State of the art of nanocrystals technology for delivery of poorly soluble drugs

Yuqi Zhou; Juan Du; Lulu Wang; Yancai Wang

doi:10.1007/s11051-016-3575-y

journal article·2016-09

State of the art of nanocrystals technology for delivery of poorly soluble drugs

Yuqi Zhou, Juan Du, Lulu Wang, Yancai Wang

Journal of Nanoparticle Research· Volume 18· Issue 9

Publisher page

Source abstract

Abstract

Formulation of nanocrystals is a distinctive approach which can effectively improve the delivery of poorly water-soluble drugs, thus enticing the development of the nanocrystals technology. The characteristics of nanocrystals resulted in an exceptional drug delivery conductance, including saturation solubility, dissolution velocity, adhesiveness, and affinity. Nanocrystals were treated as versatile pharmaceuticals that could be delivered through almost all routes of administration. In the current review, oral, pulmonary, and intravenous routes of administration were presented. Also, the targeting of drug nanocrystals, as well as issues of efficacy and safety, were also discussed. Several methods were applied for nanocrystals production including top-down production strategy (media milling, high-pressure homogenization), bottom-up production strategy (antisolvent precipitation, supercritical fluid process, and precipitation by removal of solvent), and the combination approaches. Moreover, this review also described the evaluation and characterization of the drug nanocrystals and summarized the current commercial pharmaceutical products utilizing nanocrystals technology.

Source: openaire · Quality: candidate unverified · Source record ↗

Research context

Nanomaterials

OpenAlex topics: Drug Solubulity and Delivery Systems · Crystallization and Solubility Studies · Advanced Drug Delivery Systems

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

References (100+)

Show source-provided references

1. Aditya NP, Yang H, Kim S, Ko S (2015) Fabrication of amorphous curcumin nanosuspensions using beta-lactoglobulin to enhance solubility, stability, and bioavailability. Colloids Surf B 127:114–121. doi: 10.1016/j.colsurfb.2015.01.02710.1016/j.colsurfb.2015.01.027 ↗

2. Ain-Ai A, Gupta PK (2008) Effect of arginine hydrochloride and hydroxypropyl cellulose as stabilizers on the physical stability of high drug loading nanosuspensions of a poorly soluble compound. Int J Pharm 351:282–288. doi: 10.1016/j.ijpharm.2007.09.02910.1016/j.ijpharm.2007.09.029 ↗

3. Ali HS, York P, Blagden N (2009) Preparation of hydrocortisone nanosuspension through a bottom-up nanoprecipitation technique using microfluidic reactors. Int J Pharm 375:107–113. doi: 10.1016/j.ijpharm.2009.03.02910.1016/j.ijpharm.2009.03.029 ↗

4. Ali HS, York P, Ali AM, Blagden N (2011) Hydrocortisone nanosuspensions for ophthalmic delivery: a comparative study between microfluidic nanoprecipitation and wet milling. J Control Release 149:175–181. doi: 10.1016/j.jconrel.2010.10.00710.1016/j.jconrel.2010.10.007 ↗

5. Ambrus R, Kocbek P, Kristl J, Sibanc R, Rajko R, Szabo-Revesz P (2009) Investigation of preparation parameters to improve the dissolution of poorly water-soluble meloxicam. Int J Pharm 381:153–159. doi: 10.1016/j.ijpharm.2009.07.00910.1016/j.ijpharm.2009.07.009 ↗

6. Aqil F, Munagala R, Jeyabalan J, Vadhanam MV (2013) Bioavailability of phytochemicals and its enhancement by drug delivery systems. Cancer Lett 334:133–141. doi: 10.1016/j.canlet.2013.02.03210.1016/j.canlet.2013.02.032 ↗

7. Baek I-H, Kim J-S, Ha E-S, Choo G-H, Cho W, Hwang S-J, Kim M-S (2014) Dissolution and oral absorption of pranlukast nanosuspensions stabilized by hydroxypropylmethyl cellulose. Int J Biol Macromol 67:53–57. doi: 10.1016/j.ijbiomac.2014.03.00610.1016/j.ijbiomac.2014.03.006 ↗

