Skip to main content
SpringerLink
Log in

Role of cyclodextrins in improving oral drug delivery

  • Technology Tools
  • Published:
American Journal of Drug Delivery

Abstract

The use of high-throughput screening and similar techniques in drug discovery has put a number of evolutionary pressures on drug candidates such that over time there is a tendency for them to increase in molecular weight, increase in log K(octanol/water) and decrease in water solubility. These trends provide an ever-increasing series of challenges for the drug formulator to generate effective, orally bioavailable dosage forms. An important tool in this regard is the use of cyclodextrins, especially chemically modified cyclodextrins. These starch derivatives interact via dynamic complex formation and other mechanisms in a way that camouflages undesirable physicochemical properties, including low aqueous solubility, poor dissolution rate and limited drug stability. Through these effects, cyclodextrins and their derivatives have become popular modalities for increasing oral bioavailability and absorption rate. These actions have positioned cyclodextrins as important enabling and functional excipients. This review aims to assess the use of cyclodextrins in oral and other administration routes in the context of the Biopharmaceutical Classification Systems (BCS), a US FDA-based characterization approach that bins drugs based on solubility and permeability features. Specifically, a framework based on Fickian theory as well as the Noyes-Whiney relationship is constructed to assess where cyclodextrins are likely to be useful and where their use is probably not justified. This working model is examined in the context of a number of published examples in which cyclodextrins have been applied to class I, II, III, and IV drugs and drug candidates.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Table I
Fig. 2
Table II
Table III
Table IV

Similar content being viewed by others

References

  1. Dressman J, Butler J, Hempenstall J, et al. The BCS: where do we go from here? Pharm Tech North Am 2001; 25(7): 68–76

    CAS  Google Scholar 

  2. Lipinski CA, Lombardo F, Dominy BW, et al. Experimental and computatorial approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 2001; 46: 3–26

    Article  PubMed  CAS  Google Scholar 

  3. Duchêne D, editor. New trends in cyclodextrins and derivatives. Paris: Editions de Santé, 1991

    Google Scholar 

  4. Duchêne D. Cyclodextrins and their industrial uses. Paris: Editions de Santé, 1987

    Google Scholar 

  5. Szejtli J. Cyclodextrin technology. Dordrecht: Kluwer Academic Publisher, 1988

    Google Scholar 

  6. Frömming KH, Szejtli J. Cyclodextrins in pharmacy. Dordrecht: Kluwer Academic Publishers, 1994

    Google Scholar 

  7. Loftsson T, Brewster ME. Pharmaceutical applications of cyclodextrins: 1. Drug solubilization and stabilization. J Pharm Sci 1996; 85(10): 1017–25

    Article  PubMed  CAS  Google Scholar 

  8. Rajewski RA, Stella VJ. Pharmaceutical applications of cyclodextrins: 2. In vivo drug delivery. J Pharm Sci 1996; 85(11): 1142–68

    Article  PubMed  CAS  Google Scholar 

  9. Irie T, Uekama K. Pharmaceutical applications of cyclodextrins: III. Toxicological issues and safety evaluation. J Pharm Sci 1997; 86(2): 147–62

    Article  PubMed  CAS  Google Scholar 

  10. Stella VJ, Rajewski RA. Cyclodextrins: their future in drug formulation and delivery. Pharm Res 1997; 14(5): 556–67

    Article  PubMed  CAS  Google Scholar 

  11. Uekama K, editor. Cyclodextrins in drug delivery in Adv. Drug Deliv Rev 1999; 36 (1): 1–141

    Google Scholar 

  12. D’souza VT, Lipkowitz KB, editors. Cyclodextrins: introduction. Chem Rev 1998; 98 (5): 1741–2

    Google Scholar 

  13. Lennernäs H. Human intestinal permeability. J Pharm Sci 1998; 87: 403–10

    Article  PubMed  Google Scholar 

  14. van de Waterbeemd H. The fundamental variables of the biopharmaceutics classification system (BCS): a commentary. Eur J Pharm Sci 1998; 7: 1–3

    Article  PubMed  Google Scholar 

  15. Yoshida F, Topliss JG. QSAR model for drug human oral bioavailability. J Med Chem 2000; 43: 2575–85

    Article  PubMed  CAS  Google Scholar 

  16. Amidon GL, Lennernäs H, Shah VP, et al. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 1995; 12: 413–20

    Article  PubMed  CAS  Google Scholar 

  17. Löbenberg R, Amidon GL. Modern bioavailability, bioequivalence and biopharmaceutics classification system: new scientific approaches to international regulatory standards. Eur J Pharm Biopharm 2000; 50: 3–12

    Article  PubMed  Google Scholar 

  18. Hörter D, Dressman JB. Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract. Adv Drug Deliv Rev 2001; 46: 75–87

    Article  PubMed  Google Scholar 

  19. US FDA, Center for Drug Evaluation and Research: The biopharmaceutics classification system (BCS) guidance [online]. Available from URL: http://www.fda.gov/cder/OPS/BSC_guidance.htm [Accessed 2004 Oct 18]

  20. Yu LX, Amidon GL, Polli JE, et al. Biopharmaceutics classification system: the scientific basis for biowaiver extensions. Pharm Res 2002; 19: 921–5

