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  • Review Article
  • Published:

Nanosuspensions in drug delivery

Nature Reviews Drug Discovery volume 3, pages 785–796 (2004)Cite this article

Key Points

  • Nanosuspension formulation technology has evolved to meet the needs posed by the numerous water-insoluble drug candidates emerging from high-throughput drug screening programmes that emphasize fit into hydrophobic receptor pockets.

  • Although there are numerous other technologies that can be used, nanosuspensions are ideally suited for drugs with a high crystal energy, which renders them insoluble in lipid as well as aqueous vehicles.

  • The solid state of the nanosuspension confers high weight per volume loading, which is ideal for depot delivery in which administration volume is constrained and high drug levels must be administered.

  • The reduced particle size entails high surface area, thereby increasing the dissolution rate to overcome solubility limited bioavailability.

  • Surfactants, utilizing electrostatic and steric stabilization mechanisms, coat the nanoparticles, thereby preventing their agglomeration and ensuring pharmaceutical stability.

  • Methods of manufacture involve crystallization, building nanocrystals up from the supersaturated solution state, as well as making larger particles smaller by homogenization or milling.

  • Pharmacokinetic profiles for injectables vary from rapidly soluble in the blood, to slowly dissolving, after which macrophage uptake and subsequent release greatly prolong drug delivery, while minimizing peak height. For several drug classes, this leads to improved safety, which permits higher dosing and improved efficacy.

  • Regional delivery confers increased efficacy to local target organs, while minimizing systemic toxicity, and has been demonstrated for the central nervous system, lungs and topically.

  • Numerous solubility-related issues in oral administration of drugs can be resolved, and include increased rate and extent of absorption, reduced variability of absorption, faster onset of action, higher peak drug level, improved dose proportionality and reduced fed/fasted effects.

Abstract

A surprisingly large proportion of new drug candidates emerging from drug discovery programmes are water insoluble, and therefore poorly bioavailable, leading to abandoned development efforts. These so-called 'brickdust' candidates can now be rescued by formulating them into crystalline nanosuspensions. In the process of overcoming issues involving solubility, additional pharmacokinetic benefits of the drugs so formulated have come to be appreciated. As such, insolubility issues of the past have provoked a paradigm change, which now offers novel solutions for innovative drugs of the future.

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Figure 1: Decision tree for selection of formulation approach.
Figure 2: Creation and stabilization of nanoparticles, from the perspective of surface energetics.
Figure 3: Potential energy curve for approach of two nanoparticles.
Figure 4: Engineering breakable crystals with a combination of microprecipitation and homogenization.
Figure 5: Schematic of aseptic microprecipitation/ homogenization process.
Figure 6: Trafficking of drug nanoparticles by macrophages, monocytes and neutrophils.

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References

  1. Na, G. C. et al. Physical stability of ethyl diatrizoate nanocrystalline suspension in steam sterilization. Pharm. Res. 16, 569–574 (1999).

    CAS  PubMed  Google Scholar 

  2. Horn, D. & Rieger, J. Organic nanoparticles in the aqueous phase-theory, experiment, and use. Angew. Chem. Int. Ed. 40, 4330–4361 (2001). Comprehensive, schematically illustrated analysis of the various methods of forming nanoparticles.

    CAS  Google Scholar 

  3. Muller, R. H. et al. Solid lipid nanoparticles (SLN) for controlled drug delivery — a review of the state of the art. Eur. J. Pharm. and Biopharm. 50, 161–177 (2000).

    CAS  Google Scholar 

  4. Lipinski, C. A., Lombardo, F., Dominy, B. & Feeney, P. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Reviews 23, 3–25 (1997). Provides and explanation and characterization of the increase of solubility and permeability problems observed with new drug compounds.

    CAS  Google Scholar 

  5. Yalkowsky, S. H. Techniques of Solubilization of Drugs 1–14 (Marcel Dekker, New York, 1981).

    Google Scholar 

  6. Joshi, A. Microparticulates for ophthalmic drug delivery. J. Ocular Pharm. 10, 29–45 (1994).

    CAS  Google Scholar 

  7. LeBourlais, C. et al. Ophthalmic drug delivery systems-recent advances. Prog. Retinal and Eye Res. 17, 33–58 (1998).

    CAS  Google Scholar 

  8. Weiner, M. and Bernstein, I. L. Adverse Reactions to Drug Formulation Agents (Marcel Dekker, New York, 1989).

    Google Scholar 

  9. Gad, S. C. Drug Safety Evaluation Ch. 13.8 (John Wiley and Sons, New York, 2002).

    Google Scholar 

  10. Ziller, K. H & Rupprecht, H. H. Control of crystal growth in drug suspensions. Part II: influence of polymers on dissolution and crystallization during temperature cycling. Pharm Ind. 52, 1017–1022 (1990).

