托特羅定成膜水凝膠制劑及其透皮機(jī)理研究
發(fā)布時(shí)間：2018-08-03 14:13
【摘要】：膀胱過度活動(dòng)癥(Overactive bladder, OAB)是一種常見的泌尿系統(tǒng)疾病，主要癥狀是尿急、尿頻。目前，OAB病因并不清楚，人體無(wú)明顯組織學(xué)病變，通過抑制膀胱中毒蕈堿(Muscarine, M)受體的活性可以有效的治療OAB。托特羅定是治療OAB的主導(dǎo)藥物，是一種M受體拮抗劑。M受體拮抗劑在人體肝臟內(nèi)可由P450酶代謝，通常會(huì)有一部分生成活性更高的代謝產(chǎn)物，而這些活性代謝產(chǎn)物更易與除膀胱之外的組織中的M受體結(jié)合，發(fā)生藥物不良反應(yīng)，，如口干、便秘和視力模糊等，這也是目前全球治療OAB的眾多M受體拮抗劑所面臨的問題之一。近年來，通過經(jīng)皮給藥M受體拮抗劑的辦法，可有效降低藥物肝首過效應(yīng)，使不良反應(yīng)發(fā)生率降低，但成功開發(fā)為經(jīng)皮給藥系統(tǒng)并上市的M受體拮抗劑僅有奧昔布寧一例。 大部分M受體拮抗劑不適合開發(fā)經(jīng)皮給藥系統(tǒng)，尤其是水凝膠體系，原因有兩個(gè)：首先，水凝膠往往包含大量極性溶劑，M受體拮抗劑在這些溶劑中溶解度低，尤其是水凝膠基質(zhì)中含大量水時(shí)，藥物結(jié)晶析出的問題很難解決，而且給藥后藥物結(jié)晶析出會(huì)導(dǎo)致療效低和不穩(wěn)定，此問題也是導(dǎo)致一些經(jīng)皮給藥系統(tǒng)退市的原因之一；其次，一些M受體拮抗劑自身分子結(jié)構(gòu)復(fù)雜，很難透過皮膚角質(zhì)層，導(dǎo)致透皮能力弱，很難達(dá)到較高的血藥濃度，導(dǎo)致其水凝膠生物利用度低。托特羅定在開發(fā)經(jīng)皮給藥系統(tǒng)時(shí)，除了面臨上述問題外，還存在由于藥物本身是熔點(diǎn)低、粘度高的半固體而導(dǎo)致轉(zhuǎn)移和應(yīng)用不便的問題。本研究從藥物性質(zhì)出發(fā)，在不同的藥物轉(zhuǎn)化思路基礎(chǔ)上，成功開發(fā)托特羅定成膜水凝膠的制備方法，并且科學(xué)的獲得了最終的優(yōu)選處方，成膜材料的引入進(jìn)一步改善了水凝膠的釋藥行為和應(yīng)用性，使用時(shí)療效更加穩(wěn)定，在透皮機(jī)理研究中，闡述了托特羅定透皮的分子形態(tài)和經(jīng)過的皮膚途徑，并揭示了優(yōu)選處方高生物利用度的原因。 1、托特羅定理化性質(zhì)和凝膠材料初步考察。 本部分內(nèi)容在第2章進(jìn)行，托特羅定常以其酒石酸鹽形式存在，為提高托特羅定透皮量和便于制備水凝膠，需先將酒石酸托特羅定(Tolterodine tartrate， TT)中的酒石酸去除，使其轉(zhuǎn)化為自由堿托特羅定(Tolterodine free base， TB)。TB的溶解度和油水分配系數(shù)(logP)是決定其能否成功制備水凝膠的關(guān)鍵因素。由于TB分子中含兩個(gè)苯環(huán)和大量烷烴鏈，使其在水中極微溶，溶解度僅有107.11μg/ml，當(dāng)水凝膠基質(zhì)含水量較高時(shí)，托特羅定易析出，有效的藥物透皮濃度下降，這是制備高生物利用度托特羅定成膜水凝膠的難點(diǎn)之一。另外，通常認(rèn)為logP越接近1的藥物越易透過生物膜，TB分子中含酚羥基、三級(jí)胺結(jié)構(gòu)，使其解離和帶電荷情況易受pH影響，且logP遠(yuǎn)小于1，尤其是在pH7附近時(shí)， TB分子易帶正負(fù)兩種電荷，使其logP進(jìn)一步下降，皮膚滲透性下降，這是制備高生物利用度托特羅定成膜水凝膠的難點(diǎn)二�？