8. Bao Y, Krishnan KM (2005) Preparation of functionalized and gold-coated cobalt nanocrystals for biomedical applications. J Magn Magn Mater 293:15–19. doi: 10.1016/j.jmmm.2005.01.03710.1016/j.jmmm.2005.01.037 ↗

9. Chan HK, Kwok PC (2011) Production methods for nanodrug particles using the bottom-up approach. Adv Drug Deliv Rev 63:406–416. doi: 10.1016/j.addr.2011.03.01110.1016/j.addr.2011.03.011 ↗

10. Cheng CL, Yu LX, Lee HL, Yang CY, Lue CS, Chou CH (2004) Biowaiver extension potential to BCS Class III high solubility-low permeability drugs: bridging evidence for metformin immediate-release tablet. Eur J Pharm Sci 22:297–304. doi: 10.1016/j.ejps.2004.03.01610.1016/j.ejps.2004.03.016 ↗

11. Chin WW, Parmentier J, Widzinski M, Tan EH, Gokhale R (2014) A brief literature and patent review of nanosuspensions to a final drug product. J Pharm Sci 103:2980–2999. doi: 10.1002/jps.2409810.1002/jps.24098 ↗

12. Choudhury H et al (2014) Improvement of cellular uptake, in vitro antitumor activity and sustained release profile with increased bioavailability from a nanoemulsion platform. Int J Pharm 460:131–143. doi: 10.1016/j.ijpharm.2013.10.05510.1016/j.ijpharm.2013.10.055 ↗

13. Cooper ER (2010) Nanoparticles: a personal experience for formulating poorly water soluble drugs. J Control Release 141:300–302. doi: 10.1016/j.jconrel.2009.10.00610.1016/j.jconrel.2009.10.006 ↗

14. Crisp MT, Tucker CJ, Rogers TL, Williams RO 3rd, Johnston KP (2007) Turbidimetric measurement and prediction of dissolution rates of poorly soluble drug nanocrystals. J Control Release 117:351–359. doi: 10.1016/j.jconrel.2006.11.01110.1016/j.jconrel.2006.11.011 ↗

15. Custodio JM, Wu CY, Benet LZ (2008) Predicting drug disposition, absorption/elimination/transporter interplay and the role of food on drug absorption. Adv Drug Deliv Rev 60:717–733. doi: 10.1016/j.addr.2007.08.04310.1016/j.addr.2007.08.043 ↗

16. D’Addio SM et al (2012) Effects of block copolymer properties on nanocarrier protection from in vivo clearance. J Control Release 162:208–217. doi: 10.1016/j.jconrel.2012.06.02010.1016/j.jconrel.2012.06.020 ↗

17. Das S, Suresh PK (2011) Nanosuspension: a new vehicle for the improvement of the delivery of drugs to the ocular surface. Application to amphotericin B. Nanomedicine 7:242–247. doi: 10.1016/j.nano.2010.07.00310.1016/j.nano.2010.07.003 ↗

18. Dong Y, Ng WK, Hu J, Shen S, Tan RB (2014) Clay as a matrix former for spray drying of drug nanosuspensions. Int J Pharm 465:83–89. doi: 10.1016/j.ijpharm.2014.02.02510.1016/j.ijpharm.2014.02.025 ↗

19. Donoso MD, Haskell RJ, Schartman RR (2012) Surfactant choice and the physical stability of nanosuspensions as a function of pH. Int J Pharm 439:1–7. doi: 10.1016/j.ijpharm.2012.09.01210.1016/j.ijpharm.2012.09.012 ↗

20. Dumarey M, Wikström H, Fransson M, Sparén A, Tajarobi P, Josefson M, Trygg J (2011) Combining experimental design and orthogonal projections to latent structures to study the influence of microcrystalline cellulose properties on roll compaction. Int J Pharm 416:110–119. doi: 10.1016/j.ijpharm.2011.06.01810.1016/j.ijpharm.2011.06.018 ↗

21. Epstein H, Berger V, Levi I, Eisenberg G, Koroukhov N, Gao J, Golomb G (2007) Nanosuspensions of alendronate with gallium or gadolinium attenuate neointimal hyperplasia in rats. J Control Release 117:322–332. doi: 10.1016/j.jconrel.2006.10.03010.1016/j.jconrel.2006.10.030 ↗

