An Overview on Advanced Parenteral Drug Delivery System in Clinical Disease Management
Therapeutic effect of drug depends on method by which it is delivered. Number of drug delivery system (DDS) has been developed from time immortal. One of the DDS is parenteral drug delivery system, which is firstly reported in the mid 19
century by Alexander wood.
Since then a number of technological advances have been made in the area of parenteral drug delivery leading to the development of sophisticated systems that allow drug targeting and the sustained or controlled release of parenteral medicines. The purpose of this review is to discuss and summarize some of the interesting technologies of parenteral drug delivery system that can be helpful in the management of clinical diseases. The article highlights important applications in the design of various novel delivery systems like liposomes, niosomes, nanoparticle and microparticles, cyclodextrins, emulsions, prodrug and polymeric micelles
The method by which a drug is delivered can have a significant effect on its efficacy. Some drugs have an optimum concentration range within which maximum benefit is derived and concentrations above or below this range can be toxic or produce no therapeutic benefit at all. On the other hand, the very slow progress in the efficacy of the treatment of severe diseases, has suggested a growing need for a multidisciplinary approach to the delivery of drug to targets tissues. From this, new ideas on controlling the pharmacokinetics, pharmacodynamics, non-specific toxicity, immunogenicity, biorecognition and efficacy of drugs were generated. These new strategies, emerges the need of called drug delivery systems (DDS), which are based on interdisciplinary approaches that combine polymer science, pharmaceutics, bioconjugate chemistry and molecular biology. To minimize drug degradation, to prevent harmful side-effects, to increase drug bioavailability & the fraction of the drug accumulated in the required zone, various drug delivery and drug targeting systems are in continuous research. These paper emphasis on the study of advanced parenteral drug delivery system with its application (Table 1) in reference of detail discussion of liposomes, niosomes, nanoparticles & microparticles, cyclodextrins, emulsions, prodrug (ADEPT, Polymer drug conjugates) and polymeric micelles.
Liposomes were discovered in the mid 1960s
and originally studied as cell membrane models, since then they have been gained recognition in the field of drug delivery. Liposomes are formed by the self-assembly of phospholipid molecules in an aqueous environment, shown schematically in Figure 1, the amphiphilic phospholipid molecules form a closed bilayer sphere in an attempt to shield their hydrophobic groups from the aqueous environment while still maintaining contact with the aqueous phase via the hydrophilic head group. The resulting closed sphere may encapsulate aqueous soluble drugs within the central aqueous compartment (Figure 1a) or lipid soluble drugs within the bilayer membrane (Figure 1b). Alternatively, lipid soluble drugs may be complexed with cyclodextrins and subsequently encapsulated within the liposome aqueous compartment
The encapsulation of drugs with liposomes alters drug pharmacokinetics and this may be exploited to achieve targeted therapies. Alteration of the liposome surface is necessary in order to optimize liposomal drug targeting and to achieve prolonged circulation times
liposome size between 70-200nm is necessary
. Liposomes are the most widely studied modern drug delivery system because of its amazing application for the management of following diseases.
i) Liposomal anticancer agent -
The use of liposomes as anticancer drug delivery systems was originally hampered by the realization that liposomes are rapidly cleared from the circulation and largely taken up by the liver macrophage
. It was observed that doxorubicin loaded stealth liposomes circulate for prolonged periods
and extravagate within tumours & also improve tumoricidal activity
in mice. In one study it has been reported that in patients, liposomal doxorubicin accumulates within Kaposi’s sarcoma lesions
and produces a good therapeutic response
. Liposomal doxorubicin is now licensed as Caelyx
, for the treatment of Kaposi’s sarcoma. This formulation is currently in clinical trials for ovarian cancer and could be approved shortly for use in ovarian cancer patients who have failed to respond to paclitaxel and cisplatin
ii) Liposomes as vaccine adjuvants -
Liposomal vaccines can be made by associating microbes, soluble antigens, cytokines
or deoxyribonucleic acid (DNA)
with liposomes, the latter stimulating an immune response on expression of the antigenic protein
. Liposomes encapsulating antigens, which are subsequently encapsulated within alginate lysine microcapsules
to control the antigen release and to improve the antibody response. Liposomal vaccines may also be stored dried at refrigeration temperatures for up to 12 months and still retain their adjuvanticity
iii) Liposomal anti-infective agents -
Liposomal amphotericin B (Ambisome)
, used for the treatment of systemic fungal infection. This is the first licensed liposomal preparation
. It was observed in one study that liposomal amphotericin B, by passively targeting the liver and spleen, reduces the renal
and general toxicity of the drug at normal doses.