    CAS  Google Scholar 

  11. Tabibi, S. E. & Rhodes, C. T. in Modern Pharmaceutics 3rd edn (eds Banker, G. S. & Rhodes C. T.) Ch. 9 (Marcel Dekker, New York, 1996).

    Google Scholar 

  12. Myerson, A. S. & Ginde, R. in Handbook of Industrial Crystallization (ed. Myerson, A. S.) 45–46 (Butterworth–Heinemann, Boston, 1992).

    Google Scholar 

  13. Garside, J. in Particle Design Via Crystallization (eds Ramanarayanan, R. et al.) 16–25 (AIChE Symposium Series, Vol. 87, New York, 1991).

    Google Scholar 

  14. Muller, R. H. & Peters, K. Nanosuspensions for the formulation of poorly water soluble drugs. I. Preparation by a size reduction technique. Int. J. Pharm. 160, 229–237 (1998).

    CAS  Google Scholar 

  15. Liedtke, S., Wissing, S., Muller, R. H. & Mader, K. Influence of high pressure homogenisation equipment on nanodispersions characteristics. Int. J. Pharm. 196, 183–185 (2000).

    CAS  PubMed  Google Scholar 

  16. Pandolfe, W. D. Development of the new Gaulin Micro-GapTM homogenizing valve. J. Dairy Sci. 65, 2035–2044 (1982). References 16 and 20 explain the theory and operating principles of the homogenization process quite well.

    Google Scholar 

  17. Schultz, S., Wagner, G. & Ulrich, J. On the influence of geometric parameters of a combined orifice valve on the attainable mean droplet diameter during high-pressure homogenization. Eng. Life Sci. 2, 337–340 (2002).

    CAS  Google Scholar 

  18. Kinney, R. R. et al. Homogenization valve. US Patent 5,749,650 (1998).

  19. Wilbey, A. Homogenization. J. Soc Dairy Tech. 45, 31–32 (1992).

    Google Scholar 

  20. Jahnke, S. in Emulsions and Nanosuspensions for the Formulation of Poorly Soluble Drugs (eds Muller, R. H., Benita, S. & Bohm, B.) 177–200 (Medpharm Scientific, Stuttgart, 1998).

    Google Scholar 

  21. Mohr, K. -H. High-pressure homogenization. Part I. Liquid-liquid dispersion in turbulence fields of high energy density. J. Food Engineer. 6, 177–186 (1987).

    Google Scholar 

  22. Pandolfe, W. D. Effect of dispersed and continuous phase viscosity on droplet size of emulsions generated by homogenization. J. Dispersion Sci. Tech. 2, 459–474 (1981).

    CAS  Google Scholar 

  23. Huttenrauch, R. Fundamentals of pharmaceutics. Acta Pharm. Technol. 34, 1–10 (1988). Overview of the types of imperfections in crystals and their impact on subsequent processing.

    Google Scholar 

  24. Grant, D. & York, P. Entropy of processing: a new quantity for comparing the solid state disorder of pharmaceutical materials. Int. J. Pharmaceutics 30, 161–180 (1986).

    Google Scholar 

  25. Duddu, S. P. & Grant, D. The use of thermal analysis in the assessment of crystal disruption. Thermochimica Acta. 248, 131–145 (1995)

    CAS  Google Scholar 

  26. Kipp, J. E. et al. Microprecipitation method for preparing submicron suspensions. US Patent 6,607,784 B2 (2003).

  27. Merisko-Liversidge, E., Liversidge, G. G. & Cooper, E. Nanosizing: a formulation approach for poorly-water-soluble compounds. Eur. J. Pharm Sci. 18, 113–120 (2003).

    CAS  PubMed  Google Scholar 

  28. Sarkari, M. et al. Enhanced drug dissolution using evaporative precipitation into aqueous solution. Int. J. Pharm. 243, 17–31 (2002).

