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Critical Factors Influencing the In Vivo Performance of Long-acting Lipophilic Solutions—Impact on In Vitro Release Method Design

The AAPS Journal volume 11, pages 762–770 (2009)Cite this article

Abstract

Parenteral long-acting lipophilic solutions have been used for decades and might in the future be used in the design of depots with tailored delivery characteristics. The present review highlights major factors influencing the in vivo performance of lipophilic solutions. Furthermore, an account is given of the characteristics of employed in vitro release methods with a focus on the “state” of sink condition, the stirring conditions, and the oil–water interfacial area. Finally, the capability of in vitro release data to predict the in vivo performance of drug substances administrated in the form of lipophilic solutions is discussed. It is suggested that as long as the major rate-limiting in vivo release mechanism is governed by the drug partitioning between the oil vehicle and the tissue fluid, the use of in vitro release testing in quality control appears to be realistic. With increasing lipophilicity of the drug substances and longer duration of action, the in vivo drug release process may become more complex. As discussed, practical analytical problems together with the inability of release methods to mimic two or more concomitant in vivo events may constitute severe impediments for establishment of in vitro in vivo correlations.

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References

  1. Benson HAE, Prankerd RJ. Optimisation of drug delivery 6. Modified-release parenterals. Aust J Hosp Pharm. 1998;28(2):99–104.

    CAS  Google Scholar 

  2. Chien YW. Long-acting parenteral drug formulations. J Parenter Sci Technol. 1981;35(3):106–39.

    PubMed  CAS  Google Scholar 

  3. Zuidema J, Kadir F, Titulaer HAC, Oussoren C. Release and absorption rates of intramuscularly and subcutaneously injected pharmaceuticals (II). Int J Pharm. 1994;105(3):189–207.

    Article  CAS  Google Scholar 

  4. Murdan S, Florence AT. Non-aqueous solutions and suspensions as sustained-release injectable formulations. In: Senior J, Radomsky M, editors. Sustained-release injectable products. Denver: Interpharm Press; 2000. p. 71–107.

    Google Scholar 

  5. Fredholt K, Larsen DH, Larsen C. Modification of in vitro drug release rate from oily parenteral depots using a formulation approach. Eur J Pharm Sci. 2000;11(3):231–7.

    Article  PubMed  CAS  Google Scholar 

  6. Larsen DB, Fredholt K, Larsen C. Addition of hydrogen bond donating excipients to oil solution: effect on in vitro drug release rate and viscosity. Eur J Pharm Sci. 2001;13(4):403–10.

    Article  PubMed  CAS  Google Scholar 

  7. Larsen SW, Thomsen AE, Rinvar E, Friis GJ, Larsen C. Effect of drug lipophilicity on in vitro release rate from oil vehicles using nicotinic acid esters as model prodrug derivatives. Int J Pharm. 2001;216(1–2):83–93.

    Article  PubMed  CAS  Google Scholar 

  8. Larsen C, Ostergaard J, Larsen SW, Jensen H, Jacobsen S, Lindegaard C, et al. Intra-articular depot formulation principles: role in the management of postoperative pain and arthritic disorders. J Pharm Sci. 2008;97(11):4622–54.

    Article  PubMed  CAS  Google Scholar 

  9. Burgess DJ, Hussain AS, Ingallinera TS, Chen ML. Assuring quality and performance of sustained and controlled release parenterals: workshop report. AAPS PharmSci. 2002;4(2):E7.

    Article  PubMed  Google Scholar 

  10. Burgess DJ, Crommelin DJ, Hussain AS, Chen ML. Assuring quality and performance of sustained and controlled released parenterals. Eur J Pharm Sci. 2004;21(5):679–90.

    Article  PubMed  CAS  Google Scholar 

  11. Martinez M, Rathbone M, Burgess D, Huynh M. In vitro and in vivo considerations associated with parenteral sustained release products: a review based upon information presented and points expressed at the 2007 Controlled Release Society Annual Meeting. J Control Release. 2008;129(2):79–87.

    Article  PubMed  CAS  Google Scholar 

  12. Armstrong NA, James KC. Drug release from lipid-based dosage forms. I. Int J Pharm. 1980;6(3-4):185–93.

    Article  CAS  Google Scholar 

  13. Luo J, Hubbard JW, Midha KK. The roles of depot injection sites and proximal lymph nodes in the presystemic absorption of fluphenazine decanoate and fluphenazine: ex vivo experiments in rats. Pharm Res. 1998;15(8):1485–9.

