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AAPS PharmSciTech

, 20:41 | Cite as

Drug–Lipid Conjugates for Enhanced Oral Drug Delivery

  • Tushar Date
  • Kaushani Paul
  • Navneet Singh
  • Sanyog JainEmail author
Review Article Theme: Lipid-Based Drug Delivery Strategies for Oral Drug Delivery
Part of the following topical collections:
  1. Theme: Lipid-Based Drug Delivery Strategies for Oral Drug Delivery

Abstract

Oral drug delivery route is one of the most convenient and extensively utilised routes for drug administration. But there exists class of drugs which exhibit poor bioavailability on oral drug administration. Designing of drug–lipid conjugates (DLCs) is one of the rationale strategy utilised in overcoming this challenge. This review extensively covers the various dimensions of drug modification using lipids to attain improved oral drug delivery. DLCs help in improving oral delivery by providing benefits like improved permeability, stability in gastric environment, higher drug loading in carriers, formation of self-assembled nanostructures, etc. The clinical effectiveness of DLCs is highlighted from available marketed drug products along with many DLCs in phase of clinical trials. Conclusively, this drug modification strategy can potentially help in augmenting oral drug delivery in future.

KEY WORDS

lipid–drug conjugate permeability oral drug delivery bioavailability 

Notes

References

  1. 1.
    Sastry SV, Nyshadham JR, Fix JA. Recent technological advances in oral drug delivery—a review. Pharm Sci Technolol Today. 2000;3:138–45.CrossRefGoogle Scholar
  2. 2.
    Charman WN. Lipids, lipophilic drugs, and oral drug delivery—some emerging concepts. J Pharm Sci. 2000;89:967–78.CrossRefGoogle Scholar
  3. 3.
    Taylor MD. Improved passive oral drug delivery via prodrugs. Adv Drug Deliv Rev. 1996;19:131–48.CrossRefGoogle Scholar
  4. 4.
    Abet V, Filace F, Recio J, Alvarez-Builla J, Burgos C. Prodrug approach: an overview of recent cases. Eur J Med Chem. Elsevier Masson. 2017;127:810–27.CrossRefGoogle Scholar
  5. 5.
    Wermuth CG. Designing prodrugs and bioprecursors. In: Pract Med Chem. 3rd ed. Cambridge: Academic Press; 2008. p. 721–46.CrossRefGoogle Scholar
  6. 6.
    Kokil GR, Rewatkar PV. Bioprecursor prodrugs: molecular modification of the active principle. Mini-Reviews Med Chem. 2010;10:1316–30.CrossRefGoogle Scholar
  7. 7.
    Silverman RB, Holladay MW. The organic chemistry of drug design and drug action. 3rd ed. Drug Dev. Res. The Academic Press; 2014.Google Scholar
  8. 8.
    Lambert DM. Rationale and applications of lipids as prodrug carriers. Eur J Pharm Sci. Elsevier. 2000;11:S15–27.CrossRefGoogle Scholar
  9. 9.
    Liederer BM, Borchardt RT. Enzymes involved in the bioconversion of ester-based prodrugs. J Pharm Sci Elsevier. 2006;95:1177–95.CrossRefGoogle Scholar
  10. 10.
    Huttunen KM, Raunio H, Rautio J. Prodrugs—from serendipity to rational design. Pharmacol Rev. 2011;63:750–71.CrossRefGoogle Scholar
  11. 11.
    Clas S-D, Sanchez RI, Nofsinger R. Chemistry-enabled drug delivery (prodrugs): recent progress and challenges. Drug Discov Today. Elsevier Current Trends. 2014;19:79–87.CrossRefGoogle Scholar
  12. 12.
    Lesniewska-Kowiel MA, Muszalska I. Strategies in the designing of prodrugs, taking into account the antiviral and anticancer compounds. Eur J Med Chem Elsevier Masson. 2017;129:53–71.CrossRefGoogle Scholar
  13. 13.
