本文選題：溫敏凝膠 + 泊洛沙姆�。� 參考：《山東中醫(yī)藥大學(xué)》2014年碩士論文

【摘要】：舊的]將小兒退熱藥對乙酰氨基酚(APAP)制備成外用溫敏凝膠制劑,通過經(jīng)皮吸收,避免胃腸首過效應(yīng),增加兒童用藥的順應(yīng)性,從而開發(fā)一種針對小兒退熱新劑型。 [方法] 1.APAP凝膠制劑適用性研究：參照藥典有關(guān)標(biāo)準(zhǔn),用紫外分光光度法對APAP含量進(jìn)行測定；在設(shè)計(jì)處方前對藥物的基本物理性質(zhì)、化學(xué)性質(zhì)和制劑性質(zhì)進(jìn)行考察；對APAP的油水分配系數(shù)進(jìn)行研究,測定其在水中的溶解度；考察APAP在實(shí)驗(yàn)所需的pH環(huán)境中的穩(wěn)定性,用以指導(dǎo)下一步制劑處方和工藝的研究。 2. APAP凝膠基質(zhì)的篩選：以天然高分子為主要原料,在查找文獻(xiàn)和預(yù)實(shí)驗(yàn)的基礎(chǔ)上,優(yōu)選適合外用的溫敏性水凝膠的基質(zhì)組合,制備作為釋藥載體,選擇殼聚糖(CS)/聚乙烯醇(PVA)/甘油磷酸鈉(β-GP),泊洛沙姆407(F127)/泊洛沙姆188(F68)/聚乙烯醇(PVA)兩組凝膠基質(zhì),以凝膠溫度、粘度、凝膠強(qiáng)度和脫水性為指標(biāo),采用正交設(shè)計(jì)優(yōu)化凝膠處方,并對凝膠黏度熱穩(wěn)定性進(jìn)行考察。 3. APAP凝膠制劑制備工藝及質(zhì)量標(biāo)準(zhǔn)的研究：按照2010版中國藥典標(biāo)準(zhǔn)的要求對APAP凝膠的質(zhì)量進(jìn)行了詳細(xì)考察,建立APAP凝膠劑的檢測方法,并進(jìn)行方法學(xué)驗(yàn)證,擬定了APAP凝膠的質(zhì)量標(biāo)準(zhǔn)。 4. APAP凝膠劑生物粘附性和體外釋放研究：考察了凝膠的生物粘附性、載藥量；用Franze吸收池用新鮮兔皮進(jìn)行體外滲透實(shí)驗(yàn),考察凝膠的累積釋放量。 5. APAP溫敏凝膠劑皮膚刺激性試驗(yàn)：參照“化學(xué)品急性皮膚刺激性/腐蝕性試驗(yàn)方法進(jìn)行皮膚刺激性實(shí)驗(yàn)(GBT21604-2008),觀察皮膚涂抹空白凝膠、加藥凝膠后局部是否會(huì)引起可逆性炎癥變化和不可逆性的組織損傷。采用自身對照,將凝膠基質(zhì)一次(或多次)涂敷于新西蘭白兔的皮膚上,在規(guī)定的時(shí)間間隔內(nèi),觀察動(dòng)物皮膚局部刺激作用的程度并進(jìn)行評分,以評價(jià)受試物對皮膚的刺激作用。 [結(jié)果] 1.常溫下對乙酰氨基酚在水中的溶解度為45.62g/L,說明該藥在水中略溶,在pH5.0和PH7.0緩沖溶液中略溶。在37℃,PH=5～7的弱酸性環(huán)境中溶解度較高,均在50g/L以上。測定不同PH緩沖溶液下的PAPP值,可以看到各PH條件下的分配系數(shù)介于2.6～2.8之間,隨著環(huán)境Ph的增大,分配系數(shù)逐漸減小,在Ph=5左右出現(xiàn)向上的拐點(diǎn),但總體來說相差很小,證明對乙酰氨基酚在本實(shí)驗(yàn)所需的弱酸性環(huán)境中是穩(wěn)定的,符合實(shí)驗(yàn)要求。 2.經(jīng)過對凝膠熱穩(wěn)定性的研究,可以看出P407和PVA的濃度對黏度的敏感性不大,但仍然隨溫度的上升黏度有增大的趨勢,且PVA濃度對黏度的影響對P407大；經(jīng)過對各種附加劑對凝膠的IGT、凝膠黏度影響的研究,表明P188的加入使得膠凝溫度升高,鹽類對凝膠的形成影響較為顯著,加入的鹽類中,除CaCl之外,均可使溶液的粘度增大。在選用的陰離子中,對凝膠粘度和膠凝溫度的影響次序?yàn)椋篠O42-PO43-Cl-,這些離子明顯的增加了溶液的粘度,并降低了膠凝的溫度,而陽離子Ca2+則使溶液的粘度降低,同時(shí)使凝膠的溫度升高。兩個(gè)基質(zhì)組合分別進(jìn)行三水平三因素正交實(shí)驗(yàn),由于PVA/CS/GP最優(yōu)組合的膠凝溫度和黏度都不符合要求,排除,PVA/P407/P188組合各項(xiàng)指標(biāo)均符合要求,優(yōu)化處方為4.5%PVA、5.5%P188和23%P407,在34℃、30s內(nèi)可發(fā)生凝膠化,PVA/P407/P188凝膠的制備工藝簡單可行,具有溫敏性,適合作為后期加藥實(shí)驗(yàn)的基質(zhì)。 3.在確定溫敏凝膠基質(zhì)最優(yōu)組合的基礎(chǔ)上完善整個(gè)制劑的處方,并將做成的成品按照2010版藥典二部“凝膠劑”、“對乙酰氨基酚凝膠劑”等標(biāo)準(zhǔn)的方法,對APAP溫敏凝膠劑進(jìn)行質(zhì)量考察,并擬定出對乙酰氨基酚溫敏凝膠的質(zhì)量標(biāo)準(zhǔn),經(jīng)考察,自行試制的三批制劑均符合要求。 4.