02 處方設(shè)計(jì)課件

第二章藥物制劑處方前研究和處方的設(shè)計(jì)涂家生2010年3月02處方設(shè)計(jì)內(nèi)容第一節(jié)概述第二節(jié)藥物制劑設(shè)計(jì)基礎(chǔ)第三節(jié)藥物制劑處方前工作第四節(jié)藥物制劑處方優(yōu)化第五節(jié)新藥制劑的研究與申報(bào)02處方設(shè)計(jì)第一節(jié)概述藥物制劑的設(shè)計(jì)包括：選擇給藥途徑、劑型、輔料和制備工藝02處方設(shè)計(jì)藥物開(kāi)發(fā)過(guò)程藥理活性篩選毒理學(xué)和分析方法處方前研究臨床研究處方設(shè)計(jì)和制備制劑的有效性和安全性申報(bào)臨床研究臨床研究申報(bào)生產(chǎn)02處方設(shè)計(jì)第二節(jié)藥物制劑設(shè)計(jì)的基礎(chǔ)

一、給藥途徑和劑型的確定（一）治療目的：治療的輕重緩急（速效與緩釋?zhuān)⑸渑c其它途徑）；作用時(shí)間和用藥周期；作用部位；治療人群；等等。（二）藥物的理化性質(zhì)：溶解度、油水分配系數(shù)和穩(wěn)定性等。（三）藥物的藥理學(xué)特性：是否有明顯的副作用，作用強(qiáng)弱等。（四）藥物的ADMET：吸收對(duì)制劑的設(shè)計(jì)影響大。02處方設(shè)計(jì)二、制劑設(shè)計(jì)的原則1、安全性原則：藥物本身的安全性；近年來(lái)的輔料問(wèn)題；劑型的問(wèn)題。2、有效性原則：應(yīng)確保有效，靶向性提高有利于有效性的保證。3、可控性原則：藥物的質(zhì)量可控（生產(chǎn)可控和產(chǎn)品質(zhì)量可控）。4、穩(wěn)定性原則：藥物制劑應(yīng)保證其有效期（一般要求兩年）。5、順應(yīng)性原則：醫(yī)生、患者應(yīng)能接受。02處方設(shè)計(jì)三、藥物的劑型與吸收1、固體口服制劑的吸收：生物利用度BA藥物是關(guān)鍵：BCS分類(lèi)，理化性質(zhì)的影響劑型可以改善生物利用度輔料可以改善生物利用度制劑工藝可以改善生物利用度02處方設(shè)計(jì)物質(zhì)通過(guò)生物屏障的過(guò)程被動(dòng)擴(kuò)散的因素:

-表面通透性

-物質(zhì)的濃差

-表面積通透性影響因素:

-脂溶性

-介質(zhì)pH -化合物的解離常數(shù)

途徑被動(dòng)易化主動(dòng)02處方設(shè)計(jì)BCS分類(lèi)ClassII

lowsolubilityhighpermeabilityClassIIIhighsolubilitylowpermeabilityClassI

highsolubilityhighpermeabilityClassIV

lowsolubilitylowpermeabilityPermeabilitySolubilityLowLowHighHigh02處方設(shè)計(jì)三、藥物的劑型與吸收2、皮膚、黏膜給藥：吸收途徑與藥物的關(guān)系油水分配系數(shù)的影響促吸劑02處方設(shè)計(jì)四、制劑的評(píng)價(jià)和生物利用度1、毒理學(xué)評(píng)價(jià)：制劑的安全性2、藥效學(xué)評(píng)價(jià)：有效性的確定3、藥物動(dòng)力學(xué)和生物利用度：確定和評(píng)價(jià)制劑的質(zhì)量的關(guān)鍵02處方設(shè)計(jì)生物利用度DoseDestroyedingutNotabsorbedDestroyedbygutwallDestroyedbylivertosystemiccirculation02處方設(shè)計(jì)PlasmaconcentrationTime(hours)i.v.routeoralroute絕對(duì)生物利用度(AUC)o

