| Thus far, about40%of promising pharmacological active substances havebioavailability problem due to their poor solubility, which restricts the development of newdrugs to a certain extent. Many common technologies are available today for dissolution rateenhancement, but these involve high production cost, sophisticated machinery, complicatedtechnologies, intellectual property issues, and advanced preparation methods. However, theemergence of liquisolid technology overcomes these barriers.It has been proved that the liquisolid technology can significantly increase thesolubility of water-insoluble drugs, improving the bioavailability, especially for the low dosewater-insoluble drugs.However, In order to have acceptable flowability and compactabilityfor liquisolid powder formulation, high levels of carrier and coating materials should be addedand that in turn will increase the weight of each tablet which is very difficult to swallow,formulation of the high dose insoluble-drugs as liquisolid tablets is one of the limitations ofthe liquisolid technique. Also,few research of the liquisolid technology has been reported,especially for the study of its solubilization mechanism, and the conclusion is not consistent.Therefore, further research and exploration of the solubilization mechanism in liquisolidtechnology is necessary.As a broad-spectrum antimicrobial agent, itraconazole has a superiority in lowminimum bacteriostatic concentration, high security and good efficacy, but thewater-insolubility reduce its clinical pharmacological effects. More over,during thepreparation process of itraconazole pellet,huge amounts of dichloromethane is needed todissolve the drugs and HPMC, this process need high-level equipment and cause pollution.There are also some reports about self-emulsifying formulation and solid dispersion technique, but both of them have a complex preparation process and low yield.In order to solve the problem above, this research use itraconazole as the modeldrug to build the liquisolid system with a high dose insoluble-drug. Based on thepreformulation study in physicochemical properties of API and mathematical modelestablished by Spereas et al., prescription screening, formulation optimization andinvestigationon technology are carried out for the preparation of itraconazole liquisolidcompacts. The solubilization mechanism of liquisolid technology is interpreted by theproperties study of drug solution, liquisolid powders, liquisolid compacts in liquisolid system.The main work of this research are as follows:(1)The dissolution in vitro and the solubility test of itraconazole were determined bythe high-performance liquid chromatography and UV spectrophotometry pre-establishedrespectively. The method was proved to be accurate, reliable and sensitive, after methodologyvalidation.(2)Excipients of the liquisolid formulations were screened through solubility test ofitraconazole in different liquid vehicle, the dissolution test of liquisolid compact with differentdisintegrants and the literature research.The results show as follows: choose N-methylpyrrolidone （NMP）as liquid vehicle, magnesium aluminum silicate (Neusilin US2) ascarrier and coating materials, croscarmellose sodium (VIVASOL) as the disintegrant andpovidone (PVP K30) as the precipitation Inhibitor.(3)The flowable liquid-retention potential(Φ-value=0.75) and the liquid loadfactor(L_f=0.7875) have been calculated by the mathematical model established by Spereas etal. and the angle of slide measurement.the ratio of carrier and coating material (R=20:1),theconcentration of the drug solution (92.95mg/mL,300mg/mL) and the amount of disintegrants(6%) were fixed to determine the percentage of the excipients in liquisolid compacts. Then,7 itraconazole liquisolid formulations including LS-LC,LS-PVP-0%to LS-PVP-20%wereprepared after prescription screening, formulation optimization and investigationontechnology.(4) The effect of precipitation Inhibitor PVP K30with different concentrations onstability and viscosity of the drug solution were studied, the experimental results show thatthe drug solution contained PVP had a low SI and ΔT, which means a better stability. Withthe increase of PVP concentration,both of stability and viscosity increased. It means thatprecipitation Inhibitor PVP K30can increase the stability of itraconazole supersaturatedsolution,and inhibit the nucleation and crystal growth, and that the increasing viscosity maybe one reason of the stability enhancement.(5)Carr’s index was calculated to evaluate the flowability of powders by thedetermination of bulk density and tap density. The results indicate that although liquisolidformulations contain non-volatile cosolvent, they showed lower Carr’s index than physicalmixtures. In case of constant L_f, with the increase of PVP concentration, flowability ofpowders increased.to some extent. It can be attributed to the “granulating effect” and theincreasing viscocity of powders. As the powders contained very fine particles, they could notflow very well due to a large cohesive or adhesive force as a result of high surface area for thefine particles, but “granulating effect” and the increasing viscocity of powders reduced thelarge cohesive or adhesive.however, liquisolid powders with high viscosity make the powderstickier and individual granules cannot be generated.(6)The XRD, DSC and SEM of drug, excipient and formulations were done to studythe crystalform and interaction. It shows that, the pure itraconazole was in pure crystallinestate and no interaction occurred between the drug and excipients in physicalmixture. Thetotal disappearance of the drug melting peak of all the liquisolid powders and the appearance of sharp diffraction peak of liquisolid powders without PVP indicates that drug amorphizationwas obtained partially. The adding of PVP is conducive to maintain the amorphousness ofdrug in liquisolid system.(7)For assessment of wettability, contact angle of liquisolid compacts conventionaltablets was measured according to the imaging method.The result shows that liquisolidcompacts have a better wettability. Both of the increasing PVP content and the existence ofNMP can enhance the wettability. This can be attributed to the surface active agent the NMPacts as and the hygroscopicity of PVP which facilitates wetting of drug particles bydecreasing interfacial tension between dissolution medium and tablet surface.(8)The dissolution test data have been proved to agree on the result of the viscocity,stability, contact angle measurement and the XRD, DSC, SEM determination: liquisolidtablets displayed slightly better in-vitro release characteristics than those of their directlycompressed. It is apparent that decreasing the concentration of drug solution result in aincrease of the in-vitro drug release rates displayed by the liquisolid tablets.In addition,change of PVP content have a significantly effect on the drug release. Main reasons for thisappearance are that: liquisolid technology as well as PVP (0%～1%) can increase themolecularly dispersed drug in their liquid medication, surface of drug available fordissolution,improved wetting properties and the drug solubility. However, excess PVP(5%～20%) result in a decrease of the in-vitro drug release rates due to the increased viscocity of thestagnant diffusion layer,which slow down the penetration of water into drug particles.(9) Based on testing results, the solubilization mechanism of liquisolid technologycan be interpreted as follows: Increased drug surface area, increased drug solubility andImproved wetting properties,in which the latter two are the main effect. Further more,theeffects of PVP can be ascribed tothe increase of FM, the decrease of tablets weight, the improvement of powder flowability and the enhancement of wetting propertiesThe effect of precipitation inhibitor PVP K30on the constituent part of liquisolidsystem (drug solution, liquisolid powders, liquisolid compacts) were studied for theinterpretion of the solubilization mechanism in liquisolid technology.The preparation ofitraconazole liquisolid compacts with a high dose intraconazole is accomplished. The resultsof dissolution studies indicated that the dissolution rate of intraconazole has significantlyenhanced in liquisolid compacts.The objectives of this research has been achieved:solubilization of water-insoluble drug itraconazole, the interpretion of the solubilizationmechanism in liquisolid technology and the tablets weight reduction of of high dose liquisolidcompacts. |
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