《药剂学》课程书籍文献：《drug delivery systems》英文教材PDF电子书（Second Edition，Vasant V. Ranade、Mannfred A. Hollinger）.pdf_大学文库

Preface to the First Edition The introduction of the first successful drug delivery system brought about tremendous inte est in the us into the marketplace and many are now in different stages of product devel opment.Lately,a plethora of drug delivery departments and companies have emerged partly as a result of surging interest in generic drug development and continued technological advances are occurring in this area of pharma- ce utical research. The main goal of this book has been to collect current information in one volume to further research in drug delivery and to serve as an introduc- tion to the various systems.The aim has also been simply to identify areas of potential and real improvement in the drug treatment of disease as well as to review the different approaches and methods of assessment of novel drug deliv This be contains introductory and state-of-the-art information on lipo somes,monoclonal antibodies,use of polymers,implants,oral,transdermal, miscellaneous,intranasal,and ocular forms of drug delivery.Finally,a liter- ature review on the regulatory and global aspects of drug delivery systems nted.Obviously,in this rapidly expanding field,several in must ha nown by carly 1994,wheh most of the literature was collecter e occu ed d spite 0 orts to include ific advances k We hope this effort will prove to be of value to scientists,clinicians,and product development personnel seeking information in this area and this compilation of the introductory data should serve as a useful resource tool. Theednd oeptsdbed in this book are not ouwn do we make any claims indicating such a notio n nor do we se any credit.We are indebted to scientists and authors for their permission to use or include their research work.Particularly,we express our appreciation to the following:Drs.G.Gregoriadis,U.Persson,F.H.Roerdink,R.L.Juliano and D.Mufson for liposomes,Drs.E.Tomlinson,I.Schlom,W.Lebherz,G.F. Rowland and T.Suzuta for monoclonal antibodies,Drs.F.G.Hutchinson and I.B.Ll oyd for use of polymers Drs.F.The uwes and M.Sefton for implant Drs.D.Ganderton and S.S.Davis for oral drug delivery,Dr.B.W.Barry for transdermal drug delivery,Drs.Y.W.Chien,K.S.E.Su and D.Proctor for intranasal and ocular drug delivery,Capsugel Americas and SoloHill Engi-

Preface to the First Edition The introduction of the first successful drug delivery system brought about tremendous interest in the usage of delivery systems for entry of drugs into the systemic circulation of the body. Several drug delivery products followed into the marketplace and many are now in different stages of product development. Lately, a plethora of drug delivery departments and companies have emerged partly as a result of surging interest in generic drug development and continued technological advances are occurring in this area of pharmaceutical research. The main goal of this book has been to collect current information in one volume to further research in drug delivery and to serve as an introduction to the various systems. The aim has also been simply to identify areas of potential and real improvement in the drug treatment of disease as well as to review the different approaches and methods of assessment of novel drug delivery. This book contains introductory and state-of-the-art information on liposomes, monoclonal antibodies, use of polymers, implants, oral, transdermal, miscellaneous, intranasal, and ocular forms of drug delivery. Finally, a literature review on the regulatory and global aspects of drug delivery systems is presented. Obviously, in this rapidly expanding field, several important omissions must have occurred despite our efforts to include significant advances known by early 1994, when most of the literature was collected. We hope this effort will prove to be of value to scientists, clinicians, and product development personnel seeking information in this area and this compilation of the introductory data should serve as a useful resource tool. The research ideas and concepts described in this book are not our own and neither do we make any claims indicating such a notion nor do we seek any credit. We are indebted to scientists and authors for their permission to use or include their research work. Particularly, we express our appreciation to the following: Drs. G. Gregoriadis, U. Persson, F.H. Roerdink, R.L. Juliano and D. Mufson for liposomes, Drs. E. Tomlinson, J. Schlom, W. Lebherz, G.F. Rowland and T. Suzuta for monoclonal antibodies, Drs. F.G. Hutchinson and J.B. Lloyd for use of polymers, Drs. F. Theeuwes and M. Sefton for implants, Drs. D. Ganderton and S.S. Davis for oral drug delivery, Dr. B.W. Barry for transdermal drug delivery, Drs. Y.W. Chien, K.S.E. Su and D. Proctor for intranasal and ocular drug delivery, Capsugel Americas and SoloHill Engi-

