Nanosüspansiyonlar: Hazırlama Yöntemleri ve Stabilite Sorunu

Year 2018, Volume: 38 Issue: 2, 85 - 101, 15.06.2018

Adem Eren Bektaş Afife Büşra Uğur Meltem Çetin

Abstract

Yeni keşfedilen etkin maddelerin büyük bir kısmı suda çözünmez ve biyoyararlanımları çok düşüktür. Sulu ortamdaki düşük çözünürlük sorununun üstesinden gelmek için geliştirilen farklı yaklaşımlardan birisi de nanosüspansiyonlardır ve son yıllarda, bu ilaç şekli, eşsiz özelliklerinden dolayı farmasötik alanda popülerlik kazanmıştır. Nanosüspansiyon, uygun sürfaktan ve/veya polimerler ile kararlı hale getirilmiş saf etkin madde partiküllerinin nano-boyutlu (<1000 nm, genellikle, 200-600 nm) kolloidal dağılımlarıdır. Nanosüspansiyonlar, çeşitli yöntemler (öğütme, yüksek basınçlı homojenizasyon, çöktürme vb.) kullanılarak başarıyla hazırlanmıştır. Bu derleme, nanosüspansiyonların özellikleri, kararlılığı, üstünlükleri ve sakıncaları ve aynı zamanda nanosüspansiyon hazırlama yöntemleri üzerine odaklanmaktadır.

Keywords

Hazırlama yöntemleri, nanosüspansiyonlar, stabilite

Nanosuspensions: Preparation Methods and Stability Issue

Abstract

A large proportion of newly discovered active subtances are water insoluble and have very low bioavailability. One of the different approaches developed to overcome the issue of low solubility in aqueous media is nanosuspensions and in recent years, this dosage form has gained popularity in the pharmaceutical area because of their unique properties. Nanosuspension is nano-sized (<1000 nm, generally, 200-600nm) colloidal dispersions of pure active substance particles, which are stabilized by suitable surfactants and/or polymers. Nanosuspensions are successfully prepared using various methods such as media milling, high-pressure homogenization and precipitation techniques etc. This review focus on the properties, stability, advantages and disadvantages of nanosuspensions, and also, preparation methods for nanosuspensions. 

