ADVANCES IN ORAL NANOSUSPENSION TECHNOLOGY: FORMULATION APPROACHES, CHARACTERIZATION AND RECENT APPLICATIONS

Nanosuspensions are submicron colloidal dispersions of poorly water-soluble drug particles stabilized by suitable surfactants or polymers. They have emerged as an effective drug delivery approach to overcome the challenges associated with poor aqueous solubility, low dissolution rate, and limited bioavailability of many pharmaceutical compounds. By reducing drug particle size to the nanometre range, nanosuspensions significantly increase surface area, resulting in enhanced saturation solubility, faster dissolution, and improved therapeutic efficacy. Various preparation methods, including media milling, high-pressure homogenization, precipitation, emulsion–solvent evaporation, solvent diffusion, and microemulsion techniques, have been successfully employed for laboratory-scale and industrial-scale production. The stability of nanosuspensions depends on appropriate formulation components such as stabilizers, surfactants, polymers, and cryoprotectants, which prevent particle aggregation and crystal growth. Nanosuspensions have demonstrated considerable potential in oral, parenteral, ocular, pulmonary, topical, buccal, nasal, transdermal, and brain-targeted drug delivery systems by improving drug absorption, bioavailability, and site-specific targeting while minimizing adverse effects. Furthermore, their adaptability for surface modification and incorporation into solid dosage forms broadens their pharmaceutical applications. Despite significant advancements, challenges related to long-term stability, redispersibility, large-scale manufacturing, and regulatory acceptance remain. Overall, nanosuspensions technology represents a promising strategy for enhancing the delivery and therapeutic performance of poorly soluble drugs and continues to be an important area of pharmaceutical research and development.

• Jacob S, Nair AB, Shah J. Emerging role of nanosuspensions in drug delivery systems. Biomaterials Research, 2020; 24: 3.
• Sutradhar KB, Amin ML. Increasing Possibilities of Nanosuspension. Journal of Nanotechnology, 2013; 2013: 346581.
• Patel VR, Agrawal YK. Nanosuspension: An approach to enhance solubility of drugs. Journal of Advanced Pharmaceutical Technology & Research, 2011; 2(2): 81–87.
• Jadhav SP, Singh SK, Chawra HS. Review on Nanosuspension as a Novel Method for Solubility and Bioavailability Enhancement of Poorly Soluble Drugs. Advances in Pharmacology and Pharmacy, 2023; 11(2): 117–130.
• Quadri N, Abdullah MM. Review on polyherbal nanosuspension and approaches to enhance solubility of drugs. World J. Pharm. Res., 2023 Apr 27; 10: 313-35.
• Babu, V.R., Aleem, M.A., Nikhat, S.R., Aslam, S., & Khan, M. Nanosuspension Technology for Poorly Water Soluble Drugs: An Overview. Research Journal of Pharmacy and Technology, 2011; 4(4): 515–520.
• Yadollahi R, Vasilev K, Simovic S. Nanosuspension technologies for delivery of poorly soluble drugs. Journal of Nanomaterials, 2015; 2015(1): 216375.
• Saddam H, Abdul Baquee A, Jiban D. Nanosuspension: A promising drug delivery system for poorly water soluble drug and enhanced bioavailability. Int. J. Pharm. Sci. Res., 2020; 10: 4822-32.
• Patravale VB, Date AA, Kulkarni RM. Nanosuspensions: a promising drug delivery strategy. Journal of pharmacy and pharmacology, 2004 Jul; 56(7): 827-40.
• Ahmadi Tehrani A, Omranpoor MM, Vatanara A, Seyedabadi M, Ramezani V. Formation of nanosuspensions in bottom-up approach: theories and optimization. DARU Journal of Pharmaceutical Sciences, 2019 Jun 1; 27(1): 451-73.
• Patravale, V. B., Date, A. A., & Kulkarni, R. M. (2011). Nanosuspension: An approach to enhance solubility of drugs. Journal of Advanced Pharmaceutical Technology & Research, 2(2):  81–87.
