口服控释改良释放剂型的发展ppt课件

1、Evolution of Oral Controlled/Modified Release Dosage Forms口服控释/改良释放剂型的开展.Oral CR/MR Dosage Forms口服CR/MR 剂型“Extended-Release“延伸释放“Delayed-Release“延迟释放Controlled Release Modified Release控制释放 改良释放.Potential Benefits of Controlled Release Dosage Forms控释剂型的潜在优点Enhanced activity duration for short half-li

2、fe drugs提高短半衰期药物的有效作用时间Reduction of side effects降低副反响Less frequent dosing - improved patient compliance减少给药频率-提高患者顺应性Protecting labile drugs - improved product stability维护不稳定药物-提高产品的稳定性Potential for localization of drug to site of action将药物固定于起效部位的能够性Potential for extended patent protection延伸专利维护的能够

3、性.How did we get here and where are we going?我们是如何到达如今的程度并将向哪方面开展？Oral CR/MR Dosage Forms口服CR/MR剂型.“蜡丸者, 取其难化, 而旋旋取效也 “Use wax pills for their resistance to dissolve thereby achieving the effect gradually and slowlyEarly Slow-Release Oral Dosage Forms in Chinese Medicine中药中的早期缓释口服剂型 2nd Century B.C.

4、 Animal-fats as binder for pills “Recipes for Fifty-Two Ailment, Mawangdui Medical Manuscript, dated 168 B.C. 公元前2世纪动物脂肪作为丸剂的粘合剂“52种疾病的处方， 马王堆医学手稿，日期公元前168 4th Century A.D. Wax and fat pills “Handbook of Prescriptions for Urgent Cases, Ko Hung (281-341)公元4世纪蜂蜡和脂肪丸剂肘后救卒方 “葛洪 (281-341 13th Century Wax

5、 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世纪缓慢释放的蜡丸 药物运用中的规那么和根据“Li Kao (1180-1251) & 按汤剂服用“丸者缓也,.其用药之舒缓而治之意也“Such pills are slow actingthey provide the drug gradually and slow

6、ly for treatmentEarliest record of slow-release dosage forms for therapeutic use!治疗所用缓释剂型的早期记载.Types of Long-Acting Preparations, 1959长效制剂的类型，1959Coating the active drug with gastro-resistant and slowly enterosoluble substances (e.g. fats, waxes, fatty acids, ets.)运用抗胃液和减慢肠溶解的物质包裹活性药物比如，脂肪，蜂蜡，脂肪酸等等T

7、he use of ion exchange resins to bind active drugs运用离子交换树脂与活性药物结合The formation of chemical addition compounds or complexes化学添加物或合成物的构成Impregnating or embedding the drug in a base which gradually releases the active principle将药物浸渍或包埋在一个基质中，该基质可缓慢释放活性有效成分From: J. Lazarus and J. Cooper, J. Pharm Pharma

8、col., 11, 257 (1959).Major Historical Milestones Affecting the Direction of Oral Controlled Release Dosage Forms影响口服控释剂型开展方向的主要历史里程碑Availability of semi-synthetic and synthetic polymers for enteric coating (1940s through 1990s)半合成和合成聚合物用于肠溶包衣二十世纪四十年代到九十年代Introduction of first oral sustained release

9、products by Smith Kline & French using the Spansule technology: Dexedrine (dextroamphetamine sulfate) (1952) and Contac, the cold remedy (1960). Smith Kline & French引见了首个口服继续释放产品，运用了缓释胶囊剂Spansule技术： Dexedrine右旋硫酸右苯丙胺1952和Contac复方盐酸苯丙醇胺，感冒药1960Introduction of semi-synthetic and synthetic hydrophilic

10、gel forming polymers for designing oral sustained release products (1950s and 1960s)半合成和合成亲水凝胶构成的聚合物介入口服继续释放产品设计二十世纪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发明并初次商业运用的口腔浸透药物释放系统二十世纪七十年代到八十年代.“The delayed action tablet which

11、 was an extension of the enteric coating principle, represented the initial approach in controlling the release of a drug in the gastro-intestinal tract“延迟起效片剂是肠溶包衣原理的扩展，它代表在胃肠道中控制药物释放开场起步 - Lazarus and Cooper (1959).Reasons for enteric protection肠溶包衣的目的 Prevention of gastric irritation 防止胃的刺激 Prote

12、ction of drugs unstable in gastric fluids 防止药物在胃酸条件下被破坏 Delivery of drug to local site in intestine 药物在肠道特定部位释放 Delivery of drug to best absorption site in intestine 药物在肠道最正确吸收部位释放 Delayed drug release 药物延迟释放ENTERIC COATING SYSTEMS肠溶包衣系统.Enteric Coatings肠溶包衣1884 Dr. Paul Unna introduced keratin-coat