22. Fu Q et al (2013a) Nimodipine nanocrystals for oral bioavailability improvement: role of mesenteric lymph transport in the oral absorption. Int J Pharm 448:290–297. doi: 10.1016/j.ijpharm.2013.01.06510.1016/j.ijpharm.2013.01.065 ↗

23. Fu Q et al (2013b) Nimodipine nanocrystals for oral bioavailability improvement: preparation, characterization and pharmacokinetic studies. Colloids Surf B 109:161–166. doi: 10.1016/j.colsurfb.2013.01.06610.1016/j.colsurfb.2013.01.066 ↗

24. Fuhrmann K, Gauthier MA, Leroux JC (2014) Targeting of injectable drug nanocrystals. Mol Pharm 11:1762–1771. doi: 10.1021/mp500124710.1021/mp5001247 ↗

25. Galli C (2006) Experimental determination of the diffusion boundary layer width of micron and submicron particles. Int J Pharm 313:114–122. doi: 10.1016/j.ijpharm.2006.01.03010.1016/j.ijpharm.2006.01.030 ↗

26. Gao L, Liu G, Ma J, Wang X, Zhou L, Li X (2012) Drug nanocrystals: in vivo performances. J Control Release 160:418–430. doi: 10.1016/j.jconrel.2012.03.01310.1016/j.jconrel.2012.03.013 ↗

27. Gao L et al (2013) Paclitaxel nanosuspensions coated with P-gp inhibitory surfactants: i. Acute toxicity and pharmacokinetics studies. Colloids Surf B 111:277–281. doi: 10.1016/j.colsurfb.2013.06.00410.1016/j.colsurfb.2013.06.004 ↗

28. Gardikis K, Tsimplouli C, Dimas K, Micha-Screttas M, Demetzos C (2010) New chimeric advanced drug delivery nano systems (chi-aDDnSs) as doxorubicin carriers. Int J Pharm 402:231–237. doi: 10.1016/j.ijpharm.2010.10.00710.1016/j.ijpharm.2010.10.007 ↗

29. George M, Ghosh I (2013) Identifying the correlation between drug/stabilizer properties and critical quality attributes (CQAs) of nanosuspension formulation prepared by wet media milling technology. Eur J Pharm Sci 48:142–152. doi: 10.1016/j.ejps.2012.10.00410.1016/j.ejps.2012.10.004 ↗

30. Ghosh I, Bose S, Vippagunta R, Harmon F (2011) Nanosuspension for improving the bioavailability of a poorly soluble drug and screening of stabilizing agents to inhibit crystal growth. Int J Pharm 409:260–268. doi: 10.1016/j.ijpharm.2011.02.05110.1016/j.ijpharm.2011.02.051 ↗

31. Gramdorf S, Hermann S, Hentschel A, Schrader K, Müller RH, Kumpugdee-Vollrath M, Kraume M (2008) Crystallized miniemulsions: influence of operating parameters during high-pressure homogenization on size and shape of particles. Colloids Surf A 331:108–113. doi: 10.1016/j.colsurfa.2008.07.01610.1016/j.colsurfa.2008.07.016 ↗

32. Guo JJ et al (2013) Development and in vivo/in vitro evaluation of novel herpetrione nanosuspension. Int J Pharm 441:227–233. doi: 10.1016/j.ijpharm.2012.11.03910.1016/j.ijpharm.2012.11.039 ↗

33. Han M, Yu X, Guo Y, Wang Y, Kuang H, Wang X (2014) Honokiol nanosuspensions: preparation, increased oral bioavailability and dramatically enhanced biodistribution in the cardio-cerebro-vascular system. Colloids Surf B 116:114–120. doi: 10.1016/j.colsurfb.2013.12.05610.1016/j.colsurfb.2013.12.056 ↗

34. Hanafy A, Spahn-Langguth H, Vergnault G, Grenier P, Tubic Grozdanis M, Lenhardt T, Langguth P (2007) Pharmacokinetic evaluation of oral fenofibrate nanosuspensions and SLN in comparison to conventional suspensions of micronized drug. Adv Drug Deliv Rev 59:419–426. doi: 10.1016/j.addr.2007.04.00510.1016/j.addr.2007.04.005 ↗