    Article  PubMed  CAS  Google Scholar 

  21. Yazdanian M, Briggs K, Jankovsky C, et al. The ‘high solubility’ definition of current FDA guidance on biopharmaceutical classification system may be too strict for acidic drugs. Pharm Res 2004; 21: 293–9

    Article  PubMed  CAS  Google Scholar 

  22. Szejtli J. Cyclodextrins and their inclusion complexes: Akademiai Kiadó, Budapest; 1982

    Google Scholar 

  23. Uekama K, Hirayama F, Irie T. Cyclodextrin drug carrier systems. Chem Rev 1998; 98: 2045–76

    Article  PubMed  CAS  Google Scholar 

  24. Thompson DO. Cyclodextrins-enabling excipients: their present and future use in Pharmaceuticals. Crit Rev Ther Drug Carrier Syst 1997; 14: 1–104

    Article  PubMed  CAS  Google Scholar 

  25. Evaluation of certain food additives and contaminants, WHO Technical Report Series No. 909. Geneva: World Health Organization, 2002

  26. Uekama K. Recent aspects of pharmaceutical application of cyclodextrins. J Incl Phenom Macroc Chem 2002; 44: 3–7

    Article  CAS  Google Scholar 

  27. Bergeron RJ. Cycloamylose-substrate binding. In: Attwood JL, Bavies JED, MacNicol DD, editors. Inclusion compounds. London: Academic Press, 1984: 391–443

    Google Scholar 

  28. Liu L, Guo Q-X. The driving forces in the inclusion complexation of cyclodextrins. J Incl Phenom Macroc Chem 2002; 42: 1–14

    Article  CAS  Google Scholar 

  29. Connors KA. Population characteristics of cyclodextrin complex stabilities in aqueous solution. J Pharm Sci 1995; 84: 843–8

    Article  PubMed  CAS  Google Scholar 

  30. Connors KA. The stability of cyclodextrin complexes in solution. Chem Rev 1997; 97: 1325–57

    Article  PubMed  CAS  Google Scholar 

  31. Rao VM, Stella VJ. When can cyclodextrins be considered for solubilizing purposes? J Pharm Sci 2003; 92: 927–32

    Article  PubMed  CAS  Google Scholar 

  32. Loftsson T, Magnúsdóttir A, Másson M, et al. Self-association and cyclodextrin solubilization of drugs. J Pharm Sci 2002; 91: 2307–16

    Article  PubMed  CAS  Google Scholar 

  33. Loftsson T, Másson M, Brewster ME. Self-association of cyclodextrins and cyclodextrin complexes. J Pharm Sci 2004; 93: 1091–9

    Article  PubMed  CAS  Google Scholar 

  34. Loftsson T. Effects of cyclodextrins on chemical stability of drugs in aqueous solutions. Drug Stability 1995; 1: 22–33

    CAS  Google Scholar 

  35. Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersion. Eur J Pharm Biopharm 2000; 50: 47–60

    Article  PubMed  CAS  Google Scholar 

  36. Serajuddin AT. Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems and recent break-through. J Pharm Sci 1999; 88: 1058–66

    Article  PubMed  CAS  Google Scholar 

  37. Corrigan OI, Stanley CT. Dissolution properties of phenobarbitone-β-cyclodextrin systems. Pharm Acta Helv 1981; 56: 204–8

    CAS  Google Scholar 

  38. Corrigan OI, Stanley CT. Mechanism of drug dissolution rate enhancement from β-cyclodextrin-drug systems. J Pharm Pharmacol 1982; 34: 621–6

    Article  PubMed  CAS  Google Scholar 

  39. Loftsson T, Másson M, Sigurjónsdóttir JF. Methods to enhance the complexation efficiency of cyclodextrins. STP Pharma Sci 1999; 9: 237–42

    CAS  Google Scholar 

  40. Loftsson T, Másson M. The effects of water-soluble polymers on cyclodextrins and cyclodextrin solubilization of drugs. J Drug Del Sci Tech 2004; 14: 35–43

    CAS  Google Scholar 

  41. Krishnamoorthy R, Mitra AK. Complexation of weak acids and basis with cyclodextrins: effects of substrate ionization on the estimation and interpretation of association constants. Int J Pharm Advances 1996; 1: 330–43

    Google Scholar 

  42. Redenti E, Szente L, Szejtli J. Cyclodextrin complexes of salts of acidic drugs: thermodynamic properties, structural features, and pharmaceutical applications. J Pharm Sci 2001; 90: 979–86

    Article  PubMed  CAS  Google Scholar 

  43. Redenti E, Szente L, Szejtli J. Drug/cyclodextrin/hydroxy acid multicomponent systems: properties and pharmaceutical applications. J Pharm Sci 2000; 89: 1–8

    Article  PubMed  CAS  Google Scholar 

  44. Loftsson T, Sigurdsson HH, Másson M, et al. Preparation of solid drug/cyclodextrin complexes of acidic and basic drugs. Pharmazie 2004; 59: 25–9

    PubMed  CAS  Google Scholar 

  45. Loftsson T, Matthiasson K, Másson M. The effects of organic salts on the cyclodextrin solubilization of drugs. Int J Pharm 2003; 262: 101–7

