The Study On Molding Technology And Biopharmaceutical Evaluation Of Vitamin K1 Solid Self-Emulsifying Sustained Release Tablets

Liquid oily drugs,as a member of a large family of therapeutic drugs,their potential of being development into medicines are limited because they have low water solubility,poor absorption,low bioavailability,and difficulty in being made into stable oral preparations.Therefore,to make liquid oily drugs into functional oral solid preparations by using the formulation technology has become a hot spot for more and more preparation researchers in recent years.The preparation of an oral solid preparation which is stable and has high oil content and high bioavailability is a goal that pharmaceutical researchers are constantly striving to achieve.According to the previous research of our group,the anti-coagulant rodenticide special antidote vitamin K1?VK1?was used as a model drug.Oral vitamin K1 self-emulsifying sustained release tablets were prepared by applying self emulsifying drug delivery system?SEDDS?,liquid solid technology and powder direct compression technique.VK1 is currently the main drug for the treatment of vitamin K1-dependent coagulation factor deficiency,and it is also a special antidote for long-acting anticoagulant rodenticide?LAAR?.The main form of VK1 in clinic is injection.The adverse reactions of vitamin K1?ADR?also increase year by year,especially the adverse reactions of injection.The adverse reaction events of VK1 injection are received more attention in recent years.For the consideration of clinical safe medication,it is necessary to develop a reasonable alternative delivery way of vitamin K1.Oral administration is an important way to solve the adverse reactions of vitamin K1.Vitamin K1 tablets for oral administration are rarely available in the market.Compared with the injection,the tablet could reduce a large number of adverse reactions,and the patient compliance is greatly improved,but the frequency of administration is 2-4 times per day.In addition,the LAAR half-life is as long as several months,even if the patient has a long-term administration as a maintenance treatment after the risk period,it is clinically necessary to develop a vitamin K1 oral sustained-release tablet to make the drug administration once a day.On the basis of the previous research of the research group,Tween-80 was selected as the surfactant,polyethylene glycol-400 was selected as the co-surfactant,and VK1was used as the oil phase to prepare the liquid Self-emulsifying drug delivery system?L-SEDDS?.By drawing a ternary phase diagram,the range of components was determined as follows:VK1 was 10%-40%,TW-80 was 50%-80%,and PEG-400 was10%-40%.Based on the three-phase diagram,the fitting model was established by central composite design to optimize prescription.Considering the self-emulsification ability,the particle size after dispersion,and the drug loading amount,the mass ratio of the optimal L-SNEDDS prescription is determined to be 25%?oil?of VK1,50%?surfactant?of TW-80,PEG-400 is a three component mixture of 25%?cosurfactant?.The prepared L-SNEDDS is a yellow uniform clear liquid,and a uniform and stable pale yellow nanoemulsion could be spontaneously formed in water under stirring.The Malvern particle size analyzer measured the average particle size of the dispersed nanoemulsion to be 21.15 nm and the API was 0.114.The scanning electron microscopy of the Transmission electron microscope?TEM?could also be seen that the size of the nanoemulsion droplets is around 20 nm.During the dispersion process,as the temperature and stirring speed increase,the speed of nanoemulsion formation is faster,and the speed and particle size of nanoemulsion droplets formed in different media are not much different.It could be seen that the nanoemulsion did not precipitate and the particle size of the emulsion did not increase within 24h from the stability experiment.Selecting an adsorbent with a large specific surface area to adsorb L-SNEDDS into a solid powder was an important means to solidify liquid oily drugs.The anhydrous calcium hydrogen phosphate was chosen as a solid adsorbent to prepare the liquid solid powder by liquid-solid technology.According to the theoretical knowledge of liquid-solid powder,the?-value was determined by measuring the sliding angle of the powder after adsorbing a certain amount of liquid,and when the sliding angle is 33.33°,the powder has the best fluidity and compressibility.According to the measurement results,the mass of the solid adsorbent anhydrous calcium hydrogen phosphate is calculated to be 1.365 times the mass of the L-SNEDDS.The results of pharmacokinetic experiments show that vitamin K1 could significantly increase the rate of blood entry of the drug after self-emulsification,and the bioavailability was twice that of untreated tablets.Because the commercially available vitamin K1 was 5 mg/tablet and 10 mg/tablet,and the bioavailability of the drug was doubled after self-emulsification,the vitamin K1 sustained release tablet was set to 2.5 mg/tablet.Using Hydroxypropyl Methyl Cellulose?HPMC?as the matrix material and retarder,lactose and Microcrystalline Cellulose?MCC?were used as excipients to prepare VK1 solid self nano-emulsifying drug delivery system?S-SNEDDS?tablets by direct compression of powder.The effects of different types of HPMC on the release of sustained-release tablets were investigated by single factor.As the amount of HPMC increased,the drug release decreased.The comprehensive results showed that the release effect of HPMC alone was not ideal.Therefore,HPMC K100LV and K4M were selected as the joint skeleton materials for prescription investigation.The fitting model was established by central composite design to optimize prescription.It was determined that the ratio of the selected mixed retarder to HPMC K4M and HPMC K100LV was15%of the total tablet weight.After the optimized prescription and small test process verification,the prescription and process of the pilot test were determined,and three batches of amplification experiments were carried out.From the aspects of appearance,traits,identification,content,content uniformity,related substances and in vitro release,the results of all the indicators of the three batches were in compliance with the standards.The stability of the product and the reference to the storage conditions were investigated by influencing factors test and accelerated experiment.Influencing factors test results suggest that this product should be sealed and protected from light.Through the pilot scale,the production process was determined and the intermediates that need to be controlled in the production process were determined.The method for determining the vitamin K1 content in beagle dogs by HPLC-MS/MS was established.Commercially available Mephyton??5mg/tablet?vitamin K1 has been selected as a reference preparation.The in vivo pharmacokinetics of beagle dogs was studied.Compared with the reference preparation,the vitamin K1self-emulsifying sustained-release tablets had a slower T_max,lower C_max and longer MRT in beagle dogs.It showed that the controlled-release tablets had sustained-release effect in beagle dogs.The relative bioavailability of the vitamin K1 self-emulsifying sustained-release tablets compared to the control vitamin K1 tablets was97.16%±18.93%.After inquiring domestic and foreign literatures,in addition to the research on VK1self-emulsifying skeleton sustained-release tablets,there is no relevant report,so this program is of high innovation and research value.In this study,oral vitamin K1self-emulsifying sustained-release tablets were prepared by combining SNEDDS,liquid-solid compression technology and powder direct compression technology,which not only achieved a good sustained-release effect,but also reduced the difference in patient medication and compliance.It could be known from this study that the self-emulsifying drug delivery system is a feasible technical means to improve the bioavailability of the drug,and solid solution curing is a perfect method for preparing a liquid drug into a solid dosage form.This could provide a good idea for the development of liquid oily drugs.