發(fā)布時(shí)間：2018-05-02 05:01

  本文選題：褐藻膠 + 交聯(lián)��； 參考：《中國(guó)海洋大學(xué)》2013年碩士論文

【摘要】：隨著制藥業(yè)的不斷發(fā)展,腸溶膠囊市場(chǎng)的需求量不斷增大。植物腸溶空心硬膠囊,不僅可以解決明膠膠囊原料自身性質(zhì)缺陷和原料安全性問(wèn)題,而且具有生物利用度高、劑量小、保護(hù)藥物免受胃內(nèi)酶類(lèi)或胃酸的破壞等特點(diǎn)。以褐藻膠為原料制備腸溶膠囊,不僅開(kāi)辟了褐藻資源高值化利用的新途徑,同時(shí)形成了具有自主知識(shí)產(chǎn)權(quán)的褐藻膠腸溶空心硬膠囊生產(chǎn)技術(shù)。 本論文在研究褐藻膠生物膜水蒸氣透過(guò)系數(shù)的基礎(chǔ)上,利用褐藻膠和Ca2+的交聯(lián)作用制備出褐藻膠腸溶空心硬膠囊,并對(duì)其藥物釋放度和性能進(jìn)行檢測(cè)。主要研究?jī)?nèi)容如下： 1、研究了褐藻膠生物膜的水蒸氣透過(guò)系數(shù)(WVP)。將WVP作為指標(biāo),通過(guò)單因素實(shí)驗(yàn)確定了最佳條件：甘油濃度為5%,褐藻膠濃度為8%,CMC濃度為0.1%,在氯化鈣中交聯(lián)時(shí)間為12分鐘,氯化鈣濃度2%。綜合考慮各方面因素,固定甘油濃度為5%,氯化鈣濃度為2%,選取影響褐藻膠生物膜的WVP三個(gè)關(guān)鍵因素：褐藻膠濃度、羧甲基纖維素鈉濃度和在氯化鈣溶液中的交聯(lián)時(shí)間,進(jìn)行Box-Behnken Design和響應(yīng)面(RSM)分析,得到最優(yōu)工藝條件：褐藻膠濃度、CMC濃度和在氯化鈣溶液中的交聯(lián)時(shí)間分別為8.04%,0.13%和12分鐘。在最優(yōu)條件下,實(shí)際測(cè)得的平均WVP為0.3898,與理論預(yù)測(cè)值0.3974相比,表達(dá)了很高的相關(guān)性。為后續(xù)制作褐藻膠腸溶空心硬膠囊提供了一定的指導(dǎo)意義。 2、以褐藻膠為主要原料制備了褐藻膠腸溶空心硬膠囊。通過(guò)實(shí)驗(yàn)在一次鈣化法和兩次鈣化法中確定用兩次鈣化法制備膠囊,并分別研究了兩次鈣化的鈣源、時(shí)間、濃度、溫度和烘干條件對(duì)膠囊成型性的影響,得到了最佳第一次鈣化條件：鈣源為葡萄糖酸鈣,鈣化溫度、時(shí)間、濃度分別為40℃、4min和4%,烘干溫度、時(shí)間分別為50℃、1h；最佳第二次鈣化條件：鈣源為乳酸鈣,鈣化溫度、時(shí)間和濃度分別為25℃、20min和6%時(shí),烘干溫度、時(shí)間分別為50℃、1.5h。在此條件下獲得的膠囊無(wú)頂星頂凹現(xiàn)象,且拔殼易、硬度好。為我國(guó)植物腸溶空心硬膠囊開(kāi)辟了新的發(fā)展道路。 3、對(duì)自制的褐藻膠腸溶空心硬膠囊進(jìn)行了藥物釋放度的研究,并對(duì)膠囊按照藥典和中國(guó)醫(yī)藥包裝協(xié)會(huì)的要求進(jìn)行了理化指標(biāo)的檢測(cè)。 (1)確定了L-谷氨酰胺在模擬胃溶液和模擬腸溶液中的吸收光譜,最終確定模擬胃環(huán)境實(shí)驗(yàn)選用285nm作為最佳測(cè)定波長(zhǎng),模擬腸環(huán)境實(shí)驗(yàn)選用264nm作為最佳測(cè)定波長(zhǎng)。在確定最佳測(cè)定波長(zhǎng)的基礎(chǔ)上,考察了其分別在模擬胃、腸環(huán)境中的精密度、回收率和穩(wěn)定性,結(jié)果表明：在模擬胃、腸環(huán)境中的精密度實(shí)驗(yàn)中,RSD值分別低于1.13%和1.54%；在模擬胃環(huán)境中,回收率在99.81～100.19%之間,RSD均在0.7%以下,在模擬腸環(huán)境中,回收率在99.91～100.23%之間,RSD均在0.5%以下；在模擬胃環(huán)境下,12h內(nèi)的穩(wěn)定性實(shí)驗(yàn)的RSD值均低于1.17%,在模擬腸環(huán)境下,12h內(nèi)的穩(wěn)定性實(shí)驗(yàn)的RSD值均低于1.52%,說(shuō)明本品在12h內(nèi)穩(wěn)定,本方法具有良好的穩(wěn)定性。自制的復(fù)方谷氨酰胺腸溶膠囊,在模擬胃環(huán)境中2h無(wú)藥物釋放,在模擬腸環(huán)境中第35分鐘時(shí),累計(jì)釋放度已達(dá)標(biāo)示量的70%,在60分鐘時(shí),累積釋放度達(dá)92%,符合藥典規(guī)定。 (2)對(duì)自制腸溶膠囊的規(guī)格尺寸進(jìn)行檢測(cè),其帽體長(zhǎng)度、單壁厚、口部外徑均符合中國(guó)醫(yī)藥包裝協(xié)會(huì)的規(guī)定。對(duì)自制腸溶膠囊的外觀缺陷進(jìn)行檢測(cè),其外觀色澤均勻、有光澤、無(wú)明顯色差,無(wú)裂縫、氣泡、夾皺、異色點(diǎn)、刮痕、褶皺、切絲現(xiàn)象,符合中國(guó)醫(yī)藥包裝協(xié)會(huì)的規(guī)定；對(duì)自制腸溶膠囊的理化指標(biāo)進(jìn)行檢測(cè),未出現(xiàn)漏粉、破裂現(xiàn)象,符合藥典規(guī)定；在人工胃液中,膠囊2h不崩解,在人工腸液中,2分55秒開(kāi)始崩解,符合藥典規(guī)定；干燥失重值為10.98%,小于藥典標(biāo)準(zhǔn),含水量更低,比明膠膠囊更具優(yōu)勢(shì)；灼燒殘?jiān)�值�?.08%；重金屬鉛、鉻的含量均為0,符合藥典規(guī)定；對(duì)自制腸溶膠囊的微生物限度進(jìn)行檢測(cè),細(xì)菌總數(shù)為10CFU/g,霉菌、酵母菌、大腸埃希菌均未檢出,符合藥典規(guī)定。