    CAS  PubMed  Google Scholar 

  29. Peters, K. et al. Preparation of a clofazimine nanosuspension for intravenous use and evaluation of its therapeutic efficacy in murine Mycobacterium avium infection. J. Antimcrob. Chem. 45, 77–83 (2000).

    CAS  Google Scholar 

  30. Toguchi, H. Sterility assurance of microspheres. J. Contr. Rel. 62, 51–55 (1999)

    CAS  Google Scholar 

  31. Zheng, J. Y. & Bosch, J. W. Sterile filtration of NanoCrystalTM drug formulations. Drug Develop. Ind. Pharm. 23, 1087–1093 (1997).

    CAS  Google Scholar 

  32. Konan, Y. N., Gurny, R. & Allemann, E. Preparation and characterization of sterile and freeze-dried sub-200 nm nanoparticles. Int. J. Pharm. 233, 239–252 (2002).

    CAS  PubMed  Google Scholar 

  33. Na, G. C., Stevens, H. J., Yuan, B. & Rajagopalan, N. Physical stability of ethyl diatrizoate nanocrystalline suspension in steam sterilization. Pharm. Res. 16, 569–574 (1999).

    CAS  PubMed  Google Scholar 

  34. Floyd, A. G. & Jain, S. in Pharmaceutical Dosage Forms, Disperse Systems 2nd edn Vol. 2 (eds Lieberman, H. A., Rieger, M. M.. & Banker, G. S.) 295–298 (Marcel Dekker, New York, 1996).

    Google Scholar 

  35. Akers, M. J., Fites, A. L. & Robison, R. L. Formulation design and development of parenteral suspensions. J. Parenter. Sci. Tech. 41, 88–96 (1987). Excellent overview of the issues associated with the production of parenteral suspensions, and strategies for resolving them.

    CAS  Google Scholar 

  36. Barber, T. A. in Pharmaceutical Particulate Matter: Analysis and Control Ch. 8 (Interpharm, Buffalo Grove, 1993).

    Google Scholar 

  37. Weiner, B. B. in Liquid- and Surface-Borne Particle Measurement Handbook (eds Knapp, J. Z., Barber, T. A. & Lieberman, A) Ch. 5 (Marcel Dekker, New York, 1996).

    Google Scholar 

  38. Lines, R. W. in Liquid- and Surface-Borne Particle Measurement Handbook (eds Knapp, J. Z., Barber, T. A. & Lieberman, A) Ch. 4 (Marcel Dekker, New York, 1996).

    Google Scholar 

  39. <788> Particulate Matter in Injections, Microscopic Particle Count Test. USP 27 The United States Pharmacopeia, United States Pharmacopeial Convention Inc. Rockville, Md. (2004).

  40. Shi, H. G. et al. Characterization of crystalline drug nanoparticles using atomic force microscopy and complementary techniques. Pharm. Res. 20, 479–484 (2003).

    CAS  PubMed  Google Scholar 

  41. Kuentz, M. and Rothlisberger, D. Rapid assessment of sedimentation stability in dispersions using near infrared transmission measurements during centrifugation and oscillatory rheology. Eur. J. Pharm. Biopharm. 56, 355–361 (2003).

    CAS  PubMed  Google Scholar 

  42. Giron, D. Thermal analysis and calorimetric methods in the characterisation of polymorphs and solvates. Thermochim. Acta 248, 1–59 (1995).

    CAS  Google Scholar 

  43. Yoshii, K. Application of differential scanning calorimetry to the estimation of drug purity: various problems and their solutions in purity analysis. Chem. Pharm. Bull. 45, 338–343 (1997).

    CAS  Google Scholar 

  44. Barnes, A. F. et al. A review of the applications of thermal methods within the pharmaceutical industry. J. Thermal Anal. 40, 499–509 (1993).

    CAS  Google Scholar 

  45. Higgins, J. P. Spectroscopic approach for on-line monitoring of particle size during the processing of pharmaceutical nanoparticles. Anal. Chem. 75, 1777–1785 (2003).

    CAS  PubMed  Google Scholar 

  46. Nicolaides, E. et al. Biorelevant dissolution testing to predict the plasma profile of lipophilic drugs after oral administration. Pharm. Res. 18, 380–388 (2001).

