Skip to main content
PMC home page
AAPS PharmSci logoLink to AAPS PharmSci
. 2001 Feb 28;3(1):92–99. doi: 10.1208/ps030108

pH-Dependent dissolving nano- and microparticles for improved peroral delivery of a highly lipophilic compound in dogs

F De Jaeghere 1, E Allémann 1, E Doelker 1, R Gurny 1,✉, R Cerny 2, B Galli 3, A F Steulet 3, I Müller 3, H Schütz 3
PMCID: PMC2751240  PMID: 11741259

Abstract

RR01, a new highly lipophilic drug showing extremely low water solubility and poor oral bioavailability, has been incorporated into pH-dependent dissolving particles made of a poly(methacrylic acid-co-ethylacrylate) copolymer. The physicochemical properties of the particles were determined using laser-light-scattering techniques, scanning electron microscopy, high-performance liquid chromatography, and x-ray powder diffraction. Suspension of the free drug in a solution of hydroxypropylcellulose (reference formulation) and aqueous dispersions of pH-sensitive RR01-loaded nanoparticles or microparticles were administered orally to Beagle dogs according to a 2-block Latin square design (n =6). Plasma samples were obtained over the course of 48 hours and analyzed by gas chromatography/mass spectrometry. The administration of the reference formulation resulted in a particularly high interindividual variability of pharmacokinetic parameters, with low exposure to compound RR01 (AUC0–48h of 6.5 μg.h/mL and coefficient of variation (CV) of 116%) and much higher Tmax, as compared to both pH-sensitive formulations. With respect to exposure and interindividual variability, nanoparticles were superior to microparticles (AUC0–48h of 27.1 μg.h/mL versus 17.7 μg.h/mL with CV of 19% and 40%, respectively), indicating that the particle size may play an important role in the absorption of compound RR01. The performance of pH-sensitive particles is attributed to their ability to release the drug selectively in the upper part of the intestine in a molecular or amorphous form. In conclusion, pH-dependent dissolving particles have a great potential as oral delivery systems for drugs with low water solubility and acceptable permeation properties.

KeyWords: Nanoparticles, Microparticles, Oral Administration, Poor Water Solubility, pH-Sensitive Polymer

