鉤吻素子膜控緩釋微丸的制備及其體內(nèi)外評(píng)價(jià)
發(fā)布時(shí)間：2018-07-28 14:03
【摘要】：鉤吻素子(koumine)為鉤吻中含量最高的一種生物堿單體，屬單萜吲哚類(lèi)生物堿。本課題組先期系列研究表明鉤吻素子具有高效低毒的抗慢性疼痛和抗類(lèi)風(fēng)濕性關(guān)節(jié)炎作用，提示鉤吻素子具有創(chuàng)制新型藥物的重大潛能。若將鉤吻素子制成普通口服制劑，則存在血藥濃度波動(dòng)大，服藥次數(shù)多的缺陷。為方便今后鉤吻素子的臨床應(yīng)用，可通過(guò)緩釋劑型減少給藥次數(shù)，降低服藥后血藥濃度的波動(dòng)，提高患者順應(yīng)性。本文擬通過(guò)調(diào)節(jié)Surelease包衣增重等因素以及包衣工藝的優(yōu)化以獲得體外釋藥12h的鉤吻素子膜控緩釋微丸的最佳制備工藝；采用影響因素試驗(yàn)和加速試驗(yàn)初步考察鉤吻素子緩釋微丸膠囊的穩(wěn)定性；以自制鉤吻素子普通片為參比制劑，測(cè)定鉤吻素子緩釋微丸膠囊比格犬單次口服給藥后血藥濃度-時(shí)間曲線，對(duì)其體內(nèi)釋藥特性進(jìn)行評(píng)價(jià)。 主要研究?jī)?nèi)容如下：1.鉤吻素子膜控緩釋微丸的制備 采用液相層積法制備鉤吻素子載藥微丸、底噴流化床法制備鉤吻素子膜控緩釋微丸。以微丸的收率、圓整度為指標(biāo)，采用正交試驗(yàn)優(yōu)化流化床上藥和包衣的工藝參數(shù)。上藥工藝參數(shù)優(yōu)化結(jié)果為噴液流速為35r/min、鼓風(fēng)頻率為21HZ、霧化壓力為0.03Mpa；包衣工藝參數(shù)優(yōu)化結(jié)果為噴液流速為45r/min、鼓風(fēng)頻率為19HZ、霧化壓力為0.05Mpa時(shí)，緩釋微丸制備效果良好。 以微丸的收率、圓整度和鉤吻素子體外釋放速率為評(píng)價(jià)指標(biāo)，采用單因素考察試驗(yàn)優(yōu)化篩選鉤吻素子膜控緩釋微丸處方。結(jié)果表明，羥丙甲基纖維素（HPMC）（5cps）作為黏合劑且濃度為15g/L時(shí)緩釋微丸收率提高，圓整度好；緩釋微丸的釋放速率隨著處方中包衣材料蘇麗絲（Surelease）的增加而減慢，包衣增重30%時(shí)，12h內(nèi)鉤吻素子釋放良好；緩釋微丸的釋放速率隨著隔離層HPMC（5cps）的增加而減慢，HPMC（5cps）用量為1%時(shí)，鉤吻素子12h內(nèi)釋放平穩(wěn)。綜上，單因素考察結(jié)果篩選優(yōu)化的處方如下： 緩釋微丸處方質(zhì)量（mg） 空白蔗糖丸芯10000 鉤吻素子100 HPMC300 Surelease300鉤吻素子膜控緩釋微丸含藥量為0.67%，處方工藝重現(xiàn)性和鉤吻素子釋放均一性均良好。 綜上提示，，制備的鉤吻素子膜控緩釋微丸，工藝重現(xiàn)性和釋放均一性良好，其在12h內(nèi)體外釋藥穩(wěn)定、緩慢、完全。2.鉤吻素子緩釋微丸膠囊的初步穩(wěn)定性考察 取300mg上述緩釋微丸填裝3號(hào)膠囊，得鉤吻素子緩釋微丸膠囊，規(guī)格為2mg/粒，初步考察鉤吻素子緩釋微丸膠囊的穩(wěn)定性。影響因素試驗(yàn)結(jié)果表明，鉤吻素子緩釋微丸膠囊在60℃條件下放置10天，或在相對(duì)濕度為90%中室溫放置10天，或在光照條件4000LX下放置10天，體外釋放度發(fā)生明顯變化，提示該制劑穩(wěn)定性受高溫、高濕及光照等劇烈因素影響較大。在鉤吻素子緩釋微丸膠囊穩(wěn)定性影響因素試驗(yàn)的基礎(chǔ)上進(jìn)行加速試驗(yàn)，結(jié)果顯示，緩釋微丸在溫度為40℃，相對(duì)濕度為75%下放置6個(gè)月，制劑的外觀色澤、體外釋放度均無(wú)顯著變化。這為鉤吻素子緩釋微丸膠囊貯存條件設(shè)立提供實(shí)驗(yàn)依據(jù)。3.鉤吻素子緩釋微丸膠囊在比格犬體內(nèi)的釋藥特性評(píng)價(jià) 本部分建立了比格犬鉤吻素子血藥濃度LC-MS/MS測(cè)定方法。以自制鉤吻素子普通片為參比制劑，LC-MS/MS測(cè)定鉤吻素子緩釋微丸膠囊比格犬單次口服給藥后血藥濃度-時(shí)間曲線，評(píng)價(jià)其在比格犬體內(nèi)的釋藥特性。結(jié)果表明，鉤吻素子緩釋微丸膠囊與其普通片生物等效，但未有顯著的緩釋效果，提示本膜控緩釋微丸制備及其體內(nèi)釋放特性評(píng)價(jià)有待于優(yōu)化。本研究為后續(xù)的鉤吻素子膜控緩釋微丸優(yōu)化制備提供參考。
[Abstract]:Koumine is the highest content of the alkaloid, which belongs to the monoterpene indole alkaloid. The first series of studies in this group show that the hychoidin has the effect of high efficiency and low toxicity against chronic pain and anti rheumatoid arthritis. It suggests that the hychoidin has the great potential to create new drugs. In order to facilitate the clinical application of the hychornus hychornus, it can reduce the number of drug delivery, reduce the fluctuation of blood drug concentration after taking the medicine, and improve the compliance of the patients. This paper aims to adjust the weight gain of Surelease coating, as well as the optimization of coating technology. The optimum preparation process of the in vitro release of 12h was obtained. The stability of the capsule of the sustained release pellet of the hychornin was preliminarily investigated by the influence factor test and the accelerated test. The concentration of the blood drug concentration after the single oral administration of the slow-release pellet capsule Beagle was measured by the self-made common tablet of the hychornin as the reference preparation. The time curve was used to evaluate the drug release characteristics in the body.
The main research contents are as follows: 1. preparation of the film controlled release pellets