    CAS  PubMed  Google Scholar 

  47. Dressman, J. B. & Reppas, C. In vitro–in vivo correlations for lipophilic, poorly water-soluble drugs. Euro. J. Pharm. Sci. 11 (Suppl. 2), S73–S80 (2000).

    CAS  Google Scholar 

  48. U. S. Dept. of Health and Human Services, Food and Drug Administration. Guidance for Industry: Liposome Drug Products; Chemistry, manufacturing, and controls; human pharmacokinetics and bioavailability; and labeling documentation, August 2002.

  49. Donovan, M. & Flanagan, D. in Pharmaceutical Dosage Forms, Disperse Systems 2nd edn Vol. 2. (eds Lieberman, H. A., Rieger, M. M. & Banker, G. S.) Ch. 8 (Marcel Dekker. New York, 1996).

    Google Scholar 

  50. Jia, L., Wong, J., Cerna, C. & Weitman, S. Effect of nanonization on absorption of 301029: ex vivo and in vivo pharmacokinetic correlations determined by liquid chromatography/mass spectrometry. Pharm. Res. 19, 1091–1096 (2002).

    CAS  PubMed  Google Scholar 

  51. Liversidge, G. & Cundy, K. Particle size reduction for improvement of oral bioavailability of hydrophobic drugs: I. Absolute oral bioavailability of nanocrystalline danazol in beagle dogs. Int. J. Pharm. 125, 91–97 (1995). Early paper on the improvement in oral bioavailability resulting from reducing particle size to the nano-domain.

    CAS  Google Scholar 

  52. Liversidge, G. G. & Conzentino, P. Drug particle size reduction for decreasing gastric irritancy and enhancing absorption of naproxen in rats. Int. J. Pharm. 125, 309–313 (1995).

    CAS  Google Scholar 

  53. Tong, W -Q. in Water–Insoluble Drug Formulation (ed. Liu, R.) Ch. 4 (Interpharm, Denver, 2000).

    Google Scholar 

  54. Desai, M. P. Gastrointestinal uptake of biodegradable microparticles: effect of particle size. Pharm. Res. 13, 1838–1845 (1996).

    CAS  PubMed  Google Scholar 

  55. Duchene, D. & Ponchel, G. Bioadhesion of solid oral dosage forms, why and how? Eur. J. Pharm. and Biopharm. 44, 15–23 (1997).

    CAS  Google Scholar 

  56. Behrens, I., Pena, A. I, Alonso, M. J. & Kissel, T. Comparative uptake studies of bioadhesive and non-bioadhesive nanoparticles in human intestinal cell lines and rats: the effect of mucus on particle adsorption and transport. Pharm. Res. 19, 1185–1193 (2002).

    CAS  PubMed  Google Scholar 

  57. Florence, A. T. & Hussain, N. Transcytosis of nanoparticle and dendrimer delivery systems: evolving vistas. Adv. Drug Del. Rev. 50, S69–S89 (2001).

    CAS  Google Scholar 

  58. Lamprecht, A., Schafer, U. & Lehr, C -M. Size dependent bioadhesion of micro-and nanoparticulate carriers to the inflamed colonic mucosa. Pharm Res. 18, 788–794 (2001).

    CAS  PubMed  Google Scholar 

  59. Florence, A. T. & Hussain, N. Transcytosis of nanoparticle and dendrimer delivery systems: evolving vistas. Adv. Drug Del. Rev. 50, S69–S89 (2001).

    CAS  Google Scholar 

  60. Jani, P., Halbert, G., Langridge, J. & Florence, A. Nanoparticle uptake by the rat gastrointestinal mucosa: quantitation and particle size dependency. J. Pharm. Pharmacol. 42, 821–826 (1990).

    CAS  PubMed  Google Scholar 

  61. Clark, M., Jepson, M. & Hirst, B. Exploiting M cells for drug and vaccine delivery. Adv. Drug Deliv. Rev. 50, 81–106 (2001).

    CAS  PubMed  Google Scholar 

  62. O'Driscoll, C. M. in Lymphatic Transport of Drugs (eds Charman, W. N. & Stella, V. J.) 1–35 (CRC, Florida, 1992).

    Google Scholar 

  63. Russell-Jones, G. J. et al. Vitamin B12-mediated transport of nanoparticles across Caco-2 cells. Int. J. Pharm. 179, 247–255 (1999).

