Preparation and Evaluation of Rapidly Disintegrating Fast Release Tablet of Diazepam-Hydroxypropyl-β-Cyclodextrin Inclusion Complex

DOI: 10.4236/pp.2010.11003   PDF   HTML     5,837 Downloads   15,147 Views   Citations


This study was undertaken to develop tablets of diazepam-hydroxypropyl-β-cyclodextrin inclusion complex that disintegrate within 3 minutes and release 85% of drug within 30 minutes to provide rapid action of the drug through oro-mucosal route. Formation of inclusion complex was verified using X-ray diffraction and differential scanning calorimetric studies. Enhanced of aqueous solubility, as evident from phase solubility study, and dissolution of the drug were related with the formation of inclusion complex. Among the various formulations, tablet containing inclusion complex of drug/hydroxypropyl-β-cyclodextrin in a molar ratio of 1:2, and a combination of microcrystalline cellulose/lactose in a ratio of 4:1 disintegrated in 13 seconds and released 85% drug within 9 minutes. Addition of 10% w/w polyvinyl pyrrolidone in the tablet formulation further enhanced the drug release. Accelerated stability study indicated that mean dissolution time of the drug from the tablet did not change significantly within 6 months.

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T. Giri and B. Sa, "Preparation and Evaluation of Rapidly Disintegrating Fast Release Tablet of Diazepam-Hydroxypropyl-β-Cyclodextrin Inclusion Complex," Pharmacology & Pharmacy, Vol. 1 No. 1, 2010, pp. 18-26. doi: 10.4236/pp.2010.11003.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] J. S. Schindler and J. H. Kelly, “Swallowing Disorders in the Elderly,” Laryngoscope, Vol. 112, No. 4, 2002, pp. 589-602.
[2] J. C. Ofstehage and K. Magilvy, “Oral Health and Aging,” Geriatric Nursing, Vol. 81, No. 7, 1986, pp. 238- 241.
[3] G. Motola, F. Russo, F. Mazzeo, B. Rinaldi, A. Capuano, F. Rossi and A. Filipelli, “Over-the-Counter Oral Non-steroidal Anti-Inflammatory Drugs: A Pharmacoepidemi-ologic Study in Southern Italy,” Advances in Therapy, Vol. 18, No. 5, 2001, pp. 216-222.
[4] L. Yang, S. C. James and A. Joseph, “Colon-Specific Drug Delivery: New Approaches and in Vitro/in Vivo Evaluation,” International Journal of Pharmaceutics, Vol. 235, No. 1-2, 2002, pp. 1-15.
[5] K. D. Tripathi, “Essentials of Medical Pharmacology,” 5th Edition, Jaypee Brothers Medical Publishers (P) LTD, New Delhi, 2003.
[6] L. Li, S. Gorukanti, Y. M. Choi and K. H. Kim, “Rap-id-Onset Intranasal Delivery of Anticonvulsants: Phar-macokinetic and Pharmacodynamic Evaluation in Rabbits,” International Journal of Pharmaceutics, Vol. 199, No. 1, 2000, pp. 65-76.
[7] B. Alldredge, A. Gelb, S. Isaacs, M. Corry, F. Allen, S. Ulrich, M. Gottwald, N. O’Neil, J. Neuhaus, M. Segal and D. A. Lowenstein, “Comparison of Lorazepam, DZ, and Placebo for the Treatment of Out-of-Hospital Status Epilepticus,” New England Journal of Medicine, Vol. 345, No. 9, 2001, pp. 631-637.
[8] C. O’Dell, “What Do We Tell Parents of a Child with Simple or Complex Febrile Seizures?” In: T. Z. Baram, and S. Shinnar, Eds., Febrile Seizures, San Diego, CAS Academic Press, 2002, pp. 305-316.
[9] C. O’Dell, S. Shinnar, K. Ballaban-Gil, M. Hornick, M. Sigalova, H. Kang and S. Moshe, “Rectal DZ Gel in the Home Management of Seizures in Children,” Pediatric Neurology, Vol. 33, No. 3, 2005, pp. 166-172.
[10] G. Abdelbary and R. H. Fahmy, “Diazepam-Loaded Solid lipid Nanoparticles: Design and Characterization,” AAPS PharmSciTech, Vol. 10, No. 1, 2009, pp. 211-219.
[11] E. Bechgaard, S. Gizurarason and R. K. Hjortkjaer, “Pharmacokinetic and Pharmacodynamic Response after Intranasal Administration of Diazepam to Rabbits,” Journal of Pharmacy Pharmacology, Vol. 49, No. 8, 1997, pp. 747-750.
