The Study Of Sustained Release Ivermectin Loaded Solid Dispersion

Backgroud:Parasitic diseases seriously affect the growth and health of animals,resulting in huge economic losses for the livestock and poultry industry,moreover,endangering the health of human.The current serious issues facing in the prevention and control of parasitic diseases are repeated infection of parasites and long treatment period.At present,the most effective means of controlling parasitic diseases is periodic and repeated deworming with compounds.In the parasite control programs,repeated medication is generally needed to eliminate the parasites.This is very inconvenient and time consuming and high labor costs.To improve the efficiency of compounds,it is necessary to develop the long-acting anti-parasitic drug delivery systems to maximize the therapeutic duration of drugs,minimize the dosage for repeated injections while reducing the repeated parasite reinfection.Ivermectin(IVM)is one of the most successful therapeutic drug and widely used against endoparasites and ectoparasites.Traditional ivermectin injection dosage forms are usually characterized with short plasma half-life,low bioavailability,and thus need multiple administrations over a long treatment period to obtain therapeutic efficacy.Solid dispersion(SD)is a new pharmaceutical technology,which can be used to enhance the bioavailability of poorly water soluble drugs and to sustain the drug release in vivo by using the appropriate carriers.SD techniques have attracted considerable attention in the anti-parasite agents for veterinary used as an alternative sustained release drug delivery for enhancing the therapeutic of ivermectin and reducing the dose.Methods:In this study,the ivermectin was used as a model drug,hydrogenated castor oil(HCO)was chosen as the carrier and solid dispersion was chosen as sustained release drug delivery system.The ivermectin-loaded solid sustained release dispersion was prepared by solvent-melting method.The method for the determination of IVM in solid dispersions was established using high-performance liquid chromatography(HPLC)method.The physicochemical characteristics properties of solid dispersion were investigated and a complete quality assessment system of solid dispersion was established.The morphological characteristics of IVM-SD were observed by polarizing light microscope(PLM)and scanning electron microscope(SEM).The content of IVM in IVM-SD and the recovery of IVM during the preparation process were determined by HPLC.The compatibility and interaction of the drug and carrier in IVM-SD were detected by Fourier transformed infrared spectroscopy(FTIR)and nuclear magnetic resonance(NMR).The IVM state in solid dispersion was analyzed by X-ray powder diffraction(XRPD),differential scanning calorimetry(DSC),and hot-stage microscopy(HSM).The determination of IVM-SD degradation temperature and sample drying degree were investigated by means of thermogravimetric analysis(TGA).The sustained release action of IVM-SD was confirmed by dissolution test and the release mechanism was analyzed by drug release kinetics models.The cytotoxicity of IVM-SD was evaluated on MDCK cells.To establish the basis for the selection of IVM-SD storage conditions and understand the influence of the storage processes.The IVM-SD stability tests were investigated including influencing factor tests(strong light 4500 lx,high temperature 60 ?,high humidity 90%),accelerated test(40 ?,RH75%),long-term stability tests(conventional condition 25 ?,freezing condition-20 ?,refrigerated condition 5 ?,RH60%)and UVA exposure test.The therapeutic effect of IVM-SD(SD1:3)suspension was carried out in rabbits with naturally infected with rabbit ear mite(Psoroptes cuniculi).Results:The results of drug loading and recovery indicated that the IVM could be efficiently encapsulated into solid dispersion with HCO as carrier using solvent-melting method.Polarizing light microscope and scanning electron microscope showed that the IVM-SDs were homogeneous.IVM existed in an amorphous state at a drug:carrier ratio lower than 1:3.No chemical interactions between drug and carrier were found besides hydrogen bonding between IVM and HCO,which can enhance the stability of solid dispersions.Nuclear magnetic resonance(NMR)results show that no new chemical substances were produced during the preparation of IVM-SDs.The results of thermogravimetric analysis indicated the thermal stability of IVM-SDs was improved compare to IVM,and the solvent used in the preparation was completely removed.The IVM-SDs formulations exhibited a sustained release of IVM in vitro.The drug release decreased as the drug:carrier ratios decreased,meanwhile the release kinetics of IVM were controlled via diffusion.Cytotoxicity of IVM-SD to MDCK cells was lower than native IVM.The results of influencing factors on stability tests indicated that the color of the IVM-SD turned slight yellowed under strong light irradiation,the color turned yellow and the powder of IVM-SD became agglomerated at high temperature,there was no significant change in appearance under high humidity conditions.The data of accelerated stability tests and long-term stability tests showed that IVM-SDs stored at 40?(75%relative humidity)for 6 months,25?,5? and-20?(relative humidity 60%)for 12 months did not to be recrystallized,IVM in IVM-SD still existed in amorphous state.However,the DSC spectra showed that the endothermic peaks area of IVM-SDs were broaden at 40?,and the aging of the sample may relate to the caking sclerosis.The dissolution profiles of IVM-SDs with different drug-carrier ratios were slower comparing to the fresh preparation samples under each storage condition.The results of UVA exposure test illustrated that hydrogenated castor oil had a good photo-protection effect of IVM,which may be related to the existing of hydrogen bonds in IVM-SD.Based on the results of stability test,IVM-SDs should store at dark,dry,low temperature conditions to facilitate their stability.Pharmacodynamic results showed that a single subcutaneously administration of IVM-SD(2 mg/kg)could completely kill ear mites at 14th day post treatment.The persistence period of IVM-SD against ear mite in rabbits was 42 d which was remarkably longer than a common IVM solution(IVOMEC(?)).Conclusion:In summary,the solid dispersion is a prospective sustained release drug delivery system to promote pharmacological activity and extend their efficacy of anti-parasitic agents.