(AUC)iv02處方設(shè)計(jì)第三節(jié)處方前研究

一、處方前工作的重要性1、在處方設(shè)計(jì)前應(yīng)對(duì)藥物的物理、化學(xué)性質(zhì)有一個(gè)完整的了解，這樣可以避免走彎路。2、應(yīng)考察處方的組分的相互作用：復(fù)方制劑主要成分間、輔料與主藥間的相互作用。3、治療學(xué)要求、給藥方式是設(shè)計(jì)藥物制劑的關(guān)鍵。4、只有掌握了藥物的吸收特點(diǎn)，才可以較好地設(shè)計(jì)處方、工藝。02處方設(shè)計(jì)二、處方前工作的內(nèi)容1、物理學(xué)性質(zhì)研究：2、化學(xué)性質(zhì)研究：3、生物學(xué)性質(zhì)研究：4、可以通過(guò)文獻(xiàn)查閱資料：可以避免不必要的彎路。如Internet:Google,Endnote,Pubmed,Sciencedirect,等等。期刊、CA、BA等5、可以進(jìn)行簡(jiǎn)單的實(shí)驗(yàn)：02處方設(shè)計(jì)三、藥物的理化性質(zhì)測(cè)定物質(zhì)結(jié)構(gòu)、分子式、分子量物理狀態(tài)：固體、液體、氣體等。溶解度與溶出速度熔點(diǎn)與多晶型分配系數(shù)吸濕性粉體學(xué)性質(zhì)穩(wěn)定性02處方設(shè)計(jì)02處方設(shè)計(jì)物質(zhì)結(jié)構(gòu)、分子式、分子量可以通過(guò)分子式、分子量判斷吸收的情況。結(jié)構(gòu)式可以作為藥物化學(xué)性質(zhì)的判斷依據(jù)。

02處方設(shè)計(jì)物理狀態(tài)物理狀態(tài)：固體、液體、氣體等。

1、氣態(tài)：Thegaseousstate--Gaslaws,realvsidealgases2、液態(tài)：TheLiquidstate--Criticaltemp.andpressure,vaporpressureandboilingpoint,Clausius-ClapeyronEquation3、固態(tài)：TheSolidstate--Crystallinevsamorphousstate,crystalhabit,meltingorfreezingpoint,Clapeyronequation,polymorphism. 02處方設(shè)計(jì)Kaplan理論：pH1-7

37oC,藥物溶解度<1%或/和溶出速度<0.1mg/(cm2.min)時(shí)，藥物的吸收將受限。離解平衡：Henderson-Hassalbachtheoryofdissociation：pH=pKa+log([A-]/[HA])Acids,basesandsalts：從結(jié)構(gòu)可以看出Arrhenius,Bronsted-Lowry,andLewisconceptsConjugateacid-basepairsIonizationconstant：可以測(cè)定Determination,anditsimportanceinpharmacyIonizationofWeakacids,weakbasesandsaltsPharmaceuticalbuffersandbufferequationBuffercapacityanditsdetermination. 溶解度與離解平衡pKa02處方設(shè)計(jì)02處方設(shè)計(jì)溶解度和溶出速度溶出速度:符合Noyes-WhitneyEquation02處方設(shè)計(jì)02處方設(shè)計(jì)分配系數(shù)藥物具有適中的油水分配系數(shù)是吸收的關(guān)鍵之一P=(油相中藥物的濃度/水相中藥物的濃度)常用正辛醇/水中的logP02處方設(shè)計(jì)熔點(diǎn)與多晶型