    CAS  PubMed  Google Scholar 

  64. Bittner, B. & Mountfield, R. J. Intravenous administration of poorly soluble new drug entities in early durg discovery: the potential impact of formulatin on pharmacokinetic parameters. Curr. Opinion Drug Discov. Dev. 5, 59–71 (2002).

    CAS  Google Scholar 

  65. Theis, J. G. et al. Anaphylactoid reactions in children receiving high-dose intravenous cyclosporine for reversal of tumor resistance:the causative role of improper dissolution of cremophor EL. J. Clin. Oncol. 13, 2508–2516 (1995).

    CAS  PubMed  Google Scholar 

  66. O'Dwyer, P. J. & Weiss, R. B. Hypersensitivity reactions induced by etoposide. Cancer Res. 68, 959–961 (1984).

    CAS  Google Scholar 

  67. Duma, R. J., Akers, M. J. & Turco, S. J. in Pharmaceutical Dosage Forms: Parenteral Medications 2nd edn Vol. 1 (eds Avis, K. E., Lieberman, H. A. & Lachman, L.) 17–58 (Marcel Dekker, New York, 1992).

    Google Scholar 

  68. Ward, G. H. & Yalkowsky, S. H. Studies in Phlebitis. VI. Dilution-induced precipitation of amiodarone HCl. J. Parenter. Sci. Technol. 47, 161–165 (1993).

    CAS  PubMed  Google Scholar 

  69. Davio, S. R. et al. Precipitation of the renin inhibitor ditekiren upon iv infusion; in vitro studies and their relationship to in vivo precipitation in the cynomolgus monkey. Pharm. Res. 8, 80–83 (1991).

    CAS  PubMed  Google Scholar 

  70. Davis, S. S. et al. Lipid emulsions as drug delivery systems. Ann. NY Acad. Sci. 507, 76–78 (1987b).

    Google Scholar 

  71. Yalkowsky, S. H. Techniques of Solubilization of Drugs 1–14 (Marcel Dekker, New York, 1981).

    Google Scholar 

  72. Merisko-Liversidge, E. Formulation and antitumor activity evaluation of nanocrystalline suspensions of poorly soluble anticancer drugs. Pharm. Res. 13, 272–278 (1996).

    CAS  PubMed  Google Scholar 

  73. Boedeker, B. H., Logeski, E., Kline, M. & Haynes, D. Ultra-long duration local anesthesia produced by injection of lecithin-coated tetracaine microcrystals. J. Clin Pharmacol. 34, 699–702 (1994).

    CAS  PubMed  Google Scholar 

  74. Karan, S. M. et al. Intravenous lecithin-coated microcrystals of dantrolene are effective in the treatment of malignant hyperthermia:an investigation in rats, dogs, and swine. Anesth. Analg. 82, 796–802 (1996).

    CAS  PubMed  Google Scholar 

  75. Shulman, M. Treatment of cancer pain with epidural butyl-amino benzoate suspension. Reg. Anesth. 12, 1–4 (1987).

    Google Scholar 

  76. Clement, M. A. et al. Tissue distribution and plasma clearance of a novel microcrystal-encapsulated flurbiprofen formulation. The Pharmacologist 34, 204 (1992).

    Google Scholar 

  77. Gassmann, P. et al. Hydrosols: Alternatives for the parenteral application of poorly water soluble drugs. Eur. J. Pharm. Biopharm. 40, 64–72 (1994).

    CAS  Google Scholar 

  78. Viernstein, J. & Stumpf, C. Similar central actions of intravenous methohexitone suspension and solution in the rabbit. J. Pharm. Pharmacol. 44, 66–68 (1992). The lack of agreement of the in vitro dissolution work in the Viernstein work can probably be attributed to not using a plasma-simulating solvent.

    CAS  PubMed  Google Scholar 

  79. Parikh, I. et al. Microcrystal technology-based sustained delivery of nifedipine in rats. The Pharmacologist 33, 197 (1991).

    Google Scholar 

  80. Zuidema, J., Pieters, F. A. & Duchateau, G. Release and absorption rate aspects of intramuscularly injected pharmaceuticals. Int. J. Pharm. 47, 1–12 (1988). Excellent analysis of the issues involved with intramuscular injectables, and strategies for success.

    CAS  Google Scholar 

  81. Stout, P. J. M. et al. Dissolution performance related to particle size distribution for commercially available prednisolone acetate suspensions. Drug Development Ind. Pharm. 18, 395–408 (1992).

