Studies On Solubility Enhancement Of Poorly Water-soluble Drugs By Inclusion Complexes With β-cyclodextrin And Its Derivatives

Lots of the clinical used drugs are poorly water-soluble and those drugs are slowly absorbed, which lead to lower bioavailability. β-cyclodextrin (βCD) is widely used to improve the solubility of poorly water-soluble drugs. Its unique structure provides a molecule shaped like a segment of a hallow cone with an exterior hydrophilic surface and interior hydrophobic cavity. The hydrophilic surface generates relatively better water solubility for the cyclodextrin may increase the guest's aqueous solubility. Chemical modification of any of the hydroxyl was made to enhance the relatively lower aqueous solubility of βCD to widen its application.In this paper, the inclusion complexes of poorly water-soluble drugs with βCD and its two main derivatives hydroxypropyl-β-cyclodextrin (HPβCD) and sulfobutyl ether-β-cyclodextrin (SBEβCD) were investigated using prazosin hydrochloride and oleanolic acid as model drugs.(1) The phase solubility profiles of prazosin hydrochloride with βCD or HPβCD were investigated to determine the inclusion types and calculate the stability parameters. It was found that the inclusion type of prazosin hydrochloride with βCD was B_S and that with HPβCD was A_L. Prazosin hydrochloride formed more stable complexes with βCD than with HPβCD, which might be due to a steric hindrance of substitutive group that prevented the guest molecule from entering the CD cavity.The phase solubility profiles of oleanolic acid with βCD, HPβCD and SBEβCD were also investigated. It was concluded that all inclusion complexes followed Ap type which suggested the presence of inclusion complexes of oleanolic acid and cyclodextrins with molar ratio of 1:1 and 1:2. The stability constant K_1:1 was larger than K_1:2, which suggested that 1:1 inclusion complexes were more stable than 1:2 inclusion complexes.(2) Various methods such as co-grounding, ultrasonic method and coprecipitation were employed to prepare the inclusion complexes of prazosin hydrochloride with βCD or HPβCD. Then the dissolution profiles of the inclusion complexes weredetermined and compared with those of prazosin hydrochloride alone and physical mixtures. Both the preparation technique and nature of the carriers played important roles in the dissolution performance of the systems. All the systems with HPpCD showed better performance than the corresponding one with J3CD.(3) Binary systems of prazosin hydrochloride with PCD or HPpCD prepared by various methods were characterized by differential scanning calorimetry, X-ray diffactionary and Fourier transformation-infrared spectroscopy. It was confirmed that the inclusion complexes of prazosin hydrochloride with PCD prepared by ultrasonic method and coprecipitation were formed and the inclusion complexes of prazosin hydrochloride with HPPCD prepared by all the various methods were formed.(4) The oleanolic acid monolithic osmotic pump tablet has been studied utilizing PCD, HPpCD and ( SBE) 7mPCD, respectively. The in vitro release of oleanolic acid was evaluated using the osmotic pump system. The effect of (SBE) 7mPCD as the solubilizing and osmotic agent was compared with that of PCD and HPpCD, it was found that the release rate of oleanolic acid was significantly higher with(SBE)7mpCD than that with either PCD or HPpCD. Therefore, it was concluded that (SBE) 7mPCD provided novel properties for the development of osmotic pump tablets for poorly water-soluble drugs.