• Guan W, Ma Y, Ding S, et al. The technology for improving stability of nanosuspensions in drug delivery. J Nanopart Res., 2022; 24(1): 14. doi:10.1007/s11051-022-05403-9.
• Bilgili E, Guner G. Mechanistic modeling of wet stirred media milling for production of drug nanosuspensions. AAPS Pharm Sci Tech., 2021; 22(1): 1–23. doi:10.1208/s12249-020-01876-w.
• Lynnerup JT, Eriksen JB, Bauer-Brandl A, Holsæter AM, Brandl M. Insight into the mechanism behind oral bioavailability-enhancement by nanosuspensions through combined dissolution/permeation studies. Eur J Pharm Sci., 2023; 184: 106417. doi:10.1016/j.ejps.2023.106417.
• Perrin L, Pajor-Swierzy A, Magdassi S, Kamyshny A, Ortega F, Rubio RG. Evaporation of nanosuspensions on substrates with different hydrophobicity. ACS Appl Mater Interfaces, 2018; 10(3): 3082–3093. doi:10.1021/acsami.7b15743. Zuo W, Qu W, Li N, et al. Fabrication of multicomponent amorphous bufadienolides nanosuspension with wet milling improves dissolution and stability. Cells Nanomed Biotechnol, 2018; 46(7): 1513–1522.
• Dos Santos AM, Meneguin AB, Fonseca-Santos B, et al. The role of stabilizers and mechanical processes on physico-chemical and anti-inflammatory properties of methotrexate nanosuspensions. J Drug Deliv Sci Technol., 2020; 57: 101638. doi:10.1016/j.jddst.2020.101638
• Khandbahale SV. A review-Nanosuspension technology in drug delivery system. Asian J Pharm Res., 2019; 9(2): 130–138.
• Xiang Y, Liang G, Alvaro P, et al. Resonant optical nonlinearity and fluorescence enhancement in electrically tuned plasmonic nanosuspensions. Adv Photonics Res., 2021.
• Stahr PL, Keck CM. Preservation of rutin nanosuspensions without the use of preservatives. Beilstein J Nanotechnol, 2019; 10(1): 1902–1913. Arora D, Khurana B, Rath G, Nanda S, Goyal AK. Recent advances in nanosuspension technology for drug delivery. Curr Pharm Des., 2018; 24(21): 2403–2415.
• Azimullah S, Sudhakar CK, Kumar P, et al. Nanosuspensions as a promising approach to enhance bioavailability of poorly soluble drugs: an update. J Drug Delivery Ther., 2019; 9(2): 574–582. Jin SM, Lee SN, Kim JE, et al. Overcoming Chemoimmunotherapy‐Induced Immunosuppression by Assemblable and Depot Forming Immune Modulating Nanosuspension. Adv Sci., 2021; 8(19): 2102043.
• Kovalchuk NM, Johnson D, Sobolev V, Hilal N, Starov V. Interactions between nanoparticles in nanosuspension. Adv Colloid Interface Sci., 2019; 272: 102020.
• Galinovskiy AL, Htet KM, Provatorov AS. Ultra-Jet as a Tool for Dispersing Nanosuspensions. Polym Sci Ser D., 2020; 13(2): 209–213.
• List, M.; Sucker, H. Pharmaceutical Colloidal Hydrosols for Injection. UK Patent GB2200048B, 6 February 1991. [Google Scholar].
• Junyaprasert, V.B.; Morakul, B. Nanocrystals for enhancement of oral bioavailability of poorly water-soluble drugs. Asian J. Pharm., 2015; 10; 13–23.
• Ran, Q.; Wang, M.; Kuang, W.; Ouyang, J.; Han, D.; Gao, Z.; Gong, J. Advances of combinative nanocrystal preparation technology for improving the insoluble drug solubility and bioavailability. Crystals, 2022; 12: 1200.