    Article  PubMed  CAS  Google Scholar 

  46. Li P, Tabibi E, Yalkowsky SH. Combined effect of complexation and pH on solubilization. J Pharm Sci 1998; 87: 1535–7

    Article  PubMed  CAS  Google Scholar 

  47. Loftsson T, Masson M. Cyclodextrins in topical drug formulations: theory and practice. Int J Pharm 2001; 225: 15–30

    Article  PubMed  CAS  Google Scholar 

  48. Loftsson T, Sigfússon SD, Sigurdsson HH, et al. The effects of cyclodextrins on topical delivery of hydrocortisone: the aqueous diffusion layer. STP Pharma Sci 2003; 13: 125–31

    CAS  Google Scholar 

  49. Matsuda H, Arima H. Cyclodextrins in transdermal and rectal delivery. Adv Drug Deliv Rev 1999; 36: 81–99

    Article  PubMed  CAS  Google Scholar 

  50. Legendre JY, Rault I, Petit A, et al. Effects of β-cyclodextrins on skin: implications for the transdermal delivery of piribedil and a novel cognition enhancing-drug, S-9977. Eur J Pharm Sci 1995; 3: 311–22

    Article  CAS  Google Scholar 

  51. Vitória M, Bentley B, Renata F, et al. Characterization of the influence of some cyclodextrins on the stratum corneum from the hairless mouse. J Pharm Pharmacol 1997; 49: 397–402

    Google Scholar 

  52. Arima H, Miyaji T, Irie T, et al. Possible enhancing mechanism of the cutaneous permeation of 4-biphenylylacetic acid by β-cyclodextrin derivatives in hydrophilic ointment. Chem Pharm Bull 1996; 44: 582–6

    Article  PubMed  CAS  Google Scholar 

  53. Arima H, Miyaji T, Irie T, et al. Enhancing effect of hydroxypropyl- β-cyclodextrin on cutaneous penetration activation of ethyl 4-biphenylyl acetate in hairless mouse skin. Eur J Pharm Sci 1998; 6: 53–9

    Article  PubMed  CAS  Google Scholar 

  54. Irie T, Wakamatsu K, Arima H, et al. Enhancing effects of cyclodextrins on nasal absorption of insulin in rats. Int J Pharm 1992; 84: 129–39

    Article  CAS  Google Scholar 

  55. Moffat AC, Osselton MD, Widdop B, editors. Clarke’s analysis of drugs and poisons. 3rd ed. London: Pharmaceutical Press, 2004

    Google Scholar 

  56. Luengo J, Aránguiz T, Sepúlveda J, et al. Preliminary pharmacokinetic study of different preparations of acyclovir with β-cyclodextrin. J Pharm Sci 2002; 91: 2593–8

    Article  PubMed  CAS  Google Scholar 

  57. Evrard B, Chiap P, DeTullio P, et al. Oral bioavailability in sheep of albendazole from a suspension and from a solution containing hydroxypropyl-β-cyclodextrin. J Control Release 2002; 85: 45–50

    Article  PubMed  CAS  Google Scholar 

  58. García JJ, Bolás F, Torrado JJ. Bioavailability and efficiency characteristics of two different oral liquid formulations of albendazole. Int J Pharm 2003; 250: 351–8

    Article  PubMed  Google Scholar 

  59. Castillo JA, Palomo-Canales J, Garcia JJ, et al. Preparation and characterization of albendazole β-cyclodextrin complexes. Drug Dev Ind Pharm 1999; 25: 1241–8

    Article  PubMed  CAS  Google Scholar 

  60. Fathy M, Sheha M. In vitro and in vivo evaluation of an amylobarbitone/hydroxypropyl-β-cyclodextrin complex prepared by a freeze-drying method. Pharmazie 2000; 55: 513–7

    PubMed  CAS  Google Scholar 

  61. Wong JW, Yuen KH. Improved oral bioavailability of artemisinin through inclusion complexation with β- and γ-cyclodextrins. Int J Pharm 2001; 227: 177–85

    Article  PubMed  CAS  Google Scholar 

  62. Teixeira LR, Sinisterra RD, Vieira RP, et al. Inclusion of benzaldehyde semicarbazone into β-cyclodextrin produces a very effective anticonvulsant formulation. J Incl Phenom Macroc Chem 2003; 47: 77–82

    Article  CAS  Google Scholar 

  63. Puglisi G, Santagati NA, Ventura CA, et al. Enhancement of 4-biphenylacetic acid bioavailability in rats by its β-cyclodextrin complex after oral administration. J Pharm Pharmacol 1991; 43: 430–2

    Article  PubMed  CAS  Google Scholar 

  64. Puglisi G, Ventura CA, Spadaro A, et al. Differential-effects of modified β-cyclodextrins on pharmacological activity and bioavailability of 4-biphenylacetic acid in rats after oral administration. J Pharm Pharmacol 1995; 47: 120–3

    Article  PubMed  CAS  Google Scholar 

  65. Hatanaka H, Komada F, Mishima Y, et al. Improved bioavailability of paraboronophenylalanine by cyclodextrin complexation. J Pharm Sci 1993; 82: 1054–7

    Article  PubMed  CAS  Google Scholar 

  66. El-Gindy GA, Mohammed FA, Salem SY. Preparation, pharmacokinetic and pharmacodynamic evaluation of carbamazepine inclusion complexes with cyclodextrins. STP Pharma Sci 2002; 12: 369–78

    CAS  Google Scholar 

  67. Brewster ME, Anderson WR, Meinsma D, et al. Intravenous and oral pharmacokinetic evaluation of a 2-hydroxypropyl-β-cyclodextrin-based formulation of carbamazepine in the dog: comparison with commercially available tablets and suspensions. J Pharm Sci 1997; 86: 335–9

