本文選題：脈沖給藥系統(tǒng)　切入點(diǎn)：釋藥時(shí)滯　出處：《河南大學(xué)》2016年碩士論文

【摘要】：脈沖給藥系統(tǒng)(Pulsatile delivery system)又名擇時(shí)釋藥系統(tǒng),可依據(jù)人體時(shí)辰節(jié)律特征以及疾病發(fā)作的時(shí)間規(guī)律,實(shí)現(xiàn)定時(shí)或定位釋放藥物。脈沖制劑不同于常見(jiàn)的緩控釋制劑,并不能維持恒定的血藥濃度,而是經(jīng)服用后首先經(jīng)歷一個(gè)預(yù)定的釋藥時(shí)滯(Lag Time,TLag),而后于疾病發(fā)作的特定時(shí)間或者于特定部位即刻釋放藥物以達(dá)到所需血藥濃度及組織中的藥物濃度,因此可大大減輕藥物不良反應(yīng)、機(jī)體耐受性,提高患者的用藥依從性。多微粒給藥系統(tǒng)相比于單一單元型制劑,具有優(yōu)良的釋放調(diào)節(jié)性,能夠顯著改善胃腸道藥物吸收一致性與重現(xiàn)性,所以已成為脈沖給藥系統(tǒng)的研究熱點(diǎn)。目前,口服多微粒脈沖釋藥系統(tǒng)的特定的釋藥曲線特征大多是通過(guò)制備功能性包衣薄膜的途徑實(shí)現(xiàn)。潑尼松(Prednisone,PNS)是用于治療類風(fēng)濕性關(guān)節(jié)炎常用的腎上腺皮質(zhì)激素類藥物;2013年7月31日,FDA批準(zhǔn)英國(guó)Napp制藥公司的潑尼松脈沖擇時(shí)控釋片上市,其商品名為L(zhǎng)odotra,是用于類風(fēng)濕性關(guān)節(jié)炎時(shí)辰藥物療法的一線制劑,其體內(nèi)血漿藥時(shí)曲線下面積(AUC)與市售普通制劑大致等同,但是Cmax往后推遲4~4.5h,可達(dá)到有效的遲釋效應(yīng);由于只需臨睡前服用,在很大程度上提高了患者的用藥依從性,并獲得了極為顯著的臨床療效,大大減輕了類風(fēng)濕性關(guān)節(jié)炎患者的臨床癥狀。本研究是以潑尼松為模型藥物,以丙烯酸樹(shù)脂類包衣輔料為包衣材料,運(yùn)用Glatt底噴流化床包衣技術(shù)制備包衣膜,成功制得了具有pH依賴性的、釋藥時(shí)滯為4~4.5h的脈沖微丸制劑;建立了專屬性強(qiáng)、精密度高、準(zhǔn)確性強(qiáng)的HPLC法,用于潑尼松脈沖控釋微丸含藥量、釋放度及有關(guān)物質(zhì)的測(cè)定。本實(shí)驗(yàn)運(yùn)用底噴流化床包衣技術(shù),采用混懸液上藥法制備潑尼松載藥微丸;并對(duì)載藥微丸粒徑、圓整度、脆碎度等指標(biāo)進(jìn)行考察,均符合后續(xù)的功能性包衣的要求。功能性包衣膜的制備仍采用底噴流化床包衣技術(shù),參照丙烯酸樹(shù)脂類包衣輔料使用指南,選用檸檬酸三乙酯(TEC)作為增塑劑、滑石粉(Talc)作為抗粘劑,篩選出了合適的包衣輔料為Eudragit?RS-100和Eudragit?L-100,并通過(guò)包衣增重、包衣輔料比例等單因素考察,確定了包衣增重、Eudragit?RS-100與Eudragit?L-100的比例是潑尼松脈沖控釋微丸體外釋放行為的主要影響因素,并采用星點(diǎn)設(shè)計(jì)-效應(yīng)面優(yōu)化法優(yōu)化包衣處方,最終得到了較優(yōu)的包衣處方范圍。通過(guò)對(duì)自制潑尼松脈沖控釋微丸的體外釋放曲線與各釋藥模型進(jìn)行擬合,結(jié)果表明,與Hixson-Crowell模型和一級(jí)模型的擬合度較高,證明藥物的釋放屬于擴(kuò)散與溶蝕相協(xié)同作用的機(jī)制。制劑初步穩(wěn)定性考察實(shí)驗(yàn)表明,產(chǎn)品質(zhì)量基本不受光、熱、濕等因素的影響。
[Abstract]:Pulsatile delivery system, also known as time-selective drug delivery system, can release drugs periodically or locally according to the characteristics of human body hour rhythm and the time law of disease onset. Pulse preparation is different from common slow and controlled release preparations. Can't maintain a constant blood concentration, Instead, after taking the drug, they first experience a predetermined release time lag and then immediately release the drug at a specific time during the onset of the disease, or at a specific site, to reach the required blood and tissue drug concentrations. Therefore, it can greatly reduce adverse drug reactions, body tolerance, and improve patients' compliance with medication. Compared with single unit preparation, the multi-particle drug delivery system has excellent release regulation. It can significantly improve the consistency and reproducibility of gastrointestinal drug absorption, so it has become a research hotspot in the pulse drug delivery system. The characteristic of specific release curve of oral multi-particle pulse drug delivery system is mostly achieved by the preparation of functional coating film. Prednisone PNSs