多晶型（Polymorphism）的意義:1.多晶型反映了結(jié)晶的能量不一致;2.疏水性藥物多晶型中無(wú)定晶型、亞穩(wěn)晶型、穩(wěn)定晶型的溶解度和溶出速度不一樣，故生物利用度不一樣02處方設(shè)計(jì)02處方設(shè)計(jì)多晶型及其鑒定ThermomicroscopyDifferentialScanningCalorimetryThermogravimetryMicrocalorimetry/SolutionCalorimetry(N)IRandRamanSpectroscopyX-RaydiffractionmethodsSolid-stateNMRspectroscopyPycnometry..........02處方設(shè)計(jì)02處方設(shè)計(jì)02處方設(shè)計(jì)如何改變多晶型晶型變化：晶型互變enantiotropism和晶型不可逆轉(zhuǎn)變Monotropism晶型轉(zhuǎn)變：可以通過(guò)重結(jié)晶獲得。02處方設(shè)計(jì)吸濕性吸濕性hygroscopicity:物質(zhì)從空氣中吸收水分的性質(zhì)。結(jié)晶水與吸附水可以通過(guò)熱重分析(TGA)獲得。ThermogravimetricAnalysis(TGA)measuresweightchangesinamaterialasafunctionoftemperature(ortime)underacontrolledatmosphere.吸濕曲線02處方設(shè)計(jì)TGA02處方設(shè)計(jì)粉體學(xué)性質(zhì)粉體學(xué)性質(zhì)：密度、粒徑、流動(dòng)性、電荷Micromeritics ParticlesizeSizedistributionDeterminationofparticlesizePharmaceuticalimportanceofparticlesize.02處方設(shè)計(jì)四、穩(wěn)定性研究穩(wěn)定性O(shè)rderofreactionZero,first,second,pseudo-firstorderreactionsHalf-life,rateconstantsandtheiruseFactorsaffectingdrugstabilityMoisture,air,lightandtemperatureEffectoftemperatureonreactionkineticsAcceleratedstabilitytestingNon-linearkineticsMichaelis-Mentenequation02處方設(shè)計(jì)第四節(jié)藥物制劑的處方優(yōu)化一、影響因素研究的試驗(yàn)設(shè)計(jì)法：用統(tǒng)計(jì)學(xué)的方法指導(dǎo)試驗(yàn)：包括析因設(shè)計(jì)、分式析因設(shè)計(jì)、正交設(shè)計(jì)、均勻設(shè)計(jì)、效應(yīng)面設(shè)計(jì)法等，有很多軟件可以幫助試驗(yàn)。二、優(yōu)化技術(shù)：?jiǎn)渭冃蝺?yōu)化法、效應(yīng)面02處方設(shè)計(jì)一、效應(yīng)面優(yōu)化技術(shù)對(duì)于效應(yīng)面，可以直接通過(guò)圖形分析或二次多項(xiàng)式獲得優(yōu)化。這種方法直觀、易行。但如果因素多則不易進(jìn)行。02處方設(shè)計(jì)圖形優(yōu)化技術(shù)舉例某水溶性藥物（33%）的片劑，以乳糖、微晶纖維素為填充劑，HPMC為粘合劑，交聯(lián)聚維酮作為崩解劑，微粉硅膠、硬脂酸鎂作為潤(rùn)滑劑。制備工藝為濕法制粒、壓片工藝。以5因素進(jìn)行試驗(yàn)（表1）。試驗(yàn)指標(biāo)為Y1（顆粒細(xì)粉比%）、Y2（片劑脆碎度）、Y3（硬度）以及可壓性指標(biāo)（Y4：壓力傳遞比=F1/F2*100%；Y5：壓縮指數(shù)即硬度與下沖壓力比）02處方設(shè)計(jì)表1造粒/壓片因素表操作因素區(qū)域或范圍藥物、輔料混合固定粘合劑用量X12750±250制軟材時(shí)間X24.5±1.5干燥顆粒含水量X31-3%整粒篩目X41-1.25mm與CPVP、硅膠混合時(shí)間固定與硬脂酸鎂混合時(shí)間X53.5±2.5壓力固定02處方設(shè)計(jì)實(shí)驗(yàn)結(jié)果經(jīng)實(shí)驗(yàn)設(shè)計(jì)得方程：02處方設(shè)計(jì)實(shí)驗(yàn)設(shè)計(jì)的效應(yīng)面等高線圖02處方設(shè)計(jì)02處方設(shè)計(jì)試驗(yàn)效應(yīng)面的三維圖02處方設(shè)計(jì)優(yōu)化結(jié)果可以看出整粒孔徑對(duì)各項(xiàng)指標(biāo)無(wú)影響，選用1.25mm；潤(rùn)滑劑混合時(shí)間的影響也較小，選擇3分鐘；由硬度、壓縮指數(shù)可以?xún)?yōu)化得殘留水分在3%較好；如果選擇細(xì)粉%在25-35%、壓力傳遞≥80%，脆碎度≤0.3%通過(guò)三者重疊可以獲得優(yōu)化條件。02處方設(shè)計(jì)二、單純形優(yōu)化技術(shù)單純形法是一種優(yōu)化設(shè)計(jì)方法，是求解非線性多元函數(shù)優(yōu)化值、無(wú)約束問(wèn)題的優(yōu)秀方法。特點(diǎn)：計(jì)算簡(jiǎn)便不受因素?cái)?shù)的限制因素?cái)?shù)的增加不會(huì)導(dǎo)致試驗(yàn)次數(shù)大量增加它屬于非線性動(dòng)態(tài)調(diào)優(yōu)過(guò)程02處方設(shè)計(jì)發(fā)展簡(jiǎn)史1962年，Spendley提出基本單純形法1965年，Nelder等提出改進(jìn)單純形法Routh提出加權(quán)形心法與控制加權(quán)形心法02處方設(shè)計(jì)1、基本單純形（1）雙因素基本單純形法 如果我們有一個(gè)試驗(yàn)設(shè)計(jì)，只選有兩個(gè)影響因素，即因素?cái)?shù)為2。分別取值a1和a2作為試驗(yàn)的初點(diǎn)。記為A(a1,a2)。對(duì)其余兩個(gè)點(diǎn)分別設(shè)為B和C，再設(shè)三角形的邊長(zhǎng)為a(步長(zhǎng))。那么B、C點(diǎn)就可以計(jì)算出來(lái)02處方設(shè)計(jì)圖解a2+pa2+qa2a1+pa1+qa1因素2因素1ABCDEo