    Article  PubMed  CAS  Google Scholar 

  14. Minto CF, Howe C, Wishart S, Conway AJ, Handelsman DJ. Pharmacokinetics and pharmacodynamics of nandrolone esters in oil vehicle: effects of ester, injection site and injection volume. J Pharmacol Exp Ther. 1997;281(1):93–102.

    PubMed  CAS  Google Scholar 

  15. Medlicott NJ, Waldron NA, Foster TP. Sustained release veterinary parenteral products. Adv Drug Deliv Rev. 2004;56(10):1345–65.

    Article  PubMed  CAS  Google Scholar 

  16. Dreyfuss J, Ross JJ, Shaw JM, Miller I, Schreiber EC. Release and elimination of 14C-fluphenazine enanthate and decanoate esters administered in sesame oil to dogs. J Pharm Sci. 1976;65(4):502–7.

    Article  PubMed  CAS  Google Scholar 

  17. Jann MW, Ereshefsky L, Saklad SR. Clinical pharmacokinetics of the depot antipsychotics. Clin Pharmacokinet. 1985;10(4):315–33.

    Article  PubMed  CAS  Google Scholar 

  18. Al-Hindawi MK, James KC, Nicholls PJ. Influence of solvent on the availability of testosterone propionate from oily, intramuscular injections in the rat. J Pharm Pharmacol. 1987;39(2):90–5.

    PubMed  CAS  Google Scholar 

  19. Hirano K, Ichihashi T, Yamada H. Studies on the absorption of practically water-insoluble drugs following injection V: subcutaneous absorption in rats from solutions in water immiscible oils. J Pharm Sci. 1982;71(5):495–500.

    Article  PubMed  CAS  Google Scholar 

  20. Hirano K, Ichihashi T, Yamada H. Studies on the absorption of practically water-insoluble drugs following injection. I. Intramuscular absorption from water-immiscible oil solutions in rats. Chem Pharm Bull (Tokyo). 1981;29(2):519–31.

    CAS  Google Scholar 

  21. James KC, Nicholls PJ, Roberts M. Biological half-lives of [4–14C]testosterone and some of its esters after injection into the rat. J Pharm Pharmacol. 1969;21(1):24–7.

    PubMed  CAS  Google Scholar 

  22. Liu KS, Tzeng JI, Chen YW, Huang KL, Kuei CH, Wang JJ. Novel depots of buprenorphine prodrugs have a long-acting antinociceptive effect. Anesth Analg. 2006;102(5):1445–51.

    Article  PubMed  CAS  Google Scholar 

  23. Aaes-J¢rgensen T. Pharmacokinetics of three different injectable zuclopenthixol preparations. Prog Neuro-psychopharmacol Biol Psychiatry. 1989;13(1-2):77–85.

    Article  Google Scholar 

  24. Partsch CJ, Weinbauer GF, Fang R, Nieschlag E. Injectable testosterone undecanoate has more favourable pharmacokinetics and pharmacodynamics than testosterone enanthate. Eur J Endocrinol. 1995;132(4):514–9.

    Article  PubMed  CAS  Google Scholar 

  25. Behre HM, Abshagen K, Oettel M, Hubler D, Nieschlag E. Intramuscular injection of testosterone undecanoate for the treatment of male hypogonadism: phase I studies. Eur J Endocrinol. 1999;140(5):414–9.

    Article  PubMed  CAS  Google Scholar 

  26. Tanaka T, Kobayashi H, Okumura K, Muranishi S, Sezaki H. Intramuscular absorption of drugs from oily solutions in the rat. Chem Pharm Bull. 1974;22(6):1275–84.

    PubMed  CAS  Google Scholar 

  27. Wicks SR, Kaye B, Weatherley AJ, Lewis D, Davison E, Gibson SP, et al. Effect of formulation on the pharmacokinetics and efficacy of doramectin. Vet Parasitol. 1993;49(1):17–26.

