Abstract
Purpose. The aims of this study were (i) to elucidate the transport mechanisms involved in drug release from hydrophilic matrices; and (ii) to develop an improved mathematical model allowing quantitative predictions of the resulting release kinetics.
Methods. Our previously presented model has been substantially modified, by adding: (i) inhomogeneous swelling; (ii) poorly water-soluble drugs; and (iii) high initial drug loadings. The validity of the improved model has been tested experimentally using hydroxypropyl methylcellulose (HPMC)-matrices, containing either a poorly or a freely water-soluble drug (theophylline or chlorpheniramine maleate) at various initial loadings in phosphate buffer pH 7.4 and 0.1 N HCl, respectively.
Results. By overcoming the assumption of homogeneous swelling we show that the agreement between theory and experiment could be significantly improved. Among others, the model could describe quantitatively even the very complex effect on the resulting relative release rates (first slowing down, then accelerating drug release) observed when increasing the initial loading of poorly water-soluble drugs.
Conclusions. The practical benefit of this work is an improved design model that can be used to predict accurately the required composition and dimensions of drug-loaded hydrophilic matrices in order to achieve desired release profiles, thus facilitating the development of new pharmaceutical products.
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REFERENCES
P. Colombo. Swelling-controlled release in hydrogel matrices for oral route. Adv. Drug Del. Rev. 11:37–57 (1993).
P. Gao and P. E. Fagerness. Diffusion in HPMC gels. I. Determination of drug and water diffusivity by pulsed-field-gradient spin-echo NMR. Pharm. Res. 12:955–964 (1995).
P. Gao and R. H. Meury. Swelling of hydroxypropyl methylcellulose matrix tablets. 1. Characterization of swelling using a novel optical imaging method. J. Pharm. Sci. 85:725–731 (1996).
A. R. Rajabi-Siahboomi, R. W. Bowtell, P. Mansfield, M. C. Davies, and C. D. Melia. Structure and behavior in hydrophilic matrix sustained release dosage forms: 4. Studies of water mobility and diffusion coefficients in the gel layer of HPMC tablets using NMR imaging. Pharm. Res. 13:376–380 (1996).
C. A. Fyfe and A. I. Blazek. Investigation of hydrogel formation from hydroxypropylmethylcellulose (HPMC) by NMR spectroscopy and NMR imaging techniques. Macromolecules 30:6230–6237 (1997).
R. Eyjolfsson. Hydroxypropyl methylcellulose mixtures: Effects and kinetics of release of an insoluble drug. Drug Dev. Ind. Pharm. 25:667–669 (1999).
L. Maggi, E. O. Machiste, M. L. Torre, and U. Conte. Formulation of biphasic release tablets containing slightly soluble drugs. Eur. J. Pharm. Biopharm. 48:37–42 (1999).
B.-J. Lee, S.-G. Ryu, and J.-H. Cui. Formulation and release characteristics of hydroxypropyl methylcellulose matrix tablets containing melatonin. Drug Dev. Ind. Pharm. 25:493–501 (1999).
A. T. Pham and P. I. Lee. Probing the mechanisms of drug release from hydroxypropylmethyl cellulose matrices. Pharm. Res. 11:1379–1384 (1994).
K. M. Picker. The influence of drug concentration on release from tablets made of carrageenans. Proceed. Int'l. Symp. Control. Rel. Bioact. Mater. 26:992–993 (1999).
J. W. Skoug, M. V. Mikelsons, C. N. Vigneron, and N. L. Stemm. Qualitative evaluation of the mechanism of release of matrix sustained release dosage forms by measurement of polymer release. J. Control. Rel. 27:227–245 (1993).
P. Colombo, R. Bettini, P. Santi, A. De Ascentiis, and N. A. Peppas. Analysis of the swelling and release mechanisms from drug delivery systems with emphasis on drug solubility and water transport. J. Control. Rel. 39:231–237 (1996).
R. T. C. Ju, P. R. Nixon, and M. V. Patel. Drug release from hydrophilic matrices. 1. New scaling laws for predicting polymer and drug release based on the polymer disentanglement concentration and the diffusion layer. J. Pharm. Sci. 84:1455–1463 (1995).