13、ed pills1884 Paul Unna 博士引入了角质素包衣丸剂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 acid-gelatin product, cetyl alcohol, etc. 十九世纪八十年代晚期到二十世纪30年代众多物质及其混合

14、物用于肠溶包衣，比如角质素，水杨酸苯酯，妥鲁香脂,紫胶，酪蛋白，玉米蛋白，硬脂酸，明胶甲醛产品，鞣酸明胶产品，十六烷醇 等等。1940s Cellulose acetate phthalate (CAP) introduced二十世纪四十年代引进醋酞纤维素CAP1970s Polyvinyl acetate phthalate (PVAP) and hydorxypropyl methylcellulose phthalate (HPMCP) became available二十世纪七十年代可运用聚醋酸乙烯邻苯二甲酸酯(PVAP) 和羟丙基甲基纤维素邻苯二甲酸酯HPMCP1980s - Met

15、hacrylate-methacrylic acid coplymers on the market二十世纪八十年代异丁烯酸-甲基丙烯酸共聚物出如今市场1980s to 1990s Various aqueous dispersions of enteric polymers introduced for tablet coatingshang二十世纪八十年代到二十世纪九十年代各种肠溶聚合物水分散系用于片剂包衣. The development of Spansule provided the impetus to the further development of sustained re

16、lease dosage forms in subsequent years Spansule 的开展为延释剂型在今后几年中进一步开展提供了推进力 It also stimulated numerous human studies regarding the absorption, distribution and fate of drugs delivered by such dosage forms, thus culminating the start of the study of biopharmaceutics也刺激了众多针对在运用这种剂型后吸收，分布和药物释放途径的人类研讨，因此

17、使生物药剂学的研讨开场到达顶峰.Multiparticulate Drug Delivery多颗粒药物释放CLINICAL ADVANTAGES 临床优点Disperse freely in the GI tract, invariably maximize drug absorption, reduce peak plasma fluctuation, and minimize potential side effects. 容易经过胃肠道，有利药物吸收，降低不良反响Reduce variations in gastric emptying rates and overall transit

18、 times. Thus inter- and intra-subject variability of plasma profiles is minimized. 减少因胃排空速率和转运时间不同而产生的差别。从而提高体外释放和体内血浆药物浓度的相关性High local concentration of bioactive agents, which may inherently be irritative or anesthetic, can be avoided. 防止具有刺激性和麻醉性的生物活性物质在部分浓度过高Less susceptible to dose dumping than

19、 the reservoir-type, single unit formulations. 相对于膜控释单剂量药物单元，可减少药物突释的能够性.水分蒸发水分蒸发, 聚合物塑化细小颗粒严密聚集在一同 Poorly plasticised system部分愈合的的薄膜完全愈合薄膜Tg聚合物水分散体成膜机理分散物堆积在颗粒外表.包衣薄膜基底控释膜表示图.Major Historical Milestones Affecting the Direction of Oral Controlled Release Dosage Forms影响口服控释剂型方向的主要历史里程碑Availability of

20、 semi-synthetic and synthetic polymers for enteric coating (1940s through 1990s) 在肠溶包衣中运用半合成和合成聚合物20世纪40年代至90年代。Introduction of first oral sustained release products by Smith Kline & French using the Spansule technology: Dexedrine (dextroamphetamine sulfate) (1952) and Contac, the cold remedy (1960)

21、. Smith Kline和French引入了首例口服缓释产品Dexedrine右旋安非他明硫酸盐 ，1952年和Contac感冒药，1960年 ，运用的是分时溶解药囊 Spansule 技术。Introduction of semi-synthetic and synthetic hydrophilic gel forming polymers for designing oral sustained release products (1950s and 1960s)引入半合成和合成亲水胶成型聚合物，用于设计口服延释产品20世界50年代和60年代。Invention and first c

22、ommercialization of oral osmotic drug delivery systems by ALZA (1970s through 1980s) ALZA发明并初次商业化口服浸透性药物传送系统20世纪70至80年代。.Ethylcellulose乙基纤维素Cellulose Acetate乙酸纤维素,醋酸纤维素Methacrylic Acid Copolymer甲基丙烯酸共聚物Hydroxypropyl Methylcellulose (HPMC)羟丙基甲基纤维素Hydroxypropyl Cellulose羟丙基纤维素Carbomer卡波姆Sodium Alginat

23、e海藻酸钠Polyethylene Oxide聚氧化乙烯White Wax白蜡Carnauba Wax巴西棕榈蜡Shellac紫胶PolymersOtherExamples of Release Controlling Excipients in Current Oral CR Products目前口服控释产品中释放控制辅料的实例.Earliest Example of a Controlled-Release Tablet Using Swellable & Erodible Hydrophilic Gums including HPMC运用含有羟丙基甲基纤维素的可溶胀性&易侵蚀亲水树胶的早

