DOI QR코드

DOI QR Code

Formulation Design of Sustained-Release Matrix Tablets Containing 4-Aminopyridine

유드라짓과 알긴산 나트륨 매트릭스를 이용한 4-Aminopyridine의 서방성 제제설계

  • Kim, Jeong-Soo (College of Pharmacy, Chungnam National University) ;
  • Kim, Dong-Woo (College of Pharmacy, Chungnam National University) ;
  • Lee, Gye-Won (Dept. of Pharmaceutical Engineering Konyang University) ;
  • Jee, Ung-Kil (College of Pharmacy, Chungnam National University)
  • Published : 2005.12.20

Abstract

4-Aminopyridine (AP) is a potassium channel blocker used in the treatment of neurological disorders such as multiple sclerosis and Alzheimer disease. AP‘s window of therapeutic effect appears to correlate with its plasma halflife (3.5 hours). It demonstrates pH-dependent solubility because of a weakly basic drug. In addition, the resulting release from conventional matrix tablets decreases with increasing pH-milieu of the gastrointestinal tract. The aim of this study is to design sustained release matrix tablet containing AP, overcoming this problem. $Eudragit^{\circledR}$ L 100 (EuL) and sodium alginate were used in an effort to achieve pH independent drug release. The effect of sodium alginate and EuL on drug release from matrix tablet was investigated. The drug release behavior from the different tablets was analyzed by $t_{20%},\;t_{40%},\;t_{60%}$, The exponential diffusion coefficient n, kinetic constant K were calculated according to the Korsmeyer-Peppas equation. The drug release from matrix tablets prepared with sodium alginate was decreased with increasing the content of sodium alginate in pH 7.4 while there is no significant difference in pH 1.2. The exponent n values were determined to be approximately 0.5 and 0.8 respectively, in both pH 1.2 and 7.4. These values indicate diffusion-based anomalous mechanism and erosion-based anomalous mechanism, respectively. The drug release from sodium alginate matrix tablets prepared with solid dispersion of EuL containing drug showed a slow drug release in an acidic medium and a more fast drug release in phosphate medium, compared with sodium alginate matrix tablets prepared with physical mixture. These results may be attributed to the gel forming ability of sodium alginate and pH dependent solubility of EuL. Therefore, sustained-release AP matrix tablets using sodium alginate and EuL were successfully prepared.

Keywords

References

  1. M. Davidson, Z. Zemishlany, R.C. Mohs, T.B. Horvath, P. Powchik, J.P. Blass and K.L. Davis, 4-Aminopyridine in the treatment of Alzheimer's disease, BioI. Psychiatry, 23, 485-490 (1988) https://doi.org/10.1016/0006-3223(88)90020-0
  2. F.A. Davis, D. Stefoski and J. Rush, Orally administered 4-aminopyridine improves clinical signs in multiple sclerosis, Ann. Neurol., 27, 186-192 (1990) https://doi.org/10.1002/ana.410270215
  3. J.L. Segal and S.R. Brunnemann, 4-Aminopyridine improves pulmonary function in quadriplegic humans with longstanding spinal cord injury, Pharmacotherapy, 17, 415-423 (1997)
  4. J. Evenhuis, S. Agoston, P.J. Salt, AR. de Lange, W. Wouthuyzen and W. Erdmann, Pharmacokinetics of 4-aminopyridine in human volunteers. A preliminary study using a new GLC method for its estimation, Br. J. Anaesth., 53, 567-570 (1981) https://doi.org/10.1093/bja/53.6.567
  5. K.C. Hayes, M.A. Katz, J.G. Devane, J.T.C. Hsieh, D.L. Wolfe, P.J. Porter and A. R. Blight, Pharmacokinetics of an immediate-release oral formulation of fampridine (4- Aminopyridine) in normal subjects and patients with spinal cord injury, J. Clin. Pharmacol., 43, 379-385 (2003) https://doi.org/10.1177/0091270003251388
  6. K.C. Hayes, P.J. Potter, J.T. Hsieh, M.A. Katz, A.R. Blight and R. Cohen, Pharmacokinetics and sailety of multiple oral doses of sustained-release 4-aminopyridine (fampridine-sr) in subjects with chronic, incomplete spinal cord injury, Arch Phys. Med. Rehabil., 85, 29-34 (2004) https://doi.org/10.1016/S0003-9993(03)00651-8
  7. Y. Qiu, K. Flood, K. Marsh, S. Caroll, J. Trivedi, S.P. Americ and S.L. Krill, Design of sustained-release matrlx systems for a highly water-soluble compound, ABT-089, Int. J. Pharm., 157, 43-52 (1997) https://doi.org/10.1016/S0378-5173(97)00215-9
  8. N.K. Ebube and A.B. Jones, Sustained release of acetaminophen from a heterogeneous mixture of two hydrophilic non-ionic cellulose ether polymers, Int. J. Pharm., 272, 19-27 (2004) https://doi.org/10.1016/j.ijpharm.2003.11.020
  9. E.Y. Yi, S.Y. Park, U.K. Jee and D.C. Kim, Pharmaceutical formulation and evaluation of sustained-release hydrophilic matrix tablet of cefatrizine propyleneglycol using polyethylene oxide, J. Kor.Pharm. Sci., 31, 37-41 (2001)
  10. C. Van der Veen, H. Buitendijk and C.P. Lerk, The effect of acidic excipients on the release of weakly basic drugs from the programmed release megaloporous system, Eur. J. Pharm. Biopharm., 37, 238-242 (1991)
  11. H. Juarez, G. Rico and L. Villafuerte, Influence of admixed carboxymethylcellulose on reIease of 4-aminopyridine from hydroxypropyl methylcellulose matrix tablets, Int. J. Pharm., 216, 115-125 (2001) https://doi.org/10.1016/S0378-5173(01)00583-X
  12. M.M. Talukdar and R. Kinget, Swelling and drug release behaviour of xanthan gum matrix tablets, Int. J. Pharm., 120, 63-72(1995) https://doi.org/10.1016/0378-5173(94)00410-7
  13. P. Costa and J.M. Sausa Lobo, Modeling and comparison of dissolution profiles Eur. J. Pharm, Sci., 13, 123-133 (2001) https://doi.org/10.1016/S0928-0987(01)00095-1
  14. J. Siepmann and N.A. Peppas, Modeling of drug release from delivery systems based on hydroxypropyl methyl-cellulose(HMPC), Adv. Drug Deliv. Rev. 48, 139-157 (2001) https://doi.org/10.1016/S0169-409X(01)00112-0
  15. P.L. Ritger and N.A. Peppas, A simple equation for description of solute release. II. Fickian and anomalous release from swellable devices, J. Controll. ReI., 5, 37-42 (1987) https://doi.org/10.1016/0168-3659(87)90035-6
  16. C. Alison, C. Hodsdon, J.R. Mitchell, M.C. Davies and C.D. Melia, Structure and behaviour in hydrophilic matrix sustained release dosage forms: 3. The influence of pH on the sustained-release performance and internal gel structure of sodium alginate matrices, J. Controll. ReI., 33, 143-152 (1995) https://doi.org/10.1016/0168-3659(94)00076-7