Skip to main content
PMC home page
AAPS PharmSciTech logoLink to AAPS PharmSciTech
. 2004 Apr 20;5(2):69–76. doi: 10.1208/pt050233

The influence of the copolymer composition on the diltiazem hydrochloride release from a series of pH-sensitive poly[(N-isopropylacrylamide)-co-(methacrylic acid)] hydrogels

Eva Díez-Peña 1, Paloma Frutos 2, Gloria Frutos 3, Isabel Quijada-Garrido 1,✉, José Manuel Barrales-Rienda 1
PMCID: PMC2750468  PMID: 15760091

Abstract

A series of poly[(N-isopropylacrylamide)-co-(methacrylic acid)] (P[(N-iPAAm)-co-(MAA)]) hydrogels was investigated to determine the composition that exhibits a better pH-modulated release of diltiazem hydrochloride (DIL.HCl). For this purpose hydrogel slabs were loaded with DIL.HCl by the immersion method, and its release under acidic medium (0.1N HCl, pH 1.2) and in phosphate buffer pH 7.2, using United States Pharmacopeia (USP) 24 Apparatus 1, was investigated. According to the results from the slabs, copolymers with 85% mol N-iPAAm content were selected to prepare tablets with different particle size. The effect of pH and particle size changes on DIL.HCl release from these last hydrogel tablets was investigated by a stepwise pH variation of the dissolution medium. The amount of DIL.HCl released from high N-iPAAm content copolymer slabs under acidic pH medium was not only very low but it was also released at a slow rate. In the 85% N-iPAAm tablets, significant differences between and within release profiles were found as a function of particle size and pH, respectively. A relationship between particle size and release rate has been found. The lower DIL.HCl release at acidic pH from enriched N-iPAAm copolymers is interpreted by a cooperative thermal- and pH-collapse. Although for the whole range of copolymer composition a dependence of the equilibrium of swelling on the pH was found, DIL.HCl release experiments indicated that hydrogels with 85% mol N-iPAAm are the more adequate to be used for modulated drug delivery systems. Additionally, the particle size of the tablet can be used to tailor the release rate.

Keywords: diltiazem hydrochloride, N-isoprylacrylamide, methacrylic acid, hydrogel, pH-modulated release

Full Text

The Full Text of this article is available as a PDF (190.3 KB).