• Zhang, J.; Xie, Z.; Zhang, N.; Zhong, J. Nanosuspension Drug Delivery System: Preparation, Characterization, Postproduction Processing, Dosage Form, and Application; Elsevier Inc.: Amsterdam, The Netherlands, 2017; 413–443.
• Keck, C.M.; Müller, R.H. Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation. Eur. J. Pharm. Biopharm, 2006; 62: 3–16.
• Pınar SG, Oktay AN, Karaküçük AE, Çelebi N. Formulation strategies of nanosuspensions for various administration routes. Pharmaceutics, 2023 May 17; 15(5): 1520.
• Geetha G, Poojitha U, Khan KA. Various techniques for preparation of nanosuspension-a review. International Journal of Pharma Research & Review, 2014 Sep; 3(9): 30-7.
• Lakshmi P, Kumar GA. Nanosuspension technology: A review. Int J Pharm Pharm Sci., 2010 Aug; 2(4): 35-40.
• Jadhav SP, Singh SK, Chawra HS. Review on Nanosuspension as a Novel Method for solubility and bioavailability enhancement of poorly soluble drugs. Adv Pharmacol Pharm., 2023; 11(2): 117-30.
• Byrappa K, Ohara S, Adschiri T. Nanoparticles synthesis using supercritical fluid technology - towards biomedical applications. Adv Drug Deliv Rev., 2008; 299-327.
• Bachhav, A.A.; Ahire, S.A.; Jadhav, A.G. Preformulation Study of Piroxicam. Int. J. Pharm. Sci. Res., 2019; 10: 811–818.
• Mastiholimath VS, Rajendra BA, Mannur VS, Dandagi PM, Gadad AP, Khanal P. Formulation and evaluation of cefixime nanosuspension for the enhancement of oral bioavailability by solvent-antisolvent method and its suitable method development. Indian Journal of Pharmaceutical Education and Research, 2020 Jan 1; 54(1): 55-67.
• Lakshmi P, Kumar GA. Nanosuspension technology: A review. Int J Pharm Pharm Sci., 2010 Aug; 2(4): 35-40.
• Muller RH.  Zetapotential und Partikelladung–Kurze  Theorie, praktische MeBdurchfuhrung,  Dateninterpretation. Wissenschaftliche Verlagsgesellschaft, Stuttgart, 1996.
• N Arunkumar, M Deecaraman and C Rani, Nanosuspension technology andits applications in drug delivery, Asianjournal of pharmaceutics, 2009; 168-173.
• Keck CM, Müller RH. Drug nanocrystals of poorly soluble drugs produced by high-pressure homogenization. European Journal of Pharmaceutics and Biopharmaceutics, 2006; 62(1): 3–16.
• Bhattacharjee S. DLS and Zeta Potential – What They Are and What They Are Not? Journal of Controlled Release, 2016; 235: 337–351.
• Thongrakard V, et al. Development of a Resveratrol Nanosuspension Using the Antisolvent Precipitation Method. Pharmaceutics. 2020. USP General Chapter <621> Chromatography.
• Higuchi T, Connors KA. Phase-Solubility Techniques. Advances in Analytical Chemistry and Instrumentation. 1965. OECD Guideline No. 105. Water Solubility.
• Peltonen L, et al. Study of Rheology and Polymer Adsorption onto Drug Nanoparticles in Pharmaceutical Suspensions Produced by Nanomilling. Journal of Pharmaceutical Sciences, 2017; 106(11): 3395–3401.
• Aulton ME, Taylor KMG. Aulton's Pharmaceutics: The Design and Manufacture of Medicines. 6th ed. Elsevier, 2021.
• Van Eerdenbrugh B, et al. Downscaling Drug Nanosuspension Production: Processing Aspects and Physicochemical Characterization. AAPS PharmSciTech., 2009; 10(1): 44–53.
• Chogale MM, Ghodake VN, Patravale VB. Performance Parameters and Characterizations of Nanocrystals: A Brief Review. Pharmaceutics, 2016; 8(3): 26.