Keywords

preparation methods, Nanosuspensions, stability

References

• 1. Agarwal V, Bajpai M: Nanosuspension technology for poorly soluble drugs: Recent researches, advances and patents. Recent Patents on Nanotechnology 2015, 9(3):178-194.
• 2. Yadollahi R, Vasilev K, Simovic S: Nanosuspension technologies for delivery of poorly soluble drugs. Journal of Nanomaterials 2015, 2015. doi:10.1155/2015/216375.
• 3. Shid RL, Dhole SN, Kulkarni N, Shid SL: Nanosuspension: a review. International Journal of Pharmaceutical Sciences Review and Research 2013, 22(1):98-106.
• 4. Patel VR, Agrawal YK: Nanosuspension: an approach to enhance solubility of drugs. Journal of Advanced Pharmaceutical Technology and Research 2011, 2(2):81-87.
• 5. Acartürk F. Süspansiyonlar. In: Acartürk F, Ağabeyoğlu İ, Çelebi N, Değim T, Değim Z, Doğanay T, Takka S, Tırnaksız F (eds), Modern Farmasötik Teknoloji. Türk Eczacılar Birliği Eczacılık Akademisi Yayını, Ankara, Türkiye. 2009: 301-316.
• 6. Sutradhar KB, Khatun S, Luna IP: Increasing possibilities of nanosuspension. Journal of Nanotechnology 2013, 2013. doi:10.1155/2013/346581.
• 7. Wang L, Du J, Zhou Y, Wang Y: Safety of nanosuspensions in drug delivery. Nanomedicine 2017, 13(2):455-469.
• 8. Banshraj B, Chaudhury S, Sharma S, Rajput G: A review on nanosuspensions in drug delivery. International Journal of Pharma Professional’s Research 2013, 4(3):898-904.
• 9. Schweitzer A, Sucker H: Hydrosols-alternatives for the parenteral application of poorly water soluble drugs. European Journal of Pharmaceutics and Biopharmaceutics 1994, 40(2):64–72.
• 10. Müller RH, Jacobs C, Kayser O: Nanosuspensions as particulate drug formulations in therapy. Advanced Drug Delivery Reviews 2001, 47(1):3-19.
• 11. Kumar BS, Saraswathi R, Kumar KV, Jha SK, Venkates DP, Dhanaraj SA: Development and characterization of lecithin stabilized glibenclamide nanocrystals for enhanced solubility and drug delivery. Drug Delivery 2014, 21(3):173-184.
• 12. Muller RH, Peters K, Becker R, Kruss B: Nanosuspensions for the i.v. administration of poorly soluble drugs: stability during sterilization and long-term storage. Proceedings of the Controlled Release Society 1995, 22:574–575.
• 13. Yang L, Hong J, Di J, Guo Y, Han M, Liu M, Wang X: 10-Hydroxycamptothecin (HCPT) nanosuspensions stabilized by mPEG1000- HCPT conjugate: high stabilizing efficiency and improved antitumor efficacy. International Journal of Nanomedicine 2017, 12:3681-3695.
• 14. Sattar A, Chen D, Jiang L, Pan Y, Tao Y, Huang L, Liu Z, Xie S, Yuan Z: Preparation, characterization and pharmacokinetics of cyadox nanosuspension. Scientific Reports 2017, 7(1):2289. doi: 10.1038/ s41598-017-02523-4.
• 15. Gera S, Talluri S, Rangaraj N, Sampathi S: Formulation and evaluation of naringenin nanosuspensions for bioavailability enhancement. AAPS PharmSciTech 2017. doi: 10.1208/s12249-017-0790-5.
• 16. George M, Ghosh I: Identifying the correlation between drug/stabilizer properties and critical quality attributes (CQAs) of nanosuspension formulation prepared by wet media milling technology. European Journal of Pharmaceutical Sciences 2013, 48(1-2):142-152.
• 17. Yao L, Zhao X, Li Q, Zu Y, Fu Y, Zu B, Meng X, Liu C: In vitro and in vivo evaluation of camptothecin nanosuspension: a novel formulation with high antitumor efficacy and low toxicity. International Journal of Pharmaceutics 2012, 423(2):586-588.
• 18. Wang YC, Liu ZP, Zhang DR, Gao XH, Zhang XY, Duan CX, Jia LJ, Feng FF, Huang YJ, Shen YM, Zhang QA: Development and in vitro evaluation of deacety mycoepoxydiene nanosuspension. Colloids and surfaces. B, Biointerfaces 2011, 83(2):189-197.
• 19. Chin WW, Parmentier J, Widzinski M, Tan EH, Gokhale R: A brief literature and patent review of nanosuspensions to a final drug product. Journal of Pharmaceutical Sciences 2014, 103(10):2980-2999.
• 20. Junghanns J-UAH, Müller RH: Nanocrystal technology, drug delivery and clinical applications. International Journal of Nanomedicine 2008, 3(3):295-310.
