口服控釋改良釋放劑型的發(fā)展

1、evolution of oral controlled/modified release dosage forms口服控釋/改良釋放劑型的發(fā)展oral cr/mr dosage forms口服cr/mr 劑型“extended-release”“延長釋放”“delayed-release”“延遲釋放”controlled release modified release控制釋放 改良釋放potential benefits of controlled release dosage forms控釋劑型的潛在優(yōu)點(diǎn) enhanced activity duration for short half

2、-life drugs 提高短半衰期藥物的有效作用時(shí)間 reduction of side effects 降低副反應(yīng) less frequent dosing - improved patient compliance 減少給藥頻率-提高患者順應(yīng)性 protecting labile drugs - improved product stability 保護(hù)不穩(wěn)定藥物-提高產(chǎn)品的穩(wěn)定性 potential for localization of drug to site of action 將藥物固定于起效部位的可能性 potential for extended patent protec

3、tion 延長專利保護(hù)的可能性how did we get here and where are we going?我們是如何達(dá)到現(xiàn)在的水平并我們是如何達(dá)到現(xiàn)在的水平并將向哪方面發(fā)展？將向哪方面發(fā)展？oral cr/mr dosage forms口服口服cr/mr劑型劑型“蠟丸者, 取其難化, 而旋旋取效也” “use wax pills for their resistance to dissolve thereby achieving the effect gradually and slowly”early slow-release oral dosage forms in chines

4、e medicine中藥中的早期中藥中的早期緩釋緩釋口服劑型口服劑型 2nd century b.c. animal-fats as binder for pills “recipes for fifty-two ailment”, mawangdui medical manuscript, dated 168 b.c. 公元前2世紀(jì)動(dòng)物脂肪作為丸劑的粘合劑“52種疾病的處方”， 馬王堆醫(yī)學(xué)手稿，日期公元前168 4th century a.d. wax and fat pills “handbook of prescriptions for urgent cases”, ko hung (2

5、81-341)公元4世紀(jì)蜂蠟和脂肪丸劑”肘后救卒方 “葛洪 (281-341 13th century wax pills for slow-release “rules and correspondences in the use of drugs”, li kao (1180-1251) & “medications administered as decoctions”, wang hao-ku (mid-13th century)13世紀(jì)緩慢釋放的蠟丸” 藥物使用中的規(guī)則和依據(jù)“l(fā)i kao (1180-1251) & ”按湯劑服用“丸者緩也,.其用藥之舒緩而治之意也”

6、“such pills are slow actingthey provide the drug gradually and slowly for treatment”earliest record of slow-release dosage forms for therapeutic use!治療所用緩釋劑型的早期記載types of long-acting preparations, 1959長效制劑的類型，長效制劑的類型，1959coating the active drug with gastro-resistant and slowly enterosoluble substanc

7、es (e.g. fats, waxes, fatty acids, ets.)使用抗胃液和減慢腸溶解的物質(zhì)包裹活性藥物（比如，脂肪，蜂蠟，脂肪酸等等）the use of ion exchange resins to bind active drugs使用離子交換樹脂與活性藥物結(jié)合the formation of chemical addition compounds or complexes化學(xué)添加物或合成物的形成impregnating or embedding the drug in a base which gradually releases the active principl

8、e將藥物浸漬或包埋在一個(gè)基質(zhì)中，該基質(zhì)可緩慢釋放活性有效成分major historical milestones affecting the direction of oral controlled release dosage forms影響口服控釋劑型發(fā)展方向的主要?dú)v史里程碑影響口服控釋劑型發(fā)展方向的主要?dú)v史里程碑a(chǎn)vailability of semi-synthetic and synthetic polymers for enteric coating (1940s through 1990s)半合成和合成聚合物用于腸溶包衣（二十世紀(jì)四十年代到九十年代）introduction o