    Müller RH, Olbrich C. Lipid matrix-drug conjugates particle for controlled release of active ingredient [Internet]. 2000 [cited 2018 Nov 22]. Available from: patents.google.com/patent/US6770299B1/en. Accessed 19 Sept 2018.
  14. 14.
    Adhikari P, Pal P, Das AK, Ray S, Bhattacharjee A, Mazumder B. Nano lipid-drug conjugate: an integrated review. Int J Pharm. 2017;529:629–41.CrossRefGoogle Scholar
  15. 15.
    Kondo S, Hosaka S, Hatakeyama I, Kuzuya M. Mechanochemical solid-state polymerization. IX. Theoretical analysis of rate of drug release from powdered polymeric prodrugs in a heterogeneous system. Chem Pharm Bull (Tokyo). The Pharmaceutical Society of Japan. 1998;46:1918–23.CrossRefGoogle Scholar
  16. 16.
    D’Souza AJM, Topp EM. Release from polymeric prodrugs: linkages and their degradation. J Pharm Sci. 2004;93:1962–79.CrossRefGoogle Scholar
  17. 17.
    Dash S, Murthy PN, Nath L, Chowdhury P. Kinetic modeling on drug release from controlled drug delivery systems. Acta Pol Pharm. 67:217–23.Google Scholar
  18. 18.
    Siepmann J. Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). Adv Drug Deliv Rev Elsevier. 2012;64:163–74.CrossRefGoogle Scholar
  19. 19.
    Siepmann J, Kranz H, Bodmeier R, Peppas NA. HPMC-matrices for controlled drug delivery: a new model combining diffusion, swelling, and dissolution mechanisms and predicting the release kinetics. Pharm Res. Kluwer Academic Publishers-Plenum Publishers. 1999;16:1748–56.CrossRefGoogle Scholar
  20. 20.
    Pitt GG, Cha Y, Shah SS, Zhu KJ. Blends of PVA and PGLA: control of the permeability and degradability of hydrogels by blending. J Control Release. Elsevier. 1992;19:189–99.CrossRefGoogle Scholar
  21. 21.
    Irby D, Du C, Li F. Lipid–drug conjugate for enhancing drug delivery. Mol Pharm. American Chemical Society. 2017;14:1325–38.CrossRefGoogle Scholar
  22. 22.
    Teshima M, Fumoto S, Nishida K, Nakamura J, Ohyama K, Nakamura T, et al. Prolonged blood concentration of prednisolone after intravenous injection of liposomal palmitoyl prednisolone. J Control Release. Elsevier. 2006;112:320–8.CrossRefGoogle Scholar
  23. 23.
    Signorell RD, Luciani P, Brambilla D, Leroux J-C. Pharmacokinetics of lipid-drug conjugates loaded into liposomes. Eur J Pharm Biopharm. Elsevier. 2018;128:188–99.CrossRefGoogle Scholar
  24. 24.
    Zalipsky S, Gabizon AA. Conjugate having a cleavable linkage for use in a liposome [Internet]. 2000 [cited 2018 Nov 22]. Available from: https://patents.google.com/patent/US6365179B1/en. Accessed 19 Sept 2018.
  25. 25.
    McDonald GB, Weidman M. Partitioning of polar fatty acids into lymph and portal vein after intestinal absorption in the rat. Q J Exp Physiol. Wiley/Blackwell (10.1111). 1987;72:153–9.CrossRefGoogle Scholar
  26. 26.
    Alexander P, Kucera G, Pardee TS. Improving nucleoside analogs via lipid conjugation: is fatter any better? Crit Rev Oncol Hematol. Elsevier. 2016;100:46–56.CrossRefGoogle Scholar
  27. 27.
    Wang Y, Li L, Jiang W, Larrick JW. Synthesis and evaluation of a DHA and 10-hydroxycamptothecin conjugate. Bioorg Med Chem Pergamon. 2005;13:5592–9.CrossRefGoogle Scholar
  28. 28.
