Phase-Separated Controlled Release Mechanism And Tableting Technology Of Cellulose Derivative Film Based Coated Pellets

Oral controlled-release multiple-unit dosage forms such as film-coated pellets,which can spread uniformly throughout the gastrointestinal tract?GIT?,and the defect of individual unit do not affect overall drug release behavior.Then can further reducing the local irritation of active ingredient,reducing the individual differences caused by food or gastric emptying and avoiding the phenomenon of dose dumping.More importantly,it can be compressed into tablets,which have the advantage to flexibility in splitting the tablets to achieve dose adjustment of controlled release formulations,meeting the personalized medicine which has the wide application future.However,there are high technical barriers of formulation and processes factors and it is difficult to regulate precisely of drug release behavior,and may also have pH-dependent drug release,which can cause the problem of the drug safety.At present,pellet-containing tablet is the only high-end formulation that has not been localized.In this article,metoprolol succinate?MS?was used as the model drug,and phase-separated films of water-insoluble ethyl cellulose?EC?and water-soluble hydroxypropyl cellulose?HPC?were used to design and construction of the EC/HPC-based coated pellet with small-particle size,which solved the difficulty of the bottom-spray fluidized bed technology.According to the mechanism of EC/HPC film-coated pellet,the corresponding mathematical model was constructed,and the drug release mechanism was deeper and comprehensive studied by various factors.In addition,the key technologies affecting pellet compression were studied.Finally,the pH-independent drug release from EC/HPC film-coated pellet and pellet-containing tablet were prepared.In this article,we improved the understanding of the complicated drug release mechanism?i.e.diffusion and/or osmotic pumping?from the EC/HPC coated pellets,and provided a stable and scientific carrier unit with good compressive performance for the pellet-containing tablet.It can not only increase the successful of the preparation of pellet-containing tablet,but also has guiding significance for splitting the tablet.There are five main experimental studies in this article as following:In the study of the pre-prescription,HPLC-SEC-RI method was utilized to determine the content of the HPC in the coating film and the release in vitro which media were simulate the physiological conditions of the GI tract.Results indicated that the analytical methods were accurate and reliable.In the study of the film-coated pellets,the MCC pellet with the minimum particle size of 0.1mm-0.2mm was selected as the core.Optimized formulation and processing conditions were obtained after the study of the effects of the viscosity of the drug and polymer solution,the solution temperature and the main process parameters such as the inlet air temperature and feed rate on the coating efficiency and coating time.The drug-pellet and EC/HPC coated pellet with small size produced were of good sphericity,uniform shape and lower friability.The average yield of drug-containing pellets and film-coated pellets was up to 96%and 90%,respectively.Especially,the feed rate of polymer solution can be increased to 20mL/min.This work overcome the problems of lower coating efficiency,longer time,poorer repeatability and unstable quality of small particle size pellets when using the bottom-spray fluidized bed technology,and provide an excellent carrier with strong compressive resistance for the pellet-containing tablet.In the study of the controlled release mechanisms of film-coated pellets,the effects of HPC levels and the pH,type,concentration and osmolarity of the media on the release profiles of drug from the pellets were mainly investigated,and the HPC leaching of the pellets in vitro was also studied.Meanwhile,the corresponding free film was prepared for further understand the drug release behavior by the morphology?SEM?,water uptake of the free films and mass transport across the film when fixed the initial drug concentration.Interestingly,the drug release rate from the pellets and the free film in different media was not in agreement with the HPC leaching,known release mechanism and drug solubility which have a positive correlation with the drug dissolution rate based on Noyes–Whitney equation law.The actual drug release behavior was significantly related to the type and concentration of the media,making the drug release from the EC/HPC coated pellet was pH-dependent of the release medium.In the organic acids such as acetate buffer can affect the hydrophilicity and pore structure of the EC-rich area?