Abstract
The purpose of this research was to improve the entrapment efficiency of a model hydrophilic drug substance, sodium cromoglycate, loaded inside polylactic acid nanoparticles by a modified nanoprecipitation method. The effect of formulation parameters was studied to improve the entrapment efficiency of the drug substance inside the nanoparticles. Several parameters (changes in the amount of model drug, solvent selection, electrolyte addition, pH alteration) were tested in order to increase the loading of the hydrophilic drug in the hydrophobic nanoparticles. Lowering of the pH was the most efficiency way to increase the drug loading; up to approximately 70% of the sodium cromoglycate used in the particle formation process could be loaded inside the particles. The loading efficiency without the pH change was around 10% to 15% at maximum. The crystallinity values and crystal habits of the sodium cromoglycate nanoparticles were studied (x-ray diffraction) before and after the lowering of the pH. The change in pH conditions during the nanoprecipitation process did not affect markedly the crystallinity properties of the drug substance. According to this study, it is possible to improve the entrapment efficiency of hydrophilic sodium cromoglycate inside of the nanoparticles by small changes in the process parameters without alterations in the physical properties of the original drug subtance.
KeyWords: drug loading, nanoparticles, nanoprecipitation, pH, PLA (polylactic acid)
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References
- 1.Martin TM, Bandi N, Shulz R, Roberts CB, Kompella UB. Preparation of budesonide and budesonide-PLA microparticles using supercritical fluid precipitation technology.AAPS Pharm Sci Tech. 2002;3(3):article 18. [DOI] [PMC free article] [PubMed]
- 2.Dinarvand R, Moghadam SH, Mohammadyari-Fard L, Atyabi F. Preparation of biodegradable microspheres and matrix devices containing naltrexone.AAPS Pharm Sci Tech. 2003;4(2) article 34. [DOI] [PMC free article] [PubMed]
- 3.Perugini P, Genta I, Conti B, Modena T, Pavanetto F. Long-term release of clodronate from biodegradable microspheres.AAPS Pharm Sci Tech. 2001;2(3): article 10. [DOI] [PMC free article] [PubMed]
- 4.Jeyanthi R, Mehta RC, Thanoo BC, DeLuca PP. Effect of processing parameters on the properties of peptide-containing PLGA microspheres. J Microencapsul. 1997;14:163–174. doi: 10.3109/02652049709015330. [DOI] [PubMed] [Google Scholar]
- 5.Li W-I, Anderson KW, Mehta RC, DeLuca PP. Prediction of solvent removal profile and effect on properties for peptide-loaded PLGA microspheres prepared by solvent extraction/evaporation method. J Control Release. 1995;37:199–214. doi: 10.1016/0168-3659(95)00076-3. [DOI] [Google Scholar]
- 6.Jeyanthi R, Thanoo BC, Mehta RC, DeLuca PP. Effect of solvent removal technique on the matrix characteristics of polylactide/glycolide microspheres for peptide delivery. J Control Release. 2004;38:235–244. doi: 10.1016/0168-3659(95)00125-5. [DOI] [Google Scholar]
- 7.Kreuter J. Nanoparticle-based drug delivery systems. J Control Release. 1991;16:169–176. doi: 10.1016/0168-3659(91)90040-K. [DOI] [Google Scholar]
- 8.Allémann E, Gurny R, Doelker E. Drug-loaded nanoparticles-Preparation methods and drug targeting issues. Eur J Pharm Biopharm. 1993;39:173–191. [Google Scholar]
- 9.Brannon-Peppas L. Recent advances on the use of biodegradable microparticles and nanoparticles in controlled drug delivery. Int J Pharm. 1995;116:1–9. doi: 10.1016/0378-5173(94)00324-X. [DOI] [Google Scholar]
- 10.Couvreur P, Dubernet C, Puisieux F. Controlled drug delivery with nanoparticles: Current possibilities and future trends. Eur J Pharm Biopharm. 1995;41:2–13. [Google Scholar]
- 11.Fessi H, Puisieux F, Devissaguet JP, Ammoury N, Benita S. Nanocapsule formation by interfacial polymer deposition following solvent displacement. Int J Pharm. 1989;55:R1–R4. doi: 10.1016/0378-5173(89)90281-0. [DOI] [Google Scholar]