[12] S. Gizurarson, F. K. Gudbrandsson, H. Jonsson and E. Bechgaard, “Intranasal Administration of Diazepam Aiming at the Treatment of Acute Seizures: Clinical Trials in Healthy Volunteers,” Biological and Pharmaceutical Bulletin, Vol. 22, No. 4, 1999, pp. 425-427.
[13] E. Rey, J. M. Treluyer and G. Pons, “Pharmacokinetic Optimization of Benzodiazepine Therapy for Acute Sei-zures. Focus on Delivery Routes,” Clinical Pharmacoki-netics, Vol. 36, No. 6, 1999, pp. 409-424.
[14] F. U. Knudsen, “Rectal Administration of Diazepam in Solution in the Acute Treatment of Convulsions in Infants and Children,” Archives of Disease in Childhood, Vol. 54, No. 11, 1979, pp. 855-857.
[15] E. Norris, O. Marzouk, A. Nunn, J. Mclntyre and I. Choonara, “Respiratory Depression in Children Receiving Diazepam for Acute Seizures: A Prospective Study,” De-velopmental Medicine and Child Neurology, Vol. 41, No. 5, 1999, pp. 340-343.
[16] B. R. Ogutu, C. R. J. C. Newton, J. Crawley, S. N. Mu-chohi, G. O. Otieno, G. Edwards, K. Marsh and G. O. Kokwaro, “Pharmacokinetics and Anticonvulsant Effects of Diazepam in Children with Severe Falciparum Malaria and Convulsions,” British Journal of Clinical Pharma-cology, Vol. 53, No. 1, 2002, pp.49-57.
[17] C. W. Graham, R. R. Pagano and J. T. Conner, “Pain and Clinical Thrombophlebitis Following Intravenous Diaze-pam and Lorazepam,” Anaesthesia, Vol. 33, No. 2, 1978, 188-91.
[18] C. Lehmann and G. L. Wannarka, “Bioavailability and Dose Proportionality of Intramuscular Diazepam Admi-nistered by Autoinjector,” Journal of Clinical Pharma-cology, Vol. 48, No. 4, 2008, pp. 436-444.
[19] J. G. Hardman, L. E. Limbard and A. G. Gilman, “The Pharmacological Basis of Therapeutics,” 10th Edition, McGraw-Hill Medical Publishing Division, New Delhi, 2001.
[20] A. J. Hoogstrate, J. C. Verhoef, B. Tuk and A. Pijpers, “In-Vivo Buccal Delivery of Fluorescin Isothiocyanate- Dextran 4400 with Glycodeoxycholate as an Absorption Enhancer in Pig,” Journal of Pharmaceutical Sciences, Vol. 85, No. 5, 1996, pp. 457-460.
[21] T. Keiko, O. Yasuko, N. Tsuneji, L. Thorseinn and T. Kozo, “Buccal Absorption of Ergotamine Tartrate Using the Bioadhesive Tablet System in Guinea-Pigs,” Interna-tional Journal of Pharmaceutics, Vol. 238, No. 1-2, 2002, pp. 161-170.
[22] B. S. Kuchekar, S. B. Bhise and V. Arumugam, “Design of Fast Dissolving Tablet,” Indian Journal of Pharma-ceutical Education, Vol. 35, No. 4, 2001, pp. 150-152.
[23] T. Loftsson, “Cyclodextrins and the Biopharmaceutics Classification System of Drugs,” Journal of Inclusion Phenomenon, Vol. 44, No. 1-4, 2002, pp. 63-67.
[24] M. Sugimoto, S. Narisawa, K. Matsubara, H. Yoshino, M. Nakano and T. Handa, “Effect of Formulated Ingredients on Rapidly Disintegrating Oral Tablets Prepared by the Crystalline Transition Method,” Chemical and Pharma-ceutical Bulletin, Vol. 54, No. 2, 2006, pp. 175-180.
[25] H. N. Joshi, R. W. Tejwani, M. Davidovich, V. P. Saha-srabudhe, M. Jemal, M. S. Bathala, S. A. Varia and A. T. M. Serajuddin, “Bioavailability Enhancement of a Poorly Water-Soluble Drug by Solid Dispersion in Polyethylene Glycol-Polysorbate 80 Mixture,” International Journal of Pharmaceutics, Vol. 269, No. 1, 2004, pp. 251-258.
[26] P. C. Sheen, V. K. Khetarpal, C. M. Cariola and C. E. Rowlings, “Formulation Studies of a Poorly Water-Soluble Drug in Solid Dispersions to Improve Bioavailability,” International Journal of Pharmaceutics, Vol. 118, No. 2, 1995, pp. 221-227.