35. Hu X, Chen X, Zhang L, Lin X, Zhang Y, Tang X, Wang Y (2014) A combined bottom-up/top-down approach to prepare a sterile injectable nanosuspension. Int J Pharm 472:130–139. doi: 10.1016/j.ijpharm.2014.06.01810.1016/j.ijpharm.2014.06.018 ↗

36. Ige PP, Baria RK, Gattani SG (2013) Fabrication of fenofibrate nanocrystals by probe sonication method for enhancement of dissolution rate and oral bioavailability. Colloids Surf B 108:366–373. doi: 10.1016/j.colsurfb.2013.02.04310.1016/j.colsurfb.2013.02.043 ↗

37. Jeevanandam J, Chan YS, Danquah MK (2016) Nano-formulations of drugs: recent developments, impact and challenges. Biochimie. doi: 10.1016/j.biochi.2016.07.00810.1016/j.biochi.2016.07.008 ↗

38. Juhnke M, Martin D, John E (2012) Generation of wear during the production of drug nanosuspensions by wet media milling. Eur J Pharm Biopharm 81:214–222. doi: 10.1016/j.ejpb.2012.01.00510.1016/j.ejpb.2012.01.005 ↗

39. Junyaprasert VB, Morakul B (2015) Nanocrystals for enhancement of oral bioavailability of poorly water-soluble drugs. Asian J Pharm Sci 10:13–23. doi: 10.1016/j.ajps.2014.08.00510.1016/j.ajps.2014.08.005 ↗

40. Kawakami K (2012) Modification of physicochemical characteristics of active pharmaceutical ingredients and application of supersaturatable dosage forms for improving bioavailability of poorly absorbed drugs. Adv Drug Deliv Rev 64:480–495. doi: 10.1016/j.addr.2011.10.00910.1016/j.addr.2011.10.009 ↗

41. Keck CM (2010) Particle size analysis of nanocrystals: improved analysis method. Int J Pharm 390:3–12. doi: 10.1016/j.ijpharm.2009.08.04210.1016/j.ijpharm.2009.08.042 ↗

42. Keck CM, Muller RH (2006) Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation. Eur J Pharm Biopharm 62:3–16. doi: 10.1016/j.ejpb.2005.05.00910.1016/j.ejpb.2005.05.009 ↗

43. Kesisoglou F, Panmai S, Wu Y (2007) Nanosizing–oral formulation development and biopharmaceutical evaluation. Adv Drug Deliv Rev 59:631–644. doi: 10.1016/j.addr.2007.05.00310.1016/j.addr.2007.05.003 ↗

44. Khadka P et al (2014) Pharmaceutical particle technologies: an approach to improve drug solubility, dissolution and bioavailability. Asian J Pharm Sci 9:304–316. doi: 10.1016/j.ajps.2014.05.00510.1016/j.ajps.2014.05.005 ↗

45. Kim S, Lee J (2010) Effective polymeric dispersants for vacuum, convection and freeze drying of drug nanosuspensions. Int J Pharm 397:218–224. doi: 10.1016/j.ijpharm.2010.07.01010.1016/j.ijpharm.2010.07.010 ↗

46. Kocbek P, Baumgartner S, Kristl J (2006) Preparation and evaluation of nanosuspensions for enhancing the dissolution of poorly soluble drugs. Int J Pharm 312:179–186. doi: 10.1016/j.ijpharm.2006.01.00810.1016/j.ijpharm.2006.01.008 ↗

47. Kratz F, Warnecke A (2012) Finding the optimal balance: challenges of improving conventional cancer chemotherapy using suitable combinations with nano-sized drug delivery systems. J Control Release 164:221–235. doi: 10.1016/j.jconrel.2012.05.04510.1016/j.jconrel.2012.05.045 ↗

48. Lai F, Pini E, Corrias F, Perricci J, Manconi M, Fadda AM, Sinico C (2014) Formulation strategy and evaluation of nanocrystal piroxicam orally disintegrating tablets manufacturing by freeze-drying. Int J Pharm 467:27–33. doi: 10.1016/j.ijpharm.2014.03.04710.1016/j.ijpharm.2014.03.047 ↗

