Abstract
Amlodipine besylate (AML) has become the most popular blood pressure medication for hypertensive pets. It belongs to the class I (high solubility and high permeability) according to BCS and is marketed in Europe only as white tablets equivalent to 2.5, 5.0 and 10.0 mg of amlodipine for oral administration. Unfortunately, oral AML dosage for cats and dogs is in the range 0.1–0.2 and 0.625–0.125 mg/kg/die respectively. Moreover, AML shows a slight solubility in water according to Ph. Eur. 7°. According to these considerations, the aim of this work was the complexation between soluble β-cyclodextrin polymer (CD) and AML using the solubilization/freeze-dried method to obtain powders easily dosable and soluble in water for the treatment of hypertension in pets. The complex in solution was evaluated by phase solubility studies that indicated the optimal 2:1 drug/CD ratio to form a stable complex. UV–Vis absorption and circular dichroism showed the formation of a complex with a weak bond such as confirmed by differential scanning calorimetry, infrared spectroscopy and fluorescence microscopy. In vitro dissolution/release tests were performed in water to investigate the influence of formulative parameters on drug dissolution/release properties. The inclusion of AML in CD increased its wettability, dissolution rate and solubility in water. This method could be a suitable approach for the administration of an extemporaneous solution of the antihypertensive drug to guarantee a correct dose to pets increasing the compliance.
Similar content being viewed by others
References
Brooks W.C.: Veterinary Partner. http://www.veterinarypartner.com/Content.plx?P=A&C=31&A=1215&S=0 (2009). Accessed 1 Nov 2011
Clavijo, G.A., de Clavijo, I.V., Weart, C.W.: Amlodipine: a new calcium antagonist. Am. J. Hosp. Pharm. 51(1), 59–68 (1994)
Murdoch, D., Heel, R.C.: Amlodipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cardiovascular disease. Drugs 41(3), 478–505 (1991)
Cooke, K.L., Snyder, P.S.: Calcium channel blockers in veterinary medicine. J. Vet. Intern. Med. 12(3), 123–131 (1998)
Fasani, E., Albini, A., Gemme, S.: Mechanism of the photochemical degradation of amlodipine. Int. J. Pharm. 352(1–2), 197–201 (2008)
Brewster, M.E., Loftsson, T.: Cyclodextrins as pharmaceutical solubilizers. Adv. Drug Deliv. Rev. 59, 645–666 (2007)
Nikolić, V., Nikolić, L., Stanković, M., Cakić, M., Stanojević, L., Ilić, D.: Inclusion complexes of amlodipine besylate and cyclodextrins. Cent. Eur. J. Chem. 8(4), 834–841 (2010)
Mielcarek, J., Czernielewska, A., Czarczyńska, B.: Inclusion complexes of felodipine and amlodipine with methyl-β-cyclodextrin. J. Incl. Phenom. Macrocycl. Chem. 54(1–2), 17–21 (2006)
Ling, W., Xuehua, J., Weijuan, X., Chenrui, L.: Complexation of tanshinone IIA with 2-hydroxypropyl-b-cyclodextrin: effect on aqueous solubility, dissolution rate, and intestinal absorption behavior in rats. Int. J. Pharm. 341, 58–67 (2007)
Puglisi, G., Santagati, N.A., Ventura, C.A., Pignatello, R., Panico, A.M., Spampinato, S.: Enhancement of 4-biphenylacetic acid bioavailability in rats by its β-cyclodextrin complex after oral administration. J. Pharm. Pharmacol. 43, 430–432 (1991)
Puglisi, G., Ventura, C.A., Spadaro, A., Campana, G., Spampinato, S.: Differential effects of modified β-cyclodextrins on pharmacological activity and bioavailability of 4-biphenylacetic acid in rats after oral administration. J. Pharm. Pharmacol. 47, 120–123 (1995)
Ventura, C.A., Fresta, M., Giovinazzo, C., Puglisi,` G.: Solid state characterization and in solution studies of idebenone-β-cyclodextrin inclusion complex. Acta Tecnol. Legis Medicam. VI, 56–66, N.1 (1995)
Ventura, C.A., Fresta, M., Vandelli, M.A., Cavallaro, G., Zappalà, M.T., Puglisi, G.: Preparation and physico-chemical study of inclusion complexes between idebenone and β-cyclodextrin. J. Incl. Phenom. Mol. Recognit. Chem. 24, 193–210 (1996)
Ventura, C.A., Giannone, I., Paolino, D., Pistarà, V., Corsaro, A., Puglisi, G.: Preparation of celecoxib-dimethyl-β-cyclodextrin inclusion complex: characterization and in vitro permeation study. Eur. J. Med. Chem. 40, 624–631 (2005)
Amididouche, D., Darrouzet, H., Duchene, D., Poelman, M.C.: Inclusion of retinoic acid. J. Pharm. Sci. Technol. 2(3), 171–183 (2010)
