CN108969478A - A kind of Memantine difficulty soluble salt is slow-release injected and preparation method thereof - Google Patents
A kind of Memantine difficulty soluble salt is slow-release injected and preparation method thereof Download PDFInfo
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Abstract
It is slow-release injected and preparation method thereof the invention discloses a kind of Memantine difficulty soluble salt, it is characterized by: being calculated in mass percent, including as the Memantine difficulty soluble salt 1%~30% of active constituent, stabilizer 0.1%~10%, pH adjusting agent 0%~1%, isotonic regulator 0.1%~5% and water for injection 60%~98%；The Memantine difficulty soluble salt includes one of Memantine-oleate, Memantine-linoleate, Memantine-linolenate, Memantine-arachidonate, Memantine-stearate, Memantine-laruate, Memantine-tannate, Memantine-palmitate, Memantine-embonate, Memantine-furan type hydrochlorate.The present invention uses indissoluble salt technology, is prepared for Memantine difficulty soluble salt, by reducing drug solubility, extends pharmaceutical release time.Compared with memantine, Memantine indissoluble salt solubility reduces 40~600 times, can be sustained a couple of days to several weeks.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of Memantine difficulty soluble salt is slow-release injected and its preparation side
Method.
Background technique
Alzheimer disease is a kind of nervous function retrograde degeneration's disease for carrying out sexual development, and main clinical characteristics are
Failure of memory, cognition dysfunction, human communication disorders and personality behavior change etc. seriously reduce the quality of life of patient, and
Family burden and burden on society are aggravated.The cause of disease of Alzheimer disease is not yet clear at present, therefore there is no drug that can effectively hinder
The process of Alzheimer disease is only even reversed, existing treatment means are mostly to improve certain symptoms of patient, or delay A Er
Ci Haimo disease development process.
So far, the therapeutic agent for alzheimer's disease listed only has Tacrine, donepezil, Rivastigmine, adds
Lan Tamin, huperzine and memantine.Wherein, memantine is only one by U.S. Food and Drug Administration
(FDA) ratify the drug for treating moderate to severe Alzheimer's disease.Memantine is a kind of low moderate affinity
Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist has dual regulation.When glutamate levels are lower than
When normal physiologic levels, memantine can activate the transmitting of postsynaptic nmda receptor enhancing glutamic acid；And work as glutamate levels
When higher than normal physiologic levels, the blocking nmda receptor that memantine then can be noncompetitive, confrontation excessive glutamate is caused
Excititoxic delay the development process of Alzheimer disease to prevent nerve cell apoptosis.
The memantine preparation listed both at home and abroad at present includes conventional tablet (2 times a day), oral solution (daily 2
It is secondary) and spansule (one time a day).Although oral preparation is highly-safe, convenient to take, patient is easy to receive, hydrochloric acid beauty
Buddha's warrior attendant oral preparation needs daily medication 1~2 time, for patients with Alzheimer disease, long-term administration is often needed, due to such
The illness of patient is mainly shown as memory disorders, insanity, it is difficult to which autonomous medication wrong clothes easily occurs, misses or even refuse to take, most
Treatment is caused to stop eventually, the state of an illness further deteriorates.Therefore, it needs to develop a kind of Memantine long-acting injection that can be released the drug for a long time,
The treatment time of a few days or even several months are maintained, to improve patients with Alzheimer disease compliance.
Patent CN 104127376A discloses a kind of memantine oral administration solution, has compared with tablet and inhales faster
It produces effects fruit；Patent CN 107412199 A and patent CN 107773553A individually disclose a kind of Memantine hydrochloride sustained-release capsule
Composition and a kind of memantine sustained release pellet and preparation method thereof.Compared to conventional tablet and oral administration solution, 2 are administered in the daytime
It is secondary to reduce to being administered once in the daytime, but be still to be administered daily.Patent CN 107468673A opened it is a kind of transdermal with Memantine, can be with
It avoids being administered orally for multiple daily, is changed to lagging administration, but the duration is only capable of maintaining 12h.It there is no one kind that can be sustained number at present
The Memantine sustained release preparation of its even several weeks mitigates burden on society to improve patients with Alzheimer disease compliance.
Summary of the invention
The purpose of this section is to summarize some aspects of the embodiment of the present invention and briefly introduce some preferable implementations
Example.It may do a little simplified or be omitted to avoid our department is made in this section and the description of the application and the title of the invention
Point, the purpose of abstract of description and denomination of invention it is fuzzy, and this simplification or omit and cannot be used for limiting the scope of the invention.