以IGT為指標(biāo)考察基質(zhì)最大載藥量,加入APAP確實(shí)顯著的提升凝膠的IGT,當(dāng)加藥量大于0.1g時(shí),凝膠出現(xiàn)不溶物,溶液逐漸變渾濁,膠凝時(shí)間逐漸變長,IGT超過37-C；當(dāng)加藥量為0.2g時(shí),凝膠30min內(nèi)無法形成凝膠；進(jìn)行體外釋藥實(shí)驗(yàn),以累積經(jīng)皮釋放量對時(shí)間曲線作圖,可見APAP凝膠制劑經(jīng)皮吸收量與時(shí)間具有一定的相關(guān)性,且釋放速率較恒定,在1.5h后單位面積的滲透量釋放加快,在6.0h后,釋放量出現(xiàn)拐點(diǎn),后面4個(gè)小時(shí)只釋放了不到1mg,在10h內(nèi),藥物生物膜通過共釋放了90.55%的藥量,盡管通過皮膚直接透過藥物要通過若干皮層而難以大量吸收,但本實(shí)驗(yàn)仍能證明以泊洛沙姆為基質(zhì)主要成分的溫敏凝膠具有一定的體外釋放性,并具有明顯的緩釋效果。 5.對乙酰氨基酚凝膠急性或多次經(jīng)皮給藥后對皮膚無刺激性,或輕度的皮膚刺激性,從而為對乙酰氨基酚凝膠的經(jīng)皮給藥的安全性提供了實(shí)驗(yàn)依據(jù)。 結(jié)論：對乙酰氨基酚溫敏凝膠制劑的主藥對乙酰氨基酚臨床退熱療效確切,已經(jīng)上百年的檢驗(yàn),常規(guī)劑量非常安全；其合成工藝成熟,質(zhì)量穩(wěn)定,價(jià)格低廉；制劑給藥方便,兒童順應(yīng)性好：可以避開肝腸首過效應(yīng)；分計(jì)量準(zhǔn)確,使用、儲(chǔ)存方便,具有良好的釋藥性能和透皮效果;制劑本身對皮膚無任何副作用、刺激性,可以將其制成外用溫敏制劑成為一種未來新型的治療感冒的途徑。
[Abstract]:The antipyretic antipyretic drug to acetaminophen (APAP) was prepared for external use of thermosensitive gel. Through the percutaneous absorption, it avoided the first over effect of the gastrointestinal tract and increased the compliance of the children. A new type of antipyretic dosage form for children was developed.
[method]
Study on the applicability of 1.APAP gel: the content of APAP was measured by UV Spectrophotometry with reference to the relevant standard of Pharmacopoeia; the basic physical properties, chemical properties and preparation properties of the drugs were investigated before the formulation of the prescription; the oil and water distribution coefficient of APAP was studied to determine the solubility in water; and APAP was investigated in the experiment. The stability required in the pH environment is used to guide the research on the formulation and technology of the next step.
2. APAP gel matrix screening: Based on natural polymers as the main raw material, based on searching for literature and pre experiment, the selection of substrate combination suitable for external use of thermosensitive hydrogels is prepared as a carrier of drug release, and the selection of chitosan (CS) / polyvinyl alcohol (PVA) / sodium glycerphosphate (beta -GP), poloxamer / poloxamer 188 (F68) / polyethylene (F68) / polyethylene The gel matrix was two groups of alcohol (PVA). The gel temperature, viscosity, gel strength and dehydration were used as the indexes. The gel formulation was optimized by orthogonal design, and the thermal stability of the gel viscosity was investigated.