02處方設(shè)計(jì)假設(shè)AB、AC、BC間距均為，等邊三角形可以算出B點(diǎn)為：

B=(a1+p,a2+q)根據(jù)對(duì)稱(chēng)性可知：

C=(a1+q,a2+p)可以根據(jù)等邊三角形性質(zhì)解得：02處方設(shè)計(jì)由A、B、C三點(diǎn)構(gòu)成得單純形稱(chēng)為初始單純形首先在A、B、C三點(diǎn)下分別試驗(yàn)，得出三個(gè)響應(yīng)值，比較其大小，找出最壞響應(yīng)值的點(diǎn)稱(chēng)為壞點(diǎn)此處設(shè)A為壞點(diǎn)，去掉A點(diǎn)并取A的對(duì)稱(chēng)點(diǎn)D點(diǎn)作為新試驗(yàn)點(diǎn)，比較B、C、D三點(diǎn)響應(yīng)值的好壞此處設(shè)C為壞點(diǎn)，去點(diǎn)C點(diǎn)，取其反點(diǎn)E，此時(shí)C、D、E三點(diǎn)又構(gòu)成新的單純形…………重復(fù)以上結(jié)果，最終達(dá)到優(yōu)化試驗(yàn)的目的02處方設(shè)計(jì)新試驗(yàn)點(diǎn)的計(jì)算方法

以初始單純形A、B、C為例，設(shè)A為壞點(diǎn)，A應(yīng)該去掉，求其反射點(diǎn)D，此時(shí)

