MUPs Tablet Delivery System For Hydrophilic And Hydrophobic Active Pharmaceutical Ingredients

Background and objectivesMUPs Tablets have significant advantages in clinical application and commercial production.The MUPs formulation is of tremendous technical difficulty,it requires stringent process parameters,and is impacted by many factors,Up to now,the research and development of MUPs are mainly performed in Europe,US,Japan and a few countries with advanced formulation technique.There are only few MUPs products launched.There is no mature process on MUPs reported by relevant research in China.This study use pantoprazole sodium as the freely soluble modle drug which is not stable in acid condition and mifepristone as insoluble modle drug whose solubility is pH-dependent.With such extremely different solubilities,combined with stability challenge and pH-dependent challenge,the appropriate osmotic pellets tablets were developed and characterized.The possibility to apply the pellets tablet to either soluble actives or insoluble actives were well investigated with description of technique hurdles,advantages and industrialization feasibilities.Methods1.Formulation and characterization of pantoprazole sodium MUPs tabletGastric resistant pantoprazole sodium MUPs tablet were compressed from the mixture of top coated pellets and specific microcrystalline cellulose mixture.Top coated pellets for compression were obtained by coating separating layer,enteric layer and top layer consecutively onto drug layered sugar pellets or drug containing pellet cores.With the appropriate setup of feeding speed and compression speed,the integrity of enteric membrane were well maintained after compression.The coated pellets were characterized with microscopy,counting and statistic testing.The density and sphericity were tested.The properties and thickness of each coating layer were characterized and measured by SEM.The stability of drug suspension and hydroscopicity of each layered pellets were investigated.Influence of top layer and microcrystalline cellulose mixture on the loss of gastric resistance during compression were investigated.The HPLC methods for content,related substances,release and gastric resistance determination were developed.The stressed stability and accelerated stability studies were conducted with pantoprazole sodium MUPs tablets,parallel with marketed pantoprazole sodium capsules.2.Formulation and characterization of gastric retentive mifepristone MUPs tabletA sustained release layer and mucous adhesive layer were coated onto extrusion spherized mifepristone pellets.The gastric retentive sustained release pellets were mixed with granules which were wet granulated from micronized mifepristone and compressed into MUPs tablet.The resulted MUPs tablet has two release phases,instant release and sustained release.The solubility,solubilizing methods and solubility helpers were investigated.The turning point of the solubility to pH value was determined.The dissolving of mifepristone was identified as the major impact factor of absorption.The polymer with super gastric retentive property was selected.The flow-through cell was used for release testing of mifepristone MUPs tablet and marketed tablet at pH 4.5 medium.The in-vitro adhensive experiment was performed with pig stomach.Caco-2 cell membrane was used to test the transfer rate of mifepristone either in solution or in suspension.The accelerated stability studies were conducted with mifepristone MUPs tablets,parallel with marketed common mifepristone tablets.3.In-vivo study of gastric retentive mifepristone MUPs tablet3.1 Gastric retention studyTwo study groups were designed for gastric retentive sustained-release mifepristone pellets and sustained-release mifepristone pellets without mucous adhesive coating.Tested pellets were fed with gastric syringe to fasted Sprague Dawley rats.At predetermined time intervals,the pellets remained in stomach of sacrificed rats were counted and evaluated.3.2 In-vivo pharmacokinetic study of gastric retentive mifepristone MUPs tabletTwo study groups were designed for gastric retentive sustained-release mifepristone tablets and mifepristone tablets.Tested tablets were fed with gastric syringe at the dose of 5.2 mg/kg to fasted Sprague Dawley rats.At predetermined time intervals,blood was taken and the mifepristone in plasma was extracted for HPLC quantification.The concentration of mifepristone in plasma versus time was curved and pharmacokinetic parameters were calculated.Use DAS2.2.1 software to analyze the plasma concentrations of Mifepristone,calculate the pharmacokinetics parameters of the two dosage forms.Perform independent sample t analysis on the main pharmacokinetics parameters of the two dosage forms using SPSS 19.0 statistic software.The difference between gastric retentive sustained-release mifepristone tablets and mifepristone tablets were evaluated.Results1.Formulation and characterization of pantoprazole sodium MUPs tablet1)The Suglets(?)250/355 sugar cores are not sphere which may exibit better buffering effect during pellets compression;2)The drug-layer adding alkaline substance can significantly improve the stability of the preparation;3)Addition of talc to separating layer can significantly improve the isolation effect of the drug layer and the enteric layer,enhance the stability of preparation;4)Microscopy was simpler and