Authors Vinayak (Vasant)V.Ranade,Ph.D.,is director of chemical sciences for Academic pharr aceuticals.Inc.in Lake Bluff,Illinois.He also holds a faculty Dr.Ranade earned his Ph.D.degree in organic chemistry from the Uni- versity of Bombay in 1965 and received his postdoctoral training in the College of Pharmacy at the University of Michigan,Ann Arbor.He has arch chemist for Abbott Laboratories,Mallinckrodt Inc.and ritica Care. Dr.Ranade is a member of the American Chemical Society,APhA Academy of Pharmaceutical Sciences and the honorary society,Sigma Xi. He was awarded the Council of Scientific and Industrial Research Fellow- ship,and was elected fellow of the American Institute of Chemists.He was ent of the Genia Czerniak Prize for Nuclear Medicine and Radiopharma 08y Dr.Ranade has been a reviewer for a number of scientific jounals,and his biography is listed in Who's Who and American Men and Women of Science and Technology.He has presented research work at the American Chemical Society,the APhA Academy of Pharmaceutical Sciences,and the American e of Cardiolo gy and Pha gy meetings eha than papers including original and abstracts.He is the recipient of several U.S.patents,and his research work has also been included in Canadian and European patents.He co-authored the first edition of this book titled Drug Delivery Systems published by CRC Press in 1995. Dr.Ranade's significant contributions to pharmaceutical research and development include synthesis of tumor imaging agents,formulations of cardiovascular and diuretic drugs,and chiral chromatographic separations of a variety of drugs.Dr.Ranade is also a consultant in the areas of chemical and pharamaceutical technology for some industrial organizations,securities market analysis companies,and research institutes in the U.S. Mannfred A.Hollinger,Ph.D.,is currently a professor emeritus in the Department of Medical Pharmacology and Toxicology,School of Medicine, University of California,Davis.Dr.Hollinger is the former editor of Current

Authors Vinayak (Vasant) V. Ranade, Ph.D., is director of chemical sciences for Academic Pharmaceuticals, Inc. in Lake Bluff, Illinois. He also holds a faculty position in the Department of Pharmacology at Rush-Presbyterian-St. Luke’s Medical Center in Chicago. Dr. Ranade earned his Ph.D. degree in organic chemistry from the University of Bombay in 1965 and received his postdoctoral training in the College of Pharmacy at the University of Michigan, Ann Arbor. He has worked as a research chemist for Abbott Laboratories, Mallinckrodt Inc., and DuPont Critical Care. Dr. Ranade is a member of the American Chemical Society, APhA Academy of Pharmaceutical Sciences and the honorary society, Sigma Xi. He was awarded the Council of Scientific and Industrial Research Fellowship, and was elected fellow of the American Institute of Chemists. He was the co-recipient of the Genia Czerniak Prize for Nuclear Medicine and Radiopharmacology. Dr. Ranade has been a reviewer for a number of scientific jounals, and his biography is listed in Who’s Who and American Men and Women of Science and Technology. He has presented research work at the American Chemical Society, the APhA Academy of Pharmaceutical Sciences, and the American College of Cardiology and Pharmacology meetings. He has published more than 90 papers including original and review articles, book chapters, and abstracts. He is the recipient of several U.S. patents, and his research work has also been included in Canadian and European patents. He co-authored the first edition of this book titled Drug Delivery Systems published by CRC Press in 1995. Dr. Ranade’s significant contributions to pharmaceutical research and development include synthesis of tumor imaging agents, formulations of cardiovascular and diuretic drugs, and chiral chromatographic separations of a variety of drugs. Dr. Ranade is also a consultant in the areas of chemical and pharamaceutical technology for some industrial organizations, securities market analysis companies, and research institutes in the U.S. Mannfred A. Hollinger, Ph.D., is currently a professor emeritus in the Department of Medical Pharmacology and Toxicology, School of Medicine, University of California, Davis. Dr. Hollinger is the former editor of Current

