The Preparation Of Drug-loaded Silica Solid Dispersions And Its Pharmacokinetic Traits In Rats

It is known that the solubility of the drug is a key contributory factor of bioavailability.Therefore,low solubility of drugs often leads to poor absorption,and finally low bioavailability.A research showed that the proportion of insoluble drugs?BCS?/??exceeds 75 percent in total chemical drugs approved by FDA in recent years,so it is obvious that how to improve the solubility and bioavailability of insoluble drugs is the nut to be cracked in pharmaceutics field.In recently,the solublization technology of insoluble drugs includes solid dispersions,prodrug formation,cyclodextrin inclusion compounds,liposomes,microemulsions,micelles,particle size reduction and solid-lipid nanoparticle,etc.Solid dispersion technique is widely used in pharmaceutics field,which can improve the solubility and dissolution rate of insoluble drugs,extend or control the release of drugs and raise the solubility of drugs.But solid dispersion tends to aging because it's a thermodynamics nonstable system.Therefore,a low loading rate of drugs is usually used in production.So how to overcome the aging problem and improve the loading rate has a practical significance in the research and development field of pharmaceutics.In traditional pharmaceutics field,silicon oxide?SiO2?is used as glidant,anti-caking agent,and lubricator.For the function of the drug carrier,mesoporous order SiO2 material has a mount of advantages.Firstly,more drugs can be loaded in the surface or inner channels because of its huge specific surface area and pore volume.Besides,mesoporous order SiO2 material has abundant silanol group?-Si-OH?in the surface,silanol group would interact with the hydroxyl group?-OH?in drug molecule to form the hydrogen bond,which is beneficial for the stability.And most importantly,it can be used for clinical diagnosis and treatment in terms of nontoxicity,perfect biocompatibility,and biodegradability.In this research,a common non-steroidal anti-inflammatory drugs?NSAIDs?,indomethacin?IMC?,was chosen as model drugs.polyvinylpyrrolidone k30?PVPk30?and mesoporous/non-mesoporous SiO2 material were chosen as co-carrier materials.The drug-loaded SiO2 microsphere solid dispersions were prepared successfully,and the dissolution rate and bioavailability of those samples were investigated.In this thesis,the main research contents are as follows:In the first part,the preparation and characterization of drug-loaded SiO2microsphere solid dispersion.In the beginning,based on the traditional preparation method,IMC and PVPk30 were chose to prepare the solid dispersion,and the products with the mass ratio?IMC:PVPk30?at 1:1.The Differential scanning calorimeter?DSC?result showed that in the IMC-PVPk30 solid dispersion samples,the melting peak of IMC vanished still exist in the amorphous state.So in the new drug delivery system,the mass ratio of IMC and PVPk30 was chosen as 1:1.Besides,mesoporous SiO2 materials?Syloid XDP3050,Syloid XDP3150,Syloid SP53D,Syloid 244FP?and non-mesoporous SiO2 materials?Aerosil200,Aerosil380?were applied to prepare IMC-SiO2solid dispersions and IMC-PVPk30-SiO2 solid dispersion by submersion-solvent evaporation method.Finally,IMC-SiO2 solid dispersions and IMC-PVPk30-SiO2 solid dispersion with the mass ratio at 1:1 and 1:1:1 were prepared successfully.DSC and Powder x-ray diffraction?PXRD?results showed that the melting peak of IMC disappeared practically between the IMC-SiO2 solid dispersions and IMC-PVPk30-SiO2solid dispersions,which means that IMC exists in the amorphous state in these samples and the preparation method was convenient and effective.Scanning electron microscope?SEM?results showed that the drug-loaded IMC-SiO2 solid dispersions and IMC-PVPk30-SiO2 solid dispersions have a nearly identity particle size.Compared with the mesoporous SiO2 materials and non-mesoporous SiO2 materials,the particle size increases slightly,indicating that IMC may be distributed on both the outer surface and the pore of SiO2.In the second part,the establishment of the analysis method of drug-loaded SiO2solid dispersion.In this chapter,the UV-VIS spectrophotometry was applied for the determination of the content of IMC,and the detection wavelength of IMC was 320 nm.The experiment showed that adjuvants have no effect on the detection of IMC.In the ultrapure water,50%ethanol-water solution,PBS-water?1:4?solution,and simulated intestinal fluid,the absorption value of IMC has a perfect linearity with the concentration of IMC standard series solution in the concentration between 10.0?g/mL to 40.0?g/mL,with the R² value is greater than 0.999.The stability results of solution showed that in this four medium,the RSD value of indomethacin solution?10.0?g/mL,20.0?g/mL,30.0?g/mL?were less than 0.24%,which means the IMC solution has a good solubility in 24 h.The precision results showed that in this 4 medium,the RSD value of indomethacin solution?10.0?g/mL,20.0?g/mL,30.0?g/mL?were less