    Article  PubMed  CAS  Google Scholar 

  68. Betlach CJ, Gonzalez MA, McKiernan BC, et al. Oral pharmacokinetics of carbamazepine in dogs from commercial tablets and a cyclodextrin complex. J Pharm Sci 1993; 82: 1058–60

    Article  PubMed  CAS  Google Scholar 

  69. Choudhury S, Nelson KF. Improvement of oral bioavailability of carbamazepine by inclusion in 2-hydroxypropyl-β-cyclodextrin. Int J Pharm 1992; 85: 175–80

    Article  CAS  Google Scholar 

  70. Koester LS, Bertuol JB, Groch KR, et al. Bioavailability of carbamazepine: β-cyclodextrin complex in beagle dogs from hydroxypropylmethylcellulose matrix tablets. Eur J Pharm Sci 2004; 22: 201–7

    Article  PubMed  CAS  Google Scholar 

  71. Fekkes D, Tuiten A, Bom I, et al. Pharmacokinetics of the b-carboline norharman in man. Life Sci 2001; 69: 2113–21

    Article  PubMed  CAS  Google Scholar 

  72. Hirayama F, Usami M, Kimura K, et al. Crystallization and polymorphic transition behavior of chloramphemicol palmitate in 2-hydroxypropyl-β-cyclodextrin matrix. Eur J Pharm Biopharm 1997; 5: 23–30

    CAS  Google Scholar 

  73. Tokumura T, Tsushima Y, Kayano M, et al. Enhancement of bioavailability of cinnarizine from its β-cyclodextrin complex on oral administration with DL- phenylalanine as a competing agent. J Pharm Sci 1985; 74: 496–7

    Article  PubMed  CAS  Google Scholar 

  74. Järvinen T, Järvinen K, Schwarting N, et al. β-Cyclodextrin derivatives, SBE4-b-CD and HP-b-CD, increase the oral bioavailability of cinnarizine in beagle dogs. J Pharm Sci 1995; 84: 295–9

    Article  PubMed  Google Scholar 

  75. Tokumura T, Nanba M, Tsushima Y, et al. Enhancement of bioavailability of cinnarizine from its β-cyclodextrin complex on oral administration with DL- phenylalanine as a competing agent. J Pharm Sci 1986; 75: 391–4

    Article  PubMed  CAS  Google Scholar 

  76. Yoo SD, Yoon BM, Lee HS, et al. Increased bioavailability of clomipramine after sublingual administration in rats. J Pharm Sci 1999; 88: 1119–21

    Article  PubMed  CAS  Google Scholar 

  77. Miyake K, Irie T, Hirayama F, et al. Improved solubility and oral bioavailability of cyclosporin A by hydrophilic cyclodextrin complexation. In: Torres Labandeira JJ, Vila-Jato JL, editors. Proceedings of the Ninth International Symposium on Cyclodextrins; 1998 Jun 3; Santiago de Compostela. Dordrecht: Kluwer Academic Publishers, 1999: 293–6

    Chapter  Google Scholar 

  78. Miyake K, Arima H, Irie T, et al. Enhanced absorption of cyclosporin A by complexation with dimethyl-β-cyclodextrin in bile duct-cannulated and -non-cannulated rats. Biol Pharm Bull 1999; 22: 66–72

    Article  PubMed  CAS  Google Scholar 

  79. Jain AC, Aungst BJ, Adeyeye MC. Development and in vivo evaluation of buccal tablets prepared using danazole-sulfobutylether 7β-cyclodextrin (SBE 7) complexes. J Pharm Sci 2002; 91: 1659–68

    Article  PubMed  CAS  Google Scholar 

  80. Badawy SIF, Ghorab MM, Adeyeye CM. Characterization and bioavailability of danazol-hydroxypropyl-β-cyclodextrin coprecipitates. Int J Pharm 1996; 128: 45–54

    Article  CAS  Google Scholar 

  81. Liversidge GG, Cundy KC. Particle-size reduction for improvement of oral bioavailability of hydrophobic drugs: 1. Absolute oral bioavailability of nanocrystalline danazol in beagle dogs. Int J Pharm 1995; 125: 91–7

    Article  CAS  Google Scholar 

  82. Badawy SIF, Ghorab MM, Adeyeye CM. Bioavailability of danazol-hydrox-ypropyl-β-cyclodextrin complex by different routes of administration. Int J Pharm 1996; 145: 137–43

    Article  CAS  Google Scholar 

  83. Corvi Mora P, Cirri M, Allolio B, et al. Enhancement of dehydroepianhydrosterone solubility and bioavailability by ternary complexation with α-cyclodextrin and glycine. J Pharm Sci 2003; 92: 2177–84

    Article  PubMed  CAS  Google Scholar 

  84. Uekama K, Fujinaga T, Hirayama F, et al. Improvement of the oral bioavailability of digitalis glycosides by cyclodextrin complexation. J Pharm Sci 1983; 72: 1338–41

    Article  PubMed  CAS  Google Scholar 

  85. Le Corre P, Dollo G, Chevanne F, et al. Influence of hydroxypropyl-β-cyclodextrin and dimethyl-β-cyclodextrin on diphenhydramine intestinal absorption in a rat in situ model. Int J Pharm 1998; 169: 221–8