9、f first oral sustained release products by smith kline & french using the spansule technology: dexedrine (dextroamphetamine sulfate) (1952) and contac, the cold remedy (1960). smith kline & french介紹了首個(gè)口服持續(xù)釋放產(chǎn)品，使用了緩釋膠囊劑（spansule）技術(shù)： dexedrine（右旋硫酸右苯丙胺）（1952）和contac（復(fù)方鹽酸苯丙醇胺），感冒藥（1960）introduc

10、tion of semi-synthetic and synthetic hydrophilic gel forming polymers for designing oral sustained release products (1950s and 1960s)半合成和合成親水凝膠形成的聚合物介入口服持續(xù)釋放產(chǎn)品設(shè)計(jì)（二十世紀(jì)五十年代和六十年代）invention and first commercialization of oral osmotic drug delivery systems by alza (1970s through 1980s)alza發(fā)明并首次商業(yè)使用的口腔滲透藥

11、物釋放系統(tǒng)（二十世紀(jì)七十年代到八十年代）“the delayed action tablet which was an extension of the enteric coating principle, represented the initial approach in controlling the release of a drug in the gastro-intestinal tract”“延遲起效片劑是腸溶包衣原理的擴(kuò)展，它代表在胃腸道中控制藥物釋放開始起步” - lazarus and cooper (1959)reasons for enteric protection

12、腸溶包衣的目的腸溶包衣的目的 prevention of gastric irritation 避免胃的刺激 protection of drugs unstable in gastric fluids 避免藥物在胃酸條件下被破壞 delivery of drug to local site in intestine 藥物在腸道特定部位釋放 delivery of drug to best absorption site in intestine 藥物在腸道最佳吸收部位釋放 delayed drug release 藥物延遲釋放enteric coating systems腸溶包衣系統(tǒng)腸溶包衣

13、系統(tǒng)enteric coatings腸溶包衣腸溶包衣1884 dr. paul unna introduced keratin-coated pills1884 paul unna 博士引入了角質(zhì)素包衣丸劑late 1880s to 1930s numerous substances and their combination were used for enteric coating such as keratin, salol, tolu, shellac, casein, zein, stearic acid, gelatin-formaldehyde product, tannic a

14、cid-gelatin product, cetyl alcohol, etc. 十九世紀(jì)八十年代晚期到二十世紀(jì)30年代眾多物質(zhì)及其混合物用于腸溶包衣，比如角質(zhì)素，水楊酸苯酯，妥魯香脂,紫膠，酪蛋白，玉米蛋白，硬脂酸，明膠甲醛產(chǎn)品，鞣酸明膠產(chǎn)品，十六烷醇 等等。1940s cellulose acetate phthalate (cap) introduced二十世紀(jì)四十年代引進(jìn)醋酞纖維素（cap）1970s polyvinyl acetate phthalate (pvap) and hydorxypropyl methylcellulose phthalate (hpmcp) became

15、 available二十世紀(jì)七十年代可使用聚醋酸乙烯鄰苯二甲酸酯(pvap) 和羥丙基甲基纖維素鄰苯二甲酸酯（hpmcp）1980s - methacrylate-methacrylic acid coplymers on the market二十世紀(jì)八十年代異丁烯酸-甲基丙烯酸共聚物出現(xiàn)在市場1980s to 1990s various aqueous dispersions of enteric polymers introduced for tablet coatingshang二十世紀(jì)八十年代到二十世紀(jì)九十年代各種腸溶聚合物水分散系用于片劑包衣 the development of s

16、pansule provided the impetus to the further development of sustained release dosage forms in subsequent years spansule 的發(fā)展為延釋劑型在今后幾年中進(jìn)一步發(fā)展提供了推動(dòng)力 it also stimulated numerous human studies regarding the absorption, distribution and fate of drugs delivered by such dosage forms, thus culminating the sta