A(a1,a2)、B=(a1+p,a2+q)、C=(a1+q,a2+p) D=B+C-A=(a1+p+q,a2+p+q) E=B+D-C=(a1+2p,a2+2q)即：[新試驗(yàn)點(diǎn)]＝[留下各點(diǎn)之和]－[去掉點(diǎn)]02處方設(shè)計(jì)小結(jié)對(duì)兩因素問(wèn)題A、B、C構(gòu)成初始單純形，在此三點(diǎn)上進(jìn)行試驗(yàn)規(guī)則1：去掉最壞點(diǎn)，用其對(duì)稱(chēng)反射點(diǎn)作新試點(diǎn)例A、B、C中，A為最壞點(diǎn)，去掉A點(diǎn)并取A的對(duì)稱(chēng)點(diǎn)D點(diǎn)作為新試驗(yàn)點(diǎn)。D＝[留下各點(diǎn)之和]－[去掉點(diǎn)]＝B＋C－A在B、C、D三角形中繼續(xù)使用規(guī)則1，如果C為壞點(diǎn)，去點(diǎn)C點(diǎn)，取其反點(diǎn)E，此時(shí)C、D、E三點(diǎn)又構(gòu)成新的單純形。如果最壞點(diǎn)為D那么對(duì)稱(chēng)點(diǎn)就會(huì)返回到與A重合，此時(shí)改用規(guī)則202處方設(shè)計(jì)規(guī)則2：去掉次壞點(diǎn)，用其對(duì)稱(chēng)反射點(diǎn)作新試點(diǎn)對(duì)稱(chēng)計(jì)算公式與前面相同經(jīng)過(guò)反復(fù)使用后，如果有一個(gè)點(diǎn)老是保留下來(lái)，必須使用規(guī)則3規(guī)則3：重復(fù)、停止和縮短步長(zhǎng)一般一個(gè)點(diǎn)經(jīng)3次單純形后仍未被淘汰，它可能是一個(gè)很好點(diǎn)，也可能是偶然性或試驗(yàn)誤差導(dǎo)致的假象。此時(shí)需要重復(fù)試驗(yàn)：結(jié)果不好，淘汰；結(jié)果已很滿(mǎn)意則停止試驗(yàn)反之則以它為起點(diǎn)縮短步長(zhǎng)，繼續(xù)試驗(yàn)02處方設(shè)計(jì)（2）多因素基本單純形設(shè)有n個(gè)因素n＋1個(gè)定點(diǎn)構(gòu)成的n維空間單純形，設(shè)有一點(diǎn)A=(a1,a2,

a3,…

an)，步長(zhǎng)為a則其余各點(diǎn)為：

B=(a1+p,a2+q,a3+q,……an+q)C=(a1+q,a2+p,a3+q,……an+q)(n)=(a1+q,a2+q,…an-1+p,

an+q)(n+1)=(a1+q,a2+q,a3+q,……an+p)02處方設(shè)計(jì)新點(diǎn)計(jì)算同樣按上述方法，在n+1個(gè)試驗(yàn)中找出壞點(diǎn)，取其反點(diǎn)，組成新n+1單純形，試驗(yàn)，重復(fù)至所謂壞點(diǎn)與反點(diǎn)的值無(wú)統(tǒng)計(jì)學(xué)差異。新點(diǎn)計(jì)算：[新坐標(biāo)點(diǎn)]＝2×[n留下點(diǎn)的坐標(biāo)和]/n

－[去掉點(diǎn)坐標(biāo)]02處方設(shè)計(jì)n，p，q取值對(duì)應(yīng)表n2345678pqn9101112131415pq0.966

0.943

0.926

0.911

0.901

0.892

0.883

0.259

0.236

0.219

0.204

0.194

0.185

0.176

0.878

0.872

0.865

0.861

0.855

0.854

0.848

0.171

0.165

0.158

0.154

0.148

0.147

0.141

02處方設(shè)計(jì)第五節(jié)新制劑的申報(bào)資料：處方、工藝資料；穩(wěn)定性資料；溶出度或釋放度資料；生物等效性資料。02處方設(shè)計(jì)StrategiestoimprovetheabsorptionbehaviourSolubility/DissolutionParticlesizeCrystalhabitPolymorphsPseudopolymorphs/solvatesComplexation/solubilizationDispersionintocarriersPro-drugsSaltsPermeabillityPro-drugsEnhancersPhysicalmodificationChemicalmodificationBiochemicalmodification02處方設(shè)計(jì)ONOH

O

O

OCl

O

O

ONNOClNNClClF3CNOHgriseofulvincinnarizinehalofantrinediazepamdanazolPoorlywater-solublecompounds02處方設(shè)計(jì)Physico-chemicaldescriptorsofsomepoorly

water-solublecompounds

MP Solubilityat37°C,pH7.5Drug °C MWpKa logP AqueousFastedFedGriseofulvin220352.8n/a2.214.618.438.8Diazepam125284.73.42.959.7115.6318Danazol226337.5n/a4.50.88.741.1Cinnarizine-368.57.55.8*<0.158.330.21.9Halofantrine85500.45.68.9*<0.112.660.7HCl-salt190(dec)536.7*Calculatedvalue,ACD-labsFastedmicelles5mMNaTDC/1.25mMPCFedmicelles20mMnaTDC/5mMPC02處方設(shè)計(jì)Lipidsolubilitiesofsomepoorlywater-solublecompounds