The liquid phase stratification method was used to prepare the pellets of the hychornus hychorchus, and the bottom jet fluidized bed method was used to prepare the membrane controlled release pellets of the hychornus hychornus. With the yield of the pellets and the roundness as the index, the orthogonal test was used to optimize the process parameters of the fluidized-bed coating and coating. The optimum result of the process parameters of the injection was 35r/min, the air blast frequency was 21HZ, and the atomization pressure For 0.03Mpa, the coating parameters optimization result is that the spraying liquid velocity is 45r/min, the blowing frequency is 19HZ, and the atomization pressure is 0.05Mpa. The sustained-release pellets have good preparation effect.
With the yield of pellets, the roundness and the release rate of hychornin in vitro as the evaluation index, the single factor investigation was used to optimize the formulation of the membrane controlled release pellets of the hychornus hychornus. The results showed that the yield of the sustained-release pellets was improved when the HPMC (5cps) was used as the adhesive and the concentration was 15g/L, and the release rate of the sustained release pellets was good. The rate was slowed down with the increase of the coating material, Surelease, and the release rate of 12h in the coating was 30%, and the release rate of the sustained-release pellets slowed down with the increase of HPMC (5cps) in the isolation layer. When the HPMC (5cps) dosage was 1%, the release of the 12h in the 12h was stable. As follows:
Prescription quality of sustained-release pellets (mg)
Blank sucrose pellet core 10000
Hycho 100
HPMC300
The drug content of Surelease300 was 0.67%, the reproducibility of the formulation and the uniformity of the release of the extract were good.
To sum up, the preparation of hychornin membrane controlled release pellets, the process reproducibility and release homogeneity are good. The release of the drug in 12h is stable and slow, and the preliminary stability of the complete.2. hychornin sustained-release pellet capsule
The 300mg capsule was filled with 3 capsule, and the sustained-release pellet capsule was obtained with the specification of 2mg/ particles. The stability of the capsule of the sustained release pellet of the hychioninus was preliminarily investigated. The experimental results showed that the capsules were placed for 10 days at 60, or at room temperature for 10 days in the relative humidity of 90%, or in the light strip. The release degree in vitro changed obviously for 10 days under 4000LX, suggesting that the stability of the preparation was greatly influenced by the intense factors such as high temperature, high humidity and light. The accelerated test was carried out on the basis of the influence factors of the stability of the sustained-release pellet capsule. The results showed that the sustained release pellets were at the temperature of 40, and the relative humidity was 75% under 6. There are no significant changes in the appearance and in vitro release of the preparation in vitro. This provides an experimental basis for the establishment of the storage conditions of the sustained release pellet capsule of the hychornus hychornus.3. in the evaluation of the drug release characteristics in the Beagle dog.