In view of above-mentioned technological deficiency, the present invention is proposed.
Therefore, as one aspect of the present invention, the present invention overcomes the deficiencies in the prior art, provides a kind of beauty
Buddha's warrior attendant difficulty soluble salt is slow-release injected.
In order to solve the above technical problems, the present invention provides the following technical scheme that a kind of Memantine difficulty soluble salt release injectable
Agent, in which: be calculated in mass percent, including as active constituent Memantine difficulty soluble salt 1%~30%, stabilizer 0.1%~
10%, pH adjusting agent 0%~1%, isotonic regulator 0.1%~5% and water for injection 60%~98%；The Memantine indissoluble
Salt includes Memantine-oleate, Memantine-linoleate, Memantine-linolenate, Memantine-arachidonate, U.S. dollar
Just-stearate, Memantine-laruate, Memantine-tannate, Memantine-palmitate, Memantine-pamoic acid
One of salt, Memantine-furan type hydrochlorate.
A kind of preferred embodiment slow-release injected as Memantine difficulty soluble salt of the present invention: further include, with quality hundred
Score meter, 0.1%~15% freeze drying protectant, the freeze drying protectant include trehalose, lactose, glucose, mannitol,
One of glycerol, sorbierite, polyethylene glycol, sodium carboxymethylcellulose, povidone, amino acid, ascorbic acid, albumin are several
Kind.
A kind of preferred embodiment slow-release injected as Memantine difficulty soluble salt of the present invention: the stabilizer includes sea
Mosanom, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polysorbate, Bo Luosha
Nurse, phosphatide, polyethylene glycol, povidone, polyethylene glycol-polylactic acid block copolymer, polyethylene glycol-polylactic acid glycolic acid block
One of copolymer or more than one.
A kind of preferred embodiment slow-release injected as Memantine difficulty soluble salt of the present invention: the pH adjusting agent includes
Hydrochloric acid, sodium hydroxide, sodium bicarbonate, glutamic acid, lactic acid, phosphate, acetic acid and its salt, citric acid and its salt, tartaric acid and its
One of salt or more than one；The isotonic regulator is selected from glucose, sodium chloride, glycerol, sodium sulphate, sodium alginate, sweet
Reveal one of alcohol or more than one.
A kind of preferred embodiment slow-release injected as Memantine difficulty soluble salt of the present invention: the Memantine difficulty soluble salt
It is slow-release injected that powder-type injection and the storage of dilution two parts can be stored or be divided into liquid suspension form；Its
In, the powder-type injection can be the Memantine indissoluble salt powder comprising one or more kinds of auxiliary materials, or not include
The Memantine indissoluble salt powder of any auxiliary material, the dilution can be the solution comprising one or more kinds of auxiliary materials, can also be with
It is the water for injection not comprising auxiliary material.
As another aspect of the present invention, the present invention overcomes the deficiencies in the prior art, provides the U.S. dollar
The slow-release injected preparation method of rigid difficulty soluble salt.
In order to solve the above technical problems, the present invention provides the following technical scheme that the Memantine difficulty soluble salt is sustained note
Penetrate the preparation method of agent comprising,
It prepares Memantine difficulty soluble salt: memantine and hydrochlorate is dissolved in water, under agitation, by hydrochlorate
Aqueous solution adds in memantine aqueous solution, filtering, collects filter cake, as Memantine difficulty soluble salt, to Memantine difficulty soluble salt into
Row purifying；
Memantine difficulty soluble salt is slow-release injected: dispersing the Memantine difficulty soluble salt in the aqueous solution containing auxiliary material, stirs
Mixing makes it be uniformly dispersed, and is ground using wet laid media grinder, and Memantine difficulty soluble salt suspension is obtained；Or it is Memantine is difficult
Dissolved salt be scattered in the aqueous solution containing auxiliary material obtain Memantine difficulty soluble salt be suspended just liquid obtained using high-pressure homogeneous carry out homogeneous
To Memantine difficulty soluble salt suspension；Or Memantine difficulty soluble salt is transferred in airslide disintegrating mill and is crushed, obtain micronization U.S. dollar
Rigid indissoluble salt powder.