Niosomes are unilamellar or multilamellar vesicles, where in an aqueous solution is enclosed in highly ordered bilayer made up of nonionic surfactants with or without cholesterol (chol) and dicetyl phosphate and exhibit a behavior similar to liposomes
. They can be used in the treatment of cancer and also used as vaccine adjuvant. Some of its applications are discussed here.
i) Anticancer niosomes
Anticancer niosomes, if suitably designed will be expected to accumulate within tumours. For example niosomal encapsulation of methotrexate
and doxorubicin increases drug delivery to the tumour and tumoricidal activity. It was reported that doxorubicin niosomes having size 200nm with a polyoxyethylene (molecular weight 1,000) surface are rapidly taken up by the liver
and accumulate to a lesser extent in tumour, this technology may prove advantageous for the treatment of hepaticneoplasms. It was also observed that the activity of other anticancer drugs, such as vincristine
, plumbagin and a plant derived anticancer agent
are improved on niosomal encapsulation.
ii) Niosomes at targeted site
Uptake by the liver and spleen make niosomes ideal for targeting diseases manifesting in these organs. One such condition is leishmaniasis and a number of other studies
has shown that niosomal formulations of sodium stibogluconate improve parasite suppression in the liver
spleen and bone marrow
. Niosomes may also be used as depot systems for short acting peptide drugs on intramuscular administration
iii) Niosomes as vaccine adjuvants
It was studied that niosomal antigens are potent stimulators of the cellular and humoral immune response
. The formulation of antigens as a niosome in water-in-oil emulsion further increases the activity of antigens
and hence enhanced the immunological response.
3) Nanoparticles and Microparticles
Nanoparticles and microparticles are usually prepared by the controlled precipitation of polymers solubilised in one of the phases of an emulsion
. Precipitation of the polymer out of the solvent takes place on solvent evaporation, leaving particles of the polymer suspended in the residual solvent. For particulate dispersions, the required particle size of nanoparticles lies between the range of 30-500nm while for microparticles in excess of 0.5micron. Their applications in management of diseases are discussed below.
i) Tumor targeting nanoparticles and microparticles
The accumulation of non-stealth doxorubicin nanoparticles within the Kupffer cells of the liver may be used to target hepatic neoplasms indirectly
, this is achieved by providing a depot of drug for killing nearby neoplastic tissue. Microparticles
may also be injected directly into tumours. It was observed that the direct injection of microparticles into solid tumours increases the tumoricidal activity of the drugs 5-fluorouracil
ii) Vaccine adjuvants
Nanoparticles have also been used as vaccine adjuvants. It was reported that antigens, which adsorbed onto the surface or entrapped in the matrix of polymethylmethacrylate nanoparticles induces an enhanced immunological response
. For example polymethylmethacrylate nanoparticles containing the influenza antigen may protect people against disease to a greater extent than the antigen alone.
iii) Other applications
Restenosis, defined as the re-obstruction of an artery following procedures such as angioplasty or artherectomy may be treated by the local application of dexamethasone-loaded polylactic acid co-glycolic acid nanoparticles
. Cyclosporin A, an immunosuppressant drug used to prevent graft rejection after transplantation by the inhibition of T-lymphocytes, may be targeted to regional lymph nodes by the intramuscular administration of cyclosporin A polylactic acid nanoparticles
In short it can be said that, by virtue of their small size solid nanoparticles provide opportunities for targeted parenteral therapies and may also be used as immunoadjuvants.