49. Latha S, Selvamani P, Kumar CS, Sharavanan P, Suganya G, Beniwal VS, Rao PR (2009) Formulation development and evaluation of metronidazole magnetic nanosuspension as a magnetic-targeted and polymeric-controlled drug delivery system. J Magn Magn Mater 321:1580–1585. doi: 10.1016/j.jmmm.2009.02.08910.1016/j.jmmm.2009.02.089 ↗

50. Lee J, Lee SJ, Choi JY, Yoo JY, Ahn CH (2005) Amphiphilic amino acid copolymers as stabilizers for the preparation of nanocrystal dispersion. Eur J Pharm Sci 24:441–449. doi: 10.1016/j.ejps.2004.12.01010.1016/j.ejps.2004.12.010 ↗

51. Lemke A, Kiderlen AF, Petri B, Kayser O (2010) Delivery of amphotericin B nanosuspensions to the brain and determination of activity against Balamuthia mandrillaris amebas. Nanomedicine 6:597–603. doi: 10.1016/j.nano.2009.12.00410.1016/j.nano.2009.12.004 ↗

52. Li W et al (2011) Preparation and in vitro/in vivo evaluation of revaprazan hydrochloride nanosuspension. Int J Pharm 408:157–162. doi: 10.1016/j.ijpharm.2011.01.05910.1016/j.ijpharm.2011.01.059 ↗

53. Li TJ, Huang CC, Ruan PW, Chuang KY, Huang KJ, Shieh DB, Yeh CS (2013) In vivo anti-cancer efficacy of magnetite nanocrystal–based system using locoregional hyperthermia combined with 5-fluorouracil chemotherapy. Biomaterials 34:7873–7883. doi: 10.1016/j.biomaterials.2013.07.01210.1016/j.biomaterials.2013.07.012 ↗

54. Li W et al (2014) Influence of drug physicochemical properties on absorption of water insoluble drug nanosuspensions. Int J Pharm 460:13–23. doi: 10.1016/j.ijpharm.2013.10.03810.1016/j.ijpharm.2013.10.038 ↗

55. Liu P et al (2011) Nanosuspensions of poorly soluble drugs: preparation and development by wet milling. Int J Pharm 411:215–222. doi: 10.1016/j.ijpharm.2011.03.05010.1016/j.ijpharm.2011.03.050 ↗

56. Ma Q, Sun H, Che E, Zheng X, Jiang T, Sun C, Wang S (2013) Uniform nano-sized valsartan for dissolution and bioavailability enhancement: influence of particle size and crystalline state. Int J Pharm 441:75–81. doi: 10.1016/j.ijpharm.2012.12.02510.1016/j.ijpharm.2012.12.025 ↗

57. Mathew AP, Oksman K, Karim Z, Liu P, Khan SA, Naseri N (2014) Process scale up and characterization of wood cellulose nanocrystals hydrolysed using bioethanol pilot plant. Ind Crops Prod 58:212–219. doi: 10.1016/j.indcrop.2014.04.03510.1016/j.indcrop.2014.04.035 ↗

58. Mauludin R, Muller RH, Keck CM (2009a) Development of an oral rutin nanocrystal formulation. Int J Pharm 370:202–209. doi: 10.1016/j.ijpharm.2008.11.02910.1016/j.ijpharm.2008.11.029 ↗

59. Mauludin R, Muller RH, Keck CM (2009b) Kinetic solubility and dissolution velocity of rutin nanocrystals. Eur J Pharm Sci 36:502–510. doi: 10.1016/j.ejps.2008.12.00210.1016/j.ejps.2008.12.002 ↗

60. Merisko-Liversidge E, Liversidge GG (2011) Nanosizing for oral and parenteral drug delivery: a perspective on formulating poorly-water soluble compounds using wet media milling technology. Adv Drug Deliv Rev 63:427–440. doi: 10.1016/j.addr.2010.12.00710.1016/j.addr.2010.12.007 ↗

61. Moorthi C, Kathiresan K (2013) Fabrication of highly stable sonication assisted curcumin nanocrystals by nanoprecipitation method. Drug Invent Today 5:66–69. doi: 10.1016/j.dit.2013.02.00310.1016/j.dit.2013.02.003 ↗