紤]到TB分子在pH7附近時(shí)的可能帶電情況，選擇了3種與TB相容性好的凝膠材料：陰離子型凝膠材料卡波姆980、中性凝膠材料高取代羥丙基纖維素(H-HPC)和中性凝膠材料羥丙甲基纖維素(HPMC)。初步考察了它們?cè)谒鸵掖贾械娜苊浤芰ΓY(jié)果顯示除了HPMC在無(wú)水乙醇中幾乎不溶脹外，其他條件下凝膠材料在水或無(wú)水乙醇中均有較好的溶脹能力。 2、水凝膠制備工藝和處方優(yōu)化 本部分內(nèi)容在第3章和第4章進(jìn)行，為了解決TB轉(zhuǎn)移和應(yīng)用不便的問題開發(fā)了乙醇?jí)A液轉(zhuǎn)化法和三乙醇胺轉(zhuǎn)化法兩種藥物處理方法。不同的藥物處理方法獲得的TB適合不同的成膜水凝膠制備方案，因此有乙醇?jí)A液轉(zhuǎn)化法對(duì)應(yīng)的后載藥法和三乙醇胺轉(zhuǎn)化法對(duì)應(yīng)的先載藥法兩種水凝膠制備方法。后載藥法只是對(duì)影響凝膠材料成凝膠能力、TB溶解能力和凝膠成膜能力關(guān)鍵因素的初步篩選，在此基礎(chǔ)上先載藥法更科學(xué)系統(tǒng)的進(jìn)行了處方優(yōu)化。 乙醇?jí)A液轉(zhuǎn)化法制備的TB乙醇溶液用于后載藥法制備水凝膠。首先，進(jìn)行了單因素實(shí)驗(yàn)，包括處方中卡波姆980含量、H-HPC含量對(duì)水凝膠性質(zhì)影響；基質(zhì)溶脹時(shí)用水量、時(shí)間、H-HPC粒徑和溫度對(duì)水凝膠后期保存中藥物穩(wěn)定性的影響；吐溫80、乙酸乙酯和有機(jī)硅彈性體對(duì)于增加藥物在基質(zhì)中溶解度的研究；親水性成膜材料明膠、聚乙烯醇和HPMC在水凝膠中成膜可行性研究。其次，通過Franz擴(kuò)散池進(jìn)行了水凝膠體外透皮實(shí)驗(yàn)，考察了水凝膠的體外藥物透過量、累積釋放率和穩(wěn)態(tài)釋放速率。最后，進(jìn)行了優(yōu)選處方大鼠體內(nèi)藥代動(dòng)力學(xué)考察。結(jié)果顯示：在選擇HPMCk4m為成膜材料時(shí)，后載藥法可以制備最高2%載藥量的托特羅定成膜水凝膠；吐溫80可有效的增加TB溶解度，然而含量較高時(shí)影響水凝膠成膜。含20%吐溫80的3.54%載藥量水凝膠大鼠體內(nèi)24h絕對(duì)生物利用度為21.87%，暗示了吐溫80在提高TB透皮速率方面有著明顯作用。先載藥法是在三乙醇胺轉(zhuǎn)化法前處理藥物基礎(chǔ)上制備托特羅定水凝膠的方法。根據(jù)后載藥法確定的處方中關(guān)鍵因素水、乙醇、載藥量、吐溫80、HPMC，通過三相圖的繪制，獲得了能成透明水凝膠的處方范圍，并且闡述了凝膠基質(zhì)中水分子類型對(duì)藥物析出的影響；響應(yīng)面實(shí)驗(yàn)進(jìn)一步優(yōu)化了成膜材料、吐溫80和載藥量的范圍，最終獲得24h累積釋放率最高的成膜水凝膠處方，小鼠鼠皮的體外結(jié)果顯示，其24h藥物累積釋放率為86.02%，與預(yù)測(cè)結(jié)果85.42%非常接近。另外，大鼠體內(nèi)24h絕對(duì)生物利用度為24.53%。 3、透皮機(jī)理及藥效研究 第5章和第6章進(jìn)行了透皮機(jī)理和藥效學(xué)相關(guān)的研究，目的是進(jìn)一步明確托特羅定透皮能力、透皮的分子形式和透皮經(jīng)過的角質(zhì)層途徑。 首先考察了托特羅定的皮膚滲透性和在不同皮膚結(jié)構(gòu)中的分布情況，結(jié)合優(yōu)選處方在大鼠全厚度鼠皮、表皮層、真皮層和皮下組織中的藥物穩(wěn)態(tài)釋放速率分別為15.83，18.55，37.15和81.82μgcm-2h-1，可以肯定托特羅定水凝膠適合于系統(tǒng)給藥，即局部涂抹后，藥物可透過皮膚入血到達(dá)膀胱，從而發(fā)揮治療效果。 