[Abstract]:With the continuous development of the pharmaceutical industry, the demand for the enteric capsule Market is increasing. The plant enteric coated hollow hard capsules can not only solve the defects of the properties of the gelatin capsules and the safety of the raw materials, but also have the characteristics of high bioavailability, small dosage, and protection from the internal enzymes of the stomach or the destruction of gastric acid. The preparation of enteric coated capsules not only opens a new way for the high value utilization of alga resources, but also forms the production technology of seaweed gelatin enteric hollow hard capsules with independent intellectual property rights.
In this paper, on the basis of the water vapor transmission coefficient of alginate biofilm, the gelatin enteric hollow hard capsule was prepared by the crosslinking of alginate and Ca2+, and the drug release and performance were detected. The main contents are as follows:
1, the water vapor permeation coefficient (WVP) of the alginate biofilm was studied. The optimum conditions were determined by WVP as an index. The concentration of glycerol was 5%, the concentration of alginate was 8%, the concentration of CMC was 0.1%, the crosslinking time in calcium chloride was 12 minutes, the concentration of calcium chloride concentration 2%. combined with various factors, the concentration of fixed glycerol was 5%, calcium chloride was obtained. The concentration of WVP was 2%, and three key factors affecting the biofilm of alga were selected: alginate concentration, carboxymethyl cellulose sodium concentration and crosslinking time in calcium chloride solution, Box-Behnken Design and response surface (RSM) analysis were carried out. The optimum technological conditions were obtained: alginate concentration, CMC concentration and crosslinking time in calcium chloride solution, respectively. It is 8.04%, 0.13% and 12 minutes. Under the optimal conditions, the actual measured WVP is 0.3898, and the correlation is very high compared with the theoretical prediction value 0.3974. It provides a certain guiding significance for the subsequent preparation of alginate enteric hollow hard capsules.