    CAS  Google Scholar 

  82. Moghimi, S. M., Hunter, A. C. & Murray, J. C. Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol. Rev. 53, 283–318 (2001). Comprehensive analysis of the factors involved in pharmacokinetic fate of nanoparticles, subject to uptake by the MPS or its avoidance, thereby leading to long circulation.

    CAS  PubMed  Google Scholar 

  83. Mukherjee, S., Ghosh, R. N. & Maxfield, F. R. Endocytosis. Physiol. Rev. 77, 759–803 (1997). Thorough review of intracellular redistribution following phagocytosis of nanoparticles.

    CAS  PubMed  Google Scholar 

  84. Andes, D. et al. In vivo pharmacodynamics of antifungal drugs in treatment of candidiasis, Antimicrob. Agents Chemother. 47, 1179–1186 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Rabinow, B. E. et al. Enhanced efficacy of NANOEDGE itraconazole nanosuspension in an immunosuppressed rat model infected with an itraconazole-resistant C. albicans strain. Am. Assoc. Pharma. Scientists AR6184 (2003).

  86. Donnelly, J. P. et al. Pharmacokinetics of a 14 day course of itraconazole nanocrystals given intravenously to allogeneic haematopoietic stem cell transplant (HCST) recipients. 41st Intersci. Conf. Antimicrob. Agents Chemother. A32 (2001).

  87. Sporanox (Itraconazole) injection: approved labeling. Physicians' Desk Reference 1772–1776 (Thomson PDR, Montvale, 2004).

  88. Willems, L., van der Geest, R. & de Beule, K. Itraconazole oral solution and intravenous formulations: a review of pharmacokinetics and pharmacodynamics. J. Clin. Pharm. Ther. 26, 159–169 (2001).

    CAS  PubMed  Google Scholar 

  89. McIntire, G. L. et al. Time course of nodal enhancement with CT X-ray nanoparticle contrast agents: effect of particle size and chemical structure. Investigative Radiol. 35, 91–96 (2000).

    CAS  Google Scholar 

  90. Onyuksel, H. & Rubinstein, I. Materials and methods for making improved micelle compositions; lipid bonded to water soluble polymer. US Patent 6,217,886 (2001).

  91. Wu, N. et al. Increased microvascular permeability contributes to preferential accumulation of stealth liposomes in tumor tissue. Cancer Res. 53, 3765–3770 (1993). Classic paper, providing fascinating in vivo fluorescence video microscopic analysis of the accumulation of liposomes in tumour tissue due to vascular permeability.

    CAS  PubMed  Google Scholar 

  92. Lode, J., Fichtner, I., Kreuter, J., Berndt, A., Diederichs, J. & Reszka, R. Influence of surface-modifying surfactants on the pharmacokinetic behavior of 14C-Poly (methylmethacrylate) nanparticles in experimental tumor models. Pharm. Res. 18, 1613–1619 (2001).

    CAS  PubMed  Google Scholar 

  93. Martonen, T. B. & Katz, I. M. Deposition patterns of aerosolized drugs within the human lungs. Pharm. Res. 10, 871–878 (1993).

    CAS  PubMed  Google Scholar 

  94. Chan, H. -K. & Gonda, I. Development of a systematic theory of suspension inhalation aerosols. II. Aggregates of monodisperse particles nebulized in polydisperse droplets. Int. J. Pharm. 41, 147–157 (1988).

    CAS  Google Scholar 

  95. Wiedmann, T. S., DeCastro, L. & Wood, R. W. Nebulization of NanoCrystalsTM: Production of a respirable solid-in-liquid–in-air colloidal dispersion. Pharm. Res. 14, 112–116 (1997).

    CAS  PubMed  Google Scholar 

  96. Ostrander, K. D., Bosch, H. & Bondanza, D. An in vitro assessment of a NanoCrystal™ beclomethasone dipropionate colloidal dispersion via ultrasonic nebulization. Eur. J. Pharm. and Biopharm. 48, 207–215 (1999).

    CAS  Google Scholar 

  97. Keller, M., Jauernig, J., Lintz, F -C. & Knoch, M. Nebulizer nanosuspensions: important device and formulation interactions. Resp. Drug Delivery VIII, 197–206 (2002).