>78%w/w?,which improved the permeability of the film.Also,the drug transport rate from the coated film,the water absorption of the free film and the pore size formed in the film were all have obviously positive correlation with the concentration of the acetate buffer.In contrast,the release of drug in HCl solution was dependent on the HPC levels.Increasing the levels of HPC increased the effects of high concentration of hydrogen ions on the nature of the polymer of HPC?>22%w/w?,which resulted in a lower viscosity and strength of the gel,reducing the interaction between the polymer macromolecule,and forming the larger size of pores or higher connectivity channels in polymer films,thus increasing the drug diffused from the coating film.Further findings in phosphate buffer showed a reduction in the drug release compared to that in other media,which was only sensitive to the osmolarity rather than the HPC level and pH of the buffer.Additionally,an adequate mathematical theory was used to quantitatively describe and objectively explain the experimentally measured different drug release patterns,which was consistent with the pore structure of the free film.The model considers the system specific parameters,such as the permeability coefficient of the coating film,the diffusion coefficient of the drug across the film and the contribution of osmotic pumping and diffusion mechanism to release rates.This study not only provides valuable reference for deeper and comprehensive underlying the complicated drug release behavior of the EC/HPC coated pellet,but also provides theoretical support for design and optimization of controlled release formulations that are independent of pH and other external factors.In the part of the optimization of pH-independent drug release of EC/HPC coated pellet,with the ratio of HPC and the coating weight as the main factors,the design and optimization of pH-independent release of film-coated pellets in various media were carried out by using the CCD-RSM?central composite design and response surface methodology?.Through the binomial fitting,two-dimensional contour line and three-dimensional effect surface evaluation,the level of HPC and coating weight of the optimized formulation was 22.5%w/w and 50%w/w,respectively.Comparing the observed values from the optimized formulation and predicted values,all errors are less than 5%,which indicates that the model has satisfactory predictability.Meanwhile,the drug release can maintain 16-hour zero-order release in each medium,and the values of f₂ were all above 50,regardless of the type of media.The stability data of stress testing and accelerated testing revealed that the EC/HPC coated pellets were stable.This work not only confirmed that the objectivity of the influence of media on the release of the EC/HPC coated pellet,but also obtained the pH-independent drug release of EC/HPC coated pellets which improve the safety of the controlled release formulation.In addition,in the study of the pellet tableting.According to comparing the effect of tableting method,the type,size and amount of tableting excipients,the pressure,and half tablet on the drug release of tablet.The combination of MCC 101 and KG 802exhibited good cushioning performance and high compressibility.There is no significant difference in the cumulative drug release of the whole tablet and the half tablet,also the content uniformity was accord with the requirement.In summary,the researched of the EC/HPC film-coated pellet with the small-particle size shown that the optimized formulation and process is stable and reproducible,which have a high coating efficiency and stable product quality.The study revealed that the effects of the media overcompensated that of the drug solubility to some extent for controlled-release of the coating polymers,and the drug release mechanism of different level of EC/HPC is significantly correlated with the pH,type and osmotic pressure of the release medium.It is the first time to deeply reported that the unusual differences of drug release kinetics in HCl solution at pH 1.2 and acetate buffer at pH 4.5,which was attributed to the effect of media on the property of HPC and EC,respectively,then changed the pore structure of the polymer film,making the release mechanism transformed to the effects of the combination of osmosis and diffusion.The obtained new insight on how drug release is affected by media and provided a mechanistic understanding of how this type of drug delivery system controls drug release,changing the opinion about the drug release from the EC/HPC coated pellet was mainly dependent on HPC alone,which give a deeper and comprehensive insight into underlying drug release behavior.The pH-independent drug release profile obtained by the CCD-RSM demonstrated the important significance of the controlled release characteristics of the study.In addition,the optimized range of the tablet excipient and amount were obtained,which were accord with the requirement.Our study not only improve the safety and stability of the clinical medical treatments,but also provide the theoretical and technical support for the personalized medicine.