Cyclodextrins (CDs), with lipophilic inner cavities and hydrophilic outer surfaces, are capable of interacting with a large variety of guest molecules to form noncovalent inclusion complexes. Only the modified cyclodextrins
, such as hydroxypropyl b-cyclodextrin (HP-β-CD)
and sulphobutyl b-cyclodextrin (SBE-β-CD
, are regarded as safe for parenteral use. Applications of CDs in parenteral delivery are solubilization of drugs, reduction of drug irritation at the site of administration, and stabilization of drugs unstable in the aqueous environment.
i) As a solubility enhancer
Singla et al discussed the use of CDs to enhance the solubility and stability of paclitaxel in formulations and mentioned that the approach needs further research to overcome the serious limitations of CD-based formulations
. It was studied that the solubilizing potentials of both SBE-β- and HP-β-CDs for the drugs melphalan and carmustine were qualitatively similar but the intrinsic reactivities were significantly less with SBE-β-CD
. Formation of a stable, water-soluble dexamethasone complex with sugar branched β-CDs suggested the potential of these CDs as excellent carriers in steroidal injectable formulations
. It was observed in one study that an aqueous phenytoin parenteral formulations containing HP-β-CD exhibited reduced drug tissue irritation and precipitating tendency because their pH values were significantly closer to the physiological value (7.4)
. SBE-β-CD was found to be useful in the preparation of parenteral solutions of poorly water-soluble drugs
Emulsions are usually used as a means of administering aqueous insoluble drugs by dissolution of the drugs within the oil phase
or to prevent drug hydrolysis or drug uptake by infusion sets
It is recommended that emulsions destined for the intravenous (IV) route have a submicron droplet size
, although emulsions with a droplet size of 10mm have been used parenterally. Emulsions are useful to deliver drug at particular site and helpful to reduce drug toxicity.
As drug targeting systems
It was observed that emulsion formulations, with a droplet size of 100 to 200nm, usually result in high drug liver uptake on IV injection 67-68 . Emulsions are helpful to deliver drug at particular site, active targeting may be achieved by conjugating antibodies to the distal ends of the polyoxyethylene chain emulsifiers, provided the emulsion droplets have a submicron droplet size 69 , as shown schematically in Figure 2.
ii) Reduces drug toxicity
Emulsions may also be used to reduce drug toxicity. For example use of a water in oil emulsion of amphotericin deoxycholate, as opposed to a solution, reduces the incidence and severity of renal impairment and chills in patients while still maintaining the antifungal efficacy of the drug
A prodrug is a pharmacological substance, which is administered in an inactive form. Once administered, it is metabolized in the body
into the active compound. The use of prodrugs in cancer chemotherapy as a means of targeting relatively toxic compounds to specific areas of pathology is enjoying renewed activity. Two of the technologies being evaluated at present are antibody directed enzyme prodrug therapy (ADEPT) and the use of polymeric prodrugs.
The principle behind the ADEPT approach is shown schematically in Figure 3. Basically, an antibody-enzyme conjugate is administered intravenously, localizes in tumour tissue and subsequently activates an administered prodrug predominantly within such tumours
Prodrug activating enzyme is carboxypeptidase G2. In short is I is worthy to say that proof of principle studies of the ADEPT approach have already been conducted in the clinic, although problems such as the immunogenicity of the non-human enzyme and the long half life of the active drug leading to toxic sequelae still remain to be addressed.
ii) Polymeric prodrugs -
Drug delivery with polymeric prodrugs, first envisioned 25 years ago
, involves the use of an active substance and possibly a targeting moiety, both linked via spacers to a water-soluble polymeric backbone. From this basic blueprint a number of polymer drug conjugates used for cancer chemotherapy and have been synthesized with cleavable drug polymer linkers. These include soluble polymeric prodrugs of daunorubicin
, cisplatin and 5-fluorouracil
. Passive tumour targeting with polymer drug conjugates improves the tumoricidal activity of anticancer agents
. Distribution to potential sites of toxicity, such as the distribution of doxorubicin to heart tissue
, is also decreased with polymer drug conjugates. In short, polymer drug conjugates have progressed from an elegant scientific concept to the clinic and may result in a new form of therapeutics for routine use.
