3 Drug delivery systems,second edition The liposomal gel-controlled ibuprofen release and dural permeation in vitro showed a permeation pattern favorable for maintaining con- stant drug levels.Therefore,this liposomal polaxamer gel represents a new formulation approach to increase the local epidural availability of ibuprofen 128 A sign t breakthrough was achieved in the effectiveness of adri- amycin by using its liposomal formulation coated with polyethylele glycol (PEGylation).1 The positively charged liposomal formulation of tropicamide,a my driatic cycloplegic drug,and liposomes dispersed in polycarbophil were found more effective than those with neutral liposomal dispersion 130 Antitumor activity of mitoxantrone was enhanced by using con- trolled destabilization of a liposomal drug delivery system.For this drug,programmable fusogenic vehicles with PEG with an 18-carbon acyl chain length were used.131 The ophthalmic drug delivery system consisting of oligolamellar m made up of dipalmitoylphosphatidylcholine-cholesterol-dim ethyldioctadecyl glycerol bromide in 7:4:1 molar ratio presented the highest encapsulation capacity and delivered greater amounts of the drug acyclovir into the aqueous humor than saline acyclovir or a physical liposome/drug blend.1 The use of magi osomes(liposomes with entrapped magnetic particles in their bilayers),which are magnetosens tive,may be ma neuvered to a given site in the organism.Magnetoliposomes that are strong microwave absorbers can be heated to higher temperatures, which may subsequently lead to a leakage of the entrapped drug.The beneficial effects of glucocorticoids in treating pulmonary inflamma- tory e complicated by sy vers effects.The ad- ministration o -entrapped dexamethasone h distinct vantages of enhancing the anti-inflammatory activity of the drug. Liposome-infused doxorubicin hydrochloride (DXR),an anthracy- cline anticancer antibiotic,can be effectively used on murine neuro- blastoma and may reduce the incidence of cardiac toxicity as com pared to DXRa 。135.136 Since it is known that liposomes are naturally taken up by cells of the mononuclear phagocytic system,liposome-based therapy repre- sents a convenient approach to improving the delivery of anti-HIV agents into infected cells,thereby improving the efficacy of drugs and reducing their adverse side effects.A m specific targeting of HIV-infected cells could atachedbe obtained using liposomes bearing sur A proniosome-based transdermal drug delivery system of levonorgestrel has been developed,and this system is effective in preventing contraception.13s
22 Drug delivery systems, second edition • The liposomal gel-controlled ibuprofen release and dural permeation in vitro showed a permeation pattern favorable for maintaining constant drug levels. Therefore, this liposomal polaxamer gel represents a new formulation approach to increase the local epidural availability of ibuprofen.128 • A significant breakthrough was achieved in the effectiveness of adriamycin by using its liposomal formulation coated with polyethylele glycol (PEGylation).129 • The positively charged liposomal formulation of tropicamide, a mydriatic cycloplegic drug, and liposomes dispersed in polycarbophil were found more effective than those with neutral liposomal dispersion.130 • Antitumor activity of mitoxantrone was enhanced by using controlled destabilization of a liposomal drug delivery system. For this drug, programmable fusogenic vehicles with PEG with an 18-carbon acyl chain length were used.131 • The ophthalmic drug delivery system consisting of oligolamellar system made up of dipalmitoylphosphatidylcholine-cholesterol-dimethyldioctadecyl glycerol bromide in 7:4:1 molar ratio presented the highest encapsulation capacity and delivered greater amounts of the drug acyclovir into the aqueous humor than saline acyclovir or a physical liposome/drug blend.132 • The use of magnetoliposomes (liposomes with entrapped magnetic particles in their bilayers), which are magnetosensitive, may be maneuvered to a given site in the organism. Magnetoliposomes that are strong microwave absorbers can be heated to higher temperatures, which may subsequently lead to a leakage of the entrapped drug. The beneficial effects of glucocorticoids in treating pulmonary inflammatory disorders are complicated by systemic adverse effects. The administration of liposome-entrapped dexamethasone has distinct