Mechanochemical Preparation Of Statin Drugs Systems With Enhanced Solubility And Solubilization Mechanism Studies

Statins,an inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A（HMG-CoA）reductase which can inhibit the synthesis of methyl valerate,is widely used to and control hyper-cholesterolemia and prevent cardiovascular diseases.Nonetheless,it is reported that many statins have low oral bioavailability,which may be attributed to their slow dissolution rate in the gastrointestinal tract（low intestinal uptake）.Thus,the development of the formulation of statins is restricted.Mechanochemistry is a technology which induced by the input of mechanical energy that is transferred to the solid state compounds and results in the change of crystal structure,along with new phase formation.In fact,compared with traditional“liquid phase”method,mechanochemical process offers significant advantages such as one-stage technological process,absence of solvents or melts and respective additional procedures,lowering ofunwished admixtures,high strength of formed complexes and low operating cost.In this paper,mechanochemistry was introduced to study the solubilization of insoluble statins.Solubilization systems of statins（simvastatin and atorvastatin calcium）have been prepared using mechanochemical technique to improve their solubility and enhance theirs oral bioavailability.In addition,we also evaluate the quality of the mechanical treated complexes.Moreover,pharmacokinetics and pharmacodynamics tests in vivo on laboratory animals were also carried out.The main contents of the paper are as follows:（1）Study on physicochemical properties of drugs and preparation of drug micronized system by mechanochemical methodFirst of all,the equilibrium solubility of simvastatin and atorvastatin calcium was investigated.The results showed that they are poor water solubility drugs.In addition,self-association of simvastatin in various solvents was investigated by UV/Vis and NMR techniques.HPLC analysis methods of determination content of simvastatin and atorvastatin calcium were established.Then,the micronized systems of simvastatin and atorvastatin calcium were separately prepared using a planetary mill.The results indicated that the melting enthalpy of micronized drugs was reduced and the solubility was improved slightly due to the phenomenon of"agglomeration".Based on this,it is concluded that milling of statins without additives couldn’t sufficiently help to improve theirs aqueous solubility and dissolution.（2）Preparationandcharacterizationofstatinsand hydroxypropyl-β-cyclodextrin（HP-β-CD）inclusion complexThe inclusion complexes of simvastatin and atorvastatin calcium were separately synthesized with HP-β-CD using a rolling mill.The solubility and dissolution rate of the inclusion complexes were significantly improved compared with net drugs and corresponding to physical mixtures.In the inclusion complexes,the drugs which existed in an amorphous state were located into the HP-β-CD hydrophobic cavity.The linearity of the phase solubility diagrams is classified as an A_L type and indicates the formation of inclusion complexes with 1:1stoichiometry.The complex stoichiometry has been confirmed by the Job’s method.The rapid storage assay showed that thermal stability of statins was obviously increased in the inclusion complex with HP-β-CD.（3）Preparation and characterization of statins and arabinogalactan inclusion complexesThe inclusion complexes of simvastatin and atorvastatin calcium were separately synthesized with arabinogalactan（AG）using a rolling mill.In the inclusion complexes,drugs were in an amorphous state by dispersing into the arabinogalactan branch.¹H-NMR and IR indicate that two drugs were trapped in the skeleton of arabinogalactan.The result of phase solubility analysis showed that the inclusion complexes of arabinogalactan and simvastatin had formed the mole ratio of 1:1.While the phase solubility diagram of atorvastatin calcium with arabinogalactan was Bs type according to the Higuchi and Connors theory.The solubility and dissolution rate of the complexes increased significantly compared with net drugs.Additionally,the rapid storage assay showed that thermal stability of statins was obviously increased in the inclusion complex with AG.（4）Preparation and characterization of statins and disodium glycyrrhetate solid dispersions（SDs）The solid dispersions of simvastatin and atorvastatin calcium were separately synthesized with disodium glycyrrhizinate（Na₂GA）using a rolling mill.From the investigations of the solid dispersions on preliminary pharmaceutical properties,it is found that the drugs were in amorphous state when the mass ratio of statins and disodium glycyrrhetate was 1:10.However,there were still drug crystals when the mass ratio of simvastatin and disodium glycyrrhetate was 1/2 or 1/4.The gel-permeation HPLC analysis showed the formation micelles from molecules of glycyrrhizin acid,which can include drug molecules,and glycyrrhizic acid existed in a fixed structure of single molecule.Simvastatin exists in the form of free molecules and may adsorb on the surface of glycyrrhizic acid micelles by Van der Waals’force or hydrophobic force,while atorvastatin calcium in an amorphous state by dispersing into glycyrrhizic acid micelles.The solubility and dissolution rate of the solid dispersions were significantly improved compared with net drugs and corresponding to physical mixtures,and the stability of the prepared solid dispersion is significantly improved.（5）In vivo pharmacokinetics and pharmacodynamics studyIn vivo pharmacokinetic and pharmacodynamic studies were used to evaluate the preparation quality.Pharmacokinetic tests in vivo on laboratory animals showed that the bioavailability of complexes prepared with three kinds of excipient was all improved compared with the pure drugs.The pharmacodynamics study on hyperlipidemia mice showed obvious hypolipidemic activity in the ball milling complexes compared with the net drugs.