7) Polymeric micelles
Amphiphilic block copolymers such as the Pluronics (polyoxyethylene polyoxypropylene block copolymers) self-assemble into polymeric micelles. For drug delivery purposes, hydrophobic drugs may be solubilised within the core of the micelle
or alternatively conjugated to the micelle-forming polymer
. They thus circulate for prolonged periods
and deliver more of the drug to tumour tissue when compared with administration of the drug in solution
. This property makes them a choice for the treatment of various diseases.
i) As tumoricidal and targeted agent
It was noted in one study that Pluronic micelles solubilizing epirubicin and doxorubicin increase the tumoricidal activity of these anticancer drugs
. Polymeric micelles bearing targeting ligands may also be used as drug targeting agents. For example haloperidol pluronic micelles targeted to the brain by conjugation with brain specific antibodies
The past 10 years have witnessed a real explosion in the number of technologies available to control drug biodistribution. These have been exploited to produce particulate, soluble, implantable drug delivery systems, which accumulates drug in the desired area (in-situ) of the anatomy or pathology. Drug delivery technologies such as those discussed above may be used to control drug delivery on parenteral administration. Some of the newer systems, such as liposomal doxorubicin, may soon be licensed for new indications. Additionally, the beginning of the next century may see some new formulation or drug delivery initiatives, such as the polymer drug conjugates and possibly the ADEPT systems, transformed into commercial products. Liposomes may also one day open the door to routine gene therapy in the clinic. Parenteral drug delivery systems have grown to become important technology platforms used by companies in the pharmaceutical in recent years. Parenteral in-situ drug delivery system is good study object. So it is important to study parenteral drug delivery system as it is provides rapid treatment objective to save unvaluable life of human being.
1. Bangham AD, Standish MM, Watkins JC. Diffusion of univalent ions across lamellae of swollen phospholipids. J Mol Biol 1965;13:238-52.
2. McCormack B, Gregoriadis G. Drugs-in-cyclodextrins-in-liposomes a novel concept in drug-delivery. Int J Pharm 1994;112:249-58.
3. Harashima H, Hiraiwa T, Ochi Y, Kiwada H. Size dependent liposome degradation in blood:in vivo/in vitro correlation by kinetic modelling. J Drug Target 1995;3:253-61.
4. Litzinger DC, Buiting AMJ, Rooijen NV, Huang L. Effect of liposome size on the circulation time and intraorgan distribution of amphipathic poly(ethylene glycol)-containing liposomes, Biochim Biophys. Acta 1994;1190:99-107.
5. Gabizon A, Price DC, Huberty J, Bresalier RS, Papahadjopoulos D. Effect of liposome composition and other factors on the targeting of liposomes to experimental tumours:biodistribution and imaging studies. Cancer Res 1990;50:6371-8.
6. Papahadjopoulos D, Allen TM, Gabizon A, Mayhew E, Matthay K, Huang SK, et al. Sterically stabilized liposomes: improvements in pharmacokinetics and antitumour therapeutic efficacy. Proc Natl Acad Sci USA 1991;88:11460-4.
7. Wu NZ, Da D, Rudoll TL, Needham D, Whorton AR, Dewhirst MW. Increased microvascular permeability contributes to preferential accumulation of stealth liposomes in tumor-tissue. Cancer Res 1993;53:3765-70.
8. Huang SK, Lee K-D, Hong K, Friend DS, Papahadjopoulos D. Microscopic localization of sterically stabilized liposomes in colon carcinoma-bearing mice. Ibid 1992;52:5135-43.
9. Baish JW, Gazit Y, Berk DA, Nozue M, Baxter LT, Jain RK. Role of tumor vascular architecture in nutrient and drug-delivery. Microvasc Res 1996;51:327-46.
10. Haran G, Cohen R, Bar LK, Barenholz Y. Transmembrane ammonium sulphate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases. Biochim Biophys Acta 1993;1151:201-15.
11. Gabizon A, Barenholz Y, Bialer M. Prolongation of the circulation time of doxorubicin encapsulated in liposomes containing a polyethylene glycol-derivatized phospholipid: pharmacokinetic studies in rodents and dogs. Pharm Res 1993;10:703-8.
12. Gregoriadis G, Ryman B. Fate of protein containing liposomes injected into rats. Eur J Biochem 1972;24:485-91.
13. Yuan F, Leunig M, Huang SK, Berk DA, Papahadjopoulos D, Jain RK. Microvascular permeability and interstitial penetration of sterically stabilized (stealth) liposomes in a human tumor xenograft. Cancer Res 1994;54:3352-6.