faster with less error from sample preparation and more convenient statistic calculation;5)The hydroscopicity of enteric coated pellets higher than drug layered pellets,separating coated pellets and top coated pellets.It indicates a hydroscopic challenge during enteric coating process which may reversely diffuse into separating layer and drug layer;6)5%weight increase of the top layer gave back the least loss of gastric resistance;7)Microcrystalline cellulose mixture composed of Vivapur 20:Avicel PH102(w:w=50:50)was used to achieve the least loss of gastric resistance during tablet compression and tablet weight variation;8)The stressed stability studies and accelerated stability studies showed that pantoprazole sodium MUPs tablet was more stable than marketed pantoprazole sodium capsule with estimated shelf-life of 36 months.2.Formulation and characterization of gastric retentive mifepristone MUPs tablet1)The turning point of the solubility of mifepristone versus pH value was 3.0;2)2%β-cyclodextrin solution,2%Tween-20 solution and 2%Tween-80 solution could solubilize mifepristone for more than 1000 times;3)Micronized mifepristone showed higher dissolving rate and apparent solubility;4)Mifepristone recrystallized from low pH solution when it went up to higher pH condition.The apparent solubility of mifepristone after recrystallization is 6-10 times higher than that of the micronized mifepristone at the same pH solution;5)The fumaric acid was selected as the ideal acidic micro-environment maintainer.HPMC K100 was selected as gastric retentive coating layer.The flow-through cell test showed that the gastric retentive mifepristone MUPs tablet had faster instant release phase than marketed mifepristone tablet and exhibited sustained released profile;6)The in-vitro adhensive experiment with pig stomach showed that gastric retentive mifepristone pellets have good gastroretentive effect;7)Transfer rate of mifepristone in solution through Caco-2 cell membrane was 10 times of that of mifepristone suspension.3.In-vivo study of gastric retentive mifepristone MUPs tabletIn-vivo gastric retention study showed that sustained-release mifepristone pellets without mucous adhesive coating completely dissappeared from gastric 30 minutes after fed while 66.7%gastric retentive sustained-release mifepristone pellets still remained in rat gastric 2 hours after fed.From anatomy,gastric retentive sustained-release mifepristone pellets were found entrapped in the mucous layer and spread uniformly along the mucous.Perform in-vivo pharmacokinetics research of Mifepristone gastric-retention MUPs tablets and Mifepristone tablets using rats.Use DAS2.2.1 software to analyze the plasma concentrations of Mifepristone,calculate the pharmacokinetics parameters of the two dosage forms.Perform independent sample t analysis on the main pharmacokinetics parameters of the two dosage forms using SPSS 19.0 statistic software.According to the results,Cmax and clearance(CL)of Mifepristone gastric-retention MUPs tablets are significantly lower than Mifepristone tablets(P<0.001),this indicates that Mifepristone gastric-retention MUPs tablets have retention-release profile,and the peak-valley concentration fluctuation decreases.Compared with Mifepristone tablets,the average AUC0-∞ of Mifepristone gastric-retention MUPs tablets is increased by about 99.8%(P<0.001),and the coefficient of variation decreases.This indicates that the bioavailability of Mifepristone gastric-retention MUPs tablets is significantly higher than Mifepristone tablets,and the individual difference is lower.ConclusionThis study used pantoprazole sodium as the freely soluble modle drug which is not stable in acid condition and mifepristone as insoluble modle drug whose solubility is pH-dependent.With such extremely different solubility,combined with stability challenge and pH-dependent solubility challenge,the appropriate osmotic pellets tablets were formulated and characterized.The following results were achieved:1)Pantoprazole sodium MUPs tablet showed ideal gastric resistance and was more stable than marketed pantoprazole sodium capsule;2)Gastric retentive sustained-release mifepristone MUPs showed higher bioavailability than marketed mifepristone tablet with significantly lower variability;3)from the process point of view,the study found that unsphere sugar cores may have better buffering effect during pellets compression,and the appropriate weight gain of the top layer showed excellent protection during pellets compression,and only at specific feeding speed and compression speed,the mixed excipients for pellets compression worked well to achive satisfactory pellets tablets;4)for the characterisation methods,microscope for pellets size ditermination is faster and suitable for statistic analysis,and flow-cell dissolution method could better overcome non-sink condition for insouble drugs.In conclusion,the results imply the possibility to apply the pellets tablet to either soluble actives or insoluble actives,but specific physicochemical properties and biopharmaceutical properties should be well considered in design and formulation of pellets.The findings related to modle drugs are meaningful for candidates with similar physicochemical properties and biochemical properties.The findings related to process and characterisation methods are generally useable for research and development of pellets tablets.