    Dichwalkar T, Patel S, Bapat S, Pancholi P, Jasani N, Desai B, et al. Omega-3 fatty acid grafted PAMAM-paclitaxel conjugate exhibits enhanced anticancer activity in upper gastrointestinal cancer cells. Macromol Biosci. Wiley-Blackwell. 2017;17:1600457.CrossRefGoogle Scholar
  29. 29.
    Bedikian AY, DeConti RC, Conry R, Agarwala S, Papadopoulos N, Kim KB, et al. Phase 3 study of docosahexaenoic acid-paclitaxel versus dacarbazine in patients with metastatic malignant melanoma. Ann Oncol Oxford University Press. 2011;22:787–93.CrossRefGoogle Scholar
  30. 30.
    Venugopal B, Awada A, Evans TRJ, Dueland S, Hendlisz A, Rasch W, et al. A first-in-human phase I and pharmacokinetic study of CP-4126 (CO-101), a nucleoside analogue, in patients with advanced solid tumours. Cancer Chemother Pharmacol. 2015;76:785–92.CrossRefGoogle Scholar
  31. 31.
    Pardini RS. Nutritional intervention with omega-3 fatty acids enhances tumor response to anti-neoplastic agents. Chem Biol Interact Elsevier. 2006;162:89–105.CrossRefGoogle Scholar
  32. 32.
    Effenberger K, Breyer S, Schobert R. Modulation of doxorubicin activity in cancer cells by conjugation with fatty acyl and terpenyl hydrazones. Eur J Med Chem. Elsevier Masson. 2010;45:1947–54.CrossRefGoogle Scholar
  33. 33.
    Igarashi M, Miyazawa T. Newly recognized cytotoxic effect of conjugated trienoic fatty acids on cultured human tumor cells. Cancer Lett Elsevier. 2000;148:173–9.CrossRefGoogle Scholar
  34. 34.
    Sun B, Luo C, Cui W, Sun J, He Z. Chemotherapy agent-unsaturated fatty acid prodrugs and prodrug-nanoplatforms for cancer chemotherapy. J Control Release. Elsevier. 2017;264:145–59.CrossRefGoogle Scholar
  35. 35.
    Bontemps L, Demaison L, Keriel C, Pernin C, Mathieu JP, Marti-Batlle D, et al. Kinetics of (16 123I) Iodohexadecenoic acid metabolism in the rat myocardium, influence of glucose concentration in the perfusate and comparison with (1 14C) palmitate. Eur Heart J Oxford University Press. 1985;6:91–6.CrossRefGoogle Scholar
  36. 36.
    Charbon V, Latour I, Lambert DM, Buc-Calderon P, Neuvens L, De Keyser J, et al. Targeting of drug to the hepatocytes by fatty acids. Influence of the carrier (albumin or galactosylated albumin) on the fate of the fatty acids and their analogs. Pharm Res. Kluwer Academic Publishers-Plenum Publishers. 1996;13:27–31.CrossRefGoogle Scholar
  37. 37.
    Sparreboom A, Verweij J, van der Burg ME, Loos WJ, Brouwer E, Viganò L, et al. Disposition of Cremophor EL in humans limits the potential for modulation of the multidrug resistance phenotype in vivo. Clin Cancer Res American Association for Cancer Research. 1998;4:1937–42.PubMedGoogle Scholar
  38. 38.
    Stuurman FE, Voest EE, Awada A, Witteveen PO, Bergeland T, Hals P-A, et al. Phase I study of oral CP-4126, a gemcitabine derivative, in patients with advanced solid tumors. Invest New Drugs Springer US. 2013;31:959–66.CrossRefGoogle Scholar
  39. 39.
    Pignata S, Amant F, Scambia G, Sorio R, Breda E, Rasch W, et al. A phase I-II study of elacytarabine (CP-4055) in the treatment of patients with ovarian cancer resistant or refractory to platinum therapy. Cancer Chemother Pharmacol Springer-Verlag. 2011;68:1347–53.CrossRefGoogle Scholar
  40. 40.