14. Huang SK, Martin FJ, Jay G, Vogel J, Papahadjopoulos D, Friend DS. Extravasation and transcytosis of liposomes in Kaposi’s sarcoma-like dermal lesions of transgenic mice bearing the HIV tat gene. Am J Pathol 1993;43:10-14.
15 Vaage J, Mayhew E, Martin F. Therapy of primary and metastatic mouse mammary carcinomas with doxorubicin encapsulated in long circulating liposomes. Int J Cancer 1992;51:942-8.
16. Williams SS, Alosco TR, Mayhew E, Lasic DD, Martin FJ, Bankert RB. Arrest of human lung-tumor xenograft growth in severe combined immunodeficient mice using doxorubicin encapsulated in sterically stabilized liposomes. Cancer Res 1993;53:3964-7.
17. Gabizon A, Chemla M, Tzemach D, Horowitz AT, Goren D. Liposome longevity and stability in circulation:Effects on the in vivo delivery to tumors and therapeutic efficacy of encapsulated anthracyclines. J Drug Target 1996;3:391-8.
18. Lasic D, Papahadjopoulos D. Liposomes revisited. Science 1995;267:1275-6.
19. Sturzl M, Zietz C, Eisenburg B, Goebel FD, Gillitzer R, Hofscneider PH, et al. Liposomal doxorubicin in the treatment of AIDS-associated Kaposi’s sarcoma: clinical, histological and cell biological evaluation. Res Virol 1994;145:261-9.
20. Bergin C, O’Leary A, McCreary C, Sabra K, Mulcahy F. Treatment of Kaposi’s sarcoma with liposomal doxorubicin. Am J Health-Syst Pharm 1995;52:2001-4.
21. Gregoriadis G. Engineering liposomes for drug delivery:progress and problems. TI/Biotechnology 1995;13:527-37.
22. Gregoriadis G, Saffie R, Da Souza JB. Liposome mediated DNA vaccination. FEBS Lett 1997;402:107-10.
23. Gregoriadis G. Genetic vaccines:strategies for optimization. Pharm Res 1997;15:661-9.
24. Cohen S, Bernstein H, Hewes C, Chow M, Langer R. The pharmacokinetics of, and humoral responses to, antigen delivered by microencapsulated liposomes. Proc Natl Acad Sci USA 1991;88:10440-4.
25. Kim CK, Jeong EJ. Development of dried liposome as effective immuno-adjuvant for hepatitis B surface antigen. Int J Pharm 1995;115:193-9.
26. Boswell GW, Buell D, Bekersky I. AmBisome (Liposomal amphotericin B): A comparative review. J Clin Pharmacol 1998;38:583-92.
27. Gray A, Morgan J. Liposomes in hematology. Blood Rev 1991;5:258-271.
28. Ahmad I, Agarwal A, Pal A, Guru PY, Bachhawat BK, Gupta CM. Tissue distribution and antileishmanial activity of liposomised amphotericin-B in BALB/c mice. J Biosci 1991;16:217-21.
29. Namdeo, A. and Jain, N.K., Niosomes as drug carriers.
Indian J. Pharm. Sci
., 58(2):41-46, 1996. Niosomes has been used to treat many diseases.
30. Chandraprakash KS, Udupa N, Devi PU, Pillai GK. Effect of niosome encapsulation of methotrexate, macrophage activation on tissue distribution of methotrexate and tumour size. Drug Delivery 1993;1:133-7.
31. Uchegbu IF, Double JA, Turton JA, Florence AT. Distribution, metabolism and tumoricidal activity of doxorubicin administered in sorbitan monostearate (Span 60) niosomes in the mouse, Pharm Res 1995;12:1019-24.
32. Parthasarathi G, Udupa N, Umadevi P, Pillai GK. Niosome encapsulated of vincristine sulfate: improved anticancer activity with reduced toxicity in mice. J Drug Target 1994;2:173-82.
33. Naresh RAR, Udupa N. Niosome encapsulated bleomycin. STP Pharm Sci 1996;6:61-71.
34. Naresh RAR, Udupa N, Devi PU. Niosomal plumbagin with reduced toxicity and improved anticancer activity in Balb/C mice. J Pharm Pharmacol 1996;48:1128-32.
