Preparation and Evaluation of Poly (s-caprolactone) Nanoparticles-in- Microparticles by W/O/W Emulsion Method

Document Type: Original Article

Authors

1 Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

2 Nanotechnology Center, Tabriz University of Medical Sciences, Tabriz, Iran

Abstract

Objective(s)
Theophylline, a xanthenes derivative, is still widely used as an effective bronchodilator in the management of asthmatic patients. It is used both as a prophylactic drug and to prevent acute exacerbations of asthma. The aim of study was to formulate and evaluate effect of the microencapsulation of theophylline loaded nanoparticles on the reduction of burst release.
Materials and Methods
Microparticles (simple and composite) and nanoparticles were prepared by using water-in-oil-in-water (W1/O/W2 double-emulsion solvent diffusion/evaporation method), taking different ratios of drug/polymer. Solvent systems consist of ethyl acetate and dichloromethane for microspheres and nanospheres, respectively. In the current study formulations were characterized by loading efficiency, yield, particle size, zeta potential, X-ray diffraction (XRD) and differential scanning calorimetry (DSC).
Results
In microparticles, the best drug to polymer ratio was 0.8:1 (F3). F3 formulation had minimum burst effect (37.81%), high loading efficiency (95.88%). In nanoparticles, F4 formulation (0.4:1 drug/polymer ratio) showed high production yield (40.8%), loading efficiency (99.05%), low particle size (756 nm) and minimum burst effect compared with other nanoparticle formulations. The drug loaded composite microspheres (F9) showed minimum burst effect, acceptable release and mean particle size 17.696 pm. The XRD and DSC showed stable character of theophylline in the drug loaded microspheres. The drug release was found to be diffusion and erosion controlled.
Conclusion
The burst was significantly lower with composite microparticles and may be explained by lower diffusion of the drug from double polymeric wall formed by the nanoparticles matrix followed by another diffusion step through the microparticle polymeric wall.

Keywords


1.Hombreiro-perez M, Siepmann J, Zinutti C, Lamprecht A, Ubrich N, Hoffman M, et al. Non-degradable microparticles containing a hydrophilic and/or a lipophilic drug: preparation, characterization and drug release modeling. J Control Rel 2003; 88:413-428.

2.Benoit JP, Marchais H, Rolland H, Vande V. Biodegradable microspheres: advances in production technology. In: Benita S.editors.Microencapsulation-Methods and industrial application. New York: Marcel Dekker; 1996.p.35-72.

3.Berton M, Benimetskaya L, Allemann E, Stein CA, Gurny R. Uptake of oligonucleotide-loaded nanoparticles in prostatic cancer cells and their intracellular localization. Eur J Pharm Biopharm 1999; 47:119-123.

4.Mathiowitz E, Keitz MR, Brannon L, Peppas NA. Encyclopedia of controlled drug delivery. Canada: Mathiowitz E, Wiley J and sons; 2000.

5.Yi-Yan Y, Tai-Shung C, Ngee Ping Ng. Morphology, drug distribution, and in vitro release profiles of biodegrradeble polymeric microspheres containing protein fabricated by double-emulsion solvent extraction/evaporation method. Biomaterials 2001; 22:231-241.

6.Jiang G, Thanoo BC, DeLuca PP. Effect of osmotic pressure in th solvent phase on BSA release profile from PLGA microspheres. Pharm Dev Technol 2002; 7:391-399.

7.Sheikh Hassan A, Socha M, Laprecht A, Ghazouani F EI, Sapin A, Hoffman M, et al. Effect of the microencapsulation of nanoparticles on the reduction of burst release. Int J Pharm 2007; 344:53-61.

8.Lee KE, Cho SH, Lee HB, Jeong SY, Yuk SH. Microencapsulation of lipid nanoparticles containing lipophilic drug. J Microencapsul 2003; 20:489-496.

9.Fretag T, Dashevsky A, Tillman L, Hardee GE, Bodmeier R. Improvement of the encapsulation efficiency of oligonucleotide-containing biodegradable microspheres. J Control Rel 2000; 69:197-207.

10.Stenekes RJ, Loebis AE, Lobis AE, Fernandes CM, Crommelin DJ, Hennik WE. Controlled release of liposomes from biodegradable dextran microspheres: a novel delivery concept. Pharm Res 2000; 17:690-695.

11.Dhoot NO, Wheatley MA. Microencapsulated liposomes in controlled drug delivery: strategies to modulate drug release and eliminate the burst effect. J Pharm Sci 2003; 92:679-689.

12.Maeda H, Nakagawa T, Adachi N, Sakai Y, Yamamoto T, Matsuoka A, et al. Design of long-acting formulation of protein drugs with a double-layer structure and its application to rhG-CSF. J Control Rel 2003; 91:281-297.

13.Huang YY, Chung TW, Tzeng TW. A method using biodegradable polylactides/polyethylene glycol for drug release with reduced initial burst. Int J Pharm 1999: 182:93-100.

14.Hurteaux R, Edwards-Levy F, Laurent-Maquin D, Levy MC. Coating alginate microspheres with a serum albumin-alginate membrane: application to the encapsulation of a peptide. Eur J Pharm Sci 2005; 24:187-197. 

15.Saravanan M, Bhaskar K, Srinivasa Rao G, Dhanaraju MD. Ibuprofen-loaded ethylcellulose/polystyrene microspheres: an approach to get prolonged drug release with reduced burst effect and low ethylcellulose content. J Microencapsul 2003; 20:89-302.

16.Hombreiro perez M, Zinutti C, Lamprecht A, Ubrich N, Astier A, Hoffman M, et al. The preparation and evaluation of poly(e-caprolactone) microparticles containing both a lipophilic and a hydrophilic drug. J Control Rel 2000; 65:429-438.

17.Sinha VR, Bansal K, Kaushik R, Kumria R, Trehan A. Poly- e-caprolactone microspheres and nanospheres: an overview. Int J Pharm 2004; 273:1-23.

18.Yi-Yan Y, Tai-Shung Ch, Ngee Ping Ng. Morphology, drug distribution, and in vitro release profiles of biodegradable polymeric microspheres containing protein fabricated by double-emulsion solvent extraction/evaporation method. Biomaterials 2001; 231-241.

19.Shah SS, Cha Y, Pitt CG. Poly (glycolic acid-co-DL-Lactic acid): diffusion or degradation controlled drug delivery. J Control Rel 1992; 18:261-270.

20.Lager R, Siegel R, Brown L, Leong K, Kost J, Edelman E. Controlled release three mechanism. Chemtech 1986; 2: 108-10.

21.Hoffart V, Ubrich N, Simonin C, Babak V, Vigneron C, Hoffman M, et al. Low molecular weight heparin- loaded polymeric nanoparticles: formulation, characterization, and release characteristics. Drug Dev Ind Pharm 2002; 28:1091-2000.

22."Zeta Potential of Colloids in Water and Waste Water”, ASTM Standard D 4187-82, American Society for Testing and Materials. 1985.

23.Daniel WW, Biostatic: A foundation for analysis in the health sciences. 6th ed. John Wiely & Sons Inc; 1995.

24.Youan BB, Jacson TL, Dickens L, Hernandez C, Ababio GO. Protein release profiles and morphology of biogradable microcapsules containing an oily core. J Control Rel 2001; 76:313-326.

25.Ale R, Bodmeier R. Encapsulation of water-soluble drugs by a method solvent evaporation method. Effect of process and formulation variables on drug entrapment. J Microencapsul 1999; 7: 347-355.

26.Ogawa Y, Yamamoto M, Okada H, Yashiki T, Shimamoto T. A new technique to efficiently entrap leuprolide acetate into microcapsules of poly lactics or co-polylactic/ glycolic acid. Chem Pharm Bull 1988; 36:1095-1103.

27.Sunit Kumar S, Abdul Arif M, Barik BB, Prakash ChS. Formulation and in vitro evaluation of eudragit® microspheres of stavudine. Tropical J Pharm Res 2005; 4:369-375.

28.WU JC, SU SG, Shyu SS. Effect of solvent-non-solvent pairs on the surface morphology and release behaviour of ethycellulose microcapsules prepared by non-solvent-addition phase separation method. J Microencapsul 1994; 11:297-308.

29.Pignatello R, Vandelli MA, Giunchedi P, Puglisi G. Properties of tolmetin-loaded Eudragit RL100 and Eudragit RS100 microparticled prepared by different techniques. STP Pharma Sci 1997; 7:148-157.

30.Malamataris S, Avgerinos A. Controlled release indomethacin microspheres prepared by using an emulsion solvent-diffusion technique. Int J Pharm 1990; 62:105-111.

31.Chiao CS, Price JC. Formulation, preparation and dissolution characteristics of propranolol hydrochloride microspheres. J Microencapsul 1994; 11:153-159.

32.Kim BK, Hwang SJ, Park JB, Park HJ. Preparation and characterization of drug-loaded polymethacrylate microspheres by an emulsion solvent evaporation method. J Microencapsul 1992; 19: 811-822.

33.Martin A, Bustamante P, Chun AH. Physical Pharmacy. 4th ed. Philadelphia: Lea and Febiger; 1993.

34.Turk CT, Hasgigek C, Gonul N. Evaluation of drug-polymer interaction in polymeric microspheres contains ing diltiazem hydrochloride. J Therm Analys Calori 2009; 95:865-869.

35.Ming-Guang Li, Wan-Liang Lu, JC W, Xuan Z, Hua Z, Xue-Qing W, et al. Preparation and characterization of insulin nanoparticles employing chitosan and poly(methylmethacrylate/methylmethaacrylic acid) copolymer. J Nanosci Nanotech 2006; 6:2874-2886.

36.Pignatello R, Consoli P, Puglist G. In vitro release kinetics of tolmetin from tabletted Eudragit microparticles. J Microencapsul 2000; 17:373-383.

37.Okada H, Doken Y, Ogawa Y, Toguchi T. Preparation of three-month depot injectable microspheres of leuprolein acetate using biodegradable polymers. Pharm Res 1994; 11:1143-1147.

38.Yuksel N, Kanik AE, Baykara T. Comparison of in vitro dissolution profiles by ANOVA-based, model dependent and independent methods. Int J Pharm 2000; 209:57-67.

39.Paulo Costa, Jose Manuel Sousa Lobo. Modeling and comparison of dissolution profilers. Eur J Pharm Sci 2001; 13:123-133.