    Bala V, Rao S, Bateman E, Keefe D, Wang S, Prestidge CA. Enabling oral SN38-based chemotherapy with a combined lipophilic prodrug and self-microemulsifying drug delivery system. Mol Pharm American Chemical Society. 2016;13:3518–25.CrossRefGoogle Scholar
  41. 41.
    Liu J, Liu J, Zhao D, Ma N, Luan Y. Highly enhanced leukemia therapy and oral bioavailability from a novel amphiphilic prodrug of cytarabine. RSC Adv. The Royal Society of Chemistry. 2016;6:35991–9.CrossRefGoogle Scholar
  42. 42.
    Kandula M, Sunil Kumar K, Palanichamy S, Rampal A. Discovery and preclinical development of a novel prodrug conjugate of mesalamine with eicosapentaenoic acid and caprylic acid for the treatment of inflammatory bowel diseases. Int Immunopharmacol Elsevier. 2016;40:443–51.CrossRefGoogle Scholar
  43. 43.
    Han S, Hu L, Quach T, Simpson JS, Trevaskis NL, Porter CJH. Profiling the role of deacylation-reacylation in the lymphatic transport of a triglyceride-mimetic prodrug. Pharm Res Springer US. 2015;32:1830–44.CrossRefGoogle Scholar
  44. 44.
    Han S, Hu L, Gracia, Quach T, Simpson JS, Edwards GA, et al. Lymphatic transport and lymphocyte targeting of a triglyceride mimetic prodrug is enhanced in a large animal model: studies in greyhound dogs. Mol pharm. Am Chem Soc. 2016;13:3351–61.Google Scholar
  45. 45.
    Hu L, Quach T, Han S, Lim SF, Yadav P, Senyschyn D, et al. Glyceride-mimetic prodrugs incorporating self-immolative spacers promote lymphatic transport, avoid first-pass metabolism, and enhance Oral bioavailability. Angew Chemie. Wiley-Blackwell. 2016;128:13904–9.CrossRefGoogle Scholar
  46. 46.
    Radwan AA, Alanazi FK. Targeting cancer using cholesterol conjugates. Saudi Pharm J Elsevier. 2014;22:3–16.CrossRefGoogle Scholar
  47. 47.
    Radwan A, Alanazi F, Radwan AA, Alanazi FK. Design and synthesis of new cholesterol-conjugated 5-fluorouracil: a novel potential delivery system for cancer treatment. Molecules Multidisciplinary Digital Publishing Institute. 2014;19:13177–87.CrossRefGoogle Scholar
  48. 48.
    Wolfrum C, Shi S, Jayaprakash KN, Jayaraman M, Wang G, Pandey RK, et al. Mechanisms and optimization of in vivo delivery of lipophilic siRNAs. Nat Biotechnol Nature Publishing Group. 2007;25:1149–57.CrossRefGoogle Scholar
  49. 49.
    Dahan A, Duvdevani R, Shapiro I, Elmann A, Finkelstein E, Hoffman A. The oral absorption of phospholipid prodrugs: in vivo and in vitro mechanistic investigation of trafficking of a lecithin-valproic acid conjugate following oral administration. J Control Release Elsevier. 2008;126:1–9.CrossRefGoogle Scholar
  50. 50.
    Labiner DM. DP-VPA D-Pharm. Curr Opin Investig Drugs. 2002;3:921–3.PubMedGoogle Scholar
  51. 51.
    Isoherranen N, Yagen B, Bialer M. New CNS-active drugs which are second-generation valproic acid: can they lead to the development of a magic bullet? Curr Opin Neurol. 2003;16:203–11.CrossRefGoogle Scholar
  52. 52.
    Bialer M, Johannessen S, Kupferberg H, Levy R, Loiseau P, Perucca E. Progress report on new antiepileptic drugs: a summary of the Sixth EILAT Conference (EILAT VI). Epilepsy Res. Elsevier. 2002;51:31–71.CrossRefGoogle Scholar
  53. 53.
