Investigation Of Memantine Long-acting Injections

Alzheimer’s disease(AD)is a progressive neurodegenerative disease.Its main clinical manifestations are memory loss,cognitive dysfunction,social disorder and personality behavior changes,but the pathogenesis is not clear so far.At present,the main drugs on the market for the treatment of AD are cholinesterase inhibitor(Ach EIs)and N-methyl-D-aspartate acid(NMDA)receptor antagonist.Memantine hydrochloride(MEM·HCl)is the only NMDA receptor antagonist on the market for AD and the only drug used in the treatment of moderate to severe Alzheimer’s disease.It is a low-to-moderate affinity,non-competitive,strong voltage-dependent NMDA receptor antagonist,which can block the overexcitation of NMDA receptor induced by glutamate(Glu),prevent intracellular calcium overload,and thus prevent apoptosis of nerve cells and the progression of Alzheimer’s disease.The drug on the market is mainly oral preparation,the frequency of administration is once or twice a day,which leads to poor compliance in patients with AD,it is easy to cause the phenomenon of missing and refusing to take medicine,and the blood concentration fluctuates greatly which will affect the therapeutic effect.In view of the shortcomings of the existing memantine preparation,this study intends to develop a weekly or even monthly injection of memantine,which adopts insoluble salt technology and medium grinding technology.The long-acting injection can significantly reduce the frequency of administration and improve the compliance of patients,stabilize the blood concentration and improve the therapeutic effect.In this study,an in vitro analysis method of pre-column derivatization was established,which met the methodological requirements and could be used for the determination of memantine.Then memantine pamoic acid(MEM-PAM)were prepared by direct reaction method and anti-solvent method,and the structure of the prepared crystal was confirmed by Fourier transform infrared spectroscopy(FTIR)and HNMR.In the anti-solvent method,the solvent was screened,and the crystal prepared by DMSO was preliminarily determined to be the dominant crystal form.The preparation conditions of the dominant crystal form were optimized,and the optimization factors were reaction temperature,concentration of MEM-PAM DMSO solution,feeding rate of anti-solvent,ratio of solvent to anti-solvent and stirring speed.After the optimization of the conditions,the particle size of the prepared crystal was more uniform.The physical and chemical properties of crystals prepared by reaction method and anti-solvent method were studied.The results showed that the crystal forms prepared by the two methods were different and they were both anhydrous.Form I would be transformed into Form II at 209 °C.Under 90%RH,the water absorption and weight gain of Form I and Form II were 5.69% and 0.22%,respectively,indicating that Form II had higher stability.The dissolution rate and solubility of MEM-PAM(Form I and Form II)were measured,and it was found that there was no significant difference in solubility between them.Memantine pamoic acid suspensions for injecting were prepared with Form I and Form II as main drug respectively,and their appearance,particle size distribution and in vitro release were studied.According to the experimental results,the preparation prepared from Form II released more slowly in vitro than that prepared by Form I,and it is further confirmed that Form II was the dominant crystal form;the larger the particle size,the slower the release in vitro,which could regulate the drug sustained release time by adjusting the particle size.A set of HPLC-MS/MS analysis methodology which pretreatment by precipitated protein method was established.The method was simple and reliable and could be used to determine the concentration of memantine in plasma samples.The pharmacokinetics of memantine hydrochloride aqueous solution and self-made memantine pamoic acid suspensions were studied.Memantine hydrochloride solution was given by intragastric administration.According to the blood concentration-time curve,the concentration was only 9.63 ng/m L after12 h.Therefore,the commercial preparations with memantine hydrochloride as the main drug must be given daily,or even given several times a day.The study on the pharmacokinetics of the self-made memantine pamoic acid suspension showed that F1(main drug is Form I)could be released slowly in rats for 9 d after intramuscular injection,F2 and F3(main drug are Form II)could be released in vivo for 15 d and 29 d respectively,which proved that the self-made preparation had a good sustained release effect.To sum up,according to the results of this study,the appearance of Form I was needle-like,the appearance of Form II was block,the specific surface area of bulk crystal was smaller,so the release rate was slower,and its thermal stability and hygroscopicity were better,which was more conducive to the stability of storage and preparation.In the vivo and vitro release experiments,the sustained release effects of F2 and F3 prepared by Form II were better than those prepared by Form I,and the results of pharmacokinetics showed that memantine pamoic acid suspensions had obvious sustained release effect.By adjusting the particle size of main drug,the suspension could be sustained for 15～29 d in rats,and it is expected to be injected once two week or even once a month,which can effectively reduce the frequency of drug administration and improve the compliance of patients,and the suspensions lays the foundation for the design of memantine long-acting injection and provides another possibility for the treatment of moderate to severe Alzheimer’s disease.