Study On The Inclusion Compounds Formed By Cyclodextrin Derivatives With Melatonin And Their Tablets

Solubility of drug is one of the primary problems must be considered in pharmaceutical preparation. It is also one of the key factors which strongly affect the drug bioavailability. Many organic drugs have poor water solubility. Even their saturated solution cannot reach the effective blood concentration. As a result, some drugs have been abandoned. The drug screening shows that many drugs have good pharmacological activity but low solubility. So the emphasis on recent research of pharmacy is improving the solubility of these drugs. Besides, the stability of pharmaceutical preparation is crucial point for the drug safety. Consequently, it is meaningful for pharmaceutical research to find a way to improve the solubility of non-aqueous drugs safely and effectively. In fact, for this purpose, the inclusion technique is often used. The cyclodextrin (CD) has a ringlike hollow cylinder which allowed the drug molecule to enter and form the host-guest inclusion complexes. However, its anomalous low aqueous solubility, renal toxicity and hemoylsis seriously limit its wider utilization. To overcome these disadvantages, a series of water-solubleβ-CD derivatives has been synthesized. Melatonin (MLT) is non-aqueous drug with photoconductive and low bioavailability. In present work, inclusion compounds between MLT and six kinds ofβ-CD (which are SBE1-β-CD, SBE4-β-CD, SBE7-β-CD, M-β-CD, HP-β-CD andβ-CD, respectively) were studied. The preparation and evaluation of tablets formed by six kinds of drug-β-CD inclusion complexes were also investigated. The contents and results of this study are as follows:①Continue change of molar concentration method has been used to obtain the proper ratio of CD to Melatonin. Six inclusion compounds which are MLT-β-CD, MLT-M-β-CD, MLT-HP-β-CD, MLT-SBE7-β-CD, MLT-SBE4-β-CD and MLT-SBE1-β-CD, respectively, were prepared by using ultrasonic method. The six MLT-β-CDs have been evaluated by microscopy and infrared spectroscopy.②Inclusion rate, dosage of drug in inclusion compounds and dissolution rate have been investigated. The inclusion rate and dissolution rate were regarded as the main factor to evaluate the character of these compounds. The results showed that the inclusion effects were as follows: SBE7-β-CD> SBE4-β-CD> SBE1-β-CD> M-β-CD> HP-β-CD>β-CD. The results showed that dissolution rate of the six kinds of MLT-β-CD have improved remarkably, especially for the SBE7-β-CD. ③The phase-solubility data of MLT toβ-CD, M-β-CD, HP-β-CD, SBE7-β-CD, SBE4-β-CD and SBE1-β-CD, respectively, were determined under the temperature of 25℃, 37℃and 45℃. The results indicated that the solubility of MLT in SBE7-β-CD was significantly improved. The apparent stability constant of SBE7-β-CD is highest which suggests the MLT-SBE7-β-CD inclusion complex has best stability. In addition, the apparent stability constant at 37℃is higher than that at 25℃and 45℃, indicating that the reaction would be easier happen at this temperature.④Tablets formed by MLT-SBE7-β-CD and MLT were designed by homogeneous tests. The results showed that there are no remarkable difference in appearance, weight, hardness, friability, disintegration time and content uniformity, respectively, between the two kinds of tablets. All results are consistent with the Chinese Pharmacopoeia. But the dissolution rate of MLT-SBE7-β-CD tablet is much better than MLT tablet which further verified the conclusion that MLT-SBE7-β-CD improved the solubility of MLT.