    Article  PubMed  CAS  Google Scholar 

  28. Wistuba J, Marc LC, Kamischke A, Gu YQ, Schlatt S, Simoni M, et al. Pharmacokinetics and pharmacodynamics of injectable testosterone undecanoate in castrated cynomolgus monkeys (Macaca fascicularis) are independent of different oil vehicles. J Med Primatol. 2005;34(4):178–87.

    Article  PubMed  CAS  Google Scholar 

  29. Larsen SW, Rinvar E, Svendsen O, Lykkesfeldt J, Friis GJ, Larsen C. Determination of the disappearance rate of iodine-125 labelled oils from the injection site after intramuscular and subcutaneous administration to pigs. Int J Pharm. 2001;230(1–2):67–75.

    Article  PubMed  CAS  Google Scholar 

  30. Schultz K, Mollgaard B, Fisher AN, Illum L, Larsen C. Intramuscular rate of disappearance of oily vehicles in rabbits investigated by gamma-scintigraphy. Int J Pharm. 1998;169(1):121–6.

    Article  CAS  Google Scholar 

  31. Houpert P, Combrisson H, Le NS, Autefage A, Toutain PL. Intra- vs intermuscular injections in swine. Vet Res. 1993;24(3):278–85.

    PubMed  CAS  Google Scholar 

  32. Contreras-Solis I, Gomez-Brunet A, Encinas T, Gonzalez-Bulnes A, Santiago-Moreno J, Lopez-Sebastian A. Influence of vehicle on kinetics of exogenous progesterone administered either by subcutaneous and intramuscular routes to sheep. Res Vet Sci. 2008;85(1):162–5.

    Article  PubMed  CAS  Google Scholar 

  33. Zuidema J, Pieters FAJM, Duchateau GSMJ. Release and absorption rate aspects of intramuscularly injected pharmaceuticals. Int J Pharm. 1988;47(1–3):1–12.

    Article  CAS  Google Scholar 

  34. Huang Y, Hubbard JW, Midha KK. The role of the lymphatic system in the presystemic absorption of fluphenazine after intramuscular administration of fluphenazine decanoate in rats. Eur J Pharm Sci. 1995;3(1):15–20.

    Article  CAS  Google Scholar 

  35. Matsunaga Y, Nambu K, OH-E Y, Miyazaki H, Hashimoto M. Absorption of intramuscularly administered [14C]haloperidol decanoate in rats. Eur J Drug Metab Pharmacokinet. 1987;12(3):175–81.

    Article  PubMed  CAS  Google Scholar 

  36. Oh-E Y, Miyazaki H, Matsunaga Y, Hashimoto M. Pharmacokinetics of haloperidol decanoate in rats. J Pharmacobio-Dyn. 1991;14(11):615–22.

    PubMed  CAS  Google Scholar 

  37. Belkien L, Schürmeyer T, Hano R, Gunnarsson PO, Nieschlag E. Pharmacokinetics of 19-nortestosterone esters in normal men. J Steroid Biochem. 1985;22(5):623–9.

    Article  PubMed  CAS  Google Scholar 

  38. Nambu K, Miyazaki H, Nakanishi Y, Oh-E Y, Matsunaga Y, Hashimoto M. Enzymatic hydrolysis of haloperidol decanoate and its inhibition by proteins. Biochem Pharmacol. 1987;36(10):1715–22.

    Article  PubMed  CAS  Google Scholar 

  39. Howard JR, Hadgraft J. The clearance of oily vehicles following intramuscular and subcutaneous injections in rabbits. Int J Pharm. 1983;16(1):31–9.

    Article  CAS  Google Scholar 

  40. Larsen C, Schultz K, Fisher AN, Illum L. Intramuscular fate of C-14- and I-131-labelled triglycerides. Int J Pharm. 1998;166(2):227–30.

    Article  CAS  Google Scholar 

  41. Svendsen O, Aaes-J¢rgensen T. Studies on the fate of vegetable oil after intramuscular injection into experimental animals. Acta Pharmacol Toxicol. 1979;45:352–78.

    CAS  Google Scholar 

  42. Delie F, Couvreur P, Nisato D, Michel JB, Puisieux F, Letourneux Y. Synthesis and in-vitro study of a diglyceride prodrug of a peptide. Pharm Res. 1994;11(8):1082–7.

    Article  PubMed  CAS  Google Scholar 

  43. Delie F, Letourneux Y, Nisato D, Puisieux F, Couvreur P. Oral-administration of peptides—study of a glycerolipidic prodrug. Int J Pharm. 1995;115(1):45–52.