advantages of enhancing the anti-inflammatory activity of the drug.133, 134 • Liposome-infused doxorubicin hydrochloride (DXR), an anthracycline anticancer antibiotic, can be effectively used on murine neuroblastoma and may reduce the incidence of cardiac toxicity as compared to DXR alone.135,136 • Since it is known that liposomes are naturally taken up by cells of the mononuclear phagocytic system, liposome-based therapy represents a convenient approach to improving the delivery of anti-HIV agents into infected cells, thereby improving the efficacy of drugs and reducing their adverse side effects. A more specific targeting of HIV-infected cells could be obtained using liposomes bearing surface-attached antibiotics.137 • A proniosome-based transdermal drug delivery system of levonorgestrel has been developed, and this system is effective in preventing contraception.138
Chapter one:Site-specific drug delivery using liposomes as carriers 23 The analysis of in vitro antiproliferative activity on cultured human leuke pmeaaneap Liposomes encapsulating adenosine triphosphate were prepared by sonication,and the liposomes have been evaluated for treatment of ischemic r etina.14 The intrahepatic distribution of liposom s containing glycolipid de rivatives showed that these were suitable for the selective delivery of liposomes to hepatic parenchymal cells.The authors synthesized branched-type galactoyllipid derivatives for liposome modification for the targeting of asialoglycoprotein receptors on the surface of liver cells.Gal was 1a1 up the a-and glutamic acid vi arbo I group o eleglycol spacer,and the glutamic moiety Liver accumulation of liposomes depends on the galactosyl residues The number of galactosyl residues was more effective for accumula- tion in the liver than for branching.Niosome-encapsulated ciprofox acin and no acin wer e stud: d it d that i estin ut not nas 1,absorption was signifi antly higher in comparison with that of nonliposomal parent drugs. It is known that a single liposome may carry greater than or equal to 10,000 drug molecules and that the use of PEG-conjugated immu- somes increases the drug-carrying capacity of the monoclonal dy by up to four lo in ma Specific DX-26 monoclonal antibody-mediated targeting of mycin to the rat brain was achieved by this immunoliposome-based drug de- livery system.143 The use of liposome can be helpful in optimizing sustained delivery of glucocorticoids to the lun on to the luings via topical administration.The use o onary-tar geted drug delivery system has been explored. Different sugar-coated liposomes were prepared and tested against experimental leishmaniasis in vivo using pentamidine isethionate and its methoxy derivative.Both drugs when encapsulated in sug ar-grafted li re found to be more nt in normal drug de 145 very. A significant reduction in tumor volume and increased survival time were observed in tumor-bearing mice treated with a combination of hyperthermia and thermosensitive liposome-encapsulated mel- phalan compared with animals treated with an equivalent dose of free melphalar wih or without hype erthermia.The eresults suggest that hyperthe in co on with temperatu some-encapsulated melphalan may serve asa useful targeted drug delivery system for more effective management of melanoma.14
Chapter one: Site-specific drug delivery using liposomes as carriers 23 • The analysis of in vitro antiproliferative activity on cultured human leukemic K562 cells demonstrated that ionic and neutral liposomes containing chromomycin were 1.5- and 7-fold more effective, respectively, as compared with the free drug.139 • Liposomes encapsulating adenosine triphosphate were prepared by sonication, and the liposomes have been evaluated for treatment of ischemic retina.140 • The intrahepatic distribution of liposomes containing glycolipid derivatives showed that these were suitable for the selective delivery of liposomes to hepatic parenchymal cells. The authors synthesized branched-type galactoyllipid derivatives for liposome modification for the targeting of asialoglycoprotein receptors on the surface of liver cells. Galactose was coupled to the a- and g-carboxyl groups of glutamic acid via a triethyleleglycol spacer, and the glutamic moiety bound to the lipid anchor.141 • Liver accumulation of liposomes depends on the galactosyl residues. The number of galactosyl residues was more effective for accumulation