優(yōu)選處方生物利用度高的本質(zhì)原因是水凝膠使托特羅定更易透過皮膚入血，通過傅立葉變換紅外考察了大鼠皮膚角質(zhì)層中類脂的雙分子層氫鍵變化，以及通過差式量熱掃描考查了處方中關(guān)鍵因素吐溫80和三乙醇胺對(duì)角質(zhì)層中類脂含量和熔點(diǎn)的影響，兩個(gè)實(shí)驗(yàn)結(jié)果均暗示大鼠皮膚角質(zhì)層中的類脂氫鍵的改變。優(yōu)選處方中TB的透皮活化能Ea測(cè)得8.638kcal/mol，與氯離子透過人皮膚角質(zhì)層類脂雙分子層時(shí)的活化能10.7kcal/mol接近，且水凝膠pH在7.4附近，進(jìn)一步說明托特羅定是以帶一個(gè)負(fù)電荷的離子形式跨角質(zhì)層類脂雙分子層透皮，并且佐證了角質(zhì)層中類脂結(jié)構(gòu)氫鍵的改變而帶來的流動(dòng)性變化。另外，托特羅定帶負(fù)電時(shí)，與卡波姆980的靜電排斥作用也有利于其擴(kuò)散進(jìn)入皮膚。此部分研究結(jié)果可以為3,3-二苯基丙胺類M受體拮抗劑經(jīng)皮給藥系統(tǒng)的開發(fā)奠定部分理論基礎(chǔ)。 水凝膠藥效實(shí)驗(yàn)結(jié)果顯示所優(yōu)選的托特羅定成膜水凝膠能較好的減少尿失禁大鼠12h累積排尿量，連續(xù)給藥結(jié)果顯示，水凝膠制劑可實(shí)現(xiàn)OAB長(zhǎng)期治療的目的。
[Abstract]:Overactive bladder (OAB) is a common urinary system disease. The main symptoms are urgency of urine and frequency of urine. At present, the cause of OAB is not clear. There is no obvious histology in the human body. The activity of the Muscarine, M receptor of bladder poisoning can effectively treat the OAB. Tote Luoding as the leading drug for the treatment of OAB. A M receptor antagonist,.M receptor antagonist, can be metabolized by P450 enzymes in the human liver, usually partly to produce more active metabolites, and these active metabolites are more likely to combine with M receptors in tissues outside the bladder and have adverse drug reactions, such as dry mouth, constipation, and blurred vision. This is also a global treatment. A number of M receptor antagonists in OAB are faced with one of the problems. In recent years, percutaneous administration of M receptor antagonists can effectively reduce the head over effect of the drug and reduce the incidence of adverse reactions, but the only case of the M receptor antagonist, which has been successfully developed into the percutaneous drug delivery system, is only oroxicin Bunin.