35. Baillie AJ, Coombs GH, Dolan TF, Laurie J. Non-ionic surfactant vesicles, niosomes, as a delivery system for the anti-leishmanial drug, sodium stibogluconate. Ibid1986;38:502-5.
36. Hunter CA, Dolan TF, Coombs GH, Baillie AJ. Vesicular systems (niosomes and liposomes) for delivery of sodium stibogluconate in experimental murine visceral leishmaniasis. Ibid 1988;40:161-5.
37. Carter KC, Baillie AJ, Alexander J, Dolan TF. The therapeutic effect of sodium stibogluconate in Balb/C mice infected with Leishmania donovani is organ dependent. Ibid 1988;40:370-3.
38. Williams DM, Carter KC, Baillie AJ. Visceral leishmaniasis in the Balb/C Mouse — a comparison of the in-vivo activity of 5 nonionic surfactant vesicle preparations of sodium stibogluconate. J Drug Target 1995;3:1-7.
39. Arunothayanun P, Turton JA, Uchegbu IF, Florence AT. Preparation and in vitro/in vivo evaluation of luteinizing hormone releasing hormone (LHRH)-loaded polyhedral and spherical tubular niosomes. J Pharm Sci 1999;88:34-8.
40. Brewer JM, Alexander J. The adjuvant activity of nonionic surfactant vesicles (niosomes) on the Balb/C humoral response to bovine serum albumin. Immunology 1992;75:570-5.
41. Hassan Y, Brewer JM, Alexander J, Jennings R. Immune responses in mice induced by HSV-1 glycoproteins presented with ISCOMs or NISV delivery systems. Vaccine 1996;14:1581-9.
42. Yoshioka T, Skalko N, Gursel M, Gregoriadis G, Florence AT. A nonionic surfactant vesicle-in-water-in-oil (V/W/O) system potential uses in drug and vaccine delivery. J Drug Target 1995;2:533-9.
43. Scholes PD, Coombes AGA, Illum L, Davis SS, Vert M, Davies MC. The preparation of sub-200 nm poly(lactide-co-glycolide) microspheres for site-specific drug delivery. J Control Rel 1993;25:145-53.
44. Song CX, Labhasetwar V, Murphy H, Qu X, Humphrey WR, Shebuski RJ, et al. Formulation and characterization of biodegradable nanoparticles for intravascular local drug delivery. Ibid 1997;43:197-212.
45. Kissel T, Li YX, Volland C, Gorich S, Koneberg R. Parenteral protein delivery systems using biodegradable polyesters of ABA block structure, containing hydrophobic poly(lactide-co-glycolide) A blocks and hydrophilic poly(ethylene oxide) B blocks. J Control Rel 1996;39:315-26.
46. Chiannikulchai N, Ammoury N, Caillou B, Devissaguet JP, Couvreur P. Hepatic tissue distribution of doxorubicin-loaded nanoparticles after IV administration in reticulosarcoma M5076 metastasis-bearing mice. Cancer Chemother Pharmacol 1990;26:122-6.
47. Menei P, BoisdronCelle M, Croue A, Guy G, Benoit JP. Effect of stereotactic implantation of biodegradable 5-fluorouracil-loaded microspheres in healthy and C6 glioma-bearing rats. Neurosurgery 1996;39:117-23.
48. Willmott N, Cummings J. Increased anti-tumour effect of adriamycin-loaded albumin microspheres is associated with anaerobic reduction of drug in tumour tissue. Biochem Pharmacol 1987;36:521-6.
49. Kreuter J. Nanoparticle-based drug delivery systems. J Control Rel 1991;16:169-76.
50. Labhasetwar V, Song CX, Levy RJ. Nanoparticle drug delivery system for restenosis. Adv Drug Del Rev 1997;24:63-85.
51. 179. Yoshikawa H, Seebach S. Lymphotropic delivery of cyclosporin A by intramuscular injection of biodegradable microspheres in mice. Biol Pharm Bull 1996;19:1527-9.
52. Irie T, Uekama K. Pharmaceutical applications of cyclodextrins. 3. Toxicological issues and safety evaluation. J Pharm Sci 1997;86:147-62.