4 Drug delivery systems,second edition by physical biochemists,pharmacists,and other pharmaceutical research scentiss working in university and industrial laboratories The underlying principle that drug delivery technology,per se,can bring both therapeutic and commercial value to health care products has been widely accepted.Recently,large pharmaceutical companies have their market share to generic competitors with in sing rapidity after thei patents expire.This has created an intense need for presenting"old"drugs in new forms and utilizing novel forms of delivery.As a result,companies developing new drug delivery systems seem to enjoy a good return on their investment in the form of increased revenues and market share.? In the U.S.,the Drug Price Competition and Patent Term Restoration Act (also kr own as ANDA-Exclusivity Provisic ons Act)wa s pa sed in 1984.This provided new incentives to manufacturers who can distinguish their products from the competition,with features such as longer dosage schedules,improved safety profiles,new indications for existing drugs,and new combinations.s The following chapters,which focus on the area of research and devel- opment in the drug delivery field,have been divided into five sections: ers and in mplantable drug delivery systems 3.Oral drug delivery Transdermal,intranasal,ocular,and miscellaneous drug delivery systems 5.Regulatory considerations and global outlook Drug delivery,which takes into consideration the carrier,the route,and the target,has evolved into a strategy of processes or devices designed to enhance the efficacy of therapeutic agents through controlled release.This may involve enhanced bioavailability,in proved the rapeutic index,or im od patient by Flvmn as"the use of whatever means possibleb or comp liance. Drug delivery,or contr rele physiochemical,or mechanical,to regulate a drug's access rate to the body's central compartment,or in some cases,directly to the involved tissues." Tomlinsont0 has emphasized features such as exclusive delivery to spe acc ss to ph imarily inacc ssible sites of body from uny vanted con 11 d rate a nd modality of delivery to pha macological receptors,and reduction in the amount of active principa employed.Tomlinson10n has also described the properties that are needed for site-specific carriers,as well as properties that are biological,drug-related, and carrier-related. Liposomes in drug delivery A. Regional drug delivery Most efforts to make drug therapy more efficient by direct delivery of dru to affected tissues have on local or regional injection techniques

4 Drug delivery systems, second edition by physical biochemists, pharmacists, and other pharmaceutical research scientists working in university and industrial laboratories.3–6 The underlying principle that drug delivery technology, per se, can bring both therapeutic and commercial value to health care products has been widely accepted. Recently, large pharmaceutical companies have been losing their market share to generic competitors with increasing rapidity after their patents expire. This has created an intense need for presenting “old” drugs in new forms and utilizing novel forms of delivery. As a result, companies developing new drug delivery systems seem to enjoy a good return on their investment in the form of increased revenues and market share.7 In the U.S., the Drug Price Competition and Patent Term Restoration Act (also known as ANDA-Exclusivity Provisions Act) was passed in 1984. This provided new incentives to manufacturers who can distinguish their products from the competition, with features such as longer dosage schedules, improved safety profiles, new indications for existing drugs, and new combinations.8 The following chapters, which focus on the area of research and development in the drug delivery field, have been divided into five sections: 1. Site-specific drug delivery 2. Polymers and implantable drug delivery systems 3. Oral drug delivery 4. Transdermal, intranasal, ocular, and miscellaneous drug delivery systems 5. Regulatory considerations and global outlook Drug delivery, which takes into consideration the carrier, the route, and the target, has evolved into a strategy of processes or devices designed to enhance the efficacy of therapeutic agents through controlled release. This may involve enhanced bioavailability, improved therapeutic index, or improved patient acceptance or compliance. Drug delivery, or controlled release, has been defined by Flynn as “the use of whatever means possible, be it chemical, physiochemical, or mechanical, to regulate a drug’s access rate to the body’s central compartment, or in some cases, directly to the involved tissues.”9 Tomlinson10 has emphasized features such as exclusive delivery to specific components, access to primarily inaccessible sites, protection of body from unwanted deposition, controlled rate and modality of delivery to pharmacological receptors, and reduction in the amount of active principal employed. Tomlinson10,11 has also described the properties that are needed for site-specific carriers, as well as properties that are biological, drug-related, and carrier-related. II. Liposomes in drug delivery A. Regional drug delivery Most efforts to make drug therapy more efficient by direct delivery of drugs to affected tissues have focused on local or regional injection techniques