2, alginate gelatin enteric hollow hard capsules were prepared with algin as the main raw material. The capsules were prepared by two calcification methods in the one calcification and two calcification methods, and the effects of calcium sources, time, concentration, temperature and drying conditions on the formation of the capsules were studied, and the optimum conditions for the first calcification were obtained. Calcium gluconate, calcium gluconate, temperature, time, concentration of 40 degrees, 4min and 4%, drying temperature, 50 degrees centigrade, 1H, the optimum second calcification conditions: calcium source is calcium lactate, calcium temperature, time and concentration are 25, 20min and 6%, drying temperature, time respectively 50 degrees, 1.5h. under the condition of the capsule without the top star It is a new development way for Chinese plant enteric hollow hollow capsule.
3, the drug release degree of the self-made alginate enteric coated hollow hard capsules was studied, and the physical and chemical indexes of the capsules were tested according to the Pharmacopoeia and the requirements of the Chinese Medicine Packaging Association.
(1) the absorption spectrum of L- glutamine in simulated gastric solution and simulated intestinal solution was determined. Finally, 285nm was selected as the best wavelength for simulated gastric environment experiment, and 264nm was selected as the best measurement wavelength in simulated intestinal environment experiment. On the basis of determining the optimum determination wavelength, the precision of the experiment was investigated in the simulated stomach and intestinal environment. Degree, recovery and stability, the results showed that the RSD values were lower than 1.13% and 1.54% in the simulated stomach and intestinal environment. In the simulated gastric environment, the recovery rate was from 99.81 to 100.19%, and the RSD was below 0.7%. In the simulated intestinal environment, the recovery rate was 99.91 to 100.23%, RSD was below 0.5%, 1 in the simulated stomach environment, 1 The RSD value of the stability test in 2H was lower than 1.17%. In the simulated intestinal environment, the RSD value of the stability test in 12h was lower than 1.52%. It indicated that the product was stable in 12h and the method had good stability. The self-made Compound Glutamin Entersoluble Capsules was not released in the simulated stomach environment and 2H was not released in the simulated intestinal environment, and was tired in the simulated intestinal environment for thirty-fifth minutes. The release rate of the meter has reached 70% of the indicated quantity, and the cumulative release rate reaches 92% at 60 minutes, which is in conformity with the Pharmacopoeia regulations.
(2) to test the size and size of the self-made enteric capsule, the length of the cap, the thickness of the single wall and the outer diameter of the mouth all conform to the regulations of the Chinese Medical Packaging Association. The appearance defects of the self-made enteric capsule are detected. The appearance of the capsule is uniform and lustrous, without obvious color difference, no crack, bubble, crease, color point, scratch, wrinkle and shredding. The physical and chemical indexes of the Chinese Medicine Packaging Association, testing the physical and chemical indexes of the self-made enteric capsule, did not appear to leak powder, rupture, conformed to the Pharmacopoeia regulations; in the artificial gastric juice, the capsule 2H did not collapse and began to disintegrate in the artificial intestinal fluid for 2 minutes and 55 seconds, which was in accordance with the Pharmacopoeia regulations; the dry weight loss value was 10.98%, less than the pharmacopoeia standard, the water content was lower, and the ratio. Gelatin capsule has more advantages, burning residue value is 1.08%, heavy metal lead and chromium content are 0, in accordance with the Pharmacopoeia regulations, the microbial limit of self-made enteric capsule is detected, the total number of bacteria is 10CFU/g, mould, yeast, Escherichia coli are not detected, in line with the Pharmacopoeia regulations.

【學(xué)位授予單位】：中國(guó)海洋大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2013
【分類(lèi)號(hào)】：TQ460.1

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