section one Site-specific drug delivery
section one Site-specific drug delivery
chapter one Site-specific drug delivery using liposomes as carriers* Contents Introduction. 3 II.Liposomes in drug delivery. 4 Phospholipids. III.The liposome-drug concept. A. Liposome size. B. Targeting ligands. 7 IV. Liposomes as carriers of therapeutic agents. .12 A. Application. .12 B. Manufacturers. .14 V.Recent advances. .16 Highlights of current research .17 VI Concluding remarks References. 26 I. Introduction Over the past three decades,significant advances have been made in drug delivery technology.This effort,pioneered by Alza Laboratories of Palo Alto Califo n:12 Drug delivery has now become a multidisciplinary science consisting of biopharmaceutics and pharmacokinetics.Great strides have also been made p池m and J.B.Lippincott Publishing Company,Philadelphia,PA. 3
3 chapter one Site-specific drug delivery using liposomes as carriers* Contents I. Introduction .3 II. Liposomes in drug delivery.4 A. Regional drug delivery .4 B. Chemical characteristics of liposomes.5 C. Phospholipids .6 III. The liposome-drug concept.7 A. Liposome size .7 B. Targeting ligands.7 C. Problems .8 D. Manufacturing issues .8 IV. Liposomes as carriers of therapeutic agents .12 A. Application.12 B. Manufacturers.14 V. Recent advances .16 A. Highlights of current research .17 VI. Concluding remarks .25 References.26 I. Introduction Over the past three decades, significant advances have been made in drug delivery technology. This effort, pioneered by Alza Laboratories of Palo Alto, California,1,2 among others, has been accelerated in recent years due to the substantial decline in the development of new drug entities. Drug delivery has now become a multidisciplinary science consisting of biopharmaceutics and pharmacokinetics. Great strides have also been made * Adapted from Ranade, V.V., Drug delivery systems. 1. Site specific drug delivery using liposomes as carriers, J. Clin. Pharmacol., 29, 685, 1989. With permission of the J. Clin. Pharmacol., and J.B. Lippincott Publishing Company, Philadelphia, PA
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
Drug delivery systems,second edition Figure 1.1 Schematic of a bilayer vesicle or liposome.(From Pharmaceutical Techology,Conf. Proc.,The Latest Developments in Drug Delivery Systems,Oct.1985.With permission.) Bilayer Vesicle Internal aqueous Bilayer membrane compartment Entrapped material Figure 1.2 A micrograph view of a liposome.(Reprinted by permission of The Lipo some Company,Inc.Princeton,NI.) groups.This compartmentalization has been discussed in detail by Roerdink et al.1 C. Phospholipids A variety of phospholipids can be used to prepare liposomes.The lipid most widely used is phosphatidylcholine,2324 which has been used individually or in combination with cholesterol.Cholesterol is known to condense the
6 Drug delivery systems, second edition groups. This compartmentalization has been discussed in detail by Roerdink et al.14 C. Phospholipids A variety of phospholipids can be used to prepare liposomes. The lipid most widely used is phosphatidylcholine,23,24 which has been used individually or in combination with cholesterol. Cholesterol is known to condense the Figure 1.1 Schematic of a bilayer vesicle or liposome. (From Pharmaceutical Technology, Conf. Proc., The Latest Developments in Drug Delivery Systems, Oct. 1985. With permission.) Figure 1.2 A micrograph view of a liposome. (Reprinted by permission of The Liposome Company, Inc., Princeton, NJ.)