62. Morakul B, Suksiriworapong J, Leanpolchareanchai J, Junyaprasert VB (2013) Precipitation-lyophilization-homogenization (PLH) for preparation of clarithromycin nanocrystals: influencing factors on physicochemical properties and stability. Int J Pharm 457:187–196. doi: 10.1016/j.ijpharm.2013.09.02210.1016/j.ijpharm.2013.09.022 ↗

63. Morgenthal G, Sánchez Corriols A, Bendig B (2014) A GPU-accelerated pseudo-3D vortex method for aerodynamic analysis. J Wind Eng Ind Aerodyn 125:69–80. doi: 10.1016/j.jweia.2013.12.00210.1016/j.jweia.2013.12.002 ↗

64. Moschwitzer J, Achleitner G, Pomper H, Muller RH (2004) Development of an intravenously injectable chemically stable aqueous omeprazole formulation using nanosuspension technology. Eur J Pharm Biopharm 58:615–619. doi: 10.1016/j.ejpb.2004.03.02210.1016/j.ejpb.2004.03.022 ↗

65. Mou D, Chen H, Wan J, Xu H, Yang X (2011) Potent dried drug nanosuspensions for oral bioavailability enhancement of poorly soluble drugs with pH-dependent solubility. Int J Pharm 413:237–244. doi: 10.1016/j.ijpharm.2011.04.03410.1016/j.ijpharm.2011.04.034 ↗

66. Muller RH, Runge S, Ravelli V, Mehnert W, Thunemann AF, Souto EB (2006) Oral bioavailability of cyclosporine: solid lipid nanoparticles (SLN) versus drug nanocrystals. Int J Pharm 317:82–89. doi: 10.1016/j.ijpharm.2006.02.04510.1016/j.ijpharm.2006.02.045 ↗

67. Muller RH, Gohla S, Keck CM (2011) State of the art of nanocrystals–special features, production, nanotoxicology aspects and intracellular delivery. Eur J Pharm Biopharm 78:1–9. doi: 10.1016/j.ejpb.2011.01.00710.1016/j.ejpb.2011.01.007 ↗

68. Negi LM, Tariq M, Talegaonkar S (2013) Nano scale self-emulsifying oil based carrier system for improved oral bioavailability of camptothecin derivative by P-glycoprotein modulation. Colloids Surf B 111:346–353. doi: 10.1016/j.colsurfb.2013.06.00110.1016/j.colsurfb.2013.06.001 ↗

69. Niwa T, Nakanishi Y, Danjo K (2010) One-step preparation of pharmaceutical nanocrystals using ultra cryo-milling technique in liquid nitrogen. Eur J Pharm Sci 41:78–85. doi: 10.1016/j.ejps.2010.05.01910.1016/j.ejps.2010.05.019 ↗

70. Pardeike J, Strohmeier DM, Schrodl N, Voura C, Gruber M, Khinast JG, Zimmer A (2011) Nanosuspensions as advanced printing ink for accurate dosing of poorly soluble drugs in personalized medicines. Int J Pharm 420:93–100. doi: 10.1016/j.ijpharm.2011.08.03310.1016/j.ijpharm.2011.08.033 ↗

71. Pawar VK, Singh Y, Meher JG, Gupta S, Chourasia MK (2014) Engineered nanocrystal technology: in vivo fate, targeting and applications in drug delivery. J Control Release 183:51–66. doi: 10.1016/j.jconrel.2014.03.03010.1016/j.jconrel.2014.03.030 ↗

72. Piao H, Kamiya N, Cui F, Goto M (2011) Preparation of a solid-in-oil nanosuspension containing l-ascorbic acid as a novel long-term stable topical formulation. Int J Pharm 420:156–160. doi: 10.1016/j.ijpharm.2011.08.02510.1016/j.ijpharm.2011.08.025 ↗

73. Rabinow BE (2004) Nanosuspensions in drug delivery. Nature reviews Drug discov 3:785–796. doi: 10.1038/nrd149410.1038/nrd1494 ↗

74. Rabinow B et al (2007) Itraconazole IV nanosuspension enhances efficacy through altered pharmacokinetics in the rat. Int J Pharm 339:251–260. doi: 10.1016/j.ijpharm.2007.02.03010.1016/j.ijpharm.2007.02.030 ↗