A kind of preferred embodiment of the preparation method slow-release injected as Memantine difficulty soluble salt of the present invention: the system
Standby Memantine difficulty soluble salt, including, memantine and hydrochlorate are dissolved in water, at 75 DEG C, concentration, which is respectively configured, is
The solution of 0.1mol/L under agitation adds to acid salt aqueous solution in memantine aqueous solution, 10000r/min centrifugation
10min is filtered, and collects precipitating, and hot water washs three times, for 24 hours by 40 DEG C of gained filter cake vacuum drying.
A kind of preferred embodiment of the preparation method slow-release injected as Memantine difficulty soluble salt of the present invention: it also wraps
It includes, the Memantine difficulty soluble salt suspension is added to 1%~15% freeze drying protectant, is freeze-dried, obtains powder-type
Memantine difficulty soluble salt is slow-release injected；Or disperse the micronization Memantine indissoluble salt powder in containing auxiliary material and 1%~
It in the aqueous solution of 15% freeze drying protectant, then dispenses and is freeze-dried, it is slow-release injected to obtain powder-type Memantine difficulty soluble salt.
A kind of preferred embodiment of the preparation method slow-release injected as Memantine difficulty soluble salt of the present invention: described wet
Method medium milling, abrasive media include one of polystyrene bead, zirconium oxide bead, zirconium silicate pearl.
A kind of preferred embodiment of the preparation method slow-release injected as Memantine difficulty soluble salt of the present invention: the beauty
The slow-release injected average grain diameter of Buddha's warrior attendant difficulty soluble salt is 0.2 μm~10 μm.
Beneficial effects of the present invention: the present invention uses indissoluble salt technology, is prepared for Memantine difficulty soluble salt, by reducing medicine
Object solubility extends pharmaceutical release time.Compared with memantine, Memantine indissoluble salt solubility reduces 40~600 times,
A couple of days can be sustained to several weeks.The present invention uses indissoluble salt technology, and Memantine difficulty soluble salt is prepared into suspension type Memantine indissoluble
Salt is slow-release injected, is not necessarily to special preparation equipment, plants with other long-acting injection technologies such as pro-drug, microballoon, micro-capsule, injection
Enter agent, gel, reservoir in situ are compared, preparation process is simple, it is easier to industrialized production.Memantine difficulty soluble salt of the present invention
It is slow-release injected, after drug administration by injection, sustainable drug release several weeks, solves the drawbacks of Memantine drug needs frequent drug administration, be expected to
Patients with Alzheimer disease medication compliance is significantly improved, nurse cost is reduced, mitigates burden on society.The present invention can pass through change
The acid group of Memantine indissoluble salt changes preparation partial size, adjusts slow-release time, can meet different dosing cycle request.This hair
It is bright to can avoid excessive small particle (d30The particle volume hundred of the slow-release injected middle partial size<100nm of>100nm, i.e. Memantine difficulty soluble salt
Divide than the generation lower than 30%) Memantine indissoluble salt particle, prepared Memantine difficulty soluble salt long-acting injection average grain diameter is 0.2
μm~10 μ ms in, while guaranteeing good syringeability, obtain excellent slow release effect.
Detailed description of the invention
In order to illustrate the technical solution of the embodiments of the present invention more clearly, required use in being described below to embodiment
Attached drawing be briefly described, it should be apparent that, drawings in the following description are only some embodiments of the invention, for this
For the those of ordinary skill of field, without any creative labor, it can also be obtained according to these attached drawings other
Attached drawing.Wherein:
Fig. 1, which is Memantine stearate slow-release injected (embodiment 1), Memantine palmitate is slow-release injected (implements
Example 2), the grain of Memantine oleate slow-release injected (embodiment 3) and Memantine embonate slow-release injected (embodiment 4)
Diameter distribution map.
Fig. 2 is that the Memantine embonate for preparing referring to embodiment 5 and 6 the method for embodiment is slow-release injected and ginseng
According to the grain size distribution of the Memantine suspension of 2 the method for comparative example preparation.
Fig. 3 be referring to the preparation of 1~embodiment of embodiment, 6 the method Memantine difficulty soluble salt it is slow-release injected and referring to right
Medicine of the Memantine suspension of 2 the method for ratio preparation in simulated body fluid environment (10mM phosphate buffer solution, pH7.4)
Object releasing curve diagram (n=3, Mean ± SD).