In this part, a method for the determination of the blood concentration of the hychornus hycho LC-MS/MS was established. With the homemade common tablet of the hychornin as the reference preparation, LC-MS/MS was used to determine the drug concentration time curve of the single oral administration of the slow-release pellet capsule, and the drug release characteristics were evaluated in the beagle dog. The results showed that the sustained release pellets of the hychornin were released. The capsule is bioequivalent with its common tablets, but there is no significant release effect. It suggests that the preparation of the membrane controlled release pellets and the evaluation of the release characteristics in the body need to be optimized. This study provides a reference for the subsequent optimization of the membrane controlled release pellets of the hychonnus.
【學(xué)位授予單位】：福建醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R943;R96
本文編號(hào)：2150443
[Abstract]:Koumine is the highest content of the alkaloid, which belongs to the monoterpene indole alkaloid. The first series of studies in this group show that the hychoidin has the effect of high efficiency and low toxicity against chronic pain and anti rheumatoid arthritis. It suggests that the hychoidin has the great potential to create new drugs. In order to facilitate the clinical application of the hychornus hychornus, it can reduce the number of drug delivery, reduce the fluctuation of blood drug concentration after taking the medicine, and improve the compliance of the patients. This paper aims to adjust the weight gain of Surelease coating, as well as the optimization of coating technology. The optimum preparation process of the in vitro release of 12h was obtained. The stability of the capsule of the sustained release pellet of the hychornin was preliminarily investigated by the influence factor test and the accelerated test. The concentration of the blood drug concentration after the single oral administration of the slow-release pellet capsule Beagle was measured by the self-made common tablet of the hychornin as the reference preparation. The time curve was used to evaluate the drug release characteristics in the body.
The main research contents are as follows: 1. preparation of the film controlled release pellets
The liquid phase stratification method was used to prepare the pellets of the hychornus hychorchus, and the bottom jet fluidized bed method was used to prepare the membrane controlled release pellets of the hychornus hychornus. With the yield of the pellets and the roundness as the index, the orthogonal test was used to optimize the process parameters of the fluidized-bed coating and coating. The optimum result of the process parameters of the injection was 35r/min, the air blast frequency was 21HZ, and the atomization pressure For 0.03Mpa, the coating parameters optimization result is that the spraying liquid velocity is 45r/min, the blowing frequency is 19HZ, and the atomization pressure is 0.05Mpa. The sustained-release pellets have good preparation effect.
With the yield of pellets, the roundness and the release rate of hychornin in vitro as the evaluation index, the single factor investigation was used to optimize the formulation of the membrane controlled release pellets of the hychornus hychornus. The results showed that the yield of the sustained-release pellets was improved when the HPMC (5cps) was used as the adhesive and the concentration was 15g/L, and the release rate of the sustained release pellets was good. The rate was slowed down with the increase of the coating material, Surelease, and the release rate of 12h in the coating was 30%, and the release rate of the sustained-release pellets slowed down with the increase of HPMC (5cps) in the isolation layer. When the HPMC (5cps) dosage was 1%, the release of the 12h in the 12h was stable. As follows:
Prescription quality of sustained-release pellets (mg)
Blank sucrose pellet core 10000
Hycho 100
HPMC300
The drug content of Surelease300 was 0.67%, the reproducibility of the formulation and the uniformity of the release of the extract were good.
To sum up, the preparation of hychornin membrane controlled release pellets, the process reproducibility and release homogeneity are good. The release of the drug in 12h is stable and slow, and the preliminary stability of the complete.2. hychornin sustained-release pellet capsule
The 300mg capsule was filled with 3 capsule, and the sustained-release pellet capsule was obtained with the specification of 2mg/ particles. The stability of the capsule of the sustained release pellet of the hychioninus was preliminarily investigated. The experimental results showed that the capsules were placed for 10 days at 60, or at room temperature for 10 days in the relative humidity of 90%, or in the light strip. The release degree in vitro changed obviously for 10 days under 4000LX, suggesting that the stability of the preparation was greatly influenced by the intense factors such as high temperature, high humidity and light. The accelerated test was carried out on the basis of the influence factors of the stability of the sustained-release pellet capsule. The results showed that the sustained release pellets were at the temperature of 40, and the relative humidity was 75% under 6. There are no significant changes in the appearance and in vitro release of the preparation in vitro. This provides an experimental basis for the establishment of the storage conditions of the sustained release pellet capsule of the hychornus hychornus.3. in the evaluation of the drug release characteristics in the Beagle dog.
In this part, a method for the determination of the blood concentration of the hychornus hycho LC-MS/MS was established. With the homemade common tablet of the hychornin as the reference preparation, LC-MS/MS was used to determine the drug concentration time curve of the single oral administration of the slow-release pellet capsule, and the drug release characteristics were evaluated in the beagle dog. The results showed that the sustained release pellets of the hychornin were released. The capsule is bioequivalent with its common tablets, but there is no significant release effect. It suggests that the preparation of the membrane controlled release pellets and the evaluation of the release characteristics in the body need to be optimized. This study provides a reference for the subsequent optimization of the membrane controlled release pellets of the hychonnus.
【學(xué)位授予單位】：福建醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R943;R96
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