in the liver than for branching. Niosome-encapsulated ciprofloxacin and norfloxacins were studied, and it was found that intestinal, but not nasal, absorption was significantly higher in comparison with that of nonliposomal parent drugs.142 • It is known that a single liposome may carry greater than or equal to 10,000 drug molecules and that the use of PEG-conjugated immunoliposomes increases the drug-carrying capacity of the monoclonal antibody by up to four logarithmic orders in magnitude. Specific OX-26 monoclonal antibody-mediated targeting of daunomycin to the rat brain was achieved by this immunoliposome-based drug delivery system.143 • The use of liposome can be helpful in optimizing sustained delivery of glucocorticoids to the lungs via topical administration. The use of triamcinolone acetonide phosphate liposomes as a pulmonary-targeted drug delivery system has been explored.144 • Different sugar-coated liposomes were prepared and tested against experimental leishmaniasis in vivo using pentamidine isethionate and its methoxy derivative. Both drugs, when encapsulated in sugar-grafted liposomes, were found to be more potent in comparison to normal drug delivery.145 • A significant reduction in tumor volume and increased survival time were observed in tumor-bearing mice treated with a combination of hyperthermia and thermosensitive liposome-encapsulated melphalan compared with animals treated with an equivalent dose of free melphalan, with or without hyperthermia. These results suggest that hyperthermia in combination with temperature-sensitive liposome-encapsulated melphalan may serve as a useful targeted drug delivery system for more effective management of melanoma.146
Drug delivery systems,second edition .Using virosomes prepared from the P3HRI strain of Epstein-Bar virus,the authors demonstrated that these particles fused with hu- man hepatocarcinoma cell line Li7A might be used as a drug delivery system to enhance specific macrophagic functions.147 .Use of radioprotective drugs in radiotherapy is desirable to protect normal tiss es.2-Me captopropionylglycin (MPG)showed ing results in experimental radioprotection.A statistically significant dose-dependent enhancement of protection by liposome-encapsulat- ed MPG was observed.Liposome-encapsulated MPG,as compared to free MPG,improved the viabilities of spleen and bone marrow cells for different doses of radiation 148 The nuclear enzyme,topo omerase I,was recently recognized as the target for the anticancer drug,camptothecin (CPT),and its deriva- tives.This drug was reported to display effective antitumor effects on a variety of human tumor models xenografted in nude mice.The intramuscular administration of liposome-incorporated CPT had considerable potential for the treatm ent of human neoplastic diseas- es,especially lymph node metasta Theauthorsdeveloped a lipid-based drug delivery system toprovide prolonged levels of gentamicin in local tissues after local adminis- tration.Local injection of multivesicular liposome/gentamicin pro- vided sustained drug concentrations in regional tiss es,which pro- tected against a massive bacterial challenge for at least4days Cytosine arabinoside(Ara-C)was contained in polyn ed lipo somes.Polymers such as dimyristoylphosphatidylcholine,dipalmi- toylphosphatidylcholine,and dicetyl phosphate were used and coat- ed with a derivatized polysaccharide.These liposomes were found stable in harsh environments.such as those encountered after oral administration. The authors investigated the in vivo characteristics of liposomes coat ed with a polyvinylalcohol having a long alkyl chain as a hydropho- bic moiety at the end of the molecule.This moiety reduced uptake in the reticuloendothelial system.152 In the search for an effective immunization against diseases such as cance para ase AIDS,and other viral infecti ns severa peptid s and recombinant proteins were syntr esized,examined for the ability to induce antibodies and cytotoxic T lymphocytes(CTLs), and tested for binding capability and therapeutic or prophylactic efficacy against the original target cell of the organism.The data est that small synthetic peptides,without chemica ly conjugated to the surfac s,might effective antigenic epitopes in comb lipid A for induction of antibodies and CTL .After intravenous injection in rats,the pharmacokinetics and biodis- tribution of methotrexate were significantly changed by liposomal incorporation and also by the composition of lip mes.Liposomes