Fig. 4 is to give rat Memantine stearate slow-release injected (embodiment 1, dosage respectively through intramuscular injection
125mg/kg), Memantine palmitate slow-release injected (embodiment 2, dosage 125mg/kg), Memantine oleate release injectable
Agent (embodiment 3, dosage 125mg/kg), Memantine embonate slow-release injected (4~embodiment of embodiment 6, dosage
125mg/kg), memantine solution (comparative example 1, dosage 25mg/kg) and Memantine suspension (comparative example 2, dosage
25mg/kg) blood concentration-time curve graph (n=6, Mean ± SD) in 24 hours afterwards.
Fig. 5 is to give rat Memantine stearate slow-release injected (embodiment 1, dosage respectively through intramuscular injection
125mg/kg), Memantine palmitate slow-release injected (embodiment 2, dosage 125mg/kg), Memantine oleate release injectable
After agent (embodiment 3, dosage 125mg/kg) and Memantine embonate slow-release injected (embodiment 4, dosage 125mg/kg)
Blood concentration-time curve graph (n=6, Mean ± SD) in 28 days.
Fig. 6 is to give rat Memantine embonate slow-release injected (4~embodiment of embodiment respectively through intramuscular injection
6, dosage 125mg/kg) blood concentration-time curve graph (n=6, Mean ± SD) in 28 days afterwards.
Specific embodiment
In order to make the foregoing objectives, features and advantages of the present invention clearer and more comprehensible, right combined with specific embodiments below
A specific embodiment of the invention is described in detail.
In the following description, numerous specific details are set forth in order to facilitate a full understanding of the present invention, but the present invention can be with
Implemented using other than the one described here other way, those skilled in the art can be without prejudice to intension of the present invention
In the case of do similar popularization, therefore the present invention is not limited by the specific embodiments disclosed below.
Secondly, " one embodiment " or " embodiment " referred to herein, which refers to, may be included at least one realization side of the invention
A particular feature, structure, or characteristic in formula." in one embodiment " that different places occur in the present specification not refers both to
The same embodiment, nor the individual or selective embodiment mutually exclusive with other embodiments.
Embodiment 1:
The slow-release injected preparation of Memantine-stearate:
A. Memantine-stearate synthesis
Appropriate odium stearate is weighed, is dispersed in 75 DEG C of distilled water of 100mL, stirring and dissolving, compound concentration 0.1mol/
The aqueous solution of sodium stearate of L；Appropriate hydrochloric acid Memantine is weighed, is dissolved in 75 DEG C of distilled water of 100mL, obtaining concentration is
The memantine aqueous solution of 0.1mol/L.In 75 DEG C, under stiring, above-mentioned memantine aqueous solution is added dropwise to stearic acid
In sodium water solution, 10000r/min is centrifuged 10min, filters, and collects precipitating, and hot water washs three times, by 40 DEG C of vacuum of gained filter cake
Drying is for 24 hours to get Memantine-stearate.
B. the slow-release injected preparation of Memantine-stearate
25g Memantine-stearate (in terms of Memantine) is dispersed in 250mL and contains 2% (wt) sodium carboxymethylcellulose
Aqueous solution in, aqueous solution with NaOH adjust pH be 7.4, with NaCl adjust it is isotonic, using wet laid media grinder in 1500rpm
15min is ground under revolving speed, abrasive media is 0.8mm zirconium oxide bead, obtains Memantine-stearic acid that average grain diameter is 0.865 μm
5% (wt) mannitol is added into gained suspension for salt suspension, dispenses, and it is slow to obtain Memantine-stearate for freeze-drying
Release injection.
Embodiment 2:
The slow-release injected preparation of Memantine-palmitate:
A. Memantine-palmitate synthesis
Appropriate sodium palmitate is weighed, is dispersed in 75 DEG C of distilled water of 100mL, stirring and dissolving, compound concentration 0.1mol/
The sodium palmitate aqueous solution of L；Appropriate hydrochloric acid Memantine is weighed, is dissolved in 75 DEG C of distilled water of 100mL, obtaining concentration is
The memantine aqueous solution of 0.1mol/L.In 75 DEG C, under stiring, above-mentioned memantine aqueous solution is added dropwise to palmitinic acid
In sodium water solution, 10000r/min is centrifuged 10min, filters, and collects precipitating, and hot water washs three times, by 40 DEG C of vacuum of gained filter cake
Drying is for 24 hours to get Memantine-palmitate.