Most M receptor antagonists are not suitable for the development of the transdermal drug delivery system, especially the hydrogel system. There are two reasons for it: first, the hydrogels often contain a large number of polar solvents, and the solubility of M receptor antagonists in these solvents is low, especially when a large amount of water is contained in the hydrogel matrix, and the crystallization of the drugs is difficult to solve, and the drug is given after the drug. The crystallization of M is one of the reasons for the low and unstable effect. This problem is also one of the reasons for the delisting of some transdermal drug delivery systems. Secondly, some of the M receptor antagonists have complex molecular structures, which are difficult to penetrate the cuticle of the skin, resulting in the weak transdermal capacity and difficult to reach the high blood concentration, resulting in low bioavailability of the hydrogel. Tortero In the development of the percutaneous drug delivery system, in addition to the above problems, there is a problem that the drug itself is a semi solid with low melting point and high viscosity, which leads to the inconvenience of transfer and application. In this study, the preparation method of Ttot Luoding membrane hydrogels was successfully developed on the basis of different drug properties and different drug conversion ideas. The ultimate optimum prescription was obtained. The introduction of film forming material further improved the drug release behavior and application of the hydrogel, and the effect was more stable in use. In the study of the transdermal mechanism, the molecular morphology and the skin pathway of TUTT Luoding transdermal were expounded, and the reasons for the optimization of the high bioavailability of the prescription were also revealed.
1, Tortero's theorized properties and gel materials are preliminarily investigated.
This part is carried out in the second chapter. Tote Luoding is often in the form of tartaric acid. To improve the TUTT Luoding transdermal volume and facilitate the preparation of hydrogels, tartaric acid in the tartaric acid Tote Luoding (Tolterodine tartrate, TT) should be removed to make it converted to the solubility and oil of the free alkali totte Luoding (Tolterodine free base, TB).TB. The distribution coefficient (logP) is the key factor to determine whether the hydrogel can be successfully prepared. Because the TB molecule contains two benzene rings and a large number of alkane chains, it is very soluble in water and the solubility is only 107.11 g/ml. When the water content of the hydrogel matrix is high, TUTT Luoding is easily precipitated and the effective drug permeable concentration is reduced. This is the preparation of high biological use. One of the difficulties in the ditote Luoding membrane hydrogel is that the more likely the logP is the closer to 1 of the drug through the biofilm, the TB molecule contains the phenolic hydroxyl group and the three grade amine structure, which makes its dissociation and charge charge susceptible to pH, and the logP is far less than 1, especially in the vicinity of pH7, and the TB molecules are liable to take two positive and negative charges and make their logP further decline. The decrease of skin permeability is two difficulty in preparing the high bioavailability of Ttot Luoding film hydrogels. Considering the possible electrification of TB molecules near pH7, 3 kinds of gel materials with good compatibility with TB are selected: anionic gel material carbomer 980, neutral gel material high substituted hydroxypropyl cellulose (H-HPC) and neutral gel Material hydroxypropyl methyl cellulose (HPMC). Their swelling ability in water and ethanol is preliminarily investigated. The results show that the swelling ability of gel materials in water or anhydrous ethanol is better than that of HPMC in anhydrous ethanol, except that it is almost non swelling in anhydrous ethanol.
2, optimization of preparation and prescription of hydrogels
This part is carried out in the third and fourth chapters. In order to solve the problem of TB transfer and inconvenient application, two kinds of drug treatment methods are developed by ethanol lye conversion and triethanolamine conversion. Different drug treatment methods are suitable for the preparation of different membrane hydrogels, because of the corresponding post drug loading method for the ethanol conversion method. Two hydrogels were prepared by the first drug loading method corresponding to the triethanolamine transformation method. The post loading method was a preliminary screening of the key factors affecting the gelation ability of the gel material, the solubility of TB and the ability of the gelation of the gel. On this basis, the prescription was optimized in a more scientific system.