are commonly used in the treatment of rheumatoid arthritis. On July 31, 2013, the FDA approved the listing of prednisone pulse timing controlled-release tablets from Napp Pharmaceuticals in the UK, Its trade name is Lodotra.It is a first-line preparation used in the treatment of rheumatoid arthritis. The area under the plasma drug time curve in vivo is approximately the same as that of the ordinary preparations sold on the market. However, the delay of Cmax is 4 ~ 4.5 hours later, which can achieve an effective delayed release effect. Because it only needs to be taken before bedtime, the compliance of patients is improved to a great extent, and the clinical curative effect is very remarkable, which greatly alleviates the clinical symptoms of patients with rheumatoid arthritis. In this study, prednisone was used as the model drug. Using acrylic resin coating excipients as coating materials and Glatt bottom spray fluidized bed coating technology to prepare coating film, a pH-dependent pulse pellet with a time delay of 4 ~ 4.5h was successfully prepared, which was characterized by strong specificity and high precision. The HPLC method with high accuracy was used for the determination of the content, release and related substances of prednisone pulse controlled release pellets. In this experiment, prednisone pellets were prepared by suspension method with the technology of bottom spray fluidized bed coating, and the particle size of the pellets loaded with prednisone was determined. The roundness, brittle degree and other indexes met the requirements of subsequent functional coating. The preparation of functional coating film was still made by bottom spray fluidized bed coating technology, with reference to the guidelines for the use of acrylic resin coating accessories, Using triethyl citrate (TEC) as plasticizer and talc (talc) as tackifier, Eudragit? RS-100 and Eudragit? L-100, and through the investigation of single factors, such as weight gain and proportion of coating excipient, the Eudragit? RS-100 and Eudragit? The proportion of L-100 was the main factor influencing the release behavior of prednisone pulse controlled release pellets in vitro, and the coating prescription was optimized by star design-effect surface optimization method. By fitting the in vitro release curve of prednisone pulse controlled release pellets with each release model, the results showed that the drug release curve fitted well with the Hixson-Crowell model and the first order model. It is proved that the drug release belongs to the synergistic mechanism of diffusion and dissolution, and the preliminary stability of the preparation shows that the product quality is not affected by the factors of light, heat, humidity and so on.
【學(xué)位授予單位】：河南大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2016
【分類號(hào)】：R943

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