24、期控释片剂实例.“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 tablet is worn away by the motion of the tablet in the gastro

25、-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 disintegrated rather than dissolved and the medicament contained therein

26、 is release at a substantially uniform rate.“溶胀时，在 片剂阐明构成一层相对不透水层，这可防止水进一步渗入片剂内部。在片剂外表所构成的这种柔软的粘性树胶凝胶层随片剂在胃肠道挪动而磨损， 并且一部分混合在内药物随磨损并释放。片剂新颖构成的外表与水结合并溶胀因此交换了维护性包衣。结果，片剂不仅仅是溶解而是缓慢分解并且所含药物根本以均匀速率释放。US Pat. 3,065,143, Christenson and Dale (1962)美国专利3,065,143, Christenson and Dale (1962).Mechanism of Drug

27、 Release from HPMC Matrix Tablets药物从HPMC基质片剂释放原理Dry Tablet枯燥片剂Ingestion of Tablet咽下片剂Gel Layer凝胶层Dry Core枯燥片芯Insoluble Drug - released by exposure via tablet erosion.不溶性药物经片剂侵蚀暴露释放Soluble Drug - released mainly by diffusion through the gel layer and less via tablet erosion.可溶性药物主要经过凝胶层分散而极少经过片剂侵蚀释放T

28、ablet ErosionPolymer concentration at gel surface reaches a threshold disentanglement value and dissolution/erosion of tablet takes place.片剂侵蚀凝胶外表的聚合物浓度到达崩解阈值，从而片剂发生溶出/侵蚀Growth of Gel Layer凝胶增变厚Water swelling front penetrates into the tablet, gel layer thickness increases, and soluble drug diffuses

29、out of the gel layer.水溶胀上层浸透入片剂，凝胶层厚度添加，可溶性药物经过凝胶层分散 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.初期的水协作用&溶胀片剂外表潮湿并且HPMC聚合物开场构成水合物，构成凝胶层。可溶性药物的突释作用从片剂表层开场。Source: Modif

30、ied from Dow technical brochure来源：Dow技术手册改良.Formulations are relatively straightforward 处方相对简单Standard production equipment 不需求特殊设备Reproducible release profiles resistant to drug dumping 释药重现性好，不易产生药物突释Release rate generally insensitive to compression force/tablet hardness 药物释放率不易受压片力/片芯硬度的影响Through

31、 choice of excipients /polymer level, able to modify release kinetics 经过选择辅料/聚合物程度，可以调理药物释放动力学参数Advantages优点:HYDROPHILIC MATRICES亲水凝胶骨架The most commonly used polymers are cellulose ethers 最为常用的聚合物是纤维素醚类，特别是羟丙基甲基纤维素.Dynamic Gel Thickness Development in a Swellable Matrix Tablet溶胀基质片剂中凝胶厚度的动态变化.Curren

32、t Understanding of Swelling & Erosion Controlled Systems目前对溶胀&侵蚀控制系统的了解Synchronization of swelling & erosion fronts can lead to near zero order release (e.g. in PVA and NaCMC systems)外部溶胀&侵蚀的同时发生会引发近似零级释放比如，在PVA和NaCMC 系统中In HPMC systems, the gel layer thickness continues to increase with time在HPMC系统

33、中，凝胶层厚度随时间不断添加For water soluble drugs , diffusion is the dominant mechanism with a time-dependent increase in diffusion coefficient and surface area as a result of continuous swelling对于水溶性药物，分散是主导机理，由于继续溶胀的结果，分散系数以及外表积随时间相应添加For insoluble drugs or soluble drugs at high loading, the erosion mechanism

34、 will dominate对于不溶药物或高载药量的可溶性药物，侵蚀机理占主导。.Typical Rate-Controlling Matrix Material代表性的速率-控制基质资料HPMC; HPC; PEO; Na Alginate羟丙基甲基纤维素：HPC：聚氧化乙烯：藻(朊)酸钠Examples of Swellable Tablet Products可溶胀片剂产品实例Indocin (Indomethacin; Merck)吲哚美辛； Merck Isoptin SR (Verapamil HCL; Knoll)盐酸维拉帕米； Knoll Trental (Pentoxifyll

35、ine; HMR)己酮可可碱；HMRSwelling & Erosion Controlled Matrix Systems控制溶胀&侵蚀基质系统.Osmotic Pumping Mechanism浸透泵原理US Pat 3,845,770 (1974) by F. Theeuwes and T. Higuchi美国专利3,845,770 (1974) , F. Theeuwes 和 T. Higuchi一切Precise Rate-Controlled Drug Delivery (Various Temporal Patterns)准确的控制药物释放速度各种暂时方式Delivery Rat