EquilibriumSolubility(mg/g)at37°CDruglogPSBOCaptexMaisineCapmulGriseofulvin2.20.50.91.94.4Diazepam2.918.330.344.059.1Danazol4.53.98.711.921.6Cinnarizine5.8*27.040.736.236.4Halofantrine8.9*47.389.049.126.1SBO=soybeanoil,longchaintriglyceride(C18)Captex355=mediumchaintriglyceride(C8/C10)Maisine35-1=partialglycerides(C18),mainlymono-glycerideCapmulMCM=partialglycerides(C8/C10),mainlymono-glyceride02處方設(shè)計(jì)通過(guò)前體藥物提高溶解度Phenytoinmp293?Caqueoussolubility25mg/mlpKa8.3(weakacid)lowlipidsolubilityNa-phenytoininjectableformulationat50mg/ml-pH~12-40%propyleneglycol-10%ethanol-50%waterFosphenytoinWatersolubleChemicallystableatneutralpHBioreversablet?=1mininrats=8-17mininhumanNonirritative,quantitativephenytoinreleaseafterIMorIVadm.Shelf-lifeprolongedbyadditionofCaptisol(b-cyclodextrinder.)tosolubilizephenytoinformedbydegradation02處方設(shè)計(jì)固體分散體Eutecticmixtures-mixtureoftwocomponentsatspecificratio-onemelting/crystallizationpointSolidsolutions-comparabletoliquidsolutions-consistofonephaseirrespectiveofnumberofcomponents-classifiedaccordingtomiscibility-continuous(miscibleinallproportions)-discontinuous(limitedsolubilityofeachcomponentintheother)-5%solubilityofdrugincarrierconsideredaspracticallimit-classifiedaccordingtodistributionpatternincarrier-substitutional,interstitial,amorphousLeunerandDressman2000,Eur.J.Pharm.Biopharm.50:47-60ImprovedwettingIncreasedsurfaceareaImprovedapparentsolubility(local)02處方設(shè)計(jì)固體分散體TypesofcarriersNon-solubilizingpolymericcarriers(non-micelle/emulsionforming)-highlysoluble-PEG1500-20000-PVPgradesK12-30,Mw2500-50000-effectsofMwonviscosity,solubility/dissolutionrateandmeltingpoint-effectsofdrug/polymerratioSolubilizingcarriers-formspontaneouslymicellarsolutions/emulsionuponcontactwith

aqueousmediumcansolubilizelipophiliccompounds-Gelucire(mixtureofglycerides,mixedchainlengthC8-C18,and

PEGesters)-VitaminETPGS(D-a-tocopherylPEG1000succinate)LeunerandDressman2000,Eur.J.Pharm.Biopharm.50:47-6002處方設(shè)計(jì)Complexation/solubilizationoflipophiliccompounds

(1)

cyclodextrincavitylipophilic,thermodynamicallyfavorabletoinsert

lipophiliccompoundandexcludewatermoleculescomplexationanequilibriumreaction-concentrationofdrugandcyclodextrin-temperature,

-chargestateofcompound-structureofcompound(fit)-sizeofcyclodextrincavity[Drug]+[CD][Drug?CD]KdKd=[Drug?CD]/[Drug][CD]02處方設(shè)計(jì)

aqueoussolubilityincreasedbyintroductionofsubstituentstoOH-groupshydroxypropylb-cyclodextrin(un-ionised)(Encapsin,Molecusol)sulfobutyletherb-cyclodextrin(ionised)(asNa+-salt)(Captisol)developedtoobtaincyclodextrinforparenteraldelivery-b-cyclodextrinnephrotoxicduetoprecipitationofcholesterol

complexesinkidneyComplexation/solubilizationoflipophiliccompounds(2)02處方設(shè)計(jì)Complexation/solubilizationoflipophiliccompounds(3)PhasesolubilitytechniqueLinearincreaseinamountsolubilized1:1complexesformed(drug:CD)dilutionnotlikelytoprecipitatecompoundeasytocalculateaapparentstabilityconstantPositive(AP)ornegative(AN)deviations

