本文選題：非洛地平 + 脈沖給藥系統(tǒng)��； 參考：《遼寧醫(yī)學院》2014年碩士論文

【摘要】：目的 設計非洛地平脈沖釋放片，通過均勻設計優(yōu)化藥物處方，使自制脈沖片能在預設時間爆破，并能有效快速釋放藥物。對自制脈沖片進行初步質量評價和穩(wěn)定性考察。以大耳白兔為實驗對象，建立非洛地平體內血藥濃度測定方法，研究自制非洛地平爆破型脈沖釋放片體內藥動學和生物利用度。 方法 本研究在固定包衣工藝參數(shù)的條件下，對脈沖片釋藥行為有影響的因素進行考察如：片芯組成，包衣膜處方、體外釋藥條件、輔料等；篩選對非洛地平爆破型脈沖釋放片釋藥行為有影響的膨脹劑、致孔劑、增塑劑等輔料。根據(jù)脈沖片藥物釋放10%所需時間為指標判定不同因素對脈沖片釋放藥物的影響。優(yōu)化處方工藝采用均勻設計法優(yōu)化。對自制片劑進行釋放均一性、含量及均勻度進行測定，有關物質進行檢查；考察樣品穩(wěn)定性。以市售非洛地平緩釋片為參比制劑，自制脈沖片為受試制劑。參考有關文獻及實踐經驗，建立非洛地平血藥濃度測定方法，6只健康日本大耳白兔采用兩制劑、雙周期交叉設計單次空腹服用自制非洛地平脈沖片（規(guī)格：含藥量5mg）和市售非洛地平緩釋片（規(guī)格：含藥量5mg）；采用HPLC法測定各時間點血藥濃度，繪制體內藥時曲線；根據(jù)各時間點血藥濃度計算相關藥動學參數(shù)。 結果 經過單因素考察及均勻設計優(yōu)化得到最佳處方，片芯中膨脹劑為低取代羥丙基纖維素(L-HPC),含量占片芯重10%；包衣液中增塑劑為鄰苯二甲酸二丁酯(DBP)，含量為8.5%(占EC的量)，致孔劑為PEG6000，含量為7%(占EC的量)；通過體外釋放試驗，制備的脈沖片，時滯為(4.1±0.2) h，在時滯后(1.5±0.2) h內，藥物釋放累積釋藥達到90%以上。大耳白兔口服給藥后，測定其血藥濃度，計算藥動學參數(shù)。參比制劑與受試制劑主要藥動學參數(shù)分別為：Tmax(3.50±0.547) h，(5.667±0.516) h；Cmax(51.23±5.12) ng·mL-1,（67.865±3.810）ng·mL-1；AUC0~48(351.161±42.052) ng·h·mL-1,(382.453±31.82)ng·h·mL-1;AUC0-∞(370.051±44.082)ng·h·mL-1，(409.524±18.024) ng·h·mL-1，相對生物利用度為(110.35±10.14)%，統(tǒng)計矩計算兩種制劑平均滯留時間MRT(15.307±1.43)h與(13.488±1.63) h。 結論 非洛地平爆破型脈沖片制備工藝簡單，，優(yōu)化后處方達到4h爆破設計要求，并具有良好的釋藥行為。自制樣品釋放均一性良好，含量及均勻度、有關物質檢查符合藥典規(guī)定。自制脈沖釋放片與參比制劑的藥動學參數(shù)Cmax、Tmax、AUC0~48經生物等效性分析均存在顯著性差異(P＜0.05)。本實驗制備的脈沖片Tmax顯著延遲，Cmax顯著升高,根據(jù)體內藥動學實驗結果，初步判斷自制非洛地平爆破型脈沖釋放片，在體內延遲釋藥，具有明顯的時滯及脈沖釋藥特點，有效提高非洛地平生物利用度，達到了實驗預期的設計目的，為臨床治療與研究高血壓給藥方案提供有效參考。
[Abstract]:Purpose Felodipine pulse release tablets were designed and optimized by uniform design so that the self-made pulse tablets could burst at a preset time and release drugs quickly and effectively. The quality evaluation and stability of the self-made pulsating tablets were studied. A method for the determination of plasma concentration of felodipine in rabbits was established. The pharmacokinetics and bioavailability of felodipine explosive pulse release tablets were studied. Method In this study, under the condition of fixed coating process parameters, the factors affecting the drug release behavior of pulsed tablets were investigated, such as: core composition, coating film prescription, release conditions in vitro, excipients and so on; The excipients, pore-forming agents, plasticizers and other excipients which have influence on the release behavior of felodipine explosive pulse release tablets are screened. The effect of different factors on the release of pulse tablets was determined according to the 10% time required for drug release in pulsatile tablets. The optimum prescription process was optimized by uniform design method. The release uniformity, content and evenness of the tablets were determined, the related substances were examined and the stability of the samples was investigated. Felodipine sustained-release tablets were used as reference preparation and self-made pulsating tablets as test preparation. With reference to relevant literature and practical experience, a method for the determination of blood concentration of felodipine was established in 6 healthy Japanese white rabbits with two preparations. Double cycle cross design, single fasting administration of felodipine pulse tablets (specification: 5 mg) and commercial felodipine sustained-release tablets (specification: containing 5 mg), determination of blood concentration at different time points by HPLC method, drawing in vivo drug time curve; The related pharmacokinetic parameters were calculated according to the blood concentration at each time point. Result The best prescription was obtained by single factor investigation and uniform design optimization. The swelling agent in the core is low substituted hydroxypropyl cellulose L-HPCO, which accounts for 10% of the core weight, and the plasticizer in the coating solution is dibutyl phthalate (DBP) with a content of 8.5% (the amount of EC, the pore-forming agent is PEG6000, and the content is 7% of EC; through in vitro release test, The time delay was 4.1 鹵0.2 h, and the cumulative drug release was over 90% within 1.5 鹵0.2) h. Blood concentration and pharmacokinetic parameters were measured after oral administration in rabbits. 鍙傛瘮鍒跺墏涓庡彈璇曞埗鍓備富瑕佽嵂鍔ㄥ鍙傛暟鍒嗗埆涓

本文編號：1916651