    Article  CAS  Google Scholar 

  44. Scriba GKE. Phenytoin lipid conjugates—chemical, plasma esterase-mediated, and pancreatic lipase-mediated hydrolysis in-vitro. Pharm Res. 1993;10(8):1181–6.

    Article  PubMed  CAS  Google Scholar 

  45. Scriba GKE, Lambert DM, Poupaert JH. Bioavailability of phenytoin following oral administration of phenytoin-lipid conjugates to rats. J Pharm Pharmacol. 1995;47(11):945–8.

    PubMed  CAS  Google Scholar 

  46. Alvarez FJ, Stella VJ. Pancreatic lipase-catalyzed hydrolysis of esters of hydroxymethyl phenytoin dissolved in various metabolizable vehicles, dispersed in micellar systems, and in aqueous suspensions. Pharm Res. 1989;6(7):555–63.

    Article  PubMed  CAS  Google Scholar 

  47. Crommelin DJA, Deblaey CJ. In vitro release studies on drugs suspended in non-polar media. II. The release of paracetamol and chloramphenicol from suspensions in liquid paraffin. Int J Pharm. 1980;6(1):29–42.

    Article  CAS  Google Scholar 

  48. Crommelin DJA, Deblaey CJ. In vitro release studies on drugs suspended in non-polar media. I. Release of sodium chloride from suspensions in liquid paraffin. Int J Pharm. 1980;5(4):305–16.

    Article  CAS  Google Scholar 

  49. Soderberg L, Dyhre H, Roth B, Bjorkman S. The “inverted cup”—a novel in vitro release technique for drugs in lipid formulations. J Control Release. 2006;113(1):80–8.

    Article  PubMed  CAS  Google Scholar 

  50. Larsen DB, Parshad H, Fredholt K, Larsen C. Characteristics of drug substances in oily solutions. Drug release rate, partitioning and solubility. Int J Pharm. 2002;232(1–2):107–17.

    Article  PubMed  CAS  Google Scholar 

  51. Larsen DH, Fredholt K, Larsen C. Assessment of rate of drug release from oil vehicle using a rotating dialysis cell. Eur J Pharm Sci. 2000;11(3):223–9.

    Article  PubMed  CAS  Google Scholar 

  52. Schultz K, Mollgaard B, Frokjaer S, Larsen C. Rotating dialysis cell as in vitro release method for oily parenteral depot solutions. Int J Pharm. 1997;157(2):163–9.

    Article  PubMed  CAS  Google Scholar 

  53. Larsen SW, Ostergaard J, Friberg-Johansen H, Jessen MN, Larsen C. In vitro assessment of drug release rates from oil depot formulations intended for intra-articular administration. Eur J Pharm Sci. 2006;29(5):348–54.

    Article  PubMed  CAS  Google Scholar 

  54. Larsen SW, Frost AB, Ostergaard J, Marcher H, Larsen C. On the mechanism of drug release from oil suspensions in vitro using local anesthetics as model drug compounds. Eur J Pharm Sci. 2008;34(1):37–44.

    Article  PubMed  CAS  Google Scholar 

  55. Larsen SW, Jessen MN, Ostergaard J, Larsen C. Assessment of drug release from oil depot formulations using an in vitro model—potential applicability in accelerated release testing. Drug Dev Ind Pharm. 2008;34(3):297–304.

    Article  PubMed  CAS  Google Scholar 

  56. Pedersen BT, Larsen SW, Ostergaard J, Larsen C. In vitro assessment of lidocaine release from aqueous and oil solutions and from preformed and in situ formed aqueous and oil suspensions. Parenteral depots for intra-articular administration. Drug Deliv. 2008;15(1):23–30.

    Article  PubMed  CAS  Google Scholar 

  57. Janicki S, Sznitowska M, Zebrowska W, Gabiga H, Kupiec M. Evaluation of paracetamol suppositories by a pharmacopoeial dissolution test—comments on methodology. Eur J Pharm Biopharm. 2001;52(2):249–54.

    Article  PubMed  CAS  Google Scholar 

  58. Lootvoet G, Beyssac E, Shiu GK, Aiache JM, Ritschel WA. Study on the release of indomethacin from suppositories—in vitro–in vivo correlation. Int J Pharm. 1992;85(1–3):113–20.