    Bialer M, Johannessen S, Kupferberg H, Levy R, Loiseau P, Perucca E. Progress report on new antiepileptic drugs: a summary of the Fifth EILAT Conference (EILAT V). Epilepsy Res Elsevier. 2001;43:11–58.CrossRefGoogle Scholar
  54. 54.
    Dahan A, Duvdevani R, Dvir E, Elmann A, Hoffman A. A novel mechanism for oral controlled release of drugs by continuous degradation of a phospholipid prodrug along the intestine: in-vivo and in-vitro evaluation of an indomethacin–lecithin conjugate. J Control Release. Elsevier. 2007;119:86–93.CrossRefGoogle Scholar
  55. 55.
    Dahan A, Markovic M, Epstein S, Cohen N, Zimmermann EM, Aponick A, et al. Phospholipid-drug conjugates as a novel oral drug targeting approach for the treatment of inflammatory bowel disease. Eur J Pharm Sci Elsevier. 2017;108:78–85.CrossRefGoogle Scholar
  56. 56.
    Thanki K, Prajapati R, Sangamwar AT, Jain S. Long chain fatty acid conjugation remarkably decreases the aggregation induced toxicity of amphotericin. B. Int J Pharm. Elsevier. 2018;544:1–13 Available from: https://www.sciencedirect.com/science/article/pii/S0378517318302205. Accessed 19 Sept 2018.
  57. 57.
    Kushwah V, Katiyar SS, Agrawal AK, Gupta RC, Jain S. Co-delivery of docetaxel and gemcitabine using PEGylated self-assembled stealth nanoparticles for improved breast cancer therapy. Nanomed Nanotechnol Biol Med. Elsevier. 2018;14:1629–41 Available from: https://www.sciencedirect.com/science/article/pii/S1549963418300819. Accessed 19 Sept 2018.
  58. 58.
    Olbrich C, Gessner A, Kayser O, Müller RH. Lipid-drug-conjugate (ldc) nanoparticles as novel carrier system for the hydrophilic antitrypanosomal drug diminazenediaceturate. J Drug Target. 2002;10:387–96 Available from: http://www.tandfonline.com/doi/full/10.1080/1061186021000001832. Accessed 19 Sept 2018.
  59. 59.
    Wissing S, Kayser O, Müller R. Solid lipid nanoparticles for parenteral drug delivery. Adv Drug Deliv Rev. Elsevier. 2004;56:1257–72 Available from: https://www.sciencedirect.com/science/article/pii/S0169409X04000456. Accessed 19 Sept 2018.
  60. 60.
    Trevaskis NL, Kaminskas LM, Porter CJH. From sewer to saviour—targeting the lymphatic system to promote drug exposure and activity. Nat Rev Drug Discov Nature Publishing Group. 2015;14:781–803.CrossRefGoogle Scholar
  61. 61.
    Braess J, Freund M, Hanauske A, Heil G, Kaufmann C, Kern W, et al. Oral cytarabine ocfosfate in acute myeloid leukemia and non-Hodgkin’s lymphoma—phase I/II studies and pharmacokinetics. Leukemia Nature Publishing Group. 1998;12:1618–26.Google Scholar
  62. 62.
    Saneyoshi M, Morozumi M, Kodama K, Machida H, Kuninaka A, Yoshino H. Synthetic nucleosides and nucleotides. XVI. Synthesis and biological evaluations of a series of 1-.BETA.-D-arabinofuranosylcytosine 5′-alkyl or arylphosphates. Chem Pharm Bull (Tokyo). The Pharmaceutical Society of Japan. 1980;28:2915–23.CrossRefGoogle Scholar
  63. 63.
    Borkar N, Li B, Holm R, Håkansson AE, Müllertz A, Yang M, et al. Lipophilic prodrugs of apomorphine I: preparation, characterisation, and in vitro enzymatic hydrolysis in biorelevant media. Eur J Pharm Biopharm Elsevier. 2015;89:216–23.CrossRefGoogle Scholar
  64. 64.
