Pelletization of ibuprofen-phosphatidylcholine self-assembling nanoparticles

Document Type : Research Paper

Authors

1 Department of Pharmaceutics, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

3 Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

4 Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Objective(s): Prescription of ibuprofen as a non-steroidal anti-inflammatory drug is limited by its gastrointestinal side effects and poor aqueous solubility. It was shown that phospholipid-association (PA) can lead to assembling assembly of the micellar form, thereby improving solubility  of non-steroidal anti-inflammatory drugs solubility and reducing their gastrointestinal side effects. 
Materials and Methods: Ibuprofen in PA form was prepared and its interaction, crystallinity, and particle size were evaluated. Conventional ibuprofen and PA pellets in different drug contents were prepared by extrusion-spheronization. The mMorphology, shape factors, mechanical strength, and drug content of pellets were investigated. The dissolution test also was conducted in an intestinal-simulated medium and a gastric-simulated medium. 
Results: The results showed that PA micelles of ibuprofen were demonstrated to be formed, amorphous, and in an acceptable size range. Using a suitable composition of solid components and granulation fluid, pellets with desirable size, shape, and sphericity could be produced. All pellets have had plastic mechanical properties and the strength of formulations were  decreased with increasing PA ratio. The PA-pellet formulation had faster drug release compared to conventional ibuprofen pellets, via increasing ibuprofen solubility by reducing crystallinity in solid state and micelle formation in dissolution media. Moreover, ibuprofen solubility in a gastric-simulated medium was decreased and might result in reduced gastrointestinal side effects.
Conclusion: Due to the demonstrated bioavailability advantages of PA-pellets, they can be considered for further studies.