Study on the preparation technology and quality standard of 3. APAP gel: according to the requirements of the standard of Chinese Pharmacopoeia of the 2010 edition, the quality of the APAP gel was investigated in detail, the detection method of APAP gel was established, and the method was verified, and the quality standard of the APAP gel was drawn up.
The bioadhesion and in vitro release of 4. APAP gels were studied. The bioadhesion and drug loading of the gel were investigated, and the in vitro infiltration experiment was carried out with fresh rabbit skin from the Franze absorption pool, and the cumulative release of the gel was investigated.
5. APAP thermosensitive gel skin irritation test: skin irritation test (GBT21604-2008) based on "chemical acute skin irritation / corrosive test" (chemical skin irritation test), observation of skin smear blank gel, and whether the local gel can cause reversible inflammatory changes and irreversible tissue damage. The matrix is applied to the skin of New Zealand white rabbits once or more, and the extent of local irritation of the animal skin is observed and scored in a specified time interval to evaluate the irritation of the subject to the skin.
[results]
The solubility of acetaminophen in water at 1. at normal temperature was 45.62g/L, indicating that the drug was slightly soluble in water and slightly dissolved in pH5.0 and PH7.0 buffer solutions. At 37, the solubility of the drug was higher in the weak acid environment of PH=5 ~ 7, all above 50g/L. The PAPP value under different PH buffer solutions could be measured in order to see that the distribution coefficient under each PH condition was between 2.6 and 2.8. In the meantime, with the increase of the environment Ph, the distribution coefficient gradually decreases and the inflection point is up around Ph=5, but the difference is very small in general. It is proved that acetaminophen is stable in the weak acid environment needed in this experiment, which meets the requirements of the experiment.
2. through the study of the thermal stability of the gel, it can be seen that the concentration of P407 and PVA is less sensitive to viscosity, but it still increases with the rising viscosity of the temperature, and the effect of PVA concentration on the viscosity is large to P407; after the study of the effect of various additives on the gelation of the gel and the viscosity of the gel, it is shown that the addition of P188 makes the gelation temperature. In addition, the viscosity of the gel and the gelation temperature in the selected anions are SO42-PO43-Cl-. These ions obviously increase the viscosity of the solution and reduce the temperature of the gelation, and the cationic Ca2+ is Ca2+. The viscosity of the solution was reduced and the temperature of the gel was increased. The two matrix combinations were three levels and three factors respectively. Because the gelation temperature and viscosity of the optimal combination of PVA/CS/GP were not conformed to the requirements, all the indexes of the PVA/P407/P188 combination were in conformity with the requirements. The optimum formulation was 4.5%PVA, 5.5%P188 and 23%P407, at 34, 30s. Gelation can take place. The preparation process of PVA/P407/P188 gel is simple and feasible, and has thermo sensitivity. It is suitable to be used as a substrate for later dosing experiments.
3. to improve the formulation of the whole preparation on the basis of determining the optimum combination of the temperature sensitive gel matrix, and the quality of the APAP Wen Min gel was investigated in accordance with the standard method of the 2010 edition of the Pharmacopoeia "gel" and "Paracetamol Gel", and the quality standard of the acetaminophen thermosensitive gel was drawn up. The three batches of preparations made by ourselves were all in accordance with the requirements.
4. take the IGT as the index to investigate the maximum drug loading of the matrix, adding APAP to improve the IGT of the gel. When the dosage is greater than 0.1g, the gel appears insoluble, the solution becomes turbid, the gelation time becomes longer, and the IGT exceeds the 37-C. When the dosage is 0.2g, the gel can not form the gel in 30min, and the release experiment in vitro is carried out to accumulate the skin in vitro. The release amount to the time curve, it can be seen that the APAP gel preparation has a certain correlation with the time, and the release rate is constant. The release rate of the unit area is quicker after 1.5h. After 6.0h, the release rate is inflection point, and the last 4 hours only release less than 1mg. In 10h, the drug biofilm is released by a total of 90.55%. Although the dosage is difficult to absorb through a number of cortex through the skin through the skin directly through the skin, this experiment still proves that the temperature sensitive gel with the main component of poloxamer has a certain release in vitro and has a significant slow release effect.
5. Paracetamol Gel has no irritation or mild skin irritation to the skin after acute or repeated percutaneous administration of the skin, which provides an experimental basis for the safety of Paracetamol Gel's percutaneous administration.
Conclusion: the main drug of acetaminophen thermosensitive gel has a definite effect on acetaminophen clinical antipyretic treatment. It has been tested for a hundred years, the routine dose is very safe, the synthetic process is mature, the quality is stable, the price is low, the preparation is convenient and the compliance of the children is good: it can avoid the head over effect of the liver intestines, accurate measurement, use and storage. It is convenient to save, and has good drug release and transdermal effects. The preparation itself has no side effects on the skin, irritating, and can be used as a foreign temperature sensitive preparation to become a new way to treat the cold in the future.

【學(xué)位授予單位】：山東中醫(yī)藥大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R943

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