    Article  CAS  Google Scholar 

  86. Ricevuti G, Mazzone A, Pasotti D, et al. Pharmacokinetics of dipyridamole-β-cyclodextrin complex in healthy volunteers after single and multiple doses. Eur J Drug Metab Pharmacokinet 1991; 16: 197–201

    Article  PubMed  CAS  Google Scholar 

  87. Stracciari GL, Malvisi J, Anfossi P, et al. Pharmacokinetics of dipyridamole-β-cyclodextrin complex in dogs. Arch Int Pharmacodyn 1989; 300: 7–13

    PubMed  CAS  Google Scholar 

  88. Savolainen J, Frosberg M, Taipale H, et al. Effect of aqueous solubility and dissolution characteristics on oral bioavailability of entacapone. Drug Dev Res 2000; 49: 238–44

    Article  CAS  Google Scholar 

  89. Loftsson T, Gudmundsson JA, Árnadóttir RO, et al. Sublingual delivery of 17β-estradiol from cyclodextrin containing tablets. Pharmazie 2003; 58: 358–9

    PubMed  CAS  Google Scholar 

  90. Fridriksdóttir H, Loftsson T, Gudmundsson JA, et al. Design and in vivo testing of 17β-estradiol-HPbCD sublingual tablets. Pharmazie 1996; 51: 39–42

    PubMed  Google Scholar 

  91. Hoon TJ, Dawood MY, Khan-Dawood FS, et al. Bioequivalence of 17β-estradiol hydroxypropyl-β-cyclodextrin complex in postmenopausal women. J Clin Pharmacol 1993; 33: 1116–21

    PubMed  CAS  Google Scholar 

  92. Miyaji T, Inoue Y, Acarturk F, et al. Improvement of oral bioavailability of fenbufen by cyclodextrin complexation. Acta Pharm Nord 1992; 4: 17–22

    PubMed  CAS  Google Scholar 

  93. Géczy J, Bruhwyler J, Scuvée-Moreau J, et al. The inclusion of fluoxitine into γ-cyclodextrin increases its bioavailability: behavioral, electrophysiological and pharmacokinetic studies. Psychopharmacology 2000; 151: 328–34

    Article  PubMed  Google Scholar 

  94. Zuo Z, Tam YK, Diakur J, et al. Hydroxypropyl-β-cyclodextrin-flutamide inclusion complex: II. Oral and intravenous pharmacokinetics of flutamide in the rat. J Pharm Pharm Sci 2002; 5: 292–8

    PubMed  CAS  Google Scholar 

  95. Savolainen J, Järvinen K, Taipale H, et al. Coadministration of a water-soluble polymer increases the usefulness of cyclodextrins in solid dosage forms. Pharm Res 1998; 15: 1696–701

    Article  PubMed  CAS  Google Scholar 

  96. Jayachandra Babu R, Pandit JK. Enhancement of dissolution rate and hypoglycemic activity of glibenclamide with β-cyclodextrin. STP Pharma Sci 1995; 5: 196–201

    Google Scholar 

  97. Aggarwal S, Singh PN, Mishra B. Studies on solubility and hypoglycemic activity of gliclazide β-cyclodextrin-hydroxypropylmethylcellulose complexes. Pharmazie 2002; 57: 191–3

    PubMed  CAS  Google Scholar 

  98. Sridevi S, Chauhan AS, Chalasani KB, et al. Enhancement of dissolution and oral bioavailability of gliquidone with hydroxy propyl-β-cyclodextrin. Pharmazie 2003; 58: 807–10

    PubMed  CAS  Google Scholar 

  99. Uekama K, Udo K, Irie T, et al. Improvement of dissolution and absorption characteristics of indomethacin by water-soluble α-cyclodextrin-epichlorohydrin polymer. Acta Pharm Suec 1987; 24: 27–36

    PubMed  CAS  Google Scholar 

  100. Jambhekar S, Casella R, Maher T. The physicochemical characteristics and bioavailability of indomethacin from β-cyclodextrin, hydroxyethyl-β-cyclodextrin, and hydroxypropyl-β-cyclodextrin complexes. Int J Pharm 2004; 270: 149–66

    Article  PubMed  CAS  Google Scholar 

  101. Zhao Q, Zhou H, Pesco-Koplowitz L. Pharmacokinetics of intravenous itraconazole followed by itraconazole oral solution in patients with human immunodeficiency virus infection. J Clin Pharmacol 2001; 41: 1319–28

    Article  PubMed  CAS  Google Scholar 

  102. Barone JA, Moskovitz BL, Guarnieri J, et al. Enhanced bioavailability of itraconazole in hydroxypropyl-β-cyclodextrin solution versus capsules in healthy volunteers. Antimicrob Agents Chemother 1998; 42: 1862–5

    PubMed  CAS  Google Scholar 

  103. Ahn HJ, Kim KM, Choi JS, et al. Effects of cyclodextrin derivatives on bioavailability of ketoprofen. Drug Dev Ind Pharm 1997; 23: 397–401

    Article  CAS  Google Scholar 

  104. Tenjarla S, Puranajoti P, Kasina R, et al. Preparation, characterization, and evaluation of miconazole-cyclodextrin complexes for improved oral and topical delivery. J Pharm Sci 1998; 87: 425–9

    Article  PubMed  CAS  Google Scholar 

  105. Otero-Espinar FJ, Anguiano-Igea S, García-Gonzales N, et al. Oral bioavailability of naproxen-β-cyclodextrin inclusion compound. Int J Pharm 1991; 75: 37–44