24 Drug delivery systems, second edition • Using virosomes prepared from the P3HR1 strain of Epstein–Barr virus, the authors demonstrated that these particles fused with human hepatocarcinoma cell line Li7A might be used as a drug delivery system to enhance specific macrophagic functions.147 • Use of radioprotective drugs in radiotherapy is desirable to protect normal tissues. 2-Mercaptopropionylglycine (MPG) showed promising results in experimental radioprotection. A statistically significant, dose-dependent enhancement of protection by liposome-encapsulated MPG was observed. Liposome-encapsulated MPG, as compared to free MPG, improved the viabilities of spleen and bone marrow cells for different doses of radiation.148 • The nuclear enzyme, topoisomerase I, was recently recognized as the target for the anticancer drug, camptothecin (CPT), and its derivatives. This drug was reported to display effective antitumor effects on a variety of human tumor models xenografted in nude mice. The intramuscular administration of liposome-incorporated CPT had considerable potential for the treatment of human neoplastic diseases, especially lymph node metastases.149 • The authors developed a lipid-based drug delivery system to provide prolonged levels of gentamicin in local tissues after local administration. Local injection of multivesicular liposome/gentamicin provided sustained drug concentrations in regional tissues, which protected against a massive bacterial challenge for at least 4 days.150 • Cytosine arabinoside (Ara-C) was contained in polymer-coated liposomes. Polymers such as dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, and dicetyl phosphate were used and coated with a derivatized polysaccharide. These liposomes were found stable in harsh environments, such as those encountered after oral administration.151 • The authors investigated the in vivo characteristics of liposomes coated with a polyvinylalcohol having a long alkyl chain as a hydrophobic moiety at the end of the molecule. This moiety reduced uptake in the reticuloendothelial system.152 • In the search for an effective immunization against diseases such as cancer, parasitic disease, AIDS, and other viral infections, several peptides and recombinant proteins were synthesized, examined for the ability to induce antibodies and cytotoxic T lymphocytes (CTLs), and tested for binding capability and therapeutic or prophylactic efficacy against the original target cell of the organism. The data suggest that small synthetic peptides, synthesized with or without a lipid tail, or chemically conjugated to the surface liposomes, might serve as effective antigenic epitopes in combination with liposomal lipid A for induction of antibodies and CTLs.153 • After intravenous injection in rats, the pharmacokinetics and biodistribution of methotrexate were significantly changed by liposomal incorporation and also by the composition of liposomes. Liposomes
Chapter one:Site-specific drug delivery using liposomes as carriers 25 containing a 2:1 ratio of phosphatidylcholine and cholesterol and distereoylphosphatidyl-etha olamine-N-poly(ethylene glycol)2000 most effectively prolonged blood circulation and reduced hepato- splenic and kidney uptake of methotrexate.15 Boronphenylalanine-loaded conventional and stabilized liposomes were prepared by the reversed-phase evaporation method to treat live stases by boron eutro cap Conventional icles were mposed of phosph tidylcholine an molar ratio of 1:1.To obtain stealth liposomes,polyethylene glycol was included in the lipidic bilayer.Tissue boron concentrations were determined by using inductively coupled plasma-mass spectroscopy. Results indicated that PEG-modified lipo somes accumulated boron in thera eutic ntrations in metas static tissue. Spheru nic multila vectors)composed of phos phatidylcholine,cholesterol,and polyethylene alcohol,entrapping 125-I protein A,were prepared and biodistribution was studied after IV injection in Wistar rats.Approximately 70%of the radioactivity was found in the liver and about 35%in the spleen.Oral adminis. nofⅢ-ln-NTA in fas g rats wed ignificant lioactivity in the blo od.This formulatic ion did oxicity tohuman cells and could be used asdru dve Proliposomes in the form of enteric-coated beads using glyburide were prepared.The beads were enteric-coated