    Article  CAS  Google Scholar 

  59. Schultz K. Parenteral oily depot formulations. In vitro and in vivo characterisation. Ph.D. Thesis, The Royal Danish School of Pharmacy, Copenhagen; 1997.

  60. Radd BL, Newman AC, Fegely BJ, Chrzanowski FA, Lichten JL, Walkling WD. Development of haloperidol in oil injection formulations. J Parenteral Sci Tech. 1985;39(1):48–9.

    CAS  Google Scholar 

  61. Kakemi K, Sezaki H, Muranishi S, Ogata H, Giga K. Mechanism of intestinal absorption of drugs from oil in water emulsion. II. Absorption from oily solutions. Chem Pharm Bull. 1972;20(4):715–20.

    PubMed  CAS  Google Scholar 

  62. Soderberg L, Dyhre H, Roth B, Bjorkman S. In-vitro release of bupivacaine from injectable lipid formulations investigated by a single drop technique—relation to duration of action in-vivo. J Pharm Pharmacol. 2002;54(6):747–55.

    Article  PubMed  CAS  Google Scholar 

  63. D'Souza SS, Deluca PP. Methods to assess in vitro drug release from injectable polymeric particulate systems. Pharm Res. 2006;23(3):460–74.

    Article  PubMed  CAS  Google Scholar 

  64. Iyer SS, Barr WH, Karnes HT. Profiling in vitro drug release from subcutaneous implants: a review of current status and potential implications on drug product development. Biopharm Drug Dispos. 2006;27(4):157–70.

    Article  PubMed  CAS  Google Scholar 

  65. Washington C. Drug release from microdisperse systems—a critical-review. Int J Pharm. 1990;58(1):1–12.

    Article  CAS  Google Scholar 

  66. <1092> The dissolution procedure: development and validation. Pharmacopeial Forum. 2005;31(5):1463.

  67. Washington C. Evaluation of non-sink dialysis methods for the measurement of drug release from colloids—effects of drug partition. Int J Pharm. 1989;56(1):71–4.

    Article  CAS  Google Scholar 

  68. Chidambaram N, Burgess DJ. A novel in vitro release method for submicron sized dispersed systems. AAPS PharmSci. 1999;1(3):E11.

    Article  PubMed  CAS  Google Scholar 

  69. Levy MY, Benita S. Drug release from submicronized o/w emulsion—a new in vitro kinetic evaluation model. Int J Pharm. 1990;66(1–3):29–37.

    Article  CAS  Google Scholar 

  70. Larsen DB, Joergensen S, Olsen NV, Hansen SH, Larsen C. In vivo release of bupivacaine from subcutaneously administered oily solution. Comparison with in vitro release. J Control Release. 2002;81(1-2):145–54.

    Article  PubMed  CAS  Google Scholar 

  71. Soderberg L, Dyhre H, Roth B, Bjorkman S. Ultralong peripheral nerve block by lidocaine:prilocaine 1:1 mixture in a lipid depot formulation: comparison of in vitro, in vivo, and effect kinetics. Anesthesiology. 2006;104(1):110–21.

    Article  PubMed  Google Scholar 

  72. Dibbern HW, Wirbitzki E. Possibilities for determining the active substance release from hydrophobic carriers especially as suppositories. Pharm Ind. 1983;45(10):985–90.

    CAS  Google Scholar 

  73. D'Souza SS, Deluca PP. Development of a dialysis in vitro release method for biodegradable microspheres. AAPS PharmSciTech. 2005;6(2):E323–8.

    Article  PubMed  Google Scholar 

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  1. Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, Denmark

    Susan Weng Larsen & Claus Larsen

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  1. Susan Weng Larsen
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Correspondence to Susan Weng Larsen.

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Guest Editors: Marilyn Martinez and Michael Rathbone

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Weng Larsen, S., Larsen, C. Critical Factors Influencing the In Vivo Performance of Long-acting Lipophilic Solutions—Impact on In Vitro Release Method Design. AAPS J 11, 762–770 (2009). https://doi.org/10.1208/s12248-009-9153-9

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Key words

  • depot effect
  • lipophilic solutions
  • in vitro in vivo correlations
  • in vitro release methods
  • parenteral administration