  98. Jacobs, C. & Muller, R. H. Production and characterization of a budesonide nanosuspension for pulmonary administration. Pharm. Res. 19, 189–194 (2002).

    CAS  PubMed  Google Scholar 

  99. Dailey, L. A. et al. Nebulization of biodegradable nanoparticles: impact of nebulizer technology and nanoparticle characteristics on aerosol features. J. Control. Rel. 86, 131–144 (2003).

    CAS  Google Scholar 

  100. Kraft, W. K. et al. The pharmacokinetics of nebulized nanocrystal budesonide suspension in healthy volunteers. J. Clin. Pharmacol. 44, 67–72 (2004).

    CAS  PubMed  Google Scholar 

  101. Sharma, R., Saxena, D., Dwivedi, A. & Misra, A. Inhalable microparticles containing drug combinations to target alveolar macrophages for treatment of pulmonary tuberculosis. Pharm. Res. 18, 1405–1410 (2001).

    CAS  PubMed  Google Scholar 

  102. Vyas, S. P., Kannan, M., Jain, S., Mishra, V. & Singh, P. Design of liposomal aerosols for improved delivery of rifampicin to alveolar macrophages. Int. J. Pharm. 269, 37–49 (2004).

    CAS  PubMed  Google Scholar 

  103. Foster, K. A., Yazdanian, M. & Audus, K. Microparticulate uptake mechanims of in-vitro cell culture models of the respiratory epithelium. J. Pharm. Pharmacol. 53, 57–66 (2001).

    CAS  PubMed  Google Scholar 

  104. Edwards, D. A. Large porous particles for pulmonary drug delivery. Science 276, 1868–1871 (1997).

    CAS  PubMed  Google Scholar 

  105. Evora, C. et al. Relating the phagocytosis of microparticles by alveolar macrophages to surface chemistry: the effect of 1,2-dipalmitoylphosphatidylcholine. J. Contr. Rel. 51, 143–152 (1998).

    CAS  Google Scholar 

  106. Tsapis, N., Bennett, D., Jackson, B., Weitz, D. & Edwards, D. Trojan particles: large porous carriers of nanoparticles for drug delivery. Proc. Natl Acad. Sci. USA. 99, 12001–12005 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Grossman, S. A. & Krabak, M. J. Leptomeningeal carcinomatosis. Cancer treatment reviews 25, 103–119 (1999).

    CAS  PubMed  Google Scholar 

  108. Archer, G. E. et al. Intrathecal busulfan treatment of human neoplastic meningitis in athymic nude rats. J. Neuro-Oncology. 44, 233–241 (1999).

    CAS  Google Scholar 

  109. Shulman, M., Hoseph, N. J. & Haller, C. A. Effect of epidural and subarachnoid injections of a 10% butamben suspension. Reg. Anesth. 15, 142–146 (1990). Perhaps the first paper on application of epidural injection of microsuspensions in humans.

    CAS  PubMed  Google Scholar 

  110. Koukourakis, M. et al. High intratumoural accumulation of stealth® liposomal doxorubicin (Caelyx®) in glioblastomas and in metastatic brain tumours. Brit. J. Cancer 83, 1281–1286 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Kreuter, J. Nanoparticulate systems for brain delivery of drugs. Adv. Drug Deliv. Reviews 47, 65–81 (2001).

    CAS  Google Scholar 

  112. Gessner, A., Olbrich, C., Schroder, W., Kayser, O. & Muller, R. H. The role of plasma proteins in brain targeting: species dependent protein adsorption patterns on brain-specific lipid drug conjugate (LDC) nanoparticles. Int. J. Pharm. 214, 87–91 (2001).

    CAS  PubMed  Google Scholar 

  113. Schroder, U. & Sabel, B. A. Nanoparticles, a drug carrier system to pass the blood-brain barrier, permit central analgesic effects of i.v. dalargin injections. Brain Res. 710, 121–124 (1996).

    CAS  PubMed  Google Scholar 

  114. Vanderhoff, J. W. in Pharmaceutical Dosage Forms, Disperse Systems 2nd edn Vol. 2 (Lieberman, H. A., Rieger, M. M. & Banker, G. S.) Ch. 4 (Marcel Dekker, New York, 1996).

    Google Scholar 

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Acknowledgements

Thanks to J. Kipp (Baxter Healthcare Corp.) for his input to figures 1 and 4.