53. Brewster ME, Hora MS, Simpkins JW, Bodor N. Use of 2-hydroxypropyl-beta-cyclodextrin as a solubilizing and stabilizing excipient for protein drugs. Pharm Res 1991;8:792-5.
54. Pitha J, Gerloczy A, Olivi A. Parenteral hydroxypropyl cyclodextrins intravenous and intracerebral administration of lipophiles. J Pharm Sci 1994;83:833-7.
55. Stella VJ, Lee HK, Thompson DO. The effect of Sbe4-Beta-Cd on IV methylprednisolone pharmacokinetics in rats —comparison to a cosolvent solution and 2 water-soluble prodrugs. Int J Pharm 1995;120:189-95.
56.Singla AK, Garg A, Aggarwal D. Paclitaxel and its formulations. Int J Pharm. 2002;235:179-192.
57. Shinoda T, Kagatani S, Maeda A, et al. Sugar-branched-cyclodextrins as injectable drug carriers in mice. Drug Dev Ind Pharm. 1999;25:1185-1192.
58. Ma DQ, Rajewski RA, Velde DV, Stella VJ. Comparative effects of (SBE) 7m -beta-CD and HP-beta-CD on the stability of two anti-neoplastic agents, melphalan and carmustine. J Pharm Sci. 2000; 89: 275-287.
Blanchard J, Ugwu SO, Bhardwaj R, Dorr T. Anhydrous carbopol polymer gels for the topical delivery of oxygen/water sensitive compounds. Pharm Dev Technol. 2000;7:249-255.
60. Nagase Y, Hirata M, Wada K, et al. Improvement of some pharmaceutical properties of DY-9760e by sulfobutyl ether beta-cyclodextrin. Int J Pharm. 2001;229:163-172.
61. Tarr BD, Sambandan TG, Yalkowsky SH. A new parenteral emulsion for the administration of taxol. Pharm Res 1987;4:162-5.
62. Strickley RG, Anderson BD. Solubilization and stabilization of an anti-HIV thiocarbamate, NSC 629243, for parenteral delivery, using extemporaneous emulsions. Ibid 1993;10:1076-82.
63. Lundberg B. Preparation of drug-carrier emulsions stabilized with phosphatidylcholine-surfactant mixtures. J Pharm Sci 1994;83:72-5.
64. Lundberg BB. A submicron lipid emulsion coated with amphipathic polyethylene glycol for parenteral administration of paclitaxel (Taxol). J Pharm Pharmacol 1997;49:16-21.
65. Prankerd RJ, Stella VJ. The use of oil-in-water emulsions as a vehicle for parenteral drug administration. J Parent Sci Tech 1990;44:139-49.
66. Floyd AG. Top ten considerations in the development of parenteral emulsions. PSTT 1999;2:134-43.
67. Lee MJ, Lee MH, Shim CK. Inverse targeting of drugs to reticuloendothelial system-rich organs by lipid microemulsion emulsified with Poloxamer-338. Int J Pharm 1995;113:175-87.
68. Liu F, Liu D. Long circulating emulsions (oil-in-water) as carriers for lipophilic drugs, Pharm Res 1995;12:1060-4.
69. Song YK, Liu DX, Maruyama K, Takizawa T. Antibody mediated lung targeting of long-circulating emulsions. PDA J Pharmaceut Sci Tech 1996;50:372-7.
70. Chavanet PY, Garry I, Charlier N, Caillot D, Kisterman JP, D’Athis M, et al. Trial of glucose versus fat emulsion in preparation of amphotericin for use in HIV infected patients with candidiasis. BMJ 1992;305:921-5.
71. Bagshawe KD, Sharma SK, Springer CJ, Antoniw P, Rogers GT, Burke PJ, et al. Antibody-enzyme conjugates can generate cytotoxic drugs from inactive precursors at tumor sites. Antibod Immunoconj Radiopharm 1991;4:915-22.
72. Ringsdorf H. Structure and properties of pharmacologically active polymers, J Polym Sci Polym Symp 1975;51:135-53.
73. Hurwitz E, Wilchek M, Pitha J. Soluble macromolecules as carriers of daunorubicin. J Appl Biochem 1980;2:25-30.
74. Seymour LW, Ulbrich K, Steyger PS, Brereton M, Subr V, Strohalm J, et al. Tumor tropism and anticancer efficacy of polymer-based doxorubicin prodrugs in the treatment of subcutaneous murine B16/F10 melanoma. Br J Cancer 1994;70:636-41.
