Study On The Molding Process Of Solid Self-emulsifying Tablet Of Oily Drug Vitamin K1

Brodifacoum,Bronone and other long-acting anticoagulant rodenticide(LAAR)had been widely used in agriculture,forestry and animal husbandry.As these products are inexpensive and available,there are frequent incidents of poisoning,suicide and abuse,and the common access to toxic drugs include oral and transdermal absorption.LAAR affects the liver coagulation factor synthesis by inhibiting the vitamin K epoxide reductase(VKOR)and causes bleeding.At present,large doses of vitamin K1 injection are often used to treat LAAR poisoning.However,the half-life of the LAAR is long for several months,and it is necessary for the patient to be administered for a long period of time,even if it is out of the danger period.Foreign doctors often use oral VK1 tablets and mixed micelles to increase available administrations,which can improve patients' compliance and drug safety,but oral VK1 preparations are still difficult to be acquired in domestic market currently.As a fat-soluble vitamin,vitamin K1(VK1)is is the main drug for clinical treatment of vitamin K-dependent coagulation factor deficiency.The addition of VK1 could promote the effective synthesis of coagulation protein in poisoned patients,and then restore the human coagulation process.In addition to poisoning rescue,VK1 can also be used to prevent and treat neonatal bleeding,as well as hypoprothrombinemia caused by oral anticoagulant or broad-spectrum antibiotics.Considering that VK1 is completely insoluble in water,and it can be absorbed in the gastrointestinal tract in the presence of bile salts,this topic would solubilize the drug by using natural surfactants and then solidify the liquid drug.Finally,VK1 tablets based on solid self-emulsification technology were designed and prepared.In this paper,we did preformulation study of the model drug firstly.VK1 is a transparent,yellow to orange oily viscous liquid,which is tasteless or almost tasteless,insoluble in water,and slightly soluble in ethanol.The in vitro analysis methods of VK1 was established.The dissolution test was carried out by ultraviolet spectrophotometry,and the content and related substances were determined by high performance liquid chromatography.The analytical methods were investigated for the linearity,precision and specificity and so on.The methods established are easy and accurate,which could meet the measurement requirementsBased on the VK1 mixed micelles(Konakion? MM)produced by Roche Pharmaceuticals,we selected biodegradable soybean lecithin and glycocholic acid as complex surfactants.VK1 was used as oil phase directly and polyol as cosurfactants to prepare liquid self-nanoemulsifying drug delivery system(L-SNEDDS).Based on the ternary phase diagrams,Transcutol HP was selected as the optimal surfactant,and the ratio of soybean lecithin and glycocholic acid was determined to be 3: 2.Then,the fitting model was established by central composite design,and the optimal range of each response value was defined to draw a overlapping contour map,as the particle size was less than 60 nm,the zeta potential was in the range of-25 to-20,and the dissolution rate was more than 90%.According to the actual situation in the preparation process,the amount of oil and the ratio of surfactant to cosurfactant were determined.Finally,the optimal L-SNEDDS formulation was a mixture of 22.5% VK1(oil),49.82% soy lecithin and glycocholic acid(3: 2,surfactant),and 27.68% Transcutol HP(cosurfactant).VK1 L-SNEDDS was yellow,clarified,and viscous liquid.After dilution with distilled water,a uniform nano-emulsion can be formed.The droplet size of the nano-emulsion was uniform under the transmission electron microscope,with an average of 47.74 nm and a zeta potential of-20.53 mV.During the dilution process,the self-emulsifying speed was accelerated when the temperature was higher and the stirring speed was faster.But different media(distilled water,0.1 M HCl,pH = 6.8 phosphate buffer,0.5% SDS)had little effect on the self-emulsification rate.However,the particle size after dilution was related to the type of media.The droplet size was significantly increased in 0.1M HCl media,but it was similar in the other three media.After investigation,we confirmed that L-SNEDDS stability was good,and the drug in nanoemulsions in the four media were able to maintain stability without precipitation in 6 hours after dilution.In order to convert VK1 L-SNEDDS into tablets,six kinds of carrier materials were selected as the solid adsorbents to be investigated: microcrystalline cellulose(Vivapur? PH102),lactose(Cellatose? 80),anhydrous hydrogen phosphate Calcium(Fujicalin?),magnesium aluminum silicate(Neusilin?US2),silica gel(Cab-O-Sil? M5P),and granular aerosol(Aeroperl? 300 Pharma).Firstly the microscopic morphology of different kinds of liquid solid powders were compared by scanning electron microscopy,and studing structures was helpful to understand their properties.The Neusilin?US2,in which the main drug could rapidly degrade,was ruled out in the raw material compatibility test.We also finded that the maximum adsorption capacity and the powdery properties of Vivapur? PH102 and Cellatose? 80 were poor due to their small specific surface area.In the dissolution experiment of liquisolid powders,it was found that two kinds of micro-silica gel prevented L-SNEDDS from dissolving.Thus it was determined that Fujicalin? was selected as the best solid adsorbent.It could maintain good fluidity while adsorbing large amount of liquid.The liquisolid powders would be mixed with other excipients and then solid self-emulsified tablets were prepared by direct compression.It was found that when we use less insoluble solid adsorbent,the tablets were easier to be wetted,and thus improved the dissolution rate.Similarly,reducing the amount of micrometer silica gel was also more conducive to self-emulsification process.Also the addition of disintegrating agent was very important,because the tablets contained L-SNEDDS,which caused the tablets to become sticky when contacted with water.Compared with other kinds of disintegrating agents,CMC-Na can produce a sustained and mild disintegration process,and the dissolution rate of tablets was improved as the amount of disintegrant increased.Microcrystalline cellulose and lactose were fillers in the tablets,although the addition of lactose was more conducive to self-emulsification process,but microcrystalline cellulose was an important factor in ensuring the hardness of tablets.Finally,the composition of the optimal formulation was: Fujicalin? / L-SNEDDS(1.4: 1),20% microcrystalline cellulose,37.6% lactose,15% CMC-Na,0.2% silica gel and 0.5% stearic acid magnesium.In addition,the dissolution rate of solid self-emulsifying tablets in the four dissolution media were significantly higher than those of conventional tablets,even up to 100% in 0.1M HCl and 0.5% SDS,and the particle size remained constant in the reconstitution test.In summary,solid self-emulsification technology is an effective way to improve dissolution of water-insoluble drug,which has good prospects.