75. Rahim S, Sasani Ghamsari M, Radiman S (2012) Surface modification of titanium oxide nanocrystals with PEG. Sci Iran 19:948–953. doi: 10.1016/j.scient.2012.03.00910.1016/j.scient.2012.03.009 ↗

76. Ramirez-Rigo MV, Olivera ME, Rubio M, Manzo RH (2014) Enhanced intestinal permeability and oral bioavailability of enalapril maleate upon complexation with the cationic polymethacrylate Eudragit E100. Eur J Pharm Sci 55:1–11. doi: 10.1016/j.ejps.2014.01.00110.1016/j.ejps.2014.01.001 ↗

77. Ranjita S (2013) Nanosuspensions: a new approach for organ and cellular targeting in infectious diseases. J Pharm Sci 43:1–26. doi: 10.1007/s40005-013-0051-x10.1007/s40005-013-0051-x ↗

78. Rasenack N, Hartenhauer H, Müller BW (2003) Microcrystals for dissolution rate enhancement of poorly water-soluble drugs. Int J Pharm 254:137–145. doi: 10.1016/s0378-5173(03)00005-x10.1016/s0378-5173(03)00005-x ↗

79. Ravi H, Baskaran V (2015) Biodegradable chitosan-glycolipid hybrid nanogels: a novel approach to encapsulate fucoxanthin for improved stability and bioavailability. Food Hydrocoll 43:717–725. doi: 10.1016/j.foodhyd.2014.08.00410.1016/j.foodhyd.2014.08.004 ↗

80. Setua S, Menon D, Asok A, Nair S, Koyakutty M (2010) Folate receptor targeted, rare-earth oxide nanocrystals for bi-modal fluorescence and magnetic imaging of cancer cells. Biomaterials 31:714–729. doi: 10.1016/j.biomaterials.2009.09.09010.1016/j.biomaterials.2009.09.090 ↗

81. Shegokar R, Jansch M, Singh KK, Muller RH (2011) In vitro protein adsorption studies on nevirapine nanosuspensions for HIV/AIDS chemotherapy. Nanomedicine 7:333–340. doi: 10.1016/j.nano.2010.10.01210.1016/j.nano.2010.10.012 ↗

82. Shegokar R, Muller RH (2010) Nanocrystals: industrially feasible multifunctional formulation technology for poorly soluble actives. Int J Pharm 399:129–139. doi: 10.1016/j.ijpharm.2010.07.04410.1016/j.ijpharm.2010.07.044 ↗

83. Sher P, Ingavle G, Ponrathnam S, Pawar A (2007) Low density porous carrierdrug adsorption and release study by response surface methodology using different solvents. Int J Pharm 331:72–83. doi: 10.1016/j.ijpharm.2006.09.01310.1016/j.ijpharm.2006.09.013 ↗

84. Shi L, Riziotis VA, Voutsinas SG, Wang J (2014) A consistent vortex model for the aerodynamic analysis of vertical axis wind turbines. J Wind Eng Ind Aerodyn 135:57–69. doi: 10.1016/j.jweia.2014.10.00210.1016/j.jweia.2014.10.002 ↗

85. Sinha B, Muller RH, Moschwitzer JP (2013a) Bottom-up approaches for preparing drug nanocrystals: formulations and factors affecting particle size. Int J Pharm 453:126–141. doi: 10.1016/j.ijpharm.2013.01.01910.1016/j.ijpharm.2013.01.019 ↗

86. Sinha B, Muller RH, Moschwitzer JP (2013b) Systematic investigation of the cavi-precipitation process for the production of ibuprofen nanocrystals. Int J Pharm 458:315–323. doi: 10.1016/j.ijpharm.2013.10.02510.1016/j.ijpharm.2013.10.025 ↗

87. Song N, Wu X, Gao Z, Zhou G, Zhang WJ, Liu W (2012) Enhanced expression of membrane transporter and drug resistance in keloid fibroblasts. Hum Pathol 43:2024–2032. doi: 10.1016/j.humpath.2011.12.02610.1016/j.humpath.2011.12.026 ↗