    Bala V, Rao S, Li P, Wang S, Prestidge CA. Lipophilic prodrugs of SN38: synthesis and in vitro characterization toward oral chemotherapy. Mol Pharm. American Chemical Society. 2016;13:287–94.CrossRefGoogle Scholar
  65. 65.
    Fleisher D, Bong R, Stewart BH. Improved oral drug delivery: solubility limitations overcome by the use of prodrugs. Adv Drug Deliv Rev. Elsevier. 1996;19:115–30.CrossRefGoogle Scholar
  66. 66.
    You Y-J, Kim Y, Nam N-H, Ahn B-Z. Antitumor activity of unsaturated fatty acid esters of 4′-demethyldeoxypodophyllotoxin. Bioorg Med Chem Lett Pergamon. 2003;13:2629–32.CrossRefGoogle Scholar
  67. 67.
    Naesens L, Neyts J, Balzarini J, Bischofberger N, De Clercq E. In vivo antiretroviral efficacy of oral bis(POM)-PMEA, the bis(pivaloyloxymethyl)prodrug of 9-(2-phosphonylmethoxyethyl) adenine (PMEA). Nucleosides Nucleotides Nucleic Acids. 1995;14:767–70.CrossRefGoogle Scholar
  68. 68.
    Wichitnithad W, Nimmannit U, Wacharasindhu S, Rojsitthisak P, Wichitnithad W, Nimmannit U, et al. Synthesis, characterization and biological evaluation of succinate prodrugs of curcuminoids for colon cancer treatment. Molecules Molecular Diversity Preservation International. 2011;16:1888–900.CrossRefGoogle Scholar
  69. 69.
    Charman WN, Porter CJH. Lipophilic prodrugs designed for intestinal lymphatic transport. Adv Drug Deliv Rev. 1996;19:149–69.CrossRefGoogle Scholar
  70. 70.
    Sugihara J, Furuuchi S, Ando H, Takashima K, Harigaya S. Studies on intestinal lymphatic absorption of drugs. II. Glyceride prodrugs for improving lymphatic absorption of naproxen and nicotinic acid. J Pharmacobiodyn The Pharmaceutical Society of Japan. 1988;11:555–62.CrossRefGoogle Scholar
  71. 71.
    Kumar R, Billimoria JD. Gastric ulceration and the concentration of salicylate in plasma in rats after administration of 14C-labelled aspirin and its synthetic triglyceride, 1,3-dipalmitoyl-2(2′-acetoxy-[14C]carboxylbenzoyl) glycerol. J Pharm Pharmacol. Wiley/Blackwell (10.1111). 1978;30:754–8.CrossRefGoogle Scholar
  72. 72.
    Paris GY, Garmaise DL, Cimon DG, Swett L, Carter GW, Young P. Glycerides as prodrugs. 3. Synthesis and antiinflammatory activity of [1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetyl]glycerides (indomethacin glycerides). J Med Chem Am Chem Soc. 1980;23:9–13.Google Scholar
  73. 73.
    Paris GY, Garmaise DL, Cimon DG, Swett L, Carter GW, Young P. Glycerides as prodrugs. 2. 1,3-Dialkanoyl-2-(2-methyl-4-oxo-1,3-benzodioxan-2-yl)glycerides (cyclic aspirin triglycerides) as antiinflammatory agents. J Med Chem Am Chem Soc. 1980;23:79–82.Google Scholar
  74. 74.
    Hanauer SB. Review article: high-dose aminosalicylates to induce and maintain remissions in ulcerative colitis. Aliment Pharmacol Ther. Wiley/Blackwell (10.1111). 2006;24:37–40.CrossRefGoogle Scholar
  75. 75.
    Keum N, Greenwood DC, Lee DH, Kim R, Aune D, Ju W, Hu FB, Giovannucci EL. Adult weight gain and adiposity-related cancers: a dose-response meta-analysis of prospective observational studies. JNCI: Journal of the National Cancer Institute. 2015;107(2).Google Scholar
  76. 76.