    Article  CAS  Google Scholar 

  106. Fernandes CM, Ramos P, Falcão AC, et al. Hydrophilic and hydrophobic cyclodextrins in a new sustained release oral formulation of nicardipine: in vitro evaluation and bioavailability studies in rabbits. J Control Release 2003; 88: 127–34

    Article  PubMed  CAS  Google Scholar 

  107. Chowdary KPR, Kamalakara RG. Controlled release of nifedipine from mucoadhesive tablets of its inclusion complexes with β-cyclodextrin. Pharmazie 2003; 58: 721–4

    PubMed  CAS  Google Scholar 

  108. Emara LH, Badr RM, Abd Elbary A. Improving the dissolution and bioavailability of nifedipine using solid dispersions and solubilizers. Drug Dev Ind Pharm 2002; 28: 795–807

    Article  PubMed  CAS  Google Scholar 

  109. Uekama K, Ikegami K, Wang Z, et al. Inhibitory effect of 2-hydroxypropyl-β-cyclodextrin on crystal-growth of nifedipine during storage: superior dissolution and oral bioavailability compared with polyvinylpyrrolidone K-30. J Pharm Pharmacol 1992; 44: 73–8

    Article  PubMed  CAS  Google Scholar 

  110. Wang Z, Hirayama F, Uekama K. In-vivo and in-vitro evaluations of modifiedrelease oral dosage form of nifedipine by hybridization of hydroxypropyl-β-cyclodextrin and hydroxypropylcellulose in dogs. J Pharm Pharmacol 1994; 46: 505–7

    Article  PubMed  Google Scholar 

  111. Choi H-G, Kim D-D, Jun HW, et al. Improvement of dissolution and bioavailability of nitrendipine by inclusion in hydroxypropyl- β-cyclodextrin. Drug Dev Ind Pharm 2003; 29: 1085–94

    Article  PubMed  CAS  Google Scholar 

  112. Savolainen J, Järvinen K, Matilainen L, et al. Improved dissolution and bioavailability of phenytoin by sulfobutylether-β-cyclodextrin (SBE)7m-β-CD) and hydroxypropyl-β-cyclodextrin (HP-b-CD) complexation. Int J Pharm 1998; 165: 69–78

    Article  CAS  Google Scholar 

  113. Uekama K, Otagiri M, Irie T, et al. Improvement of dissolution and absorption characteristics of phenytoin by a water-soluble β-cyclodextrin-epichlorohydrin polymer. Int J Pharm 1985; 23: 35–42

    Article  CAS  Google Scholar 

  114. Tanino T, Ogiso T, Iwaki M. Effect of sugar-modified β-cyclodextrins on dissolution and absorption characteristics of phenytoin. Biol Pharm Bull 1999; 22: 298–304

    Article  PubMed  CAS  Google Scholar 

  115. Woodcock BG, Acerbi D, Merz PG, et al. Supermolecular inclusion of piroxicam with β-cyclodextrin: pharmacokinetic properties in man. Eur J Rheumatol Inflamm 1993; 12: 12–28

    PubMed  CAS  Google Scholar 

  116. McEwen J. Clinical pharmacology of piroxicam-β-cyclodextrin: implications for innovative patient care. Clin Drug Invest 2000; 19Suppl. 2: 27–31

    CAS  Google Scholar 

  117. Elkheshen SA, Ahmed SM, Al-Quadeib BT. Inclusion complexes of piroxicam with β-cyclodextrin derivatives in comparison with the natural β-cyclodextrin, 2nd communication: in vitro and in vivo drug availability. Pharm Ind 2002; 64: 708–15

    CAS  Google Scholar 

  118. Kimura E, Bersani-Amado CA, Sudo LS, et al. Pharmacokinetic profile of piroxicam β-cyclodextrin, in rat plasma and lymph. Gen Pharmacol 1997; 28: 695–8

    Article  PubMed  CAS  Google Scholar 

  119. Deroubaix X, Stockis A, Allemon AM, et al. Oral bioavailability of CHF1194, an inclusion complex of piroxicam and β-cyclodextrin, in healthy-subjects under single-dose and steady-state conditions. Eur J Clin Pharmacol 1995; 47: 531–6

    Article  PubMed  CAS  Google Scholar 

  120. Hashimoto N, Fujioka T, Hayashi K, et al. Renin inhibitor: relationship between molecular structure and oral absorption. Pharm Res 1994; 11: 1443–7

    Article  PubMed  CAS  Google Scholar 

  121. Lin H-S, Chan SY, Low KSY, et al. Kinetic study of a 2-hydroxypropyl-β-cyclodextrin based formulation of all-trans-retinoic acid in Sprague-Dawley rats after oral or intravenous administration. J Pharm Sci 2000; 89: 260–7

    Article  PubMed  CAS  Google Scholar 

  122. Chavanpatil M, Dawre FD, Shakleya DS, et al. Enhancement of oral bioavailability of rofecoxib using β-cyclodextrin. J Incl Phenom Macroc Chem 2002; 44: 145–9

    Article  CAS  Google Scholar 

  123. Miyake K, Arima H, Hirayama F, et al. Improvement of solubility and oral bioavailability of rutin by complexation with 2-hydroxypropyl- β-cyclodextrin. Pharm Dev Technol 2000; 5: 399–407