with Eudragit L-100 by a fluidized bed-coating process using triethyl citrate asa plasti- The study of enter -coated be exhibited en hanced dissolution as compared with the pure drug VI.Concluding remarks Liposomes sessa number of favorable properties which,theoretically may enable them to function as drug delivery systems. -However,limi- tations exist.First,they are unable to cross the capillary endothelial cells in most organs except the liver,114 and second,many cell types have a limited capacity to phagocytize particles like liposomes nay eem to be attractive carriers of drugs to macrophe as has been demonstrated by the succes ssful app treatment of certain forms of cancer.The use of liposomes also appears to be of significant benefit in the reduction of toxicity of certain anticancer drugs.Potentially important results have also been obtained with the appli- cation of liposomes for the delivery of other drugs.s5.115-119 Problems concerning large production of liposomes as pharmaceu- tical products,acute and chronic toxicity,and immunogenicity of lipo om preparations are certainly important aspects of liposome-based technology and theyeutenio before thepiionfi as a drug delivery system can be contemplated.2 22 Recently,Klimchak and Lenk have addressed some of these topics.Finally,Roerdink et al.in
Chapter one: Site-specific drug delivery using liposomes as carriers 25 containing a 2:1 ratio of phosphatidylcholine and cholesterol and distereoylphosphatidyl-ethanolamine-N-poly(ethylene glycol) 2000 most effectively prolonged blood circulation and reduced hepatosplenic and kidney uptake of methotrexate.154 • Boronphenylalanine-loaded conventional and stabilized liposomes were prepared by the reversed-phase evaporation method to treat liver metastases by boron neutron capture therapy. Conventional vesicles were composed of phosphatidylcholine and cholesterol in a molar ratio of 1:1. To obtain stealth liposomes, polyethylene glycol was included in the lipidic bilayer. Tissue boron concentrations were determined by using inductively coupled plasma-mass spectroscopy. Results indicated that PEG-modified liposomes accumulated boron in therapeutic concentrations in metastatic tissue.155 • Spherulites (noncationic multilamellar vectors) composed of phosphatidylcholine, cholesterol, and polyethylene alcohol, entrapping 125-I protein A, were prepared and biodistribution was studied after IV injection in Wistar rats. Approximately 70% of the radioactivity was found in the liver and about 35% in the spleen. Oral administration of III-In-NTA in fasting rats showed a significant increase of radioactivity in the blood. This formulation did not show cytotoxicity to human cells and could be used as a drug delivery system.156 • Proliposomes in the form of enteric-coated beads using glyburide were prepared. The beads were enteric-coated with Eudragit L-100 by a fluidized bed-coating process using triethyl citrate as a plasticizer. The dissolution study of enteric-coated beads exhibited enhanced dissolution as compared with the pure drug.157 VI. Concluding remarks Liposomes possess a number of favorable properties which, theoretically, may enable them to function as drug delivery systems.109–113 However, limitations exist. First, they are unable to cross the capillary endothelial cells in most organs except the liver,114 and second, many cell types have a limited capacity to phagocytize particles like liposomes. Liposomes may seem to be attractive carriers of drugs to macrophages, as has been demonstrated by the successful application of liposomes in the treatment of certain forms of cancer. The use of liposomes also appears to be of significant benefit in the reduction of toxicity of certain anticancer drugs. Potentially important results have also been obtained with the application of liposomes for the delivery of other drugs.85,115–119 Problems concerning large-scale production of liposomes as pharmaceutical products, acute and chronic toxicity, and immunogenicity of liposome preparations are certainly important aspects of liposome-based technology and they require careful attention before the clinical application of liposomes as a drug delivery system can be contemplated.82,120–122 Recently, Klimchak and Lenk have addressed some of these topics.123 Finally, Roerdink et al.14 in