36、e Independent of pH不依赖PH的释放速度Rate-Controlling Semipermeable Membrane控制半浸透薄膜速度Cellulose Acetate醋酸纤维素Push Layer (Swellable Hydrophilic Polymers)挤压层可溶胀亲水性聚合物Polyethylene Oxide聚氧化乙烯Selected Examples所选实例Procardia XL (Nifedipine; Pfizer)硝苯地平,； PfizerCovera-HS (Verapamil HCl; Searle)盐酸维拉帕米； SearleDynaCirc

37、CR (Isradipine; Norvartis)依拉地平； Norvartis Concerta (Methylphenidate HCl; McNeil)盐酸哌甲酯； McNeil .Controlled-Release OROS Delivery Systems (Osmotic Pump)控释口腔浸透的浸透泵缓释剂 OROS 释放系统浸透泵.Elementary Osmotic Pump初级浸透泵Constant release rate is maintained by a constant osmotic driving force (from excess soluble dr

38、ug and/or osmotic adjuvant)经过继续浸透驱动力坚持恒定的释放率从极易溶药物和/或浸透佐剂Push-Pull Osmotic Pump推-拉浸透泵Constant release rate is maintained by the constant swelling of hydrogel push layer经过水凝胶挤压层继续溶胀坚持恒定释放率Useful for delivering low solubility drugs (in a suspension)对释放不易溶药物有用在混悬液中Pulsatile delivery feasible with multi

39、ple compartments (OROS Tri-Layer)可行的多层室脉冲式释放 OROS 三层Can be adapted for liquid formulations (L-OROS)适用于液体处方 L-OROS Osmotic Pumping Mechanism:浸透泵原理Release Characteristics释放特征.Phenylpropanolamine OROS Tablet1st Osmotic Tablet Product: “Acutrimn-去甲麻黄碱OROS片剂第一个浸透泵片剂产品：“AcutrimIn Vivo () & In Vitro () Del

40、ivery Profiles体内() & 体内 () 释放曲线Predicted & Experimental Plasma Concentration Profiles期望&实验血浆浓度Good and Lee (1984).Membrane Systems - Drug core surrounded by a rate-controlling membrane (e.g., microcapsules & coated drug pellets, granules or beads)膜系统-药芯为速率控制膜包围比如，微胶囊&包衣药物小丸，颗粒或小球Matrix Systems - Dru

41、g dissolved or dispersed in a carrier matrix (e.g., microspheres, beads, pellets, granules & tablets)基质系统-药物溶解或分散于载体基质中比如，微球，小球，小丸，颗粒& 片剂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

42、tablets) 混合系统-膜系统和基质系统的结合运用比如，包衣小丸或串珠包埋到片剂基质中，包衣基质串珠，压制包衣基质片剂Oral CR/MR Dosage Form Classifications口服CR/MR剂型分类.Oral CR Mechanisms口服CR机理Diffusion 分散Dissolution溶出Swelling & Erosion 溶胀& 侵蚀Geometry/Area Changes几何外形/面积变化Nonuniform Drug Distribution/Gradient matrix不均一药物分布/梯度基质Solution-Diffusion溶解-分散Osmoti

43、c Pumping浸透泵Matrix Systems基质系统Membrane Systems膜系统.Achievable Release Profiles完成的释放曲线First Order (including t dependence) 一级包括t 依赖性Zero-Order零级Bimodal (including accelerated release)双峰包括加速释放Pulsatile (including delayed release)脉冲式包括延迟释放.Major Development Impacting Oral Controlled Release Since the 19

44、50s自二十世纪五十年代以来影响口服控制剂型的主要开展The emergence of Physical Pharmacy and Pharmacokinetics as new disciplines in the 1960s二十世纪六十年代作为一种新学科出现的物理药剂学和药物代谢动力学The establishment of controlled release as a field which has grown more interdisciplinary since the 1970s自二十世纪七十年代开场，控释作为一个学科交叉开展的领域开场建立Significant progres

45、s in the understanding of GI physiology and its impact on controlled release delivery对胃肠道生理学及其对控释释放的影响出现了艰苦提高Integration of biopharmaceutics and pharmacokinetics into the design of oral controlled release dosage forms生物药剂学和药代动力学与口服控释释放剂型设计的整合.Major Development Impacting Oral Controlled Release Since

46、 the 1950s (continued)自二十世纪五十年代以来影响口服控制剂型的主要开展续Greater knowledge on material properties, drug release mechanisms, and physicochemical factors affecting the oral dosage form design and performance对影响口服剂型设计和性能的资料性质，药物释放原理和物理化学因子的更多认识Proliferation of novel drug delivery technologies新型药物释放技术的添加Major advances in analytical chemistry, instrumenta