    Fumagalli G, Marucci C, Christodoulou MS, Stella B, Dosio F, Passarella D. Self-assembly drug conjugates for anticancer treatment. Drug Discov Today. Elsevier Current Trends. 2016;21:1321–9.CrossRefGoogle Scholar
  77. 77.
    Reddy LH, Marque P-E, Dubernet C, Mouelhi S-L, Desmaële D, Couvreur P. Preclinical toxicology (subacute and acute) and efficacy of a new squalenoyl gemcitabine anticancer nanomedicine. J Pharmacol Exp Ther American Society for Pharmacology and Experimental Therapeutics. 2008;325:484–90.CrossRefGoogle Scholar
  78. 78.
    Kawabata K, Takakura Y, Hashida M. The fate of plasmid dna after intravenous injection in mice: involvment of scavenger receptors in its hepatic uptake. Pharm Res. 1995;12:825–30 Available from: https://link.springer.com/article/10.1023/A:1016248701505. Accessed 19 Sept 2018.
  79. 79.
    Gupta A, Asthana S, Konwar R, Chourasia MK. An insight into potential of nanoparticles-assisted chemotherapy of cancer using gemcitabine and its fatty acid prodrug: a comparative study. J Biomed Nanotechnol. 2013;9:915–25.CrossRefGoogle Scholar
  80. 80.
    Maiti K, Mukherjee K, Gantait A, Saha BP, Mukherjee PK. Curcumin–phospholipid complex: preparation, therapeutic evaluation and pharmacokinetic study in rats. Int J Pharm. 2007;330:155–63.CrossRefGoogle Scholar
  81. 81.
    Chue P, Chue J. A review of paliperidone palmitate. Expert Rev Neurother. 2012;12:1383–97.CrossRefGoogle Scholar
  82. 82.
    ARISTADA® (aripiprazole lauroxil) | Every 2 Months (1064 mg) [Internet]. [cited 2018 Sep 15]. Available from: https://www.aristada.com/. Accessed 19 Sept 2018.
  83. 83.
    Meltzer HY, Risinger R, Nasrallah HA, Du Y, Zummo J, Corey L, et al. A randomized, double-blind, placebo-controlled trial of aripiprazole lauroxil in acute exacerbation of schizophrenia. J Clin Psychiatry. 2015;76:1085–90.CrossRefGoogle Scholar
  84. 84.
    Rautio J, Kärkkäinen J, Sloan KB. Prodrugs—recent approvals and a glimpse of the pipeline. Eur J Pharm Sci. Elsevier B.V. 2017;109:146–61.CrossRefGoogle Scholar
  85. 85.
    Hanaoka K, Suzuki M, Kobayashi T, Tanzawa F, Tanaka K, Shibayama T, et al. Antitumor activity and novel DNA-self-strand-breaking mechanism of CNDAC (1-(2-C-cyano-2-deoxy-?-d-ARABINO-Pentofuranosyl) cytosine) and itsN4-palmitoyl derivative (CS-682). Int J Cancer Wiley-Blackwell. 1999;82:226–36.CrossRefGoogle Scholar
  86. 86.
    Painter GR, Almond MR, Trost LC, Lampert BM, Neyts J, De Clercq E, et al. Evaluation of hexadecyloxypropyl-9-R-[2-(Phosphonomethoxy)propyl]- adenine, CMX157, as a potential treatment for human immunodeficiency virus type 1 and hepatitis B virus infections. Antimicrob Agents Chemother. American Society for Microbiology Journals. 2007;51:3505–9.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Tushar Date
    • 1
  • Kaushani Paul
    • 1
  • Navneet Singh
    • 1
  • Sanyog Jain
    • 1
    Email author
  1. 1.Centre for Pharmaceutical Nanotechnology, Department of PharmaceuticsNational Institute of Pharmaceutical Education and Research (NIPER)NagarIndia

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