The TB ethanol solution prepared by the ethanol lye conversion method was used to prepare the hydrogel by the drug loading method. First, a single factor experiment was carried out, including the content of carbomer 980 in the prescription, the effect of H-HPC content on the properties of hydrogel, the effect of water consumption, time, H-HPC particle size and temperature on the stability of the drug in the later storage of the water. Twain 80, The solubility of ethyl acetate and organosilicon elastomers to increase the solubility of drugs in the matrix; the feasibility study on the film formation of hydrophilic gelatin, polyvinyl alcohol and HPMC in hydrogel. Secondly, the in vitro transdermal experiment of hydrogels was carried out through the Franz diffusion pool, and the drug permeation, the cumulative release rate and the steady state of the gel in vitro were investigated. The release rate. Finally, the pharmacokinetics of the optimized prescription rats were investigated. The results showed that, when the HPMCk4m was selected as the film forming material, the tote Luoding film hydrogel with the maximum dose of 2% was prepared by the post loading method; Twain 80 could effectively increase the solubility of TB, while the high content of the gel could affect the formation of the hydrogel membrane. It contained 20% Twain 80. 3. The absolute bioavailability of 24h in 54% loading hydrogel rats was 21.87%, suggesting that Twain 80 had an obvious effect on improving the transdermal rate of TB. The first drug loading method was the preparation of TUTT Luoding hydrogel on the basis of the triethanolamine conversion process. The key factors for the formulation of the medicine were water, ethanol, and drug loading. Quantity, Twain 80, HPMC, the formulation range of transparent hydrogel was obtained through the drawing of three phase diagram, and the effect of water molecular type on the drug precipitation in the gel matrix was expounded. The response surface experiment further optimized the film forming material, Twain 80 and the range of drug loading, and finally obtained the film formulation with the highest cumulative release rate of 24h. The in vitro results of mouse skin showed that the cumulative release rate of 24h was 86.02%, which was very close to the predicted results of 85.42%. In addition, the absolute bioavailability of 24h in rats was 24.53%.
3, study on transdermal mechanism and efficacy
In the fifth and sixth chapters, the transdermal mechanism and pharmacodynamics related studies were carried out to further clarify the transdermal capacity of TUTT Luoding, the molecular form of transdermal and the cuticle pathway of transdermal passage.
First, the skin permeability and distribution in different skin structures of totte Luoding were investigated. The steady-state release rates of drug homeostasis in rat skin, epidermis, dermis and subcutaneous tissue were 15.83,18.55,37.15 and 81.82 gcm-2h-1 respectively. It was sure that Ttot Luoding hydrogel was suitable for system administration. After topical application, the drugs can reach the bladder through skin and blood, so as to play a therapeutic effect.
The essential reason for the optimization of the bioavailability of the prescription is that the hydrogel makes Tote Luoding more easily permeable through the skin. The hydrogen bonds in the bilayer of the lipid in the cuticle of the rat skin are examined by Fu Liye transform infrared, and the key factors in the cuticle are examined by the differential calorimetry, which are the key factors of Twain 80 and triethanolamine. The effects of the amount and melting point of the two experimental results all suggest the changes in the hydrogen bonds of the lipid in the cuticle of the rat's skin. The optimum prescription of the transdermal activation energy of TB in the prescription Ea is 8.638kcal/mol, which is close to the activation energy 10.7kcal/mol of the chloride ion through the bilayer of the human skin stratum corneum, and the hydrogel pH is near 7.4, further explaining Tote Luoding In the form of a negative charged ion, the transdermal permeation of the lipid bilayer of the stratum corneum is transacted, and the change of the hydrogen bond of the lipid structure in the stratum corneum is confirmed. In addition, the electrostatic repulsion with the carbomer 980 in the totte Luoding belt is beneficial to its diffusion into the skin. The result of this study can be 3,3- two. A theoretical basis for the development of the transdermal drug delivery system of phenylalanine M receptor antagonists is provided.
The results of hydrogel efficacy test showed that the preferred tot Luoding membrane hydrogel could reduce the cumulative urine volume of 12h in urinary incontinence rats. The results of continuous drug delivery showed that the hydrogel could achieve the long-term treatment of OAB.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R943
本文編號(hào)：2161995
[Abstract]:Overactive bladder (OAB) is a common urinary system disease. The main symptoms are urgency of urine and frequency of urine. At present, the cause of OAB is not clear. There is no obvious histology in the human body. The activity of the Muscarine, M receptor of bladder poisoning can effectively treat the OAB. Tote Luoding as the leading drug for the treatment of OAB. A M receptor antagonist,.M receptor antagonist, can be metabolized by P450 enzymes in the human liver, usually partly to produce more active metabolites, and these active metabolites are more likely to combine with M receptors in tissues outside the bladder and have adverse drug reactions, such as dry mouth, constipation, and blurred vision. This is also a global treatment. A number of M receptor antagonists in OAB are faced with one of the problems. In recent years, percutaneous administration of M receptor antagonists can effectively reduce the head over effect of the drug and reduce the incidence of adverse reactions, but the only case of the M receptor antagonist, which has been successfully developed into the percutaneous drug delivery system, is only oroxicin Bunin.