2 Drug delivery systems,second edition their review article point out that"despite some early remarkable successes liposomes are by no means a panacea for pharmacotherapy in general."Their observation still seems to be aptly justified. References 1.Urquhart,J.Assessing adverse reaction reports on old drugs in new dosage orms.In The Latest Developments osprug Delvery systems Conterence Proceedings,Pharmt.Tec 11,3 2.Urquhart,J.and Nicho K.,Delivery systems and pharmacodynamics in arug re earch an d development opments in Drug ms Conference Proceedings,Pharm.Tech.,13-16,1985 3.Anderson, J.M.and Kim,S.W.,Ed.,Advances in Drug Delivery Systems,Vol. am,198 4.Robinson Controlled Drug Delivery Fundamentals and e,NY,19% 5.Tirrell,D.A Donaru a,L.G.,an Turek,A.B.,Ma cules as Drugs and Materials,New York Academy of Sciences 6.Bruck. Controlled Drug Delivery,Vols.1 and 2,CRC Press,Inc.,Boca 7. Tyle, Fundamentals and Applications,Marcel Dekker ai,J.,Drug delivery system in light of the new legal situation.In The tes Pharm 9. Flynn,G.L rations in contro led release drug delivery system,Pharm n,E,Bi particul delivery usng Eds CH 1987 3265 11. n,E,(Path ogy a the temp al and atial drug de y.In site-speci omlinso ,1986.1-26. Davis Eds.,Jo e 12. ,G.,The "P er concept:its de 1A1 Iohn Wil GVol.1-3.CRC Pre Gregoriadis 13.Juliano,R.L.,Liposomes as arug deli ivery system,Trends in Pha macol.Sci. 729411981 14.Roe dink.E.H.Dae .T.Bakker-Woudenbe rg L.A.J.M.Storm,G.Crom t n epho nd Llo I.G.Eds.VCH Ho od Ltd.Chiche 66-80,1987 vd-Jones 15.Juliano,R.L. and La n.D.Li asadrug delive .In Drus ery Sys RL Ed Oxford Uni versity Press 189226.198
26 Drug delivery systems, second edition their review article point out that “despite some early remarkable successes, liposomes are by no means a panacea for pharmacotherapy in general.” Their observation still seems to be aptly justified. References 1. Urquhart, J., Assessing adverse reaction reports on old drugs in new dosage forms. In The Latest Developments in Drug Delivery Systems Conference Proceedings, Pharm. Tech., 11, 32–34, 1987. 2. Urquhart, J. and Nichols, K., Delivery systems and pharmacodynamics in new drug research and development. In The Latest Developments in Drug Delivery Systems Conference Proceedings, Pharm. Tech., 13–16, 1985. 3. Anderson, J.M. and Kim, S.W., Ed., Advances in Drug Delivery Systems, Vol. 3, Elsevier, Amsterdam, 1988. 4. Robinson, J.R. and Lee, H.L., Eds., Controlled Drug Delivery Fundamentals and Applications, 2nd ed., Marcel Dekker, NY, 1987. 5. Tirrell, D.A., Donaruma, L.G., and Turek, A.B., Macromolecules as Drugs and as Carriers for Biologically Active Materials, New York Academy of Sciences, New York, 1985. 6. Bruck, S.D., Ed., Controlled Drug Delivery, Vols. 1 and 2, CRC Press, Inc., Boca Raton, FL, 1983. 7. Tyle, P., Drug Delivery Device Fundamentals and Applications, Marcel Dekker, New York, 1988. 8. Shacknai, J., Drug delivery systems in light of the new legal situation. In The Latest Developments in Drug Delivery Systems Conference Proceedings, Pharm. Tech., 54–59, 1985. 9. Flynn, G.L., Considerations in controlled release drug delivery system, Pharm. Tech., 6, 33–39, 1982. 10. Tomlinson, E., Biological opportunities for site-specific drug delivery using particulate carriers. In Drug Delivery Systems: Fundamentals and Techniques, Johnson, P. and Lloyd-Jones, J.G., Eds., VCH Ellis Horwood Ltd., Chichester, 1987, 32–65. 11. Tomlinson, E., (Patho)physiology and the temporal and spatial aspects of drug delivery. In Site-Specific Drug Delivery, Cell Biology, Medical and Pharmaceutical Aspects, Tomlinson, E. and Davis, S.S., Eds., John Wiley & Sons, Chichester, 1986, 1–26. 12. Gregoriadis, G., The liposome drug carrier concept: its development and future. In Liposomes in Biological Systems, Gregoriadis, G. and Allison, A.C., Eds., John Wiley & Sons, New York. Also see Liposome Technology, Gregoriadis, G. Vol. 1–3, CRC Press, Inc., Boca Raton, FL, 1980. 13. Juliano, R.L., Liposomes as a drug delivery system, Trends in Pharmacol. Sci., 2, 39–41, 1981. 14. Roerdink, F.H., Daemen, T., Bakker-Woudenberg, I.A.J.M., Storm, G., Crommelin, D.J.A., and Schephof, G.L., Therapeutic utility of liposomes. In Drug Delivery Systems: Fundamentals and Techniques, Johnson, P. and Lloyd-Jones, J.G., Eds., VCH Horwood Ltd., Chichester, 66–80, 1987. 15. Juliano, R.L. and Layton, D., Liposomes as a drug delivery system. In Drug Delivery Systems, Juliano, R.L., Ed., Oxford University Press, 189–236, 1980