17、rt of the study of biopharmaceutics也刺激了眾多針對(duì)在使用這種劑型后吸收，分布和藥物釋放途徑的人類研究，因而使生物藥劑學(xué)的研究開始到達(dá)頂峰multiparticulate drug delivery多顆粒藥物釋放clinical advantages （臨床優(yōu)點(diǎn)）disperse freely in the gi tract, invariably maximize drug absorption, reduce peak plasma fluctuation, and minimize potential side effects. 容易通過胃腸道，有利藥物

18、吸收，降低不良反應(yīng)reduce variations in gastric emptying rates and overall transit times. thus inter- and intra-subject variability of plasma profiles is minimized. 減少因胃排空速率和轉(zhuǎn)運(yùn)時(shí)間不同而產(chǎn)生的差異。從而提高體外釋放和體內(nèi)血漿藥物濃度的相關(guān)性high local concentration of bioactive agents, which may inherently be irritative or anesthetic, can be

19、 avoided. 避免具有刺激性和麻醉性的生物活性物質(zhì)在局部濃度過高less susceptible to dose dumping than the reservoir-type, single unit formulations. 相對(duì)于膜控釋單劑量藥物單元，可減少藥物突釋的可能性水分蒸發(fā)水分蒸發(fā), 聚合物塑化細(xì)小顆粒緊密聚集在一起 poorly plasticised system部分愈合的的薄膜完全愈合薄膜tg聚合物水分散體成膜機(jī)理聚合物水分散體成膜機(jī)理分散物堆積在顆粒表面包衣薄膜包衣薄膜基底基底控釋膜示意圖major historical milestones affecting

20、the direction of oral controlled release dosage forms影響口服控釋劑型方向的主要?dú)v史里程碑影響口服控釋劑型方向的主要?dú)v史里程碑a(chǎn)vailability of semi-synthetic and synthetic polymers for enteric coating (1940s through 1990s) 在腸溶包衣中使用半合成和合成聚合物（20世紀(jì)40年代至90年代）。introduction of first oral sustained release products by smith kline & french

21、using the spansule technology: dexedrine (dextroamphetamine sulfate) (1952) and contac, the cold remedy (1960). smith kline和french引入了首例口服緩釋產(chǎn)品dexedrine（右旋安非他明硫酸鹽 ，1952年）和contac（感冒藥，1960年） ，使用的是分時(shí)溶解藥囊（ spansule ）技術(shù)。introduction of semi-synthetic and synthetic hydrophilic gel forming polymers for desig

22、ning oral sustained release products (1950s and 1960s)引入半合成和合成親水膠成型聚合物，用于設(shè)計(jì)口服延釋產(chǎn)品（20世界50年代和60年代）。invention and first commercialization of oral osmotic drug delivery systems by alza (1970s through 1980s) alza發(fā)明并首次商業(yè)化口服滲透性藥物傳遞系統(tǒng)（20世紀(jì)70至80年代）。ethylcellulose乙基纖維素cellulose acetate乙酸纖維素,醋酸纖維素methacrylic a

23、cid copolymer甲基丙烯酸共聚物hydroxypropyl methylcellulose (hpmc)羥丙基甲基纖維素hydroxypropyl cellulose羥丙基纖維素carbomer卡波姆sodium alginate海藻酸鈉polyethylene oxide聚氧化乙烯white wax白蠟carnauba wax巴西棕櫚蠟shellac紫膠polymersotherearliest example of a controlled-release tablet using swellable & erodible hydrophilic gums includi

24、ng hpmc使用含有使用含有羥丙基甲基纖維素的可溶脹性可溶脹性&易侵蝕親水樹膠的早易侵蝕親水樹膠的早期控釋片劑實(shí)例期控釋片劑實(shí)例“in swelling, a relatively water impermeable barrier is formed at the surface of the tablet which prevents further entry of water into the interior of the tablet. this soft mucilaginous gum gel barrier formed on the surface of the

25、tablet is worn away by the motion of the tablet in the gastro-intestinal tract, and some of the admixed medicinal agent is carried away with it and released. the fresh surface of the tabletbecomes hydrated and swells thus renewing the protective coating. as a result, the tablet is slowly disintegrat