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Authors and Affiliations

  1. Senior Director, Strategic Technical Development, Baxter Healthcare Corporation, Baxter Technology Park, Round Lake, 60073, Illinois, USA

    Barrett E. Rabinow

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  1. Barrett E. Rabinow
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Competing interests

B. R. is employed by Baxter Healthcare Corporation which commercializes NANOEDGE a nanosuspension drug delivery platform.

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DATABASES

Entrez Gene

P-glycoprotein

Glossary

SOLID LIPID NANOPARTICLES

Sub-micron-sized spherical lipid carriers of lipid-soluble drug molecules. They are typically formed by heating an aqueous lipid mixture above the melting point of the lipid, adding drug, homogenizing, then cooling to freeze the drug within the the solid lipid spheres.

HIGH-THROUGHPUT SCREENING

An automated instrumental process for detecting the binding of tens of thousands of drug candidates to an isolated protein receptor target that mediates a disease process, thereby identifying worthwhile leads for development.

LOG P

Log of the octanol–water partition coefficient, which is a measure of a drug's lipophilicity. Defined as the ratio of un-ionized drug distributed between the octanol and water phases at equilibrium. Higher values imply greater lipophilicity.

WATER INSOLUBLE

Less than 0.1 mg per ml solubility in water.

CYCLODEXTRINS

5–8mer of cyclic linked amylose or glucan molecules that forms a hydrophobic interior to accommodate an insoluble compound, and a hydrophilic exterior to solubilize in water.

BIOAVAILABILITY

A measure of the rate and extent of drug absorption from an administered dose, expressed as a ratio to an intravenously administered dose.

ARRHENIUS EXPRESSION

A mathematical equation that relates the rate of a chemical reaction, k, to change in temperature, T: k = Ae−E/RT. E is the activation energy or barrier for the crucial step in the reaction, and R is the gas constant.

POLYMORPH

One of several distinct crystal packing arrangements, potentially having a different energy of formation and melting point than other polymorphic forms of the same molecule. Its formation might be favored in preference to other polymorphs by manipulation of temperature, solvent and degree of supersaturation.

MONOCYTE PHAGOCYTIC SYSTEM

(MPS) The system of cells deployed throughout the body tissues, derived from monocyte precursor cells, which functionally police interstitial fluid and blood for unwanted particulate contamination, removing them by phagocytosis.

CMAX

Highest drug concentration in a plot of the plasma drug concentration versus time.

AREA UNDER THE CURVE

(AUC). Area under the curve of a plot of plasma drug concentration versus time, measured after administration of a drug.

FED/FASTED EFFECTS

A difference in the absorption of a drug depending on the fed or fasted state of the test animal.

OSTWALD RIPENING

The tendency for a particle dispersion to grow in diameter over time, by a process in which the smaller particles dissolve preferentially, because of their higher solubility, with subsequent crystallization onto larger particles, making them even larger.

PHAGOLYSOSOME

A cytoplasmic vesicular compartment consisting of the union of a phagosome with a lysosome, containing enzymes and acid environment designed to digest microbial particles.

t1/2

Half-life of plasma drug concentration, a measure of the duration of action of a drug.

PHOSPHOLIPID-PEG

A molecule consisting of phospholipid covalently bonded to a polyethylene glycol polymer, used as a reagent to coat a drug or drug delivery vehicle with a polyethylene glycol (PEG) surface, thereby conferring longer blood circulation time.

PHAGOCYTOSIS

Process of removal of particulate matter, bacteria, viruses, degraded cell debris, and so on by any of several mechanisms (for example, complement activation, opsonization or receptor mediation) involving extension of the cell membrane to surround and engulf the object, followed by severance of the membrane leading to a distinct vesicle within the cytoplasm of the cell, termed the phagosome.

OMMAYA RESERVOIR

A system for the delivery of a flowable drug formulation to the ventricles of the brain, involving a compartment for containment implanted in a proximal subcutaneous location.

PEGYLATION

Coating, either covalently or by physical adsorption, a polyetheylene glycol polymer onto a drug molecule, surface or particle, rendering it less hospitable to the deposition of opsonizing proteins which mediate phagocytosis. Such coated drugs and particles typically manifest extended circulation times in blood.

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Rabinow, B. Nanosuspensions in drug delivery. Nat Rev Drug Discov 3, 785–796 (2004). https://doi.org/10.1038/nrd1494

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