fromlinearity-presenceofalsoothercomplexratiosthan1:1-morecomplicatedtoestimateB-typediagramswhenprecipitationof

complexoccurs-typicalforb-cyclodextrin(lowsolubility)HiguchiandConnors1965,Adv.Anal.Chem.Instr.4:117-21202處方設(shè)計(jì)PhysiologicaleffectsofcyclodextrinsDuetocapacityofcyclodextrinstosolubilizeendogenous/membranecomponents-phospholipids/a-CD-cholesterol/b-CDandderivatives-bilesalts/b-CDandderivativesIonizedsubstituentsandhighdegreeofsubstitutionSBE7-b-CD(Captisol)-highaqueoussolubility-unabletoform1:2complexeswithcholesterollowhaemolysislownephrotoxicityb-CDefficientsolubilizer

ofcholesterolbutcomplexhaslowsolubility

causeofnephrotoxicity02處方設(shè)計(jì)FromCaptisoltechnicalpresentation,CyDex,Inc.2000Effectofdrugchargeoncomplexationbehaviourwithneutralandanionicb-cyclodextrin02處方設(shè)計(jì)J?rvinenetal1995,J.Pharm.Sci84:295-299Cinnarizinebioavailabilitydosedwithb-cyclodextrinderivativescomparedtocyclodextrin-freeformulationsBAfromcyclodextrinformulations>>cyclodextrin-freedespitehighbindingconstantsHP-b-CDsolution>SBE4-b-CDsolution>SBE4-b-CDsolidcomplexDogmaynotbeagoodmodelforcinnarizineabsorption-highandvariablegastricpH-BAinhumanfromkonventionaltabletsrelatedtogastricpH

lowpHfairBAStudiedindogs02處方設(shè)計(jì)Commercialcyclodextrinbaseddrugproducts02處方設(shè)計(jì)IncreasedBAwithfattyfoodoflipophiliccompoundlipidformulationpotentialstrategyincreasedsolubilizationofcompoundpotentialforreducedmetabolism/effluxpotential/dangerforintestinallymphatictransportLipidsasformulationstrategyOilycarriersmayfunctionalsoforhydrophiliccompounds-protectionagainstintestinalproteases-improvedstabilityinthepresenceofphysiologicalsurfactants-alteredcellpermeability

NewandKirby1997,Adv.DrugDel.Rev.25:59-69

02處方設(shè)計(jì)ThefattyfoodeffectlipidformulationeffectIncreasedsolubilizationofpoorlywater-solublecompounds-slowergastricemptying(lipidchainlengthdependent)increasedgastricandintestinalsecretion(lipidchainlengthdependent)-increasedvolume

-increasedBSandPLconcentration-digestionproductsoflipidsincorporatedintomixedmicellesPotentialchangestophysicalbarrierfunction-increasedmembranepermeability(mainlymediumchainlipids)Potentialchangestothebiochemicalbarrierfunction-effectsonP-GP-effectsonintestinalmetabolismStimulationofintestinallymphatictransportoflipids(lipidchainlengthdependent)-potentialpathwayforhighlylipophilic(lipidsoluble)compounds02處方設(shè)計(jì)Gastric/GILumenProcessingoflipidsandco-administereddrugEnterocyteSystemicCirculationDigestionSolubilizationAbsorptionLymphatictransportPortalblood(Lipo)proteinbindingSiteofactionDispersionanddigestionAbsorptionandmetabolismDistributionPDandPKprofilesGastricDuodenalBile(BS/PL)02處方設(shè)計(jì)

IntestinalPre-absorptiveProcessesemulsionvesiclesmicellessoapsDrugIII.Destabilisationofmicelles

absorptionII.TraffickingofdrugdistributionbetweencolloidalspeciesI.Lipiddigestionunstirredwater-layeracidicmicro-climate02處方設(shè)計(jì)DDDDDDDDDDDDDDDDDDrugEmulsiondroplets

bilesaltsfattyacidphospholipidmonoglyceridediglycerideDistributionofdrugsolubilizedin