State of the art of nanocrystals--special features, production, nanotoxicology aspects and intracellular delivery.

Drug nanocrystals are the latest, broadly introduced nanoparticulate carrier to the pharmaceutical market from the year 2000 onwards. The special features of nanocrystals for the delivery of poorly soluble drugs are briefly reviewed (saturation solubility, dissolution velocity, adhesiveness). The industrially relevant bottom up (precipitation) and top down production technologies (pearl milling, high pressure homogenization, combination technologies) are presented. As nanotoxicological aspects, the effect of size, degradability versus biopersistency and intracellular uptake are discussed, classifying the nanocrystals in the low/non-risk group. Intracellular uptake plays a minor or no role for dermal and oral nanocrystals, but it plays a key role for intravenously injected nanocrystals (e.g. nevirapine, paclitaxel, itraconazole). Uptake by the macrophages of the mononuclear phagocytic system (MPS, liver spleen) can modify/optimize blood profiles via prolonged release from the MPS (itraconazole), but also target toxicity by too high organ concentrations and thus cause nanotoxicity. The balance in the competitive intracellular uptake by MPS and the target cells (e.g. blood-brain barrier) decides about therapeutic efficiency. The concept of "differential protein adsorption" to modulate this balance is shown for its applicability to nanocrystals for intracellular delivery to the cells of the blood-brain barrier (atovaquone).

[1]  G. Liversidge,et al.  Particle size reduction for improvement of oral bioavailability of hydrophobic drugs: I. Absolute oral bioavailability of nanocrystalline danazol in beagle dogs , 1995 .

[2]  D. A. Kharkevich,et al.  Analgesic activity of the hexapeptide dalargin adsorbed on the surface of polysorbate 80-coated poly(butyl cyanoacrylate) nanoparticles , 1995 .

[3]  Elaine Merisko-Liversidge,et al.  Nanosizing: a formulation approach for poorly-water-soluble compounds. , 2003, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[4]  G. Liversidge,et al.  The surface modified drug nanoparticles , 1992 .

[5]  M. Lück,et al.  Complement activation by model drug carriers for intravenous application: determination by two-dimensional electrophoresis. , 1999, Biomaterials.

[6]  B. Paulke,et al.  Protein rejecting properties of PEG-grafted nanoparticles: influence of PEG-chain length and surface density evaluated by two-dimensional electrophoresis and bicinchoninic acid (BCA)-proteinassay. , 2006, Die Pharmazie.

[7]  G. Liversidge,et al.  Drug particle size reduction for decreasing gastric irritancy and enhancing absorption of naproxen in rats , 1995 .

[8]  P. Couvreur,et al.  Nanocapsules: A new type of lysosomotropic carrier , 1977, FEBS letters.

[9]  Claus-Michael Lehr,et al.  Nanoparticles--an efficient carrier for drug delivery into the hair follicles. , 2007, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[10]  R. Müller,et al.  Surface characteristics and the interaction of colloidal particles with mouse peritoneal macrophages. , 1987, Biomaterials.

[11]  D. Hochstrasser,et al.  Colloidal carriers for intravenous drug targeting: Plasma protein adsorption patterns on surface‐modified latex particles evaluated by two‐dimensional polyacrylamide gel electrophoresis , 1993, Electrophoresis.

[12]  D. Crommelin,et al.  Liposomes and biotherapeutics , 1991, Biotherapy.

[13]  오연균.  Surfactant의 광범위 이용 , 2003 .

[14]  R. Müller,et al.  Production and characterization of testosterone undecanoate-loaded NLC for oral bioavailability enhancement , 2011, Drug development and industrial pharmacy.

[15]  J. Kreuter.  Influence of the surface properties on nanoparticle-mediated transport of drugs to the brain. , 2004, Journal of nanoscience and nanotechnology.

[16]  J. Pardeike.  Nanosuspensions and nanostructured lipid carriers for dermal application , 2009 .

[17]  R. Müller,et al.  Resveratrol nanosuspensions for dermal application--production, characterization, and physical stability. , 2009, Die Pharmazie.

[18]  J. Pardeike,et al.  Dermal and ocular safety of the new phospholipase A2 inhibitors PX-18 and PX-13 formulated as drug nanosuspension. , 2009, Journal of biomedical nanotechnology.

[19]  Joseph Wong,et al.  Itraconazole IV nanosuspension enhances efficacy through altered pharmacokinetics in the rat. , 2007, International journal of pharmaceutics.

[20]  Rajeswari Challa,et al.  Cyclodextrins in drug delivery: An updated review , 2005, AAPS PharmSciTech.

[21]  J. Pardeike,et al.  Neuroprotective effects of a nanocrystal formulation of sPLA2 inhibitor PX-18 in cerebral ischemia/reperfusion in gerbils , 2009, Brain Research.

[22]  Alexander T. Florence,et al.  The Oral Absorption of Micro- and Nanoparticulates: Neither Exceptional Nor Unusual , 1997, Pharmaceutical Research.