than0.15%,which demonstrate that the method has a good precision.The recovery results showed in these four mediums,the mean recovery rate was between 98.9%¹03.1%,the RSD value less than 0.21%,which means that the recovery meets the relevant requirements.The content determination experiment of IMC showed that in all the solid dispersion samples,the real mass fraction of IMC-SiO2 solid dispersions and IMC-PVPk30-SiO2 solid dispersions were about 50 percent and 33 percent respectively,which are close to the theoretic mass fraction.The dissolution experiment showed that compared with IMC bulk substance and IMC-PVPk30 solid dispersion,the drug-loaded SiO2 solid dispersion delivery system has a competitive advantage in improving the dissolution rate.Compared with IMC-SiO2 solid dispersions,IMC-PVPk30-SiO2 solid dispersions have a more prevalent advantage,especially,IMC-PVPk30-XDP3050 solid dispersion and IMC-PVPk30-Aerosil380 solid dispersion have the fast dissolution rate.Hence,The IMC-SiO2 solid dispersions,IMC-PVPk30-SiO2 solid dispersions prepared by XDP3050 and Aerosil380 were chose in the following experiments.In the third part,the investigation of the stability test of drug-loaded SiO2microsphere solid dispersion samples.In this chapter,factors such as temperature,humidity,light were set as experiment parameters to test the stability of solid dispersion samples during a period of time.The results of strong-light experiment showed that after 10 days,all of the samples have a stable state during the strong-light environment?the illuminancy between 4000±500 Lx?,the appearance,color,content and the dissolution rate in 15^thmin in simulated intestinal fluid?D15?of samples have no obvious change.The results of high-temperature experiment showed that after 10 days,all of the samples have a stable state during the high-temperature environment?the temperature is 60??,the appearance,color,content,and D15 of samples have no obvious change.The results of high-humidity experiment showed that after 10 days,during the high-humidity environment?the RH equals to 90%±5%,the temperature is25??,the appearance of IMC-XDP3050 SD?1:1?and IMC-Aerosil 380 SD?1:1?have changed dramatically,which mainly demonstrate the strong hygroscopic of part of samples,and agglomeration phenomenon occurred.The experiment result showed that IMC solid dispersion should be preserved in seal and drying environment.Results of the long-term tests showed that during the high-temperature environment?the RH equals to75%±10,the temperature is 25±2??,except the IMC-PVPk30 solid dispersion?1:1?have occurred the agglomeration phenomenon after 3 months.The appearance,color,content and the D15 of all of the other solid dispersions have no obvious change.In the last part,the pharmacokinetics experiment of drug-loaded SiO2 solid dispersion.In this chapter,the HPLC method was chosen to detect the content of IMC in the plasma samples.Rats were chosen as the model animal,one dosage of IMC solid dispersions was given by the intragastric administration.The results of specificity experiment showed that the retention time of IMC and naproxen sodium?internal standard substance?was 8.75min and 5.76min,respectively.The endogenous substances in the plasma samples have no influence on the determination of IMC and naproxen sodium.The linearity experiment showed that when the concentration of IMC was between 0.1⁴0.0?g/mL,the ratio of peak area IMC and naproxen sodium have a good linearity with the concentration of IMC.The stability experiment showed that all of the RSD value of 0.2,1.0,32.0?g/mL solutions were less than 6.06%,which means that the indomethacin-plasma solution has a good stability in this environment.The accuracy and precision results showed that in 0.2,1.0,32.0?g/mL solutions,the RSD value of within-day precision results were less than 6.370%,the RSD value of day-to-day precision results were less than 5.900%,which is meet the requirement of the analysis method of biological samples.The recovery results showed that in the rat plasma solution,the extraction recovery of IMC and naproxen sodium was between89.9%¹06.0%and 96.3¹06.7%.The matrix effect results showed that in the rat plasma solution,the extraction recovery of IMC and naproxen sodium was between90.4%¹03.6%and 94.6%¹02.3%,which meets the relevant requirement.The pharmacokinetics experiment showed that,compared with IMC bulk substance,the solid dispersion samples have a shorter Tmax,and a higher Cmax.The relative bioavailability of IMC-PVPk30 SD?1:1?,IMC-PVPk30-XDP3050 SD?1:1:1?and IMC-PVPk30-Aerosil380 SD?1:1:1?was 303.6,190.9 and 226.4,respectively,which indicated that the solid dispersion technology has a splendid advantage in improving the bioavailability of insoluble drugs.All in all,in this thesis,IMC-PVPk30-SiO2 solid dispersions have a more excellent stability a shorter Tmax,a higher Cmax and a higher relative bioavailability.So it is not difficult to show that the SiO2 materials play a potential role in the new drug delivery system.