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Drug–Lipid Conjugates for Enhanced Oral Drug Delivery

  • Review Article
  • Theme: Lipid-Based Drug Delivery Strategies for Oral Drug Delivery
  • Published:
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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.

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References

  1. Sastry SV, Nyshadham JR, Fix JA. Recent technological advances in oral drug delivery—a review. Pharm Sci Technolol Today. 2000;3:138–45.

    CAS  Google Scholar 

  2. Charman WN. Lipids, lipophilic drugs, and oral drug delivery—some emerging concepts. J Pharm Sci. 2000;89:967–78.

    CAS  PubMed  Google Scholar 

  3. Taylor MD. Improved passive oral drug delivery via prodrugs. Adv Drug Deliv Rev. 1996;19:131–48.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  5. Wermuth CG. Designing prodrugs and bioprecursors. In: Pract Med Chem. 3rd ed. Cambridge: Academic Press; 2008. p. 721–46.

    Google Scholar 

  6. Kokil GR, Rewatkar PV. Bioprecursor prodrugs: molecular modification of the active principle. Mini-Reviews Med Chem. 2010;10:1316–30.

    CAS  Google Scholar 

  7. Silverman RB, Holladay MW. The organic chemistry of drug design and drug action. 3rd ed. Drug Dev. Res. The Academic Press; 2014.

  8. Lambert DM. Rationale and applications of lipids as prodrug carriers. Eur J Pharm Sci. Elsevier. 2000;11:S15–27.

    CAS  PubMed  Google Scholar 

  9. Liederer BM, Borchardt RT. Enzymes involved in the bioconversion of ester-based prodrugs. J Pharm Sci Elsevier. 2006;95:1177–95.

    CAS  PubMed  Google Scholar 

  10. Huttunen KM, Raunio H, Rautio J. Prodrugs—from serendipity to rational design. Pharmacol Rev. 2011;63:750–71.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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. 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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  16. D’Souza AJM, Topp EM. Release from polymeric prodrugs: linkages and their degradation. J Pharm Sci. 2004;93:1962–79.

    PubMed  Google Scholar 

  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.

  18. Siepmann J. Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). Adv Drug Deliv Rev Elsevier. 2012;64:163–74.

    Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  21. Irby D, Du C, Li F. Lipid–drug conjugate for enhancing drug delivery. Mol Pharm. American Chemical Society. 2017;14:1325–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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. 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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Google Scholar 

  46. Radwan AA, Alanazi FK. Targeting cancer using cholesterol conjugates. Saudi Pharm J Elsevier. 2014;22:3–16.

    PubMed  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  50. Labiner DM. DP-VPA D-Pharm. Curr Opin Investig Drugs. 2002;3:921–3.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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. 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. 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. 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. 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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Charman WN, Porter CJH. Lipophilic prodrugs designed for intestinal lymphatic transport. Adv Drug Deliv Rev. 1996;19:149–69.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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).

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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. 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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  81. Chue P, Chue J. A review of paliperidone palmitate. Expert Rev Neurother. 2012;12:1383–97.

    CAS  PubMed  Google Scholar 

  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. 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.

    PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

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Date, T., Paul, K., Singh, N. et al. Drug–Lipid Conjugates for Enhanced Oral Drug Delivery. AAPS PharmSciTech 20, 41 (2019). https://doi.org/10.1208/s12249-018-1272-0

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