Keywords


1.  Rainsford KD. Ibuprofen: Pharmacology, efficacy and safety. Inflammopharmacology. 2009;17(6):275–342. 
2. Whittle BJR. Cox-1 and Cox-2 products in the gut: therapeutic impact of Cox-2 inhibitors. Gut. 2000;47(3):320–325.
 3. Adams SS, Bough RG, Cliffe EE, Lessel B, Mills RFN. Absorption, distribution and toxicity of ibuprofen. Toxicol Appl Pharmacol. 1969;15:310–330.
4. Amirinejad M, Haghighizadeh A, Nejabat M, Etemad L, Rajabi O. Synthesis, optimization, and evaluation of the inclusion complex of ibuprofen-hydroxypropylbeta-cyclodextrin: An in vitro and in silico Study. ChemistrySelect. 2023;8(11): e202204396. 
5. Pignatello R, Ferro M, Puglisi G. Preparation of solid dispersions of nonsteroidal anti-inflammatory drugs with acrylic polymers and studies on mechanisms of drug-polymer interactions. AAPS PharmSciTech. 2002;3:35-45.
 6. Halen P, Murumkar P, Giridhar R, Yadav M. Prodrug designing of NSAIDs. Mini-Reviews Med Chem. 2008;9(1):124–139.
7. Amirinejad M, Davoodi J, Abbaspour MR, Akhgari A, Hadizadeh F, Badiee A. Preparation, characterization and improved release profile of ibuprofen-phospholipid association. J Drug Deliv Sci Technol. 2020;60:101951.
8. Omidfar F, Gheybi F, Davoodi J, Amirinejad M, Badiee A. Nanophytosomes of hesperidin and of hesperetin: Preparation, characterization, and in vivo evaluation. Biotechnol Appl Biochem. 2022;70(2):846-856.
9. Pei Q, Hu X, Liu S, Li Y, Xie Z, Jing X. Paclitaxel dimers assembling nanomedicines for treatment of cervix carcinoma. J Control Release. 2017;254:23-33.
10. Wang Z, Zhuang M, Sun T, Wang X, Xie Z. Self-assembly of glutamic acid linked paclitaxel dimers into nanoparticles for chemotherapy. Bioorganic Med Chem Lett. 2017;27(11): 2493-2496
11. Ismail M, Ling L, Du Y, Yao C, Li X. Liposomes of dimeric artesunate phospholipid: a combination of dimerization and self-assembly to combat malaria. Biomaterials. 2018;163:76–87.
12. Farias B V., Haeri F, Khan SA. Linking polymer hydrophobicity and molecular interactions to rheology and tribology in phospholipid-containing complex gels. J Colloid Interface Sci. 2021;584:134–144.
13. Singh VK, Pandey PM, Agarwal T, Kumar D, Banerjee I, Anis A, et al. Development of soy lecithin based novel self-assembled emulsion hydrogels. J Mech Behav Biomed Mater. 2016;55:250–263.
14. Abashzadeh S, Dinarvand R, Sharifzadeh M, Hassanzadeh G, Amini M, Atyabi F. Formulation and evaluation of an in situ gel forming system for controlled delivery of triptorelin acetate. Eur J Pharm Sci. 2011;44(4):514– 521.
15. Lasic DD. Mixed micelles in drug delivery. Nature. 1992;355:379–382.
16. Sessa G, Weissmann G. of Lysozyme into Liposomes. J Biol Chem. 1970;245(13):3295–3301. 
17. Cole ET, Cadé D, Benameur H. Challenges and opportunities in the encapsulation of liquid and semi-solid formulations into capsules for oral administration. Adv Drug Deliv Rev. 2008;60(6):747–756.
18. Kotlowska H, Szymanska M, Sznitowska M. Comparison of different liquid and semisolid vehicles selected for oral administration of pellets and minitablets with diazepam: in vitro investigation. AAPS PharmSciTech. 2020;21:1–7.
19. Durig T, Karan K. Binders. Wet granulation. In: Narang A, Badawy S, editors. Handbook of Pharmaceutical Wet Granulation. 1st ed. Washington: Ashland LLC; 2019.
20. Moneghini M, Perissutti B, Princivalle F, Martellos S. Rapidly dissolving extrudates prepared by a warm extrusion process. J Drug Deliv Sci Technol. 2008;18(5):351–357. 
21. Akhgari A, Sadeghi F, Garekani HA. Combination of time-dependent and pH-dependent polymethacrylates as a single coating formulation for colonic delivery of indomethacin pellets. Int J Pharm. 2006;320(1–2):137–142.
22. Beringhs AO, Souza FM, de Campos AM, Ferraz HG, Sonaglio D. Technological development of Cecropia glaziovi extract pellets by extrusion-spheronization. Rev. Bras. Pharmacogn. 2013;23(1):160–168.
23. Kaffash E, Saremnejad F, Abbaspour M, Mohajeri SA, Garekani HA, Jafarian AH, et al. Statistical optimization of alginate-based oral dosage form of 5-aminosalicylic acid aimed to colonic delivery: in vitro and in vivo evaluation. J Drug Deliv Sci Technol. 2019;52:177–188. 
24. Rekhi GS, Sidwell R. Sizing of granulation. In: Parikh DP, editor. Handbook of pharmaceutical granulation technology. 1st ed. CRC Press; 2016.
25. Filho OPS, Oliveira LAR, Martins FS, Borges LL, De Freitas O, Da Conceição EC. Obtainment of pellets using the standardized liquid extract of Brosimum gaudichaudii Trécul (Moraceae). Pharmacogn Mag. 2015;11(41):170–175.
26. Vergote GJ, Vervaet C, Van Driessche I, Hoste S, De Smedt S, Demeester J, et al. An oral controlled release matrix pellet formulation containing nanocrystalline ketoprofen. Int J Pharm. 2001;219(1–2):81–87.
27. Costa FO, Pais AACC, Sousa JJS. Analysis of formulation effects in the dissolution of ibuprofen pellets. Int J Pharm. 2004;270(1–2):9–19.
28. Costa FO, Sousa JJS, Pais AACC, Formosinho SJ. Comparison of dissolution profiles of Ibuprofen pellets. J Control Release. 2003;89(2):199–212.
29. Kaffash E, Badiee A, Akhgari A, Akhavan Rezayat N, Abbaspour M, Saremnejad F. Development and characterization of a multiparticulate drug delivery system containing indomethacin-phospholipid complex to improve dissolution rate. J Drug Deliv Sci Technol. 2019;53:101177.
 30. Lustig-Gustafsson C, Kaur Johal H, Podczeck F, Newton JM. The influence of water content and drug solubility on the formulation of pellets by extrusion and spheronisation. Eur J Pharm Sci. 1999;8(2):147–152.
 31. Wang QF, Li SM, Zhang YY, Zhang H. Modulating drug loading and release profile of β-cyclodextrin polymers by means of cross-linked degree. Yaoxue Xuebao. 2011;46(2):221–226.
32. Chopra S, Venkatesan N, Betageri G V. Formulation of lipid bearing pellets as a delivery system for poorly soluble drugs. Int J Pharm. 2013;446(1–2):136–144. 
33. Lichtenberger LM, Barron M, Marathi U. Association of phosphatidylcholine and NSAIDs as a novel strategy to reduce gastrointestinal toxicity. Drugs Today. 2009;45(12):877–890. 
34. Desai MP, Labhasetwar V, Amidon GL, Levy RJ. Gastrointestinal uptake of biodegradable microparticles: effect of particle size. Pharm Res. 1996;13(12):1838–1845. 
35. Jani P, Halbert GW, Langridge J, Florence AT. Nanoparticle uptake by the rat gastrointestinal mucosa: quantitation and particle size dependency. J Pharm Pharmacol. 1990;42(12):821–826.