• Müller RH, Peters K. Nanosuspensions for the Formulation of Poorly Soluble Drugs. International Journal of Pharmaceutics, 1998; 160(2): 229–237.
• Wang Y, Zheng Y, Zhang L, Wang Q, Zhang D. Stability of nanosuspensions in drug delivery. Journal of Controlled Release, 2013; 172(3): 1126–1141. (Comprehensive review on nanosuspension stability.)
• Lachman L, Lieberman HA, Kanig JL. The Theory and Practice of Industrial Pharmacy. 3rd ed. Lea & Febiger, 1986.
• European Pharmacopoeia (Ph. Eur.) Chapters 2.6.1 (Sterility) and 2.6.12 (Microbiological Examination).
• Patil, A. S., Hegde, R., Gadad, P. M., Dandagi, P. M., Masareddy, R., & Bolmal, U. (2021). Exploring the Solvent-Anti-solvent Method of Nanosuspension for Enhanced Oral Bioavailability of Lovastatin. Turkish Journal of Pharmaceutical Sciences, 18(5): 514–549.
• Pirincci Tok, Y., Mesut, B., Güngör, S., Sarıkaya, A. O., Aldeniz, E. E., Dude, U., & Özsoy, Y. (2023). Systematic Screening Study for the Selection of Proper Stabilizers to Produce Physically Stable Canagliflozin Nanosuspension by Wet Milling Method. Bioengineering, 10(8): 927.
• Pawar SS, Dahifale BR, Nagargoje SP, Shendge RS. Nanosuspension technologies for delivery of drugs. Nanosci Nanotech Res., 2017; 4(2): 59-66.
• Shahidulla SM, Miskan R, Sultana S. Nanosuspensions in pharmaceutical sciences: A comprehensive review. Situations, 2023 Jul; 8: 9.
• Goel S, Sachdeva M, Agarwal V. Nanosuspension technology: recent patents on drug delivery and their characterizations. Recent patents on drug delivery & formulation, 2019 Jun 1; 13(2): 91-104.
• REVIEW ON NANOSUSPENSION DRUGDELIVERY SYSTEMUmaRani.G, Lavanya.K, March 2024; 11(3).
• Singh AK, Verma A, Jaiswal S, Mishra A, Khan I, Shukla H. Nanosuspension as Novel Drug Delivery Approach: A Review. Safety, 6: 8.
• Verma AK, Bindal MC. Nanosuspensions: advantages and disadvantages. Indian Journal of Novel Drug Delivery, 2012; 4(3): 179-88.
• Pu X, Sun J, Li M, He Z. Formulation of nanosuspensions as a new approach for the delivery of poorly soluble drugs Curr Nanosci, 2009; 5: 417–27.
• Mathew M, Krishnakumar K, Dineshkumar B, Nair SK. Antibiotics nanosuspension: A review. J Drug Deliv Ther, 2017; 7: 128-31.
• Hernandez-Trejo N, Kayser O, Steckel H, Muller RH. Characterization of nebulized bupravaquone nanosuspensions-Effect of nebulization technology J Drug Target, 2005; 13: 499–507.
• Heidi MM, Yun-Seok R, Xiao W. Nanomedicine in pulmonary delivery Int J Nanomed, 2009; 4: 299–319.
• Mishra S. Nanosuspension in advanced drug delivery. Int J AdvPharm Sci., 2017; 1: 56-65.
• Narkhede K. A brief review on nano-pharmaceuticaltechnology. J Pharm Sci., 2015; 5: 520-8.
• Reimondez-Troitin˜o S et al. Nanotherapies for the treatment ofocular diseases. Eur J Pharm Biopharm, 2015; 95: 279-293.
• Malamatari M, Taylor KM, Malamataris S, Douroumis D, Kachrimanis K. Pharmaceutical nanocrystals: Productionby wet milling and applications. Drug Discov Today, 2018; 23: 534‑47.
• Mirza RM. A nanocrystal technology: To enhance solubility of poorly water soluble drugs. J Appl Pharm Res., 2017; 5: 1-13.