26、ed rather than dissolved and the medicament contained therein is release at a substantially uniform rate.”“溶脹時(shí)，在 片劑表明形成一層相對(duì)不透水層，這可防止水進(jìn)一步滲入片劑內(nèi)部。在片劑表面所形成的這種柔軟的粘性樹膠凝膠層隨片劑在胃腸道移動(dòng)而磨損， 并且一部分混合在內(nèi)藥物隨磨損并釋放。片劑新鮮形成的表面與水結(jié)合并溶脹因而替換了保護(hù)性包衣。結(jié)果，片劑不僅僅是溶解而是緩慢分解并且所含藥物基本以均勻速率釋放?！眜s pat. 3,065,143, christenson and dale (19

27、62)美國專利3,065,143, christenson and dale (1962)mechanism of drug release from hpmc matrix tablets藥物從hpmc基質(zhì)片劑釋放原理dry tablet干燥片劑ingestion of tablet咽下片劑gel layer凝膠層dry core干燥片芯insoluble drug - released by exposure via tablet erosion.不溶性藥物經(jīng)片劑侵蝕暴露釋放soluble drug - released mainly by diffusion through the ge

28、l layer and less via tablet erosion.可溶性藥物主要通過凝膠層擴(kuò)散而極少經(jīng)過片劑侵蝕釋放tablet erosionpolymer concentration at gel surface reaches a threshold disentanglement value and dissolution/erosion of tablet takes place.片劑侵蝕凝膠表面的聚合物濃度達(dá)到崩解閾值，從而片劑發(fā)生溶出/侵蝕growth of gel layer凝膠增變厚凝膠增變厚water swelling front penetrates into th

29、e tablet, gel layer thickness increases, and soluble drug diffuses out of the gel layer.水溶脹上層滲透入片劑，凝膠層厚度增加，可溶性藥物通過凝膠層擴(kuò)散 initial hydration & swellingtablet surface wets and hpmc polymer begins to hydrate, forming a gel layer. initial burst of soluble drug is released from the tablet surface layer

30、.初期的水合作用初期的水合作用&溶脹溶脹片劑表面濕潤并且hpmc聚合物開始形成水合物，形成凝膠層?？扇苄运幬锏耐会屪饔脧钠瑒┍韺娱_始。source: modified from dow technical brochure來源：dow技術(shù)手冊(cè)改進(jìn)formulations are relatively straightforward 處方相對(duì)簡單standard production equipment 不需要特殊設(shè)備reproducible release profiles resistant to drug dumping 釋藥重現(xiàn)性好，不易產(chǎn)生藥物突釋release rate ge

31、nerally insensitive to compression force/tablet hardness 藥物釋放率不易受壓片力/片芯硬度的影響through choice of excipients /polymer level, able to modify release kinetics 通過選擇輔料/聚合物水平，可以調(diào)節(jié)藥物釋放動(dòng)力學(xué)參數(shù)advantages（優(yōu)點(diǎn)）:hydrophilic matrices親水凝膠骨架the most commonly used polymers are cellulose ethers 最為常用的聚合物是纖維素醚類，特別是羥丙基甲基纖維素d

32、ynamic gel thickness development in a swellable matrix tablet溶脹基質(zhì)片劑中凝膠厚度的動(dòng)態(tài)變化current understanding of swelling & erosion controlled systems目前對(duì)溶脹目前對(duì)溶脹&侵蝕控制系統(tǒng)的理解侵蝕控制系統(tǒng)的理解synchronization of swelling & erosion fronts can lead to near zero order release (e.g. in pva and nacmc systems)外部溶脹&

33、;侵蝕的同時(shí)發(fā)生會(huì)引發(fā)近似零級(jí)釋放（比如，在侵蝕的同時(shí)發(fā)生會(huì)引發(fā)近似零級(jí)釋放（比如，在pva和和nacmc 系系統(tǒng)中）統(tǒng)中）in hpmc systems, the gel layer thickness continues to increase with time在hpmc系統(tǒng)中，凝膠層厚度隨時(shí)間不斷增加 for water soluble drugs , diffusion is the dominant mechanism with a time-dependent increase in diffusion coefficient and surface area as a resu