B. the slow-release injected preparation of Memantine-palmitate
25g Memantine-palmitate (in terms of Memantine) is dispersed in the water that 250mL contains 2% sodium carboxymethylcellulose
In solution, it is 7.4 that aqueous solution NaOH, which adjusts pH, isotonic with NaCl adjusting, using wet laid media grinder in 1500rpm revolving speed
Lower grinding 15min, abrasive media are 0.8mm zirconium oxide bead, and it is mixed to obtain Memantine-palmitate that average grain diameter is 0.719 μm
5% mannitol is added into gained suspension for suspension, dispenses, and it is slow-release injected to obtain Memantine-palmitate for freeze-drying.
Embodiment 3:
The slow-release injected preparation of Memantine-oleate:
A. Memantine-oleate synthesis
Appropriate enuatrol is weighed, is dispersed in 75 DEG C of distilled water of 100mL, stirring and dissolving, compound concentration 0.1mol/L
Aqueous solution sodium oleate；Appropriate hydrochloric acid Memantine is weighed, is dissolved in 75 DEG C of distilled water of 100mL, obtaining concentration is 0.1mol/L
Memantine aqueous solution.In 75 DEG C, under stiring, above-mentioned memantine aqueous solution is added dropwise to aqueous solution sodium oleate
In, 10000r/min is centrifuged 10min, collects upper layer oily thick liquid, and hot water washs three times, by gained oily thick liquid 40
DEG C vacuum drying for 24 hours to get Memantine-oleate.
B. the slow-release injected preparation of Memantine-oleate
25g Memantine-oleate (in terms of Memantine) is dispersed in 250mL and contains the water-soluble of 2% sodium carboxymethylcellulose
In liquid, it is 7.4 that aqueous solution NaOH, which adjusts pH, isotonic with NaCl adjusting, using wet laid media grinder under 1500rpm revolving speed
15min is ground, abrasive media is 0.8mm zirconium oxide bead, Memantine-oleate suspension that average grain diameter is 0.504 μm is obtained,
5% mannitol is added into gained suspension, dispenses, it is slow-release injected to obtain Memantine-oleate for freeze-drying.
Embodiment 4:
The slow-release injected preparation of Memantine-embonate:
A. Memantine-embonate synthesis
Appropriate pamoic acid sodium is weighed, is dispersed in 75 DEG C of distilled water of 100mL, stirring and dissolving, compound concentration is
The pamoic acid sodium water solution of 0.1mol/L；Appropriate hydrochloric acid Memantine is weighed, is dissolved in 75 DEG C of distilled water of 100mL, obtains dense
Degree is the memantine aqueous solution of 0.2mol/L.In 75 DEG C, under stiring, above-mentioned memantine aqueous solution is added dropwise to double
In hydroxyl naphthoic acid sodium water solution, 10000r/min is centrifuged 10min, filters, and collects filter cake, and hot water washs three times, by gained filter cake 40
DEG C vacuum drying for 24 hours to get Memantine-embonate.
B. the slow-release injected preparation of Memantine-embonate
25g Memantine-embonate (in terms of Memantine) is dispersed in 250mL and contains 2% sodium carboxymethylcellulose
In aqueous solution, it is 7.4 that aqueous solution NaOH, which adjusts pH, isotonic with NaCl adjusting, is turned using wet laid media grinder in 1500rpm
Speed is lower to grind 15min, and abrasive media is 0.8mm zirconium oxide bead, obtains Memantine-pamoic acid that average grain diameter is 0.671 μm
5% mannitol is added into gained suspension for salt suspension, dispenses, freeze-drying, obtains Memantine-embonate sustained release note
Penetrate agent.
Embodiment 5:
The slow-release injected preparation of Memantine-embonate:
Memantine-embonate (in terms of Memantine) prepared by 25g embodiment 4 is dispersed in 250mL and contains 2% carboxylic
In the aqueous solution of sodium carboxymethylcellulose pyce and 0.5% polyoxyethylene sorbitan monoleate, it is 7.40 that aqueous solution NaOH, which adjusts pH, with NaCl adjusting etc.
It seeps, is transferred in high pressure homogenizer, 40MPa is recycled 3 times, and 100Mpa is recycled 10 times, obtains the U.S. dollar that average grain diameter is 2.572 μm
Rigid indissoluble salt suspension.5% mannitol is added into gained suspension, dispenses, freeze-drying obtains Memantine-pamoic acid
Salt is slow-release injected.