Most M receptor antagonists are not suitable for the development of the transdermal drug delivery system, especially the hydrogel system. There are two reasons for it: first, the hydrogels often contain a large number of polar solvents, and the solubility of M receptor antagonists in these solvents is low, especially when a large amount of water is contained in the hydrogel matrix, and the crystallization of the drugs is difficult to solve, and the drug is given after the drug. The crystallization of M is one of the reasons for the low and unstable effect. This problem is also one of the reasons for the delisting of some transdermal drug delivery systems. Secondly, some of the M receptor antagonists have complex molecular structures, which are difficult to penetrate the cuticle of the skin, resulting in the weak transdermal capacity and difficult to reach the high blood concentration, resulting in low bioavailability of the hydrogel. Tortero In the development of the percutaneous drug delivery system, in addition to the above problems, there is a problem that the drug itself is a semi solid with low melting point and high viscosity, which leads to the inconvenience of transfer and application. In this study, the preparation method of Ttot Luoding membrane hydrogels was successfully developed on the basis of different drug properties and different drug conversion ideas. The ultimate optimum prescription was obtained. The introduction of film forming material further improved the drug release behavior and application of the hydrogel, and the effect was more stable in use. In the study of the transdermal mechanism, the molecular morphology and the skin pathway of TUTT Luoding transdermal were expounded, and the reasons for the optimization of the high bioavailability of the prescription were also revealed.
1, Tortero's theorized properties and gel materials are preliminarily investigated.
This part is carried out in the second chapter. Tote Luoding is often in the form of tartaric acid. To improve the TUTT Luoding transdermal volume and facilitate the preparation of hydrogels, tartaric acid in the tartaric acid Tote Luoding (Tolterodine tartrate, TT) should be removed to make it converted to the solubility and oil of the free alkali totte Luoding (Tolterodine free base, TB).TB. The distribution coefficient (logP) is the key factor to determine whether the hydrogel can be successfully prepared. Because the TB molecule contains two benzene rings and a large number of alkane chains, it is very soluble in water and the solubility is only 107.11 g/ml. When the water content of the hydrogel matrix is high, TUTT Luoding is easily precipitated and the effective drug permeable concentration is reduced. This is the preparation of high biological use. One of the difficulties in the ditote Luoding membrane hydrogel is that the more likely the logP is the closer to 1 of the drug through the biofilm, the TB molecule contains the phenolic hydroxyl group and the three grade amine structure, which makes its dissociation and charge charge susceptible to pH, and the logP is far less than 1, especially in the vicinity of pH7, and the TB molecules are liable to take two positive and negative charges and make their logP further decline. The decrease of skin permeability is two difficulty in preparing the high bioavailability of Ttot Luoding film hydrogels. Considering the possible electrification of TB molecules near pH7, 3 kinds of gel materials with good compatibility with TB are selected: anionic gel material carbomer 980, neutral gel material high substituted hydroxypropyl cellulose (H-HPC) and neutral gel Material hydroxypropyl methyl cellulose (HPMC). Their swelling ability in water and ethanol is preliminarily investigated. The results show that the swelling ability of gel materials in water or anhydrous ethanol is better than that of HPMC in anhydrous ethanol, except that it is almost non swelling in anhydrous ethanol.
2, optimization of preparation and prescription of hydrogels
This part is carried out in the third and fourth chapters. In order to solve the problem of TB transfer and inconvenient application, two kinds of drug treatment methods are developed by ethanol lye conversion and triethanolamine conversion. Different drug treatment methods are suitable for the preparation of different membrane hydrogels, because of the corresponding post drug loading method for the ethanol conversion method. Two hydrogels were prepared by the first drug loading method corresponding to the triethanolamine transformation method. The post loading method was a preliminary screening of the key factors affecting the gelation ability of the gel material, the solubility of TB and the ability of the gelation of the gel. On this basis, the prescription was optimized in a more scientific system.