Duchene, D., Vaution, C., Glomot, F.: Amelioration de la dissolution et de la biodisponibilitè des principles actifs par inclusion dans ls cyclodextrines. STP Pharma. 1, 323–332 (1985)
Somagoni, J.M., Dharani, S., Panakanti, P.K., Koorelli, S., Manda, S., Madhusudan, R.Y.: Stereospecific dissolution of inclusion complexes of amlodipine base and its besylate enantiomers with hydroxypropyl-β-cyclodextrin. Lat. Am. J. Pharm. 30(7), 1309–1316 (2011)
Somagoni, J., Reddy, S., Katakam, V.K., Koorelli, S., Manda, S., et al.: Preparation of inclusion complexes of amlodipine base and its besylate and maleate salts with hydroxy propyl β-cyclodextrin—a study on stereospecific dissolution. Pharm. Anal. Acta 2, 123 (2011). doi:10.4172/2153-2435.1000123v
Vélaz, I., Isasi, J.R., Sánchez, M., Uzqueda, M., Ponchel, G.: Structural characteristics of some soluble and insoluble β-cyclodextrin polymers. J. Incl. Phenom. Macrocycl. Chem. 57(1–4), 65–68 (2007)
Loftsson, T., Brewster, M.E.: Pharmaceutical applications of cyclodextrins 1 drug solubilization and stabilization. J. Pharm. Sci. 85(10), 1017–1025 (1996)
Nianbing, L., Jianping, D., Hongqing, C., Guonan, C.: Determination of the binding constant for the inclusion complex between procaine hydrochloride and b-cyclodextrin by capillary electrophoresis. Talanta 59, 493–499 (2003)
Benesi, H.A., Hildebrand, J.H.: A spectrophotometric investigation of the interaction of iodine with aromatic hydrocarbons. J. Am. Chem. Soc. 71, 2703–2707 (1949)
Guo, Q.X., Liu, H.Y., Ruan, X.Q., Zheng, X.Q., Shi, Y.Y., Liu, Y.C.: Experimental and theoretical studies on the inclusion complexation of β-cyclodextrin with phenothiazine derivatives. J. Incl. Phenom. Macrocycl. Chem. 35, 487–496 (1999)
Göktürk, S., Çalıskan, E., Talman, R.Y., Var Marmara, U.: A study on solubilization of poorly soluble drugs by cyclodextrins and micelles: complexation and binding characteristics of sulfamethoxazole and trimethoprim. http://www.tswj.com/aip/718791.pdf. Accessed 12 March 2012
Higuchi, T., Connors, K.A.: Phase-solubility techniques. Adv. Anal. Chem. Instrum. 4, 117–212 (1965)
Chadna, R., Kashid, N., Saini, A.: Account of analytical employed techniques for the determination of thermodynamics of inclusion complexation of drugs with cyclodextrins. J. Sci. Ind. Res. 63, 211–229 (2004)
Spulber, M., Pinteala, M., Harabagiu, V., Simionescu, B.C., Fifere, A.: Spectroscopic characterization of α-cyclodextrin–sulconazole inclusion complexes. Determination of binding constants by Rose–Drago approximation. Rom. Soc. Med. Mycol. Mycotoxicol. 2(2), 189–192 (2008)
Loftsson, T., Hreinsdottir, D., Masson, M.: Evaluation of cyclodextrin solubilization of drugs. Int. J. Pharm. 302, 18–28 (2005)
Fernandes, C., Viera, M.T., Veiga, F.: Physicochemical chraracterization and in vitro dissolution behavior of nicardipine–cyclodextrins inclusion compounds. Eur. J. Pharm. Sci. 15, 79–88 (2002)
Ammar, H.O., Salama, H.A., Ghorab, M., Mahmoud, A.A.: Inclusion complexation of glimepiride in dimethyl-β-cyclodextrin. Asian J. Pharm. Sci. 2(2), 44–55 (2007)
Cupka, P., Bella, J., Martvon, A.: Synthesis and spectral properties of substituted 1,4 dihydropiridines and 1,4,5,6,7,8-hexahydroquinolines. Collect. Czechoslov. Chem. Commun. 52, 742–775 (1987)
Jadhav, G.S., Vavia, P.R., Nandedkar, D.T.: Danazol-β-cyclodextrin binary system: a potential application in emergency contraception by the oral route. AAPS PharmSciTech. 8(2), Article 35 (2007). doi:10.1208/pt0802035
Xiang, T.X., Andersoon, B.D.: Inclusion complexes of purine nucleosides with cyclodextrins: II. Investigation of inclusion complex geometry and cavity microenvironment. Int. J. Pharm. 59(1), 45–55 (1990)
Marini, A., Berbenni, V., Bruni, G., Mustarelli, P., Giordano, F., Villa, M.: Thermoanalytical and spectroscopic characterization of betacyclodextrin/ketoprofen inclusion complexes. J. Incl. Phenom. Mol. Recognit. Chem. 22, 221–234 (1995)
Acknowledgments
We would like to thank Dr. Angelo Basile for his useful contribution.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lauro, M.R., Carbone, C., Auditore, R. et al. A new inclusion complex of amlodipine besylate and soluble β-cyclodextrin polymer: preparation, characterization and dissolution profile. J Incl Phenom Macrocycl Chem 76, 19–28 (2013). https://doi.org/10.1007/s10847-012-0168-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10847-012-0168-y