【摘要】：目的：本文以質(zhì)量源于設(shè)計(jì)（Quality by Design，QbD）理念為基礎(chǔ)，進(jìn)行鹽酸二甲雙胍緩釋片的開發(fā)，要求制備的二甲雙胍緩釋片和指定的參比制劑釋放曲線相似，并具有良好的穩(wěn)定性。旨在探討QbD在藥物開發(fā)中的實(shí)際應(yīng)用，同時(shí)建立二甲雙胍緩釋片的制備技術(shù)，為深度開發(fā)二甲雙胍制劑提供技術(shù)儲備。 方法：（1）首先確認(rèn)了產(chǎn)品的質(zhì)量目標(biāo)（Quality Target Product Profile，QTPP），在此基礎(chǔ)上，從用藥的安全性和有效性出發(fā)，分析、確認(rèn)產(chǎn)品的關(guān)鍵質(zhì)量屬性（CriticalQuality Attributes，CQAs），對本課題而言，我們關(guān)注的CQAs是鹽酸二甲雙胍的釋放度和含量。（2）利用風(fēng)險(xiǎn)評估的方法，結(jié)合CQAs，分析、擬定處方篩選中的高風(fēng)險(xiǎn)因素，通過一項(xiàng)含有3個(gè)中心點(diǎn)的22全因子實(shí)驗(yàn)設(shè)計(jì)（DOE），確認(rèn)關(guān)鍵物料屬性（CMAs）對CQAs的影響程度并制定控制策略，通過嚴(yán)格控制物料配比，使物料因素可能導(dǎo)致的風(fēng)險(xiǎn)降低。（3）利用風(fēng)險(xiǎn)評估的方法，結(jié)合CQAs，分析、擬定了工藝開發(fā)中的高風(fēng)險(xiǎn)因素，通過一項(xiàng)含有3個(gè)中心點(diǎn)的24-1部分因子實(shí)驗(yàn)，確認(rèn)關(guān)鍵工藝參數(shù)（CPPs），同時(shí)獲取關(guān)鍵工藝參數(shù)控制的設(shè)計(jì)空間，制定合適的控制空間，，將風(fēng)險(xiǎn)降低至可接受水平。（4）建立了鹽酸二甲雙胍緩釋片的釋放度檢測方法，以相似因子評價(jià)法比較制備的二甲雙胍緩釋片和參比制劑的釋放曲線相似性。（5）進(jìn)行了穩(wěn)定性試驗(yàn)，包括影響因素試驗(yàn)、加速試驗(yàn)、長期試驗(yàn)。（6）研究了制備的二甲雙胍緩釋片釋放機(jī)制。 結(jié)論：（1）處方篩選實(shí)驗(yàn)表明，殼聚糖和羥丙基甲基纖維素（HPMC）的比例是影響釋放度的關(guān)鍵因素，當(dāng)殼聚糖用量占?xì)ぞ厶呛虷PMC總量的5%時(shí)，可獲取最佳的相似因子f2，因此確定了最終處方。（2）工藝研究實(shí)驗(yàn)表明，制粒攪拌槳轉(zhuǎn)速、制粒時(shí)間以及片劑硬度是對釋放度產(chǎn)生顯著影響的關(guān)鍵工藝參數(shù)。在此基礎(chǔ)上，我們獲得了關(guān)鍵工藝參數(shù)的設(shè)計(jì)空間，并在此基礎(chǔ)上設(shè)置了控制空間：攪拌槳速度260-440rpm，制粒時(shí)間120-360s，片劑硬度90-118N。（3）在既定處方、工藝條件下生產(chǎn)的二甲雙胍緩釋片與參比制劑的釋放曲線具有較好的相似性。（4）既定的處方、工藝條件下制備的二甲雙胍緩釋片具有良好的穩(wěn)定性，加速和長期條件下6個(gè)月，藥物含量和釋放度沒有顯著變化。（5）本實(shí)驗(yàn)制備的二甲雙胍緩釋片藥物釋放機(jī)制為Fick’s擴(kuò)散。 結(jié)果：開發(fā)的鹽酸二甲雙胍緩釋片與參比制劑具有較好的釋放一致性，能夠達(dá)到預(yù)期的目標(biāo)，試驗(yàn)中所獲取的方程模型和制定的控制空間能夠較好地預(yù)測和控制產(chǎn)品質(zhì)量，表明以質(zhì)量源于設(shè)計(jì)（QbD）理念為基礎(chǔ)進(jìn)行的藥物開發(fā)，能夠高效地獲得預(yù)期結(jié)果，通過建立合理的控制空間來控制關(guān)鍵因素，能夠提高工藝的靈活性和穩(wěn)健性，保證穩(wěn)定的產(chǎn)品質(zhì)量。
[Abstract]:Aim: to develop metformin hydrochloride sustained-release tablets based on the concept of (Quality by Design,QbD. The release curve of metformin sustained-release tablets is similar to that of reference tablets and has good stability. To explore the practical application of QbD in drug development and to establish the preparation technology of metformin sustained-release tablets to provide technical reserve for the further development of metformin preparation. Methods: (1) the product quality target (Quality Target Product Profile,QTPP) was first confirmed. On this basis, the key quality attributes (CriticalQuality Attributes,CQAs) of the product were analyzed and confirmed from the safety and effectiveness of the drug. The CQAs we are concerned with is the release and content of metformin hydrochloride. (2) using the method of risk assessment and CQAs, analysis, we develop the high risk factors for prescription screening. Through a 22-factor experimental design with three center points, (DOE), is used to confirm the influence of (CMAs) on CQAs, and the control strategy is worked out, and the material ratio is strictly controlled. (3) using the method of risk assessment and CQAs, analysis, the high risk factors in process development are drawn up, and a 24-1 partial factor experiment with three central points is carried out. Confirm that the key process parameter (CPPs), simultaneously obtain the design space of the key process parameter control, make the appropriate control space, reduce the risk to the acceptable level. (4) establish the release rate detection method of metformin hydrochloride sustained-release tablets, The similarity of release curves between metformin sustained-release tablets and reference preparations was compared by similarity factor evaluation method. (5) Stability tests, including influence factor test, accelerated test, were carried out. (6) the release mechanism of metformin sustained-release tablets was studied. Conclusion: (1) the ratio of chitosan to hydroxypropyl methyl cellulose (HPMC) is the key factor affecting the release rate. The best similarity factor f _ 2 can be obtained when the amount of chitosan accounts for 5% of the total amount of chitosan and HPMC. Therefore, the final formulation was determined. (2) the experimental results showed that the speed of the agitator, the time of pelleting and the hardness of the tablet were the key technological parameters which had a significant effect on the release rate. On this basis, we obtained the design space of the key process parameters, and on this basis set up the control space: the speed of impeller 260-440 rpm, the granulation time 120-360s, the tablet hardness 90-118N. (3) in the prescribed prescription, The release curve of metformin sustained-release tablets was similar to that of reference preparations. (4) the prepared metformin sustained-release tablets had good stability. The drug content and release rate did not change significantly at 6 months after accelerated and long-term conditions. (5) the drug release mechanism of metformin sustained-release tablets prepared in this study was Fick's diffusion. Results: the developed metformin sustained-release tablets had good release consistency with the reference preparation and could achieve the expected goal. The equation model and control space obtained in the experiment could predict and control the quality of the product. The results show that the drug development based on the concept of (QbD) design can effectively obtain the expected results, control the key factors by establishing a reasonable control space, and improve the flexibility and robustness of the process. Ensure stable product quality.
【學(xué)位授予單位】：蘇州大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R943

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