Chapter one:Site-specific drug delivery using liposomes as carriers such as intra-arterial or infusions into body cavities,such as the peritoneum The benefits of regional therapy include reducing systemi toxicity and achieving peak drug levels directly at the target site.However,these methods of administration have met with limited success.For example,although intra-arterial injections effectively concentrate drugs at certain tumor sites in others the drug is cleared from the system so rapidly that the benefits are not realized.Currently delivery systems cdrugs and affect only the afflicted tissues. ers ar trying to design drug A carrier system that has received considerable attention in this regard is liposomes. B. Chemical characteristics of liposomes Liposomal affinity for various tissues can be modified by synthesizing lipo ontaining phe holipids with varic id con figura tions.Th fatty cropartic les may be either solid or liquid at defined temper atures. ltering the charge on the liposome vesicle can greatlyn its distribution in the body.Negatively charged vesicles,for example,enter the cell by fusion.This allows the drug to be discharged into the cell cyto- plasm.Neutral vesicles,on the other hand,are incorporated into the cell by phago 。Thi exp drolytic syst Positive neutral-liposomal vesi more slowly than those negatively charged What is a liposome made of and how does it look?The liposome is a microparticulate,ranging in size from 0.03 um to 10 um,consisting of a bilayer of phospholipid e ous space.A variety of amphi- pathi encapsulating an aqu ic lip s can be us sed to fo bilayer.The e lipi the wate phase.Hydrophobic hydrocarbon moieties adhere together in the bilaver thus forming close,concentric,bimolecular lipid leaflets separating aqueous compartments. Drug 1.2).The of the uin heposome depends upon the physichemcalch teristics of the drug and the composition of the constituent lipids.21 Stable liposomes from phospholipids are formed only at temperatures above the gel to liquid-crystalline"phase transition temp erature (Tc).This represents the meltin g point of the acyl chains.All phospholipids have a characteristic contingent upon th i group and on the length and degree of unsaturation of the acyl chains.2 temperature,phospholipids form a liquid-crystalline phase that constitutes increased mobility of the acyl chains.A reduction in temperature below the Tc creates a transition to a more rigid gel state.This results in restrained mobility of the tightly packed ac I chains.When the liquid molecules rrange themselves to form closed bilayer structure f and solutes,drugs are trapped between the adjacent planes of the polar head

Chapter one: Site-specific drug delivery using liposomes as carriers 5 such as intra-arterial or infusions into body cavities, such as the peritoneum. The benefits of regional therapy include reducing systemic toxicity and achieving peak drug levels directly at the target site. However, these methods of administration have met with limited success. For example, although intra-arterial injections effectively concentrate drugs at certain tumor sites, in others the drug is cleared from the system so rapidly that the benefits are not realized. Currently, pharmaceutical researchers are trying to design drug delivery systems that will localize drugs and affect only the afflicted tissues. A carrier system that has received considerable attention in this regard is liposomes.12–17 B. Chemical characteristics of liposomes Liposomal affinity for various tissues can be modified by synthesizing liposomes containing phospholipids with various fatty-acid chain configurations. These microparticles may be either solid or liquid at defined temperatures.18,19 Altering the charge on the liposome vesicle can greatly influence its distribution in the body. Negatively charged vesicles, for example, enter the cell by fusion. This allows the drug to be discharged into the cell cytoplasm. Neutral vesicles, on the other hand, are incorporated into the cell by phagocytosis. This exposes the drug to the lysosomal hydrolytic system of the cells. Positive- and neutral-liposomal vesicles are cleared more slowly than those negatively charged. What is a liposome made of and how does it look? The liposome is a microparticulate, ranging in size from 0.03 mm to 10 mm, consisting of a bilayer of phospholipid encapsulating an aqueous space. A variety of amphipathic lipid molecules can be used to form the bilayer.20 The lipid molecules arrange themselves by exposing their polar head groups towards the water phase. Hydrophobic hydrocarbon moieties adhere together in the bilayer, thus forming close, concentric, bimolecular lipid leaflets separating aqueous compartments. Drug molecules can either be encapsulated in the aqueous space or intercalated into the bilayer (see Figure 1.1 and Figure 1.2). The exact location of the drug in the liposome depends upon the physiochemical characteristics of the drug and the composition of the constituent lipids.21 Stable liposomes from phospholipids are formed only at temperatures above the “gel to liquid-crystalline” phase transition temperature (Tc). This represents the melting point of the acyl chains. All phospholipids have a characteristic Tc, which is contingent upon the nature of the polar head group and on the length and degree of unsaturation of the acyl chains.21,22 Above the transition temperature, phospholipids form a liquid-crystalline phase that constitutes increased mobility of the acyl chains. A reduction in temperature below the Tc creates a transition to a more rigid gel state. This results in restrained mobility of the tightly packed acyl chains. When the liquid molecules arrange themselves to form closed bilayer structures containing water and solutes, drugs are trapped between the adjacent planes of the polar head