    Article  PubMed  CAS  Google Scholar 

  124. Arcari M, Brambilla A, Brandt A, et al. Nuovo complesso di inclusione tra la silibina e la b-ciclodextrina: velocità di sissoluzione in vitro e assorbimento in vivo in confronto a formulazioni tradizionali. Boll Chim Farm 1992; 131: 205–9

    PubMed  CAS  Google Scholar 

  125. Seo H, Tsuruoka M, Hashimoto T, et al. Enhancement of oral bioavailability of spironolactone by β- and γ-cyclodextrin complexation. Chem Pharm Bull 1983; 31: 286–91

    Article  PubMed  CAS  Google Scholar 

  126. Kaukonen AM, Lennernäs A, Mannermaa JP. Water-soluble β-cyclodextrins in pediatric oral solutions of spironolactone: preclinical evaluation of spironolactone bioavailability from solutions of β-cyclodextrin derivatives in rats. J Pharm Pharmacol 1998; 50: 611–9

    Article  PubMed  CAS  Google Scholar 

  127. Soliman OAE, Kimura K, Hirayama F, et al. Amorphous spirolactone-hydrox-ypropylated cyclodextrin complexes with superior dissolution and oral bioavailability. Int J Pharm 1997; 149: 73–83

    Article  CAS  Google Scholar 

  128. Arima H, Yunomae K, Miyake K, et al. Comparative studies of the enhancing effects of cyclodextrins on the solubility and oral bioavailability of tacrolimus in rats. J Pharm Sci 2001; 90: 690–701

    Article  PubMed  CAS  Google Scholar 

  129. Pitha J, Harman SM, Michel ME. Hydrophilic cyclodextrin derivatives enable effective oral administration of steroidal hormones. J Pharm Sci 1986; 75: 165–7

    Article  PubMed  CAS  Google Scholar 

  130. Stuenkel CA, Dudley RE, Yen SSC. Sublingual administration of testosterone-hydroxypropyl-β-cyclodextrin inclusion complex simulates episodic androgen release in hypogonadal men. J Clin Endocrinol Metab 1991; 72: 1054–9

    Article  PubMed  CAS  Google Scholar 

  131. Vakily M, Pasutto FM, Daneshtalab M, et al. Inclusion complexation of heptakis (2,6-di-O-ethul)-β-cyclodextrin with tiaprofenic acid: pharmacokinetic consequences of a pH-dependent release and stereoselective dissolution. J Pharm Sci 1995; 84: 1014–9

    Article  PubMed  CAS  Google Scholar 

  132. Veiga F, Fernandes C, Teixeira T. Oral bioavailability and hypoglycemie activity of tolbutamide/cyclodextrin inclusion complexes. Int J Pharm 2000; 202: 165–71

    Article  PubMed  CAS  Google Scholar 

  133. Kimura K, Hirayama F, Arima H, et al. Effects of aging on crystallization, dissolution and absorption characteristics of amorphous tolbutamide-2-hydrox-ypropyl-β-cyclodextrin complex. Chem Pharm Bull (Tokyo) 2000; 48: 646–50

    Article  CAS  Google Scholar 

  134. Uekama K, Horiuchi Y, Kikuchi M, et al. Enhanced dissolution and oral bioavailability of α-tocopheryl esters by dimethyl-β-cyclodextrin complexation. J Incl Phenom 1988; 6: 167–74

    Article  CAS  Google Scholar 

  135. Ventura P, Panini R, Montosi G, et al. Ursodeoxycholic acid complexation with 2-hydroxypropyl-β-cyclodextrin increases ursodeoxycholic acid biliary excretion after single oral administration to rats. Pharmacology 2001; 62: 107–12

    Article  PubMed  CAS  Google Scholar 

  136. Panini R, Vandelli MA, Forni F, et al. Improvement of ursodeoxycholic acid bioavailability by 2-hydroxypropyl-β-cyclodextrin complexation in healthy volunteers. Pharmacol Res 1995; 31: 205–9

    Article  PubMed  CAS  Google Scholar 

  137. Amselem S, Friedman D, Yogev A, et al. Formulation development for a zidovudine chemical delivery system: 2. Towards oral and non-parenteral dosage forms. Int J Pharm 1995; 125: 31–43

    Article  CAS  Google Scholar 

  138. Goodman Gilman A, Rall TW, Nies AS, et al., editors. The pharmacological basis of therapeutics. New York: McGraw-Hill, 1992

    Google Scholar 

  139. Ahuja N, Singh A, Singh B. Rofecoxib: an update on physicochemical, ISSN pharmaceutical, Pharmacodynamic and pharmacokinetic aspects. J Pharm Pharmacol 2003; 55: 859–94

    Article  PubMed  CAS  Google Scholar 

  140. Kobayashi Y, Ito S, Itai S, et al. Physicochemical properties and bioavailability of carbamazepine polymorphs and dihydrate. Int J Pharm 2000; 193: 137–46

    Article  PubMed  CAS  Google Scholar 

  141. Popovic J, Mikov M, Jakovljevic V. Pharmacokientics of carbamazepine derived from a new tablet formulation. Eur J Drug Metab Pharmacokinet 1995; 20: 297–300

    Article  PubMed  CAS  Google Scholar 

  142. Anderson PO, Knoben JE, Troutman WG, editors. Handbook of clinical drug data. 9th ed. Stamford: Appelton & Lange, 1999

