Studies On Prostaglandin E₁-Hydroxypropyl-β-Cyclodextrin Complex And Its Two New Dosage Forms-Nasal Powders And Sublingual Tablets

Prostaglandin E₁ (PGE₁) with poor aqueous solubility and chemical stability was used as a model drug in this paper. Firstly, the solubility, chemical stability of PGE₁ and their respective affecting factors were investigated and a solid PGE₁ complex with hydroxypropyl-β-cyclodextrin (HP-β-CD) having greater aqueous solubility and better safetythan natural cyclodextrins was prepared. Then, two new dosage forms--PGE₁-HP-β-CDcomplex nasal powders and sublingual tablets were developed and their in vitro qualities and in vivo pharmacodynamics were intensively studied.In the study of PGE₁ aqueous solubility, the effect of media pH, HP-β-CD alone and both on the solubility of the drug was investigated. The results showed that the solubility of PGE₁ was significantly improved by increasing the media pH or addition of HP-β-CD. Furthermore, a synergistic solubilizing effect was produced when increasing media pH combined with the addition of HP-β-CD.In the study of the stability of PGE₁ aqueous solution, effect of pH, HP-β-CD, ionic strength, and ethanol on the stability of PGE₁ solution was investigated, respectively. The results demonstrated that PGE₁ solution was most stable at pH 3.0-4.0 and very unstable under strongly acidic or basic pH conditions. HP-β-CD could obviously increase the stability of PGE₁ solution under strongly acidic or alkaline conditions, but slightly promote the drug degradation at neutral pHs. In addition, the stability of PGE₁ solution was not affected by solution ionic strength, but significantly improved by ethanol.In the study of the complexation of PGE₁ with HP-β-CD in solution, the host-guest molecular interactions, complexing molar ratio, complex steric conformation, change of thermodynamic parameters were studied by lots of methods such as UV absorption spectroscopy, phase solubility method, circular dichroism spectroscopy, nuclear magnetic resonance and equimolar series method. The results indicated that a 1:1 molar ratio soluble PGE₁ complex with HP-β-CD could form in aqueous solution and the phase solubility diagram exhibited A₁-type. The conformation of PGE₁-HP-β-CD complex is that the p-hydroxyketo moiety-containing five-membered ring of PGE₁ molecules was probably included within the hydrophobic cavity of HP-β-CD molecules. Additionally, the changes of thermodynamic parameters determined such as Gibbs free energy change (â–³G), enthalpy change(â–³H), and...