References

  • 1.Ungell A-L. In vitro absorption studies and their relevance to absorption from the GI tract. Drug Dev Ind Pharm. 1997;23:879–892. doi: 10.3109/03639049709148694. [DOI] [Google Scholar]
  • 2.Chan OH, Schmid HL, Stilgenbauer LA, Howson W, Horwell DC, Stewart BH. Evaluation of a targeted prodrug strategy to enhance oral absorption of poorly water-soluble compounds. Pharm Res. 1998;15:1012–1018. doi: 10.1023/A:1011969808907. [DOI] [PubMed] [Google Scholar]
  • 3.Devane J. Oral drug delivery technology: Addressing the solubility/permeability paradigm. Pharm Technol. 1998;22:68–80. [Google Scholar]
  • 4.Humberstone AJ, Charman WN. Lipid-based vehicles for the oral delivery of poorly water soluble drugs. Adv Drug Delivery Rev. 1997;25:103–128. doi: 10.1016/S0169-409X(96)00494-2. [DOI] [Google Scholar]
  • 5.Liversidge GG, Cundy KC. Particle size reduction for improvement of oral bioavailability of hydrophobic drugs: I. Absolute oral bioavailability of nanocrystalline danazol in beagle dogs. Int J Pharm. 1995;125:91–97. doi: 10.1016/0378-5173(95)00122-Y. [DOI] [Google Scholar]
  • 6.Sugimoto M, Okagaki T, Narisawa S, Koida Y, Nakajima K. Improvement of dissolution characteristics and bioavailability of poorly water-soluble drugs by novel cogrinding method using water-soluble polymer. Int J Pharm. 1998;160:11–19. doi: 10.1016/S0378-5173(97)00293-7. [DOI] [Google Scholar]
  • 7.Serajuddin ATM, Sheen P-C, Mufson D, Bernstein DF, Augustine MA. Effect of vehicle amphiphilicity on the dissolution and bioavailability of poorly water-soluble drug from solid dispersions. J Pharm Sci. 1988;77:414–417. doi: 10.1002/jps.2600770512. [DOI] [PubMed] [Google Scholar]
  • 8.Leroux JC, Cozens R, Roesel JL, Galli B, Kubel F, Doelker E, Gurny R. Pharmacokinetics of a novel HIV-1 protease inhibitor incorporated into biodegradable or enteric nanoparticles following intravenous and oral administration to mice. J Pharm Sci. 1995;84:1387–1391. doi: 10.1002/jps.2600841202. [DOI] [PubMed] [Google Scholar]
  • 9.Leroux JC, Cozens R, Roesel JL, Galli B, Doelker E, Gurny R. pH-Sensitive nanoparticles an effective means to improve the oral delivery of HIV-1 protease inhibitors in dogs. Pharm Res. 1996;13:485–487. doi: 10.1023/A:1016073416332. [DOI] [PubMed] [Google Scholar]
  • 10.Jaeghere F, Allémann E, Kubel F, Galli B, Cozens R, Doelker E, Gurny R. Oral bioavailability of a poorly water soluble HIV-1 protease inhibitor incorporated into pH-sensitive nanoparticles: effect of the particle size and nutritional state. J Control Release. 2000;68:291–298. doi: 10.1016/S0168-3659(00)00272-8. [DOI] [PubMed] [Google Scholar]
  • 11.Jaeghere F, Allémann E, Kubel F, Galli B, Doelker E, Gurny R. pH-Sensitive microparticles as oral delivery systems for antiinfective agents of poor water solubility. Proc 2nd World Meeting APGI/APV. 1998;2:559–560. [Google Scholar]
  • 12.Leroux JC, Allémann E, Doelker E, Gurny R. New approach for the preparation of nanoparticles by an emulsification-diffusion method. Eur J Pharm Biopharm. 1995;41:14–18. [Google Scholar]
  • 13.Quintanar-Guerrero D, Fessi H, Allémann E, Doelker E. Influence of stabilizing agents and preparative variables on the formation of poly(D,L-lactic acid) nanoparticles by an emulsification-diffusion technique. Int J Pharm. 1996;143:133–141. doi: 10.1016/S0378-5173(96)04697-2. [DOI] [Google Scholar]
  • 14.Allémann E, Doelker E, Gurny R. Drug loaded poly(lactic acid) nanoparticles produced by a reversible salting-out process: purification of an injectable dosage form. Eur J Pharm Biopharm. 1993;39:13–18. [Google Scholar]
  • 15.Giunchedi P, Torre ML, Maggi L, Conti B, Conte U. Cellulose acetate trimetillate ethylcellulose blends for nonsteroidal anti-inflammatory drug (NSAID) microspheres. J Microencapsulation. 1996;13:89–98. doi: 10.3109/02652049609006805. [DOI] [PubMed] [Google Scholar]
  • 16.Labouret A, Thioune O, Fessi H, Devissaguet JP, Puisieux F. Application of an original process for obtaining colloidal dispersions of some coating polymers preparation, characterization, industrial scale-up. Drug Dev Ind Pharm. 1995;21:229–241. doi: 10.3109/03639049509048106. [DOI] [Google Scholar]
  • 17.Maa Y-F, Nguyen P-AT, Hsu SW. Spray-drying of air-liquid interface sensitive recombinant human growth hormone. J Pharm Sci. 1998;87:152–159. doi: 10.1021/js970308x. [DOI] [PubMed] [Google Scholar]

Articles from AAPS PharmSci are provided here courtesy of American Association of Pharmaceutical Scientists

RESOURCES