割り付け，体部標的病変に 1 日 1 回最長 4 週間塗布し，ベースライン時からの乾癬症状の改善度で有効性を評価した。また，両治験薬は標的病変以外の病変部にも実施可能な範囲で塗布した。主要評価項目である 4 週時の標的病変の全般改善度は，Cal/BDP フォーム剤群 98.9％（86/87 例），Cal/BDP 群 93.7％（89/95 例）で，両群間に統計学的な有意差は認められなかった。1 週時および 2 週時の全般改善度は Cal/BDP フォーム剤群では Cal/BDP 群に比べて有意に高く，臨床症状の総スコア減少や略治に至った被験者割合も Cal/BDP フォーム剤群では Cal/BDP 群に比べて早期から高かった。治験薬塗布に要した時間が以前の外用薬と比べて「短縮」したと評価した被験者は，Cal/BDP フォーム剤群（39.5％）では Cal/BDP 群（4.3％）に比べて有意に増加（オッズ比：7.29，p＜0.001）していた。副作用が Cal/BDP フォーム剤群の 3 例で認められたが，いずれも軽度であった。本試験で Cal/BDP フォーム剤は，臨床症状の速やかな改善，高い有効性，良好な忍容性を示し，さらに，塗布時間を短縮し，塗布し易い剤形であることを示した。以上により，Cal/BDP フォーム剤は尋常性乾癬外用治療の中心になると期待される。

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HBP 0.1%及び0.5%含有クリーム, 及びをラットに体重100 g当たり150 mg 1ヵ月間経皮投与 (背部皮膚塗布) して, その亜急性毒性と回復性を検索し, 以下の成績を得た。(1) 塗布濃度に応じた生長抑制と塗布部皮膚の被毛伸長の抑制が観察されたが, 死亡例は認められなかった。(2) 摂食量はやや減少し, 摂水量に著変は認められなかった。(3) 血液学的検査ではリンパ球数の減少による総白血球数の減少, 並びに赤血球数, 血色素量, ヘマトクリット値の増加が認められた。(4) 血液生化学的検査において比較的用量一反応関係の認められた変化は, 総コレステロール量の増加とトリグリセライド量の減少のみであった。(5) 尿検査, 眼底検査に著変は認められなかった。(6) 臓器では副腎, 脾, 胸腺, 腸間膜リンパ節に重量減少が認められ, また骨髄及び皮膚とともに退行性の組織像が観察された。(7) HBPのクリーム及びによって生ずる変化は雌より雄, よりクリーム剤に強く認められた。しかし, これらの変化はいずれも corticosteroidsに共通して認められる変化と一致し, HBPに特異的な変化は観察されなかった。また, 休薬により回復することから可逆的なものと考えられた。(研究期間:昭和52年6月～昭和52年11月)

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Commercially available corticosteroid ointments and creams were investigated in terms of physical evaluation. In 33 products of commercial ointments and about 50 of creams, the presence of particles or crystals of corticosteroid and the occurance of recrystallization in these products were studied by polarizing microscopic method. In addition, the measurement of yield of these products was made with the spread meter. Results were as follows:
1) Crystals of corticosteroid were observed in 25 of 33 ointment products and in 30 out of 50 cream products.
2) Diameters of corticosteroid particles existed in ointment products, ranging from 100μm to 200 kem, were smaller rhan those in cream products.
3) 73% of ointment products showed yield value ranging from 4000 to 10000 dyne/ cm², while 70% of cream products showed the value below 4000 dyne/ cm².

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Trend of the labeling of the drug code on ethical ointments in tube (including creams and jellies) was investigated by means of questionnaires. Drug codes were indicated at 37.5% of 456 preparations surveyed. While 69.9% of the companies selling or manufacturing ointment products did not put the drug code on any of their preparations, 15.1% of the companies labeled the drug code on all of their products. The larger the number of products per company became, the higher the rate of preparations wearing the drug code was. Drug codes were printed on labels in 65.9% of the preparations, and on the tube in 32.9%. More than 37% of the companies surveyed had no plan to use the drug code for their ointment products.
It is generally recognized that the drug code is useful to identify such preparations as tablets and capsules. Therefore, wider labeling of the code on ointments is desired.

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Increment in amount of medicines prepared in hospital pharmacy was analyzed statistically on the basis of monthly summation of the amount. The number and amount of external liquid preparations, number of ointment preparations and times of regenerations of ion-exchange resin showed close relationship with the month number. The number and amount of oral liquid preparations, number of powder preparations, that of ophthalmic solutions or nasal drops and of clinical reagents exhibited reciprocal relationships with the month number. When the residuals were determined by Run test and Durbin-Watson ratio after significant correlations were estimated with straight lines, the number of oral liquid preparations, number and amount of external liquid preparations, number of ophthalmic solutions or nasal drops, that of ointments and times of regenerations of ionexchange resin were not distributed along the straight lines.

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