[27] P. Mura, A. Manderioli, G. Bramanti and L. Ceccarelli, “The Properties of Solid Dispersions of Naproxen in Various Polyethylene Glycols,” Drug Development and Industrial Pharmacy, Vol. 22, No. 9-10, 1996, pp. 909- 916.
[28] T. Kai, Y. Akiama, S. Nomura and M. Sato, “Oral Ab-sorption Improvement of Poorly Soluble Drug Using Solid Dispersion Technique,” Chemical and Pharmaceutical Bulletin, Vol. 44, No. 3, 1996, pp. 568-571.
[29] C. Leuner and J. Dressman, “Improving Drug Solubility for Oral Delivery Using Solid Dispersions,” European Journal of Pharmaceutical Sciences, Vol. 50, No. 1, 2000, pp. 47-60.
[30] T. Loftsson, “Cyclodextrin Complexation,” US Patent, 1995, 5472954.
[31] M. Gohel, M. Patel, A. Amin, R. Agarwal, R. Dave and N. Bariya, “Formulation Design and Optimization of Mouth Dissolve Tablets of Nimesulide Using Vacuum Drying Technique,” AAPS PharmSciTech, Vol. 5, No. 3, 2004, Article 36.
[32] S. Chutimaworapan, G. C. Ritthidej, E. Yonemochi, T. Oguchi and K. Yamamoto, “Effect of Water-Soluble Car-riers on Dissolution Characteristics of Nifedipine Solid Dispersions,” Drug Development and Industrial Phar-macy, Vol. 26, No. 11, 2000, pp. 1141-1150.
[33] H. G. Choi, K. M. Kim, H. W. Jun, B. K. Yoo and C. S. Yong, “Improvement of Dissolution and Bioavailability of Nifedipine by Inclusion in Hydroxypropyl-β-Cyclo- dextrin,” Drug Development and Industrial Pharmacy, Vol. 29, No. 10, 2003, pp. 1085-1094.
[34] H. J. Ahn, K. M. Kim, S. J. Choi and C. K. Kim, “Effects of Cyclodextrin Derivatives on Bioavailability of Keto-profen,” Drug Development and Industrial Pharmacy, Vol. 23, No. 4, 1997, pp. 397-401.
[35] A. Latrofa, G. Trapani, M. Franco, M. Serra, M. Muggi-roni, F. P. Franizzi, A. Cutrignelli and G. Liso, “Com-plexation of Phenytoin with Some Hydrophilic Cyclodex-trins: Effect on Aqueous Solubility, Dissolution Rate and Anti-Convulsant Activity in Mice,” European Journal of Pharmaceutics and Biopharmaceutics, Vol. 52, No. 1, 2001, pp. 65-73.
[36] T. Higuchi and K. A. Connors, “Phase-Solubility Tech-niques,” Advances in Analytical Chemistry and Instru-mentation, Vol. 53, No. 4, 1965, pp. 117-212.
[37] Y. Watanable, K. I. Koizumi, Y. Zama, M. Kiriyama and M. Matsumoto, “New Compressed Tablet Rapidly Disin-tegrating in Saliva in the Mouth Using Crystalline Cellu-lose and a Disintegrant,” Biological and Pharmaceutical Bulletin, Vol. 18, No. 9, 1995, pp. 1308-1310.
[38] K. I. Koizumi, Y. Watanable, K. Morita, N. Utoguchi and M.Matsumoto, “New method for preparing high-porosity rapidly saliva soluble compressed tablets using mannitol with camphor, a subliming material,” International Journal of Pharmaceutics, Vol. 152, No. 1, 1997, pp. 127- 131.
[39] H. A. Lieberman, L. Lachman and J. B. Schwartz, “Pharmaceutical Dosage Forms: Tablets Vol. 2,” 2nd Edition, Marcel Dekker, New York, 1990, pp. 1-71.
[40] Y. Bi, H. Sunada, Y. Yonezawa, K. Danjo, A. Otsuka and K. Iida, “Preparation and Evaluation of a Compressed Tablet Rapidly Disintegrating in the Oral Cavity,” Chem-ical and Pharmaceutical Bulletin, Vol. 44, No. 11, 1996, pp. 2121-2127.
[41] R. C. Rowe, P. J. Sheskey and P. J. Weller, “Handbook of Pharmaceutical Excipients,” 4th Edition, Pharmaceutical Society of Great Britain, London, 2003.
[42] K. A. Khan, “The Concept of Dissolution Efficiency,” Journal of Pharmacy and Pharmacology, Vol. 27, No. 1, 1975, pp. 48-49.

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