The Application Study Of New Lyophilization Technique In New Dosage Forms

About three-quarter bioactive drugs are hydrophobic compounds. Usually the oral bioavailability of hydrophobic drug is low due to the low aqueous solubility. The clinical application of those hydrophobic drugs that needed to be administered by parenteral route is limited due to the problem of solubility. Otherwise, some hydrophobic drugs are unstable and would decompose during preparation and storage. Cyclodextrin complex, solid dispersion and liposomes have been recognized as important technology due to the solubility and stability of hydrophobic drugs could be improved by these new dosage techniques. Whereas there are practical limitations of the preparation methods related to these new dosage forms, and are difficult for industrial scaling up. Developing new simple and efficiency technology remains one of the most challenging aspects of drug development. In this dissertation, tert-butyl alcohol (TBA) was introduced as the solvent of hydrophobic drugs and cyclodextrin complex, solid dispersion and liposomes loaded hydrophobic drug were prepared by lyophilization.Preparation of hydrophobic drug cyclodextrin complex: Based on the study of monophase solution, two novel methods were developed. 1) The hydrophobic drug in TBA and cyclodextrin solution in water were mixed in a suitable volume ratio, and subsequently freeze dried. 2) Both hydrophobic drug and HPβCD were dissolved in TBA, which is subsequently lyophilized to give the hydrophobic drug HPβCD complex in the form of a porous powder. Based on the data from DSC, SEM and XRD, the drugs were amorphous in freeze-dried samples. The FTIR spectra indicated that a drug cyclodextrin interaction took place in the freeze dried complex. Dissolution experiments showed that the hydrophobic drug dissolved rapidly from the cyclodextrin complex in aqueous medium. TBA was found to be a suitable freeze drying medium for the preparation of hydrophobic drug cyclodextrin complex. Nimodipine HPβCD complex was successfully prepared by lyophilization TBA/water co-solvent system. Nimodipine HPβCD complex had a significantly higher AUC compared with physical mixture and commercial tablet after orally administration to rats. The absorption rate was enhanced and the peak time was shortened.Preparation of hydrophobic drug solid dispersion: Pure TBA was used as the solvent of hydrophobic drug and hydrophilic carriers such as PEG1500, PEG4000, PEG6000, PVP and Poloxamer 188. TBA-water co-solvent system was used as the medium of hydrophobic drug and hydrophilic carriers, for example maltose. After the homogeneous solution contained hydrophobic drug and hydrophilic carrier was obtained, the solvent was removed by freeze drying and hydrophobic drug solid dispersions were obtained. DSC results showed hydrophobic drug was dispersed in hydrophilic carriers as molecular form; FTIR spectra implied hydrogen bond had been formed between drug and hydrophilic carder; micrographs showed the crystal of drug was disappeared in solid dispersions and new solid phase had been formed. The in vitro release experiment results indicated the dissolution rate of hydrophobic drug was accelerated markedly in lyophilized solid dispersions. These results proved hydrophobic drug solid dispersions had been formed after this technique.Preparation nimodipine liposomes by lyophilization monophase solution: lipids, nimodipine and sugar were dissolved in TBA-water co-solvent and sterilized, then the solvent was removed by lyophilization and proliposome loaded nimodipine was obtained. On addition of aqueous medium, liposomal nimodipine with high entrapment efficiency and homogeneous particle size distribution was obtained. The in vivo efficiency of liposome nimodipine was studied by intravenously administration to mice at a single dose of 4 mg/kg. The pharmacokinetic parameters of nimodipine changed significantly when encapsulated in liposomes. The ratios of AUC values of nimodipine liposomes to solution were 1.70 and 1.62 in plasma and cerebric tissue respectively. The clearance of nimodipine encapsulated in liposomes was reduced and the elimination half life prolonged. The in vivo pharmacokinetic results provided an evidence that liposomes could efficiently transfer nimodipine into brain tissue. Liposome nimodipine is a promising alternative to commercial injection.TBA is an excellent freeze-drying medium due to its high vapor pressure and high melting point. It is a good solvent for hydrophobic drugs. Preparation hydrophobic drug cyclodextrin complex, solid dispersion and liposomes by lyophilization TBA or TBA-water co-solvent system is a simple, efficient, energy-conserving technique and can easily be scaled up. It is expected to have more application in modifying the physicochemical characteristics of hydrophobic drugs and improving their absorption and pharmacodynamic properties.