Design And Physicochemical Properties Investigation Of Drug-drug Supramolecular Complexes Of Four Non-steroidal Anti-inflammatory Drugs Including Diclofenac

Objective Inflammation,as the most common initial symptom of various diseases,is the body’s defense mechanism to stimulation,which can be acute or chronic.Inflammation changes from short-term to long-term will consume immune tolerance and lead to significant physiological changes in cells,tissues and organs of body,which ultimately increases the risk of of people suffering from noncommunicable diseases.Non-steroidal anti-inflammatory drugs(NSAIDs)are used as first-line drugs in the treatment of inflammation due to their antipyretic,analgesic and anti-inflammatory effects.According to the statistics,there are more than 73 million prescriptions of NSAIDs are written every year,and about 30 million people take NSAIDs orally every day.However,most of the familiar NSAIDs belong to Class II drugs of the Biopharmaceutics Classification System(BCS),with the characteristics of low aqueous solubility and high permeability.The low solubility of NSAIDs may cause many problems in using and producing these drugs,especially regarding the onset of action.Previous studies have shown that the aqueous solubility of NSAIDs improved through the formation of drug supramolecular complexes and thus a fast onset of action.Under these circumstances,drug-drug supramolecular complex formed by NSAIDs combined with other therapeutic drugs opens up a new way to realize the synergetic therapy of inflammation and other diseases on the basis of improving the water solubility of NSAIDs.Methods Based on the principle of crystal engineering,Non-steroidal anti-inflammatory drugs such as diclofenac(DFA),flufenamic acid(FFA),Mefenamic acid(MFA)and niflumic acid(NFA)were selected as the concerned objects,and twenty clinical therapeutic drugs were selected as coformers.Eventually,seven drug-drug supramolecular complexes of NSAIDs formed with enoxacin(EX)and lamotrigine(LAM)named DFA-EX,DFA-LAM,FFA-EX,FFA-LAM,MFA-LAM,NFA-EX and NFA-LAM were successfully prepared by solvent evaporation.They were further verified by X-ray diffraction,thermodynamic analysis and infrared spectroscopy,and then dissolution behavior of DFA,FFA,MFA and NFA were evaluated by solubility and intrinsic dissolution rate and antibacterial activity of DFA-EX,FFA-EX,NFA-EX,and EX by antibacterial experiments.Results As shown by single crystal X-diffraction results,DFA-EX and NFA-EX crystallize in the monoclinic P 21/c space group,and DFA-LAM,FFA-EX,FFA-LAM,MFA-LAM and NFA-LAM crystallize in the triclinic P-1 space group,except that the stoichiometric ratio of FFA-EX is 1:2,the rest are 1:1.The solubility experiment shows that the solubility of DFA-EX and DFA-LAM in pure water is 3.16 and 1.85 times higher than that of DFA,and that of FFA-EX and FFA-LAM is 5.89 and 3.65 times higher than that of FFA.The solubility of MFA-LAM is increased by 11.12 times compared to MFA,and that of NFA-EX and NFA-LAM are increased by 2.60 and 3.28 times compared to NFA.The intrinsic dissolution rates are all significantly higher than that of pure drugs.On this basis,the synergetic effect of drug-drug supramolecular complexes of NSAIDs was further explored through the study of the in vitro antibacterial activity of EX.As shown in the results,the antibacterial activity of DFA-EX,FFA-EX and NFA-EX against Escherichia coli(E.coli),Shigella flexneri(Sh.flexneri),Staphylococcus aureus(S.aureus)and Staphylococcus albus(S.albus),was improved compared with that of EX,from high to low was FFA-EX>DFA-EX>NFA-EX>EX.The cell membrane of bacteria is mainly composed of lipids and proteins,and substances with higher liposolubility are easier to pass through the cell membrane.The liposolubility of the drug is expressed by the oil-water partition coefficient(LogP).The LogP of drug-drug supramolecular complexes is higher than EX and the increase of liposolubility is consistent with the enhance of antibacterial activity.Furthermore,the water solubility is lower than that of EX and the mechanism of the decrease of water solubility is explained by fitting the solubility-pH curve with Ksp and Henderson-Hasselbalch equation,which confirm the increase in liposolubility.Therefore,the formation of drug-drug supramolecular complexes between NSAIDs and EX result in the the decrease of aqueous solubility and the increase of liposolubility,which finally bring about the enhancement of its antibacterial activity.Conclusions(1)After the formation of drug-drug supramolecular complexes,the water solubility of NSAIDs consisting of DFA,FFA,MFA and NFA was improved,which provides the possibility for the rapid onset of action;(2)The physiochemical properties of EX were modulated to enhance in vitro antibacterial activity,which further provides experimental support for the realization of synergistic effect of NSAIDs and EX.