• 21. Malamatari M, Somavarapu S, Taylor KM, Buckton G: Solidification of nanosuspensions for the production of solid oral dosage forms and inhalable dry powders. Expert Opinion on Drug Delivery 2016, 13(3):435-450.
• 22. Kavitha VB, Neethu CS, Dineshkumar B, Krishnakumar K, John A: Nanosuspension formulation: an improved drug delivery system. Nanoscience and Nanotechnology: An International Journal 2014, 4(1):1-5.
• 23. Öner L, Gürsoy RN. Nanokristaller. In: Gürsoy AZ (ed), Nanofarmasötikler ve Uygulamaları. Kontrollü Salım Sistemleri Derneği, İstanbul, Türkiye. 2014: 125-133.
• 24. Velmula M, Pavuluri P, Rajashekar S, Rao VUM: Nanosuspension technology for poorly soluble drugs - a review. World Journal of Pharmacy and Pharmaceutical Sciences 2015, 4(7):1612-1625.
• 25. Ye L, Miao M, Li S, Hao K: Nanosuspensions of a new compound, ER-β005, for enhanced oral bioavailability and improved analgesic efficacy. International Journal of Pharmaceutics 2017, 531(1):246- 256.
• 26. Talekar M, Ganta S, Amiji M, Jamieson S, Kendall J, Denny WA, Garg S: Development of PIK-75 nanosuspension formulation with enhanced delivery efficiency and cytotoxicity for targeted anti-cancer therapy. International Journal of Pharmaceutics 2013, 450(1-2):278-289.
• 27. Gao Y, Li Z, Sun M, Guo C, Yu A, Xi Y, Cui J, Lou H, Zhai G: Preparation and characterization of intravenously injectable curcumin nanosuspension. Drug Delivery 2011,18(2):131-142.
• 28. Pyo SM, Hespeler D, Keck CM, Müller RH: Dermal miconazole nitrate nanocrystals – formulation development, increased antifungal efficacy&skin penetration, International Journal of Pharmaceutics 2017, 531(1): 350-359.
• 29. Sinico C, Pireddu R, Pini E, Valenti D, Caddeo C, Fadda AM, Lai F: Enhancing topical delivery of resveratrol through a nanosizing approach. Planta Medica 2017, 83(5):476-481.
• 30. Rabinow BE: Nanosuspensions in drug delivery. Nature Reviews Drug Discovery 2004, 3(9):785-796.
• 31. Shegokar R, Singh KK: Surface modified nevirapine nanosuspensions for viral reservoir targeting: In vitro and in vivo evaluation. International Journal of Pharmaceutics 2011, 421(2):341-352.
• 32. Kayser O: A new approach for targeting to cryptosporidium parvum using mucoadhesive nanosuspensions: research and applications. International Journal of Pharmaceutics 2001, 214(1-2):83–85.
• 33. Müller RH, Jacobs C: Buparvaquone mucoadhesive nanosuspension: preparation, optimisation and long-term stability. International Journal of Pharmaceutics 2002, 237(1–2):151–161.
• 34. Krause KP, Kayser O, Mäder K, Gust R, Müller RH: Heavy metal contamination of nanosuspensions produced by high-pressure homogenisation. International Journal of Pharmaceutics 2000, 196(2):169-172.
• 35. Itoh K, Pongpeerapat A, Tozuka Y, Oguchi T, Yamamoto K: Nanoparticle formation of poorly water-soluble drugs from ternary ground mixtures with PVP and SDS. Chemical and Pharmaceutical Bulletin (Tokyo) 2003, 51(2):171-174.
• 36. Kulkarni RR, Phadtare DG, Saudagar RB: A novel approach towards nanosuspension. Asian Journal of Pharmaceutical Research 2015, 5(4):186-194.
• 37. Salazar J, Müller RH, Möschwitzer JP: Combinative particle size reduction technologies for the production of drug nanocrystals. Journal of Pharmaceutics 2014, 2014. doi:10.1155/2014/265754.
• 38. Pireddu R, Sinico C, Ennas G, Marongiu F, Muzzalupo R, Lai F, Fadda AM: Novel nanosized formulations of two diclofenac acid polymorphs to improve topical bioavailability. European Journal of Pharmaceutical Sciences 2015, 77:208-215.
• 39. Kanthamneni N, Valiveti S, Patel M, Xia H, Tseng Y-C: Enhanced bioavailability of danazol nanosuspensions by wet milling and high- pressure homogenization. International Journal of Pharmaceutical Investigation 2016, 6(4):218-224.
• 40. Liu T, Müller RH, Möschwitzer JP: Systematical investigation of a combinative particle size reduction technology for production of resveratrol nanosuspensions. AAPS PharmSciTech 2017, 18(5):1683-1691.
• 41. 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.
• 42. Verma S, Huey BD, Burgess DJ: A scanning probe microscopy method for nanosuspension stabilizer selection. Langmuir 2009, 25(21):12481–12487.