    Google Scholar 

  143. Kann J, Krol G, Raemsch K, et al. Bioequivalence and metabolism of nitrendipine administered orally to healthy volunteers. J Cardiovasc Pharmacol 1984; 6Suppl. 7: S968–73

    PubMed  CAS  Google Scholar 

  144. Veiga M-D, Ahsan F. Hydroxypropyl gamma cyclodextrin as a solubilizer and dissolution enhancing agent: the case of tolbutamide — a poorly water-soluble drug. In: Torres Labandeira JJ, Vila-Jato JL, editors. Proceedings of the Ninth International Symposium on Cyclodextrins; 1998 Jun 3; Santiago de Compostela. Dordrecht: Kluwer Academic Publishers, 1999: 321–4

    Chapter  Google Scholar 

  145. Peeters J, Neeskens P, Tollenaere JP, et al. Characterization of the interaction of 2-hydroxypropyl-β-cyclodextrin with itraconazole at pH 2, 4, and 7. J Pharm Sci 2002; 91: 1414–22

    Article  PubMed  CAS  Google Scholar 

  146. Brewster ME, Verreck G, Chun I, et al. The use of polymer-based electrospun nanofibers containing amorphous drug dispersions for the delivery of poorly water-soluble Pharmaceuticals. Pharmazie 2004 May; 59(5): 387–91

    PubMed  CAS  Google Scholar 

  147. Benet LZ, Øie S, Schwartz JB. Design and optimization of dosage regimens; pharmacokinetic data. In: Hardman JG, Limbird LE, Molinoff PB, et al., editors. Goodman & Gilman’s the pharmaceutical basis of therapeutics. New York: McGraw-Hill, 1996: 1752

    Google Scholar 

  148. Miyake K, Hirayama F, Uekama K. Solubility and mass and nuclear magnetic resonance spectroscopic studies on interaction of cyclosporin A with dimethyl-α- and β-cyclodextrins in aqueous solution. J Pharm Sci 1999; 88: 39–45

    Article  PubMed  CAS  Google Scholar 

  149. Loftsson T. Cyclodextrins and the biopharmaceutics classification system. J Incl Phenom Macroc Chem 2002; 44: 63–7

    Article  CAS  Google Scholar 

  150. Lemesle-Lamache V, Wouessidjewe D, Chéron M, et al. Study of β-cyclodextrin and ethylated β-cyclodextrin salbutamol complexes, in vitro evaluation of sustained-release behavior of salbutamol. Int J Pharm 1996; 141: 117–24

    Article  CAS  Google Scholar 

  151. Zannou EA, Streng WH, Stella VJ. Osmotic properties of sulfobutylether and hydroxypropyl cyclodextrins. Pharm Res 2001; 18: 1226–31

    Article  PubMed  CAS  Google Scholar 

  152. Stella VJ, Rao VM, Zannou EA. The pharmaceutical use of Captisol®: some surprising observations. J Incl Phenom Macroc Chem 2002; 44: 29–33

    Article  CAS  Google Scholar 

  153. Koester LS, Xavier CR, Mayorga P, et al. Influence of β-cyclodextrin complexation on carbamazepine release from hydroxypropyl methylcellulose matrix tablets. Eur J Pharm Biopharm 2003; 55: 85–91

    Article  PubMed  CAS  Google Scholar 

  154. Rao VM, Haslam JL, Stella VJ. Controlled and complete release of a model poorlywater-soluble drug, prednisolone, from hydroxypropyl methylcellulose matrix tablets using (SBE) (7M)-β-cyclodextrin as a solubilizing agent. J Pharm Sci 2001; 90: 807–16

    Article  PubMed  CAS  Google Scholar 

  155. Yano H, Hirayama F, Kamada M, et al. Colon-specific delivery of prednisolone-appended α-cyclodextrin conjugate: alleviation of systemic side effect after oral administration. J Control Release 2002; 79: 103–12

    Article  PubMed  CAS  Google Scholar 

  156. Hirayama F, Kamada M, Yano H, et al. Prolonged plasma levels of ketoprofen after oral administration of its α-cyclodextrin conjugate/ethylcellulose dispersion in rats. J Incl Phenom Macroc Chem 2002; 44: 159–61

    Article  CAS  Google Scholar 

  157. Marttin E, Verhoef JC, Merkus FWHM. Efficiency, safety and mechanism of cyclodextrins as absorption enhancers in nasal delivery of peptide and protein drugs. J Drug Target 1998; 6: 17–36

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

Financial support from the University of Iceland Research Fund is gratefully acknowledged. The authors have provided no information on conflicts of interest that are directly relevant to the content of this manuscript.

Author information

Authors and Affiliations

  1. Faculty of Pharmacy, University of Iceland, Hofsvallagata 53, Reykjavik, IS-107, Iceland

    Thorsteinn Loftsson & Már Másson

  2. Department of Pharmaceutical Sciences, Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium

    Marcus E. Brewster

Authors
  1. Thorsteinn Loftsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marcus E. Brewster
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Már Másson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thorsteinn Loftsson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Loftsson, T., Brewster, M.E. & Másson, M. Role of cyclodextrins in improving oral drug delivery. Am J Drug Deliv 2, 261–275 (2004). https://doi.org/10.2165/00137696-200402040-00006

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00137696-200402040-00006

Keywords

Search

Navigation