References

  • 1.Colombo P, Bettini R, Santi P, De Ascentiis A, Peppas NA. Analysis of the swelling and release mechanisms from drug delivery systems with emphasis on drug solubility and water transport. J Control Release. 1996;39:231–237. doi: 10.1016/0168-3659(95)00158-1. [DOI] [Google Scholar]
  • 2.Kim H, Fassihi R. Application of binary polymer systems in drug release rate modulation: Influence of formulation variable and hydrodynamic conditions on release kinetics. J Pharm Sci. 1997;86:323–328. doi: 10.1021/js960307p. [DOI] [PubMed] [Google Scholar]
  • 3.Conte U, Maggi A, Colombo L, Lamanna A. Multi-layered hydrophilic matrixes as constant release devices. J Control Release. 1993;26:39–47. doi: 10.1016/0168-3659(93)90207-L. [DOI] [Google Scholar]
  • 4.Conte U, Maggi L. Modulation of the dissolution profiles from Geomatrix (R) multi-layer matrix tablets containing drugs of different solubility. Biomaterials. 1996;17:889–896. doi: 10.1016/0142-9612(96)83284-4. [DOI] [PubMed] [Google Scholar]
  • 5.Evans DF, Pye G, Bramley R, Clark AG, Dyson TJ, Hardcastle JD. Measurement of gastrointestinal pH profiles in normal ambulant human subjects. Gut. 1988;29:1035–1041. doi: 10.1136/gut.29.8.1035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Jeong B, Kim SW, Bae YH. Thermosensitive sol-gel reversible hydrogels. Adv Drug Deliver Rev. 2002;54:37–51. doi: 10.1016/S0169-409X(01)00242-3. [DOI] [PubMed] [Google Scholar]
  • 7.Chen GH, Hoffman AS. Graft copolymers that exhibit temperature-induced phase transitions over a wide range of pH. Nature. 1995;373:49–52. doi: 10.1038/373049a0. [DOI] [PubMed] [Google Scholar]
  • 8.Yoshida R, Uchida K, Kaneko Y, Sakai K, Kikuchi A, Sakurai Y, Okano T. Comb-type grafted hydrogels with rapid deswelling response to temperature changes. Nature. 1995;374:240–242. doi: 10.1038/374240a0. [DOI] [Google Scholar]
  • 9.Kwon IC, Bae YH, Kim SW. Electrically credible polymer gels for controlled release of drugs. Nature. 1991;354:291–293. doi: 10.1038/354291a0. [DOI] [PubMed] [Google Scholar]
  • 10.Brazel CS, Peppas NA. Synthesis and characterization of thermo- and chemomechanically responsive poly[(N-isopropylacrylamide)-co-(methacrylic acid)] hydrogels. Macromolecules. 1995;28:8016–8020. doi: 10.1021/ma00128a007. [DOI] [Google Scholar]
  • 11.Bae YH, Okano T, Hsu R, Kim SW. Thermosensitive polymers as on-off switches for drug release. Makcromol Chem-Rapid. 1987;8:481–485. doi: 10.1002/marc.1987.030081002. [DOI] [Google Scholar]
  • 12.Gutowska A, Bae YH, Jacobs H, Feijen J, Kim SW. Thermosensitive interpenetrating polymer networks-synthesis, characterization, and macromolecular release. Macromolecules. 1994;27:4167–4175. doi: 10.1021/ma00093a018. [DOI] [Google Scholar]
  • 13.Pham AT, Lee PI. Probing the mechanism of drug release from hydroxylpropyl methyl cellulose (HPMC) matrices. Pharm Res. 1994;11:1379–1384. doi: 10.1023/A:1018975318805. [DOI] [PubMed] [Google Scholar]
  • 14.Moeckel JE, Lippold BC. Zero-order drug release from hydrocolloid matrixes. Pharm Res. 1993;10:1066–1070. doi: 10.1023/A:1018931210396. [DOI] [PubMed] [Google Scholar]
  • 15.Colombo P, Bettini R, Massimo G, Catellani PL, Santi P, Peppas NA. Drug diffusion front movement is important in drug release control from swellable matrix tablets. J Pharm Sci. 1995;84:991–997. doi: 10.1002/jps.2600840816. [DOI] [PubMed] [Google Scholar]
  • 16.Brazel CS, Peppas NA. Pulsatile local delivery of thrombolytic and antithrombotic agents using poly[(N-isopropylacrylamide)-co-(methacrylic acid)] hydrogels. J Control Release. 1996;39:57–64. doi: 10.1016/0168-3659(95)00134-4. [DOI] [Google Scholar]
  • 17.Huglin MB, Liu Y, Velada JL. Thermoreversible swelling behaviour of hydrogels based on N-isopropylacrylamide with acidic comonomers. Polymer. 1997;38:5785–5791. doi: 10.1016/S0032-3861(97)00135-3. [DOI] [Google Scholar]
  • 18.Vakkalanka SK, Brazel CS, Peppas NA. Temperature- and pH-sensitive terpolymers for modulated delivery of streptokinase. J Biomat Sc-Polym E. 1996;8:119–129. doi: 10.1163/156856296X00192. [DOI] [PubMed] [Google Scholar]
  • 19.Yang HH, Zhu QZ, Chen S, et al. Fluorescence immunoassay system based on the use of a pH-sensitive phase-separating polymer. Anal Biochem. 2001;296:167–173. doi: 10.1006/abio.2001.5184. [DOI] [PubMed] [Google Scholar]
  • 20.Zhang K, Wu XY. Modulated insulin permeation across a glucose-sensitive polymeric composite membrane. J Control Release. 2002;80:169–178. doi: 10.1016/S0168-3659(02)00024-X. [DOI] [PubMed] [Google Scholar]
  • 21.Kono K, Okabe H, Morimoto K, Takagishi T. Temperature-dependent permeability of polyelectrolyte complex capsule membranes having N-isopropylacrylamide domains. J Appl Polym Sci. 2000;77:2703–2710. doi: 10.1002/1097-4628(20000919)77:12<2703::AID-APP180>3.0.CO;2-P. [DOI] [Google Scholar]