75. Nichifor M, Schacht EH, Seymour LW. Polymeric prodrugs of 5-fluorouracil. J Control Rel 1997;48:165-78.
76. Maeda M, Takasuka N, Suga T, Uehara N, Hoshi A. Antitumor-activity of a new series of platinum complexes — trans(+/-)-1,2-cyclohexanediammineplatinum(Ii) conjugated to acid polysaccharides. Anti-Cancer Drugs 1993;4:167-71.
77. Yeung TK, Hopewell JW, Simmonds RH, Seymour LW, Duncan R, Bellini O, et al. Reduced cardiotoxicity of doxorubicin given in the form of N-(2- hydroxypropyl)methacrylamide conjugates — an experimental-study in the rat. Cancer Chemother Pharmacol 1991;29:105-11.
78. Kabanov AV, Batrakova EV, Melik-Nubarov NS, Fedoseev NA, Dorodnich Y, Alakhov VY, et al. A new class of drug carriers; micelles of poly(oxyethylene)-poly(oxypropylene) block copolymers as microtainers for drug targeting from blood in brain. J Control Rel 1992;22:141-58.
79. Batrakova EV, Dorodnych TY, Klinskii EY, Kliushnenkova EN, Shemchukova OB, Goncharova ON, et al. Anthracycline antibiotics non-covalently incorporated into the block copolymer micelles: In vivo evaluation of anti-cancer activity. Br J Cancer 1996;74:1545-52.
80. Yokayama M, Miyauchi M, Yamada N, Okano T, Kataoka K, Inoue S. Polymer micelles as novel drug carrier: adriamycin-conjugated poly(ethylene glycol)-poly(aspartic acid) block copolymer. J Contr Rel 1990;11:269-78.
81. Kwon GS, Yokoyama M, Okano T, Sakurai Y, Kataoka K. Biodistribution of micelle-forming polymer drug conjugates. Pharm Res 1993;10:970-4.
82. Kwon G, Suwa S, Yokoyama M, Okano T, Sakurai Y, Kataoka K. Enhanced tumor accumulation and prolonged circulation times of micelle-forming poly(ethylene oxide-aspartate) block copolymer-adriamycin conjugates. J Control Rel 1994;29:17-23.
83. Garvin KL, Miyano JA, Robinson D, Giger D, Novak J, Radio S. Polylactide/polyglycolide antibiotic implants in the treatment of osteomyelitis. A canine model. J Bone Joint Surg. Am Vol 1994;76:1500-6.
84. Fujita T, Tamura T, Yamada H, Yamamoto A, Muranishi S. Pharmacokinetics of mitomycin C (MMC) after intraperitoneal administration of MMC-gelatin gel and its anti-tumor effects against sarcoma-180 bearing mice. J Drug Target 1997;4:289-96.
Table 1: Main applications of Parenteral drug delivery system
||Drug delivery technology||
Passive tumour targeting
Passive targeting to lung
Targeting to regional lymph
Targeting to cell surface
Passive tumour targeting
Sustained release depot at
point of injection
Lipophilic drug solubilisation for
Targeting to cell surface antigens
ii) Polymer drug
|8||Polymeric micelles||Active tumour targeting|
Figure 1: Liposomes 1a) = aqueous soluble drug encapsulated in aqueous compartment; 1b) = a hydrophobic drug in the liposome bilayer.
Figure 2: Targeted emulsion droplet bearing covalently linked antibodies
Figure 3: Principle behind ADEPT approach to drug targeting. Step 1 — injection of
antibody enzyme conjugate; step 2 — activation of the prodrug
Kapoor Shweta* , Ramoliya Rajesh, Shrivatava Satyaendra, Dubey Darshan, Jain Sanjay
* For correspondence
Smriti College of Pharmaceutical Education, 4/1 Piplia Kumar Kakad, Mayakhedi road,
Indore (MP) 452010 Tel: +91-731-2802262 Fax: +91-731-2802467