R. T. C. Ju, P. R. Nixon, M. V. Patel, and D. M. Tong. Drug release from hydrophilic matrices. 2. A mathematical model based on the polymer disentanglement concentration and the diffusion layer. J. Pharm. Sci. 84:1464–1477 (1995).
P. Gao, P. R. Nixon, and J. W. Skoug. Diffusion in HPMC gels. II. Prediction of drug release rates from hydrophilic matrix extended-release dosage forms. Pharm. Res. 12:965–971 (1995).
P. Gao, J. W. Skoug, P. R. Nixon, T. R. Ju, N. L. Stemm, and K.-C. Sung. Swelling of hydroxypropyl methylcellulose matrix tablets. 2. Mechanistic study of the influence of formulation variables on matrix performance and drug release. J. Pharm. Sci. 85:732–740 (1996).
R. T. C. Ju, P. R. Nixon, and M. V. Patel. Diffusion coefficients of polymer chains in the diffusion layer adjacent to a swollen hydrophilic matrix. J. Pharm. Sci. 86:1293–1298 (1997).
I. Katzhendler, A. Hoffman, A. Goldberger, and M. Friedman. Modeling of drug release from erodible tablets. J. Pharm. Sci. 86:110–115 (1997).
J. Siepmann, K. Podual, M. Sriwongjanya, N. A. Peppas, and R. Bodmeier. A new model describing the swelling and drug release kinetics from hydroxypropyl methylcellulose tablets. J. Pharm. Sci. 88:65–72 (1999).
J. Siepmann, H. Kranz, R. Bodmeier, and N. A. Peppas. HPMC-matrices for controlled drug delivery: A new model combining diffusion, swelling and dissolution mechanisms and predicting the release kinetics. Pharm. Res. 16:1748–1756 (1999).
J. Siepmann, H. Kranz, N. A. Peppas, and R. Bodmeier. Calculation of the required size and shape of hydroxypropyl methylcellulose matrices to achieve desired drug release profiles. Int. J. Pharm., 201:151–164 (2000).
J. Crank. The Mathematics of Diffusion, 2nd ed., Clarendon Press, Oxford, 1975.
H. Fujita. Diffusion in polymer-diluent systems. Fortschr. Hochpolym.-Forsch. 3:1–47 (1961).
B. Narasimhan and N. A. Peppas. Disentanglement and reptation during dissolution of rubbery polymers. J. Polym. Sci., Polym. Phys. 34:947–961 (1996).
B. Narasimhan and N. A. Peppas. On the importance of chain reptation in models of dissolution of glassy polymers. Macromolecules 29:3283–3291 (1996).
B. Narasimhan and N. A. Peppas. Molecular analysis of drug delivery systems controlled by dissolution of the polymer carrier. J. Pharm. Sci. 86:297–304 (1997).
A. A. Noyes and W. R. Whitney. Ñber die Auflösungsgeschwindigkeit von festen Stoffen in ihren eigenen Lösungen. Z. physikal. Chem. 23:689–692 (1897).
R. Bodmeier and O. Paeratakul. Process and formulation variables affecting the drug release from chlorpheniramine maleate-loaded beads coated with commercial and self-prepared aqueous ethyl cellulose pseudolatexes. Int. J. Pharm. 70:59–68 (1991).
R. Bodmeier and H. Chen. Evaluation of biodegradable poly(lactide) pellets prepared by direct compression. J. Pharm. Sci. 78: 819–822 (1989).
L. T. Fan and S. K. Singh. Controlled release: A quantitative treatment, Springer-Verlag, Berlin, 1989.
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Siepmann, J., Peppas, N.A. Hydrophilic Matrices for Controlled Drug Delivery: An Improved Mathematical Model to Predict the Resulting Drug Release Kinetics (the “sequential Layer” Model). Pharm Res 17, 1290–1298 (2000). https://doi.org/10.1023/A:1026455822595
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DOI: https://doi.org/10.1023/A:1026455822595