Embodiment 6:
The slow-release injected preparation of Memantine-embonate:
By Memantine-embonate (in terms of Memantine) prepared by 25g embodiment 4 into airslide disintegrating mill, adjustment
Feed 0.3~0.4MPa of nozzle pressure, and crushing nozzle pressure is 0.6MPa, obtains micronization beauty of the average grain diameter at 3.273 μm
Buddha's warrior attendant-embonate.The above-mentioned micronization Memantine of 25g-embonate (in terms of Memantine) is dispersed to containing 2% carboxymethyl
In the aqueous solution of sodium cellulosate and 5% mannitol, adjusting pH with NaOH is 7.40, and isotonic, packing is adjusted with NaCl, and freezing is dry
It is dry, it is slow-release injected to obtain Memantine-embonate.
Comparative example 1:
Memantine solution
25g memantine (in terms of Memantine) is dissolved to the aqueous solution that 250mL contains 2% sodium carboxymethylcellulose
In, adjusting pH with NaOH is 7.4, and isotonic with NaCl adjusting, packing obtains memantine solution.
Comparative example 2:
Memantine mixed suspension injection
A. the synthesis of Memantine
Appropriate sodium hydroxide is weighed, is dispersed in 100mL distilled water, stirring and dissolving, compound concentration is the hydrogen of 0.1mol/L
Aqueous solution of sodium oxide；Appropriate hydrochloric acid Memantine is weighed, is dissolved in 100mL distilled water, the hydrochloric acid beauty that concentration is 0.1mol/L is obtained
Buddha's warrior attendant aqueous solution.Under stiring, above-mentioned memantine aqueous solution is added dropwise in sodium hydrate aqueous solution, is filtered, filter cake is used
Water washing is distilled three times to get Memantine.
B. the preparation of Memantine mixed suspension injection
25g Memantine is dispersed in 250mL to contain in the aqueous solution of 2% sodium carboxymethylcellulose, aqueous solution NaOH tune
Saving pH is 7.4, isotonic with NaCl adjusting, and 15min, abrasive media are ground under 1500rpm revolving speed using wet laid media grinder
For 0.8mm zirconium oxide bead, the Memantine suspension that average grain diameter is 1.257 μm is obtained, 5% sweet dew is added into gained suspension
Alcohol dispenses, and freeze-drying obtains Memantine mixed suspension injection.
Embodiment 7:
The slow-release injected partial size of Memantine difficulty soluble salt and size distribution
Respectively by Memantine difficulty soluble salt prepared by 1~embodiment of embodiment 6 prepared by slow-release injected, comparative example 2
Memantine mixed suspension injection is uniformly mixed with dilution, forms suspension.The 20 above-mentioned suspensions of μ L are taken, respectively with corresponding Memantine
The saturated aqueous solution of difficulty soluble salt is decentralized medium, using the S3500 type particle size analyzer of Microtrac company of the U.S., carries out grain
Degree analysis, particle size distribution figure are as depicted in figs. 1 and 2.
The results show that the slow-release injected partial size of Memantine difficulty soluble salt referring to prepared by 1~embodiment of embodiment 6 is small
In 10 μm, there is good syringeability.Show that Memantine difficulty soluble salt according to the present invention is slow-release injected that preparation method has
There is excellent durability.
The present invention can adjust slow-release time, delay by changing the acid group of Memantine indissoluble salt or changing preparation partial size
It releases the time to be differed by 5 days to 28 days, different dosing cycle request can be met.
The present invention can avoid the generation of excessive small particle Memantine indissoluble salt particle, the prepared long-acting note of Memantine difficulty soluble salt
Agent average grain diameter is penetrated in 0.2 μm~10 μ ms, while guaranteeing good syringeability, obtains excellent slow release effect.
Embodiment 8:
The slow-release injected vitro drug release of Memantine difficulty soluble salt
It is suspended and is infused using dialysis measurement Memantine difficulty soluble salt slow-release injected (1~embodiment of embodiment 6) and Memantine
Penetrate the vitro drug release behavior of agent (comparative example 2).Memantine difficulty soluble salt prepared by 1~embodiment of embodiment 6 is delayed respectively
It releases Memantine mixed suspension injection prepared by injection, comparative example 2 to be uniformly mixed with dilution, forms suspension.It is accurate respectively