  • 22.Xue W, Champ S, Huglin MB. Observations on some copolymerizations involving N-isopropylacrylamide. Polymer. 2000;41:7575–7581. doi: 10.1016/S0032-3861(00)00171-3. [DOI] [Google Scholar]
  • 23.Diez-Peña E, Quijada-Garrido I, Barrales-Rienda JM, Wilhelm M, Spiess HW. NMR studies of the structure and dynamics of polymers gels based on N-isopropylacrylamide (N-iPAAm) and methacrylic acid (MAA) Macromol Chem. 2002;203:491–502. doi: 10.1002/1521-3935(20020201)203:3<491::AID-MACP491>3.0.CO;2-1. [DOI] [Google Scholar]
  • 24.Diez-Peña E, Quijada-Garrido I, Frutos P, Barrales-Rienda JM. Thermal properties of cross-linked poly (N-isopropylacrylamide) [P(N-iPAAm)], poly(methacrylic acid) [P(MAA)], their random copolymers [P(N-iPAAM)-co-(MAA)], and sequential interpenetrating polymer networks (IPNs) Macromolecules. 2002;35:2667–2675. doi: 10.1021/ma011520x. [DOI] [Google Scholar]
  • 25.Diez-Peña E, Quijada-Garrido I, Barrales-Rienda JM. On the water swelling behaviour of poly(N-isopropylacrylamide) [P(N-iPAAm)], poly(methacrylic acid) [P(MAA)], their random copolymers and sequential interpenetrating polymer networks (IPNs) Polymer. 2002;43:4341–4348. doi: 10.1016/S0032-3861(02)00270-7. [DOI] [Google Scholar]
  • 26.Diez-Peña E, Quijada-Garrido I, Barrales-Rienda JM. Influence of the hydrogen bonding on the swelling behavior of P[(N-iPAAm)-co-(MAA)] copolymers: A case of autocatalytic swelling kinetics. Macromolecules. 2002;35:8882–8888. doi: 10.1021/ma020895v. [DOI] [Google Scholar]
  • 27.Fukui E, Miyamura N, Uenua K, Kobayashi M. Preparation of enteric coated timed-release press-coated tablets and evolution of their function by in vitro and in vivo tests for colon targeting. Int J Pharm. 2000;204:7–15. doi: 10.1016/S0378-5173(00)00454-3. [DOI] [PubMed] [Google Scholar]
  • 28.Pillay V, Fassihi R. Electrolyte-induced composition heterogeneity: A model for rate-controlled oral dry delivery. J Pharm Sci. 1999;88:1140–1144. doi: 10.1021/js9901054. [DOI] [PubMed] [Google Scholar]
  • 29.Fukui E, Uemura K, Kobayashi M. Studies on applicability of press-coated tablets using hydroxypropylcellulose (HPC) in the outer shell for timed-release preparations. J Control Release. 2000;68:215–223. doi: 10.1016/S0168-3659(00)00261-3. [DOI] [PubMed] [Google Scholar]
  • 30.Sawada T, Sako K, Yoshihara K, Nakamura K, Yokohama S, Hayashi S. Timed-release formulation to avoid drug-drug interaction between diltiazem and midazolam. J Pharm Sci. 2003;92:790–797. doi: 10.1002/jps.10336. [DOI] [PubMed] [Google Scholar]
  • 31.Kim SW, Bae YH, Okano T. Hydrogels, swelling, drug loading and release. Pharm Res. 1992;9:283–290. doi: 10.1023/A:1015887213431. [DOI] [PubMed] [Google Scholar]
  • 32.United States Pharmacopoeia Convention . United States Pharmacopeia: USP 24-NF 19. 24th ed. Rockville, MD: Mack Printing Company; 2000. [Google Scholar]
  • 33.Pillay V, Fassihi R. In situ electrolyte interactions in and disk-composed configuration system for up-curving and constant drug delivery. J Control Release. 2000;67:55–65. doi: 10.1016/S0168-3659(00)00192-9. [DOI] [PubMed] [Google Scholar]
  • 34.Bell CL, Peppas NA. Modulation of drug permeation through interpolymer complexed hydrogels for drug delivery applications. J Control Release. 1996;39:201–207. doi: 10.1016/0168-3659(95)00154-9. [DOI] [Google Scholar]
  • 35.Gazzaniga A, Iamartino P, Maffione G, Sangalli ME. Oral delayed-release system for colonic specific delivery. Int J Pharm. 1994;108:77–83. doi: 10.1016/0378-5173(94)90418-9. [DOI] [Google Scholar]
  • 36.Frutos P, Pabón C, Lastres JL, Frutos G. In vitro release of metoclopramide from hydrophobic matrix tablets: Influence of hydrodynamic conditions on kinetic release parameters. Chem Pharm Bull (Tokyo) 2001;49:1267–1271. doi: 10.1248/cpb.49.1267. [DOI] [PubMed] [Google Scholar]
  • 37.Heskins M, Guillet JE. Solution properties of poly(N-isopropylacrylamide) J Macromol Sci Chem A2. 1968;8:1441–1455. doi: 10.1080/10601326808051910. [DOI] [Google Scholar]
  • 38.Kratz K, Hellweg T, Eimer W. Influence of charge density on the swelling of colloidal poly[(N-isopropylacrylamide)-co-(acrylic acid)] microgels. Colloid Surface A. 2000;170:137–149. doi: 10.1016/S0927-7757(00)00490-8. [DOI] [Google Scholar]
  • 39.Korsmeyer RW, Gurny R, Doelker EM, Buri P, Peppas NA. Mechanism of solute release from porous hydrophilics polymers. Int J Pharm. 1983;15:25–35. doi: 10.1016/0378-5173(83)90064-9. [DOI] [PubMed] [Google Scholar]
  • 40.Peppas NA. Analysis of Fickian and non-Fickian drug release from polymers. Pharm Acta Helv. 1985;60:110–111. [PubMed] [Google Scholar]

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

RESOURCES