34、lt of continuous swelling 對(duì)于水溶性藥物，擴(kuò)散是主導(dǎo)機(jī)理，由于持續(xù)溶脹的結(jié)果，擴(kuò)散系數(shù)以及表面積隨時(shí)間相應(yīng)增加 for insoluble drugs or soluble drugs at high loading, the erosion mechanism will dominate 對(duì)于不溶藥物或高載藥量的可溶性藥物，侵蝕機(jī)理占主導(dǎo)。typical rate-controlling matrix material代表性的速率-控制基質(zhì)材料hpmc; hpc; peo; na alginate羥丙基甲基纖維素：hpc：聚氧化乙烯：藻(朊)酸鈉examples o

35、f swellable tablet products可溶脹片劑產(chǎn)品實(shí)例indocin (indomethacin; merck)（吲哚美辛； merck ）isoptin sr (verapamil hcl; knoll)（鹽酸維拉帕米； knoll ）trental (pentoxifylline; hmr)（己酮可可堿；hmr）swelling & erosion controlled matrix systems控制溶脹控制溶脹&侵蝕基質(zhì)系統(tǒng)侵蝕基質(zhì)系統(tǒng)osmotic pumping mechanism滲透泵原理滲透泵原理us pat 3,845,770 (1974)

36、by f. theeuwes and t. higuchi美國專利3,845,770 (1974) , f. theeuwes 和 t. higuchi所有precise rate-controlled drug delivery (various temporal patterns)精確的控制藥物釋放速度（各種暫時(shí)模式）delivery rate independent of ph不依賴ph的釋放速度rate-controlling semipermeable membrane控制半滲透薄膜速度cellulose acetate醋酸纖維素push layer (swellable hydro

37、philic polymers)擠壓層（可溶脹親水性聚合物）polyethylene oxide聚氧化乙烯selected examples所選實(shí)例procardia xl (nifedipine; pfizer)（硝苯地平,； pfizer）covera-hs (verapamil hcl; searle)（鹽酸維拉帕米； searle）dynacirc cr (isradipine; norvartis)）（依拉地平； norvartis ）concerta (methylphenidate hcl; mcneil)（鹽酸哌甲酯； mcneil ） controlled-release o

38、ros delivery systems (osmotic pump)控釋控釋口腔滲透的滲透泵緩釋劑（ oros ）釋放系統(tǒng)（滲透泵）swstcspcdtdvdtdm)(elementary osmotic pump初級(jí)滲透泵constant release rate is maintained by a constant osmotic driving force (from excess soluble drug and/or osmotic adjuvant)通過持續(xù)滲透驅(qū)動(dòng)力保持恒定的釋放率（從極易溶藥物和/或滲透佐劑）push-pull osmotic pump推-拉滲透泵const

39、ant release rate is maintained by the constant swelling of hydrogel push layer通過水凝膠擠壓層持續(xù)溶脹保持恒定釋放率useful for delivering low solubility drugs (in a suspension)對(duì)釋放不易溶藥物有用（在混懸液中）pulsatile delivery feasible with multiple compartments (oros tri-layer)可行的多層室脈沖式釋放（ oros 三層）can be adapted for liquid formulat

40、ions (l-oros)適用于液體處方（ l-oros ）osmotic pumping mechanism:滲透泵原理release characteristics釋放特征phenylpropanolamine oros tablet1st osmotic tablet product: “acutrim”n-去甲麻黃堿oros片劑第一個(gè)滲透泵片劑產(chǎn)品：“acutrim”in vivo () & in vitro () delivery profiles體內(nèi)體內(nèi)() & 體內(nèi)體內(nèi) () 釋放曲線predicted & experimental plasma conc