[23]  D. Begley,et al.  Direct Evidence That Polysorbate-80-Coated Poly(Butylcyanoacrylate) Nanoparticles Deliver Drugs to the CNS via Specific Mechanisms Requiring Prior Binding of Drug to the Nanoparticles , 2003, Pharmaceutical Research.

[24]  Ranjita Shegokar,et al.  20 years of lipid nanoparticles (SLN and NLC): present state of development and industrial applications. , 2011, Current drug discovery technologies.

[25]  Rainer H. Müller,et al.  20 Years of Lipid Nanoparticles (SLN & NLC): Present State of Development & Industrial Applications , 2011 .

[26]  R. Müller,et al.  The role of apolipoprotein E in uptake of atovaquone into the brain in murine acute and reactivated toxoplasmosis , 2009, Journal of drug targeting.

[27]  Barrett E. Rabinow,et al.  Nanosuspensions in drug delivery , 2004, Nature Reviews Drug Discovery.

[28]  J. Kreuter,et al.  Significant Transport of Doxorubicin into the Brain with Polysorbate 80-Coated Nanoparticles , 1999, Pharmaceutical Research.

[29]  Helmut Hahn,et al.  Atovaquone Nanosuspensions Show Excellent Therapeutic Effect in a New Murine Model of Reactivated Toxoplasmosis , 2001, Antimicrobial Agents and Chemotherapy.

[30]  G. Storm,et al.  Liposomes: From the Bench to the Bed , 2003, Journal of liposome research.

[31]  K. Voigt,et al.  Lymphatic absorption and metabolism of orally administered testosterone undecanoate in man , 1976, Klinische Wochenschrift.

[32]  R. Müller.  Colloidal Carriers for Controlled Drug Delivery and Targeting: Modification, Characterization, and In Vivo Distribution , 1991 .

[33]  R. Müller,et al.  Production and characterisation of highly concentrated nanosuspensions by high pressure homogenisation. , 2001, International journal of pharmaceutics.

[34]  R. Müller,et al.  Nanosuspensions as a new approach for the formulation for the poorly soluble drug tarazepide. , 2000, International journal of pharmaceutics.

[35]  Gert Storm,et al.  Sheddable Coatings for Long-Circulating Nanoparticles , 2007, Pharmaceutical Research.

[36]  Matthew J. Fisher,et al.  Cremophor EL-containing paclitaxel-induced anaphylaxis: a call to action. , 2009, Community oncology.

[37]  S. Davis,et al.  Polyhydroxybutyrate as a drug carrier. , 1989, Critical reviews in therapeutic drug carrier systems.

[38]  J. Pardeike,et al.  Secretory phospholipase A2 inhibitor PX-18 preserves microvascular reactivity after cerebral ischemia in piglets. , 2009, Microvascular research.

[39]  Peter Ramge,et al.  Apolipoprotein-mediated Transport of Nanoparticle-bound Drugs Across the Blood-Brain Barrier , 2002, Journal of drug targeting.

[40]  N Hussain,et al.  Factors affecting the oral uptake and translocation of polystyrene nanoparticles: histological and analytical evidence. , 1995, Journal of drug targeting.

[41]  R. Müller,et al.  New method for the effective production of ultrafine drug nanocrystals. , 2006, Journal of nanoscience and nanotechnology.

[42]  M. Oyewumi,et al.  Nanotechnology in Drug Development and Life Cycle Management , 2009 .

[43]  A. Florence,et al.  Nanoparticle Uptake by the Rat Gastrointestinal Mucosa: Quantitation and Particle Size Dependency , 1990, The Journal of pharmacy and pharmacology.

[44]  L. C. Collins-Gold,et al.  Parenteral emulsions for drug delivery , 1990 .

[45]  R. Cavalli,et al.  Solid Lipid Nanoparticles in Lymph and Plasma After Duodenal Administration to Rats , 1998, Pharmaceutical Research.

[46]  J. Crison,et al.  A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and in Vivo Bioavailability , 1995, Pharmaceutical Research.

[47]  R. Müller,et al.  Surfactant, but not the size of solid lipid nanoparticles (SLN) influences viability and cytokine production of macrophages. , 2001, International journal of pharmaceutics.

[48]  L. Szente,et al.  Highly soluble cyclodextrin derivatives: chemistry, properties, and trends in development. , 1999, Advanced drug delivery reviews.

[49]  R. Cavalli,et al.  Duodenal administration of solid lipid nanoparticles loaded with different percentages of tobramycin. , 2003, Journal of pharmaceutical sciences.

[50]  V. Vogel,et al.  Encapsulation of water-insoluble drugs in poly(butyl cyanoacrylate) nanoparticles. , 2009, Journal of nanoscience and nanotechnology.

[51]  A. Beezer,et al.  The relationship between particle size and solubility , 1992 .

[52]  G W Halbert,et al.  The Uptake and Translocation of Latex Nanospheres and Microspheres after Oral Administration to Rats , 1989, The Journal of pharmacy and pharmacology.

[53]  W. Oyen,et al.  Labelled Stealth liposomes in experimental infection: an alternative to leukocyte scintigraphy? , 1996, Nuclear medicine communications.