• 43. Verma S, Kumar S, Gokhale R, Burgess DJ: Physical stability of nanosuspensions: investigation of the role of stabilizers on Ostwald ripening. International Journal of Pharmaceutics 2011, 406(1-2):145- 152.
• 44. Quan P, Shi K, Piao H, Piao H, Liang N, Xia D, Cui F: A novel surface modified nitrendipine nanocrystals with enhancement of bioavailability and stability. International Journal of Pharmaceutics 2012, 430(1-2):366-371.
• 45. Verma S. Effect of process parameters and the role of stabilizers in nanosuspension stability-Doctoral Dissertations, AAI3401983- 2009.; 2017 May 14. Available from: http:/http://digitalcommons.uconn. edu/dissertations/AAI3401983. [Website]
• 46. Hong C, Dang Y, Lin G, Yao Y, Li G, Ji G, Shen H, Xie Y: Effects of stabilizing agents on the development of myricetin nanosuspension and its characterization: an in vitro and in vivo evaluation. International Journal of Pharmaceutics 2014, 477(1-2):251-260.
• 47. Guo L, Kang L, Liu X, Lin X, Di D, Wu Y, Kong D, Deng Y, Song Y: A novel nanosuspension of andrographolide: Preparation, characterization and passive liver target evaluation in rats. European Journal of Pharmaceutical Sciences 2017, 104:13-22.
• 48. Choi JY, Yoo JY, Kwak HS, Nam BU, Lee J: Role of polymeric stabilizers for drug nanocrystal dispersions. Current Applied Physics 2005, 5(5):472–474.
• 49. Dolenc A, Kristl J, Baumgartner S, Planinsek O: Advantages of celecoxib nanosuspension formulation and transformation into tablets. International Journal of Pharmaceutics 2009, 376(1-2):204-212.
• 50. Ghosh I, Schenck D, Bose S, Ruegger C: Optimization of formulation and process parameters for the production of nanosuspension by wet media milling technique: Effect of Vitamin E TPGS and nanocrystal particle size on oral absorption. European Journal of Pharmaceutical Sciences 2012, 47(4):718–728.
• 51. Ghosh I, Bose S,Vippagunta R, Harmon F: Nanosuspension for improving the bioavailability of a poorly soluble drug and screening of stabilizing agents to inhibit crystal growth. International Journal of Pharmaceutics 2011, 409(1-2):260–268.
• 52. Deng J, Huang L, Liu F: Understanding the structure and stability of paclitaxel nanocrystals. International Journal of Pharmaceutics 2010, 390(2):242–249.
• 53. Aghajani M, Shahverdi AR, Rezayat SM, Amini MA, Amani A: Preparation and optimization of acetaminophen nanosuspension through nanoprecipitation using microfluidic devices: an artificial neural networks study. Pharmaceutical Development Technology 2013, 18(3):609-618.
• 54. Chen X, Matteucci ME, Lo CY, Johnston KP, Williams RO 3rd: Flocculation of polymer stabilized nanocrystal suspensions to produce redispersible powders. Drug Development and Industrial Pharmacy 2009, 35(3):283-296.
• 55. de Waard H, Hinrichs WL, Frijlink HW: A novel bottom–up process to produce drug nanocrystals: Controlled crystallization during freeze-drying. Journal of Controlled Release 2008, 128(2):179–183.
• 56. Gao L, Liu G, Wang X, Liu F, Xu Y, Ma J: Preparation of a chemically stable quercetin formulation using nanosuspension technology. International Journal of Pharmaceutics 2011, 404(1-2):231–237.
• 57. Möschwitzer J, Achleitner G, Pomper H, Müller RH: Development of an intravenously injectable chemically stable aqueous omeprazole formulation using nanosuspension technology. European Journal of Pharmaceutics and Biopharmaceutics 2004, 58(3):615–619.
• 58. Wang WP, Hul J, Sui H, Zhao YS, Feng J, Liu C: Glabridin nanosuspension for enhanced skin penetration: formulation optimization, in vitro and in vivo evaluation. Pharmazie 2016, 71(5):252-257.
• 59. Maulidin R, Müller RH: Preparation and storage stability of rutin nanosuspensions. Journal of Pharmaceutical Investigation 2013, 43(5):395–404.
• 60. Kakran M, Shegokar R, Sahoo NG, Gohla S, Li L, Müller RH: Longterm stability of quercetin nanocrystals prepared by different methods. Journal of Pharmacy and Pharmacology 2012, 64(10):1394–1402.
• 61. Mahesh KV, Singh SK, Gulati M:A comparative study of top-down and bottom-up approaches for the preparation of nanosuspensions of glipizide. Powder Technology 2014, 256(1):436-449.