The TB ethanol solution prepared by the ethanol lye conversion method was used to prepare the hydrogel by the drug loading method. First, a single factor experiment was carried out, including the content of carbomer 980 in the prescription, the effect of H-HPC content on the properties of hydrogel, the effect of water consumption, time, H-HPC particle size and temperature on the stability of the drug in the later storage of the water. Twain 80, The solubility of ethyl acetate and organosilicon elastomers to increase the solubility of drugs in the matrix; the feasibility study on the film formation of hydrophilic gelatin, polyvinyl alcohol and HPMC in hydrogel. Secondly, the in vitro transdermal experiment of hydrogels was carried out through the Franz diffusion pool, and the drug permeation, the cumulative release rate and the steady state of the gel in vitro were investigated. The release rate. Finally, the pharmacokinetics of the optimized prescription rats were investigated. The results showed that, when the HPMCk4m was selected as the film forming material, the tote Luoding film hydrogel with the maximum dose of 2% was prepared by the post loading method; Twain 80 could effectively increase the solubility of TB, while the high content of the gel could affect the formation of the hydrogel membrane. It contained 20% Twain 80. 3. The absolute bioavailability of 24h in 54% loading hydrogel rats was 21.87%, suggesting that Twain 80 had an obvious effect on improving the transdermal rate of TB. The first drug loading method was the preparation of TUTT Luoding hydrogel on the basis of the triethanolamine conversion process. The key factors for the formulation of the medicine were water, ethanol, and drug loading. Quantity, Twain 80, HPMC, the formulation range of transparent hydrogel was obtained through the drawing of three phase diagram, and the effect of water molecular type on the drug precipitation in the gel matrix was expounded. The response surface experiment further optimized the film forming material, Twain 80 and the range of drug loading, and finally obtained the film formulation with the highest cumulative release rate of 24h. The in vitro results of mouse skin showed that the cumulative release rate of 24h was 86.02%, which was very close to the predicted results of 85.42%. In addition, the absolute bioavailability of 24h in rats was 24.53%.
3, study on transdermal mechanism and efficacy
In the fifth and sixth chapters, the transdermal mechanism and pharmacodynamics related studies were carried out to further clarify the transdermal capacity of TUTT Luoding, the molecular form of transdermal and the cuticle pathway of transdermal passage.
First, the skin permeability and distribution in different skin structures of totte Luoding were investigated. The steady-state release rates of drug homeostasis in rat skin, epidermis, dermis and subcutaneous tissue were 15.83,18.55,37.15 and 81.82 gcm-2h-1 respectively. It was sure that Ttot Luoding hydrogel was suitable for system administration. After topical application, the drugs can reach the bladder through skin and blood, so as to play a therapeutic effect.
The essential reason for the optimization of the bioavailability of the prescription is that the hydrogel makes Tote Luoding more easily permeable through the skin. The hydrogen bonds in the bilayer of the lipid in the cuticle of the rat skin are examined by Fu Liye transform infrared, and the key factors in the cuticle are examined by the differential calorimetry, which are the key factors of Twain 80 and triethanolamine. The effects of the amount and melting point of the two experimental results all suggest the changes in the hydrogen bonds of the lipid in the cuticle of the rat's skin. The optimum prescription of the transdermal activation energy of TB in the prescription Ea is 8.638kcal/mol, which is close to the activation energy 10.7kcal/mol of the chloride ion through the bilayer of the human skin stratum corneum, and the hydrogel pH is near 7.4, further explaining Tote Luoding In the form of a negative charged ion, the transdermal permeation of the lipid bilayer of the stratum corneum is transacted, and the change of the hydrogen bond of the lipid structure in the stratum corneum is confirmed. In addition, the electrostatic repulsion with the carbomer 980 in the totte Luoding belt is beneficial to its diffusion into the skin. The result of this study can be 3,3- two. A theoretical basis for the development of the transdermal drug delivery system of phenylalanine M receptor antagonists is provided.
The results of hydrogel efficacy test showed that the preferred tot Luoding membrane hydrogel could reduce the cumulative urine volume of 12h in urinary incontinence rats. The results of continuous drug delivery showed that the hydrogel could achieve the long-term treatment of OAB.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R943
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