41、entration profiles期望期望&試驗(yàn)血漿濃度試驗(yàn)血漿濃度good and lee (1984)membrane systems - drug core surrounded by a rate-controlling membrane (e.g., microcapsules & coated drug pellets, granules or beads)膜系統(tǒng)-藥芯為速率控制膜包圍（比如，微膠囊&包衣藥物小丸，顆?；蛐∏颍﹎atrix systems - drug dissolved or dispersed in a carrier matrix (

42、e.g., microspheres, beads, pellets, granules & tablets)基質(zhì)系統(tǒng)-藥物溶解或分散于載體基質(zhì)中（比如，微球，小球，小丸，顆粒& 片劑）hybrid sysrtems - a combination of membrane and matrix systems (e.g., coated pellets or beads imbeded in a tablet matrix, coated matrix beads, press-coated matrix tablets) 混合系統(tǒng)-膜系統(tǒng)和基質(zhì)系統(tǒng)的聯(lián)合使用（比如，包衣小丸或

43、串珠包埋到片劑基質(zhì)中，包衣基質(zhì)串珠，壓制包衣基質(zhì)片劑）oral cr/mr dosage form classifications口服口服cr/mr劑型分類劑型分類oral cr mechanisms口服cr機(jī)理diffusion 擴(kuò)散dissolution溶出swelling & erosion 溶脹& 侵蝕geometry/area changes幾何形狀/面積變化nonuniform drug distribution/gradient matrix不均一藥物分布/梯度基質(zhì)solution-diffusion溶解-擴(kuò)散osmotic pumping滲透泵matrix sy

44、stems基質(zhì)系統(tǒng)membrane systems膜系統(tǒng)achievable release profiles完成的釋放曲線 first order (including t dependence) 一級(jí)（包括t 依賴性） zero-order零級(jí) bimodal (including accelerated release)雙峰（包括加速釋放） pulsatile (including delayed release)脈沖式（包括延遲釋放）major development impacting oral controlled release since the 1950s自二十世紀(jì)五十年代以

45、來影響口服控制劑型的自二十世紀(jì)五十年代以來影響口服控制劑型的主要發(fā)展主要發(fā)展the emergence of physical pharmacy and pharmacokinetics as new disciplines in the 1960s二十世紀(jì)六十年代作為一種新學(xué)科出現(xiàn)的物理藥劑學(xué)和藥物代謝動(dòng)力學(xué)二十世紀(jì)六十年代作為一種新學(xué)科出現(xiàn)的物理藥劑學(xué)和藥物代謝動(dòng)力學(xué)the establishment of controlled release as a field which has grown more interdisciplinary since the 1970s自二十世紀(jì)七十年

46、代開始，控釋作為一個(gè)學(xué)科交叉發(fā)展的領(lǐng)域開始建立自二十世紀(jì)七十年代開始，控釋作為一個(gè)學(xué)科交叉發(fā)展的領(lǐng)域開始建立significant progress in the understanding of gi physiology and its impact on controlled release delivery對(duì)胃腸道生理學(xué)及其對(duì)控釋釋放的影響出現(xiàn)了重大進(jìn)步integration of biopharmaceutics and pharmacokinetics into the design of oral controlled release dosage forms生物藥劑學(xué)和藥代動(dòng)力

47、學(xué)與口服控釋釋放劑型設(shè)計(jì)的整合major development impacting oral controlled release since the 1950s (continued)自二十世紀(jì)五十年代以來影響口服控制劑型的主要發(fā)展（續(xù)）自二十世紀(jì)五十年代以來影響口服控制劑型的主要發(fā)展（續(xù)）greater knowledge on material properties, drug release mechanisms, and physicochemical factors affecting the oral dosage form design and performance對(duì)影響口服劑型設(shè)計(jì)和性能的材料性質(zhì)，藥物釋放原理和物理化學(xué)因子的更多認(rèn)識(shí)proliferation of novel drug delivery technologies新型藥物釋放技術(shù)的增加major advances in analytical chemistry, instrumentation, computer modeling, process eq