88. Sosnik A, Das Neves J, Sarmento B (2014) Mucoadhesive polymers in the design of nano-drug delivery systems for administration by non-parenteral routes: a review. Prog Polym Sci 39:2030–2075. doi: 10.1016/j.progpolymsci.2014.07.01010.1016/j.progpolymsci.2014.07.010 ↗

89. Sun B, Yeo Y (2012) Nanocrystals for the parenteral delivery of poorly water-soluble drugs. Curr Opin Solid State Mater Sci 16:295–301. doi: 10.1016/j.cossms.2012.10.00410.1016/j.cossms.2012.10.004 ↗

90. Sun W, Tian W, Zhang Y, He J, Mao S, Fang L (2012) Effect of novel stabilizers–cationic polymers on the particle size and physical stability of poorly soluble drug nanocrystals. Nanomed–Nanotechnol 8:460–467. doi: 10.1016/j.nano.2011.07.00610.1016/j.nano.2011.07.006 ↗

91. Teeranachaideekul V, Junyaprasert VB, Souto EB, Muller RH (2008) Development of ascorbyl palmitate nanocrystals applying the nanosuspension technology. Int J Pharm 354:227–234. doi: 10.1016/j.ijpharm.2007.11.06210.1016/j.ijpharm.2007.11.062 ↗

92. Thorat AA, Dalvi SV (2012) Liquid antisolvent precipitation and stabilization of nanoparticles of poorly water soluble drugs in aqueous suspensions: recent developments and future perspective. Chem Eng J 181–182:1–34. doi: 10.1016/j.cej.2011.12.04410.1016/j.cej.2011.12.044 ↗

93. Ting Y, Jiang Y, Ho C-T, Huang Q (2014) Common delivery systems for enhancing in vivo bioavailability and biological efficacy of nutraceuticals. J Funct Foods 7:112–128. doi: 10.1016/j.jff.2013.12.01010.1016/j.jff.2013.12.010 ↗

94. Tran T-H, Nguyen T-D (2011) Controlled growth of uniform noble metal nanocrystals: aqueous-based synthesis and some applications in biomedicine. Colloids Surf B 88:1–22. doi: 10.1016/j.colsurfb.2011.07.01710.1016/j.colsurfb.2011.07.017 ↗

95. Tuomela A et al (2015) Solid formulations by a nanocrystal approach: critical process parameters regarding scale-ability of nanocrystals for tableting applications. Int J Pharm 485:77–86. doi: 10.1016/j.ijpharm.2015.03.00910.1016/j.ijpharm.2015.03.009 ↗

96. Van Eerdenbrugh B, Froyen L, Van Humbeeck J, Martens JA, Augustijns P, Van Den Mooter G (2008a) Alternative matrix formers for nanosuspension solidification: dissolution performance and X-ray microanalysis as an evaluation tool for powder dispersion. Eur J Pharm Sci 35:344–353. doi: 10.1016/j.ejps.2008.08.00310.1016/j.ejps.2008.08.003 ↗

97. Van Eerdenbrugh B, Van den Mooter G, Augustijns P (2008b) Top-down production of drug nanocrystals: nanosuspension stabilization, miniaturization and transformation into solid products. Int J Pharm 364:64–75. doi: 10.1016/j.ijpharm.2008.07.02310.1016/j.ijpharm.2008.07.023 ↗

98. Van Eerdenbrugh B, Vermant J, Martens JA, Froyen L, Van Humbeeck J, Augustijns P, Van den Mooter G (2009) A screening study of surface stabilization during the production of drug nanocrystals. J Pharm Sci 98:2091–2103. doi: 10.1002/jps.2156310.1002/jps.21563 ↗

99. Verma S, Kumar S, Gokhale R, Burgess DJ (2011) Physical stability of nanosuspensions: investigation of the role of stabilizers on Ostwald ripening. Int J Pharm 406:145–152. doi: 10.1016/j.ijpharm.2010.12.02710.1016/j.ijpharm.2010.12.027 ↗

100. Waksman R et al (2004) Oral rapamycin to inhibit restenosis after stenting of de novo coronary lesions. JACC 44:1386–1392. doi: 10.1016/j.jacc.2004.06.06910.1016/j.jacc.2004.06.069 ↗