| Toltrazuril,alias toluenetriazinone,is a broad-spectrum anticoccidial triazinone derivative and has strong bactericidal effect on 6 species of Eimeria,including giant,brucella,and tender,widely used in the prevention and treatment of coccidiosis in poultry and mammals.The totrazuril dosage form is very simple in the market,and there is only Bayer's totrazuril solution,sold as a commodity,and the content is as low as 2.5%.Due to its poor solubility in water(0.41 ?g/mL at 25?)and its low stability,it is prone to precipitation and discoloration.To sum up,to find a carrier material with high water solubility and / or better biocompatibility and easy to industrial production has always been a hot spot in the field of antiparasitic drug.Clathrate compound is a class of organic crystals.It contains two types of structural units: one is a compound capable of trapping other compounds in the cavity of its structural skeleton,ie,a host molecule;the other is a compound trapped in a cavity,ie,a guest molecule.?-Cyclodextrins and their derivatives are increasingly used in the pharmaceutical industry for their size-appropriate cavity structure,which can increase the solubility of drug in the water,reduce the side effects of drug toxicity,mask the adverse drug odor,and have a certain degree of controlled release.SBE-?-CD is highly water soluble and is a ?-CD derivative developed by Cydex in the United States in 1990.Compared with ?-CD,SBE-?-CD has better biocompatibility and is more easily combined with drug molecules to form non-covalent bonds.Therefore,it has broad prospects for pharmaceutical excipients.In order to improve the dissolution properties of toltrazuril,this study prepared Tol/SBE-?-CD inclusion complex,with toltrazuril used as a model drug,and Physically characterized the inclusion compound.Finally,using commercially available toltrazuril solution as a reference,thoroughly studied the pharmacokinetics of toltrazuril inclusion in broiler chicken.1.A method for the determination of content in and outside and in vitro was established: ultraviolet spectrophotometry,and the standard curve equation was A = 0.0481 C + 0.0249(R = 0.9995).The method can be used for the determination of the content of the samples in vitro.2.The solubilizing effect of the excipient SBE-?-CD on Tol was investigated by phase solubility and the apparent stability constants were calculated.The thermodynamic parameters were calculated,and the possibility of inclusion interaction and the inclusion ratio of the inclusion product were inferred.The results showed that SBE-?-CD had extremely significant solubilizing effect on toltrazuril,and the apparent stability constant was the highest at 45?.The phase solubility curve was AL type,and SBE-?-CD and drug formed 1 : 1 inclusion compound,original drug and auxiliary material have inclusion potential.3.Taking the encapsulation rate and drug loading as the comprehensive evaluation index(d),including temperature(A),subject-to-substance ratio(B),pH value(C)and solvent concentration(D),to design the optimization of response surface method.The optimal formulation and process are: At 41.3?,accurately weigh the cyclodextrin and toxotriene(main: guest = 3.1:1)cyclodextrin in 18.6 mL of pH=9.9 phosphate buffer.Toltrazuril was dissolved in 8 mL of methanol and reacted for 3 h at 400 r/min with magnetic stirring.Rotated to 10 mL at 40 ? and filtered through a 0.45 ?m filter to obtain a clathrate solution.For the long-term preservation of the unstable system,the inclusion compound solution was made into a freezedried powder and the freeze-drying process was optimized.Finally,the freeze-drying process was obtained as follows: no protection agent,pre-freezing at-20? for 3 hours,-79? continued Freeze for 12 h,finally freeze-dried at-50? for 20 h,and program temperature to 30?(4 h)to obtain freeze-dried inclusion compound powder.4.The drug loading was 5.51±0.71%,The saturated solubility of the inclusion compound freeze-dried powder at 37? is 37409.27 ?g/mL,while the saturation solubility of the original drug is 0.631 ?g/mL,and the solubility is increased by 59,286 times.The results of infrared spectroscopy(IR),thermal analysis(DSC),X-ray diffraction(XRD)and scanning electron microscopy(SEM)showed that the new inclusion complex was formed in the freeze dry powder,and nuclear magnetic resonance(1H-NMR)showed that the inclusion trajectory of the inclusion compound was the main drug from the cyclodextrin into the cyclodextrin cavity from the large port of cyclodextrin.The accelerated test showed that the lyophilized powder of the drug was dry,sealed and preserved.5.Using broiler chicken as a model animal,the pharmacokinetics of toltrazuril in the only commercially available toltrazuril solution(2.5%)and the freeze-dried powder of the inclusion complex was compared.The pharmacokinetic data of the two preparations showed that the pharmacokinetic process of toltrazuril in broilers was in accordance with the two compartment model.And the solubility is far greater than the only commercial product of the toltrazuril solution.The absorption rate in broiler chicken is fast,the elimination half-life is long,and the average retention is long,and the area under the curve is large.The relative bioavailability of toltrazuril solution is significantly improved,and the toltrazuril lyophilized powder has the potential to be further developed as a new drug product of toltrazuril.This study not only enriched the anticoccidial drug toltrazuril but also provided a reference for the further development of sulfobutyl ether-?-cyclodextrin as a solubilizing excipient. |
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