- 12.Barichello J, Morishita M, Takayama K, Nagai T. Encapsulation of hydrophilic and lipophilic drugs in PLGA nanoparticles by the nanoprecipitation method. Drug Dev Ind Pharm. 1999;25:471–476. doi: 10.1081/DDC-100102197. [DOI] [PubMed] [Google Scholar]
- 13.Govender T, Stolnik S, Garnett MC, Illum L, Davis SS. PLGA nanoparticles prepared by nanoprecipitation: drug loading and release studies of a water soluble drug. J Control Release. 1999;57:171–185. doi: 10.1016/S0168-3659(98)00116-3. [DOI] [PubMed] [Google Scholar]
- 14.Peltonen L, Koistinen P, Karjalainen M, Häkkinen A, Hirvonen J. The effect of cosolvents on the formulation of nanoparticles from low-molecular-weight poly(1)lactide.AAPS Pharm Sci Tech. 2002; 3(4) article 32. [DOI] [PMC free article] [PubMed]
- 15.Peltonen L, Koistinen P, Hirvonen J. Preparation of nanoparticles by the nanoprecipitation of low molecular weight poly(I)lactide. STP Pharma Sci. 2003;13:299–304. [Google Scholar]
- 16.Herrmann J, Bodmeier R. Somatostatin containing biodegradable microspheres prepared by a modified solvent evaporation method based on w/o/w multiple emulsions. Int J Pharm. 1995;126:129–138. doi: 10.1016/0378-5173(95)04106-0. [DOI] [Google Scholar]
- 17.Freytag T, Dashevsky A, Tillman L, Hardee GE, Bodmeier R. Improvement of the encapsulation efficiency of oligonucleotide-containing biodegradable microspheres. J Control Release. 2000;69:197–207. doi: 10.1016/S0168-3659(00)00299-6. [DOI] [PubMed] [Google Scholar]
- 18.Han K, Lee K-D, Gao Z-G, Park J-S. Preparation and evaluation of poly(L-lactic acid) microspheres containing rhEGF for chronic gastric ulcer healing. J Control Release. 2001;75:259–269. doi: 10.1016/S0168-3659(01)00400-X. [DOI] [PubMed] [Google Scholar]
- 19.Bodmeier R, McGinity JW. Solvent selection in the preparation of poly(DL-lactide) microspheres prepared by the solvent evaporation method. Int J Pharm. 1988;43:179–186. doi: 10.1016/0378-5173(88)90073-7. [DOI] [Google Scholar]
- 20.Schugens C, Laruelle N, Nihant N, Grandfils C, Jérome R, Teyssié P. Effect of the emulsion stability on the morphology and porosity of semicrystalline poly 1-lactide microparticles prepared by w/o/w double emulsion-evaporation. J Control Release. 1994;32:161–176. doi: 10.1016/0168-3659(94)90055-8. [DOI] [Google Scholar]
- 21.Mehta RC, Thanoo BC, DeLuca PP. Peptide containing microspheres from low molecular weight and hydrophilic poly(d,1-lactide-co-glycolide) J Control Release. 2004;41:249–257. doi: 10.1016/0168-3659(96)01332-6. [DOI] [Google Scholar]
- 22.Witschi C, Doelker E. Influence of the microencapsulation method and peptide loading on poly(lactic acid) and poly(lactic-co-glycolic acid) degradation during in vitro testing. J Control Release. 1998;51:327–341. doi: 10.1016/S0168-3659(97)00188-0. [DOI] [PubMed] [Google Scholar]
- 23.Lamprecht A, Ubrich N, Hombreiro Pérez M, Lehr C-M, Hoffman M, Maincent P. Influences of process parameters on nanoparticle preparation performed by a double emission pressure homogenization technique. Int J Pharm. 2000;196:177–182. doi: 10.1016/S0378-5173(99)00422-6. [DOI] [PubMed] [Google Scholar]
- 24.Görner T, Gref R, Michenot D, Sommer F, Tran MN, Dellacherie E. Lidocaine-loaded biodegradable nanospheres. I. Optimization of the drug incorporation into the polymer matrix. J Control Release. 1999;57:259–268. doi: 10.1016/S0168-3659(98)00121-7. [DOI] [PubMed] [Google Scholar]
- 25.Uchida T, Yoshida K, Nakada Y, et al. Preparation and characterization of polylactic acid microspheres containing water-soluble anesthetics with small molecular weight. Chem Pharm Bull (Tokyo) 1997;45:513–517. doi: 10.1248/cpb.45.513. [DOI] [PubMed] [Google Scholar]
- 26.Niwa T, Takeuchi H, Hino T, Kunou N, Kawashima Y. Preparations of biodegradable nanospheres of water-sobuble and insoluble drugs with D,L-lactide/glycolide copolymer by a novel spontaneous emulsification solvent diffusion method, and the drug release behavior. J Control Release. 1993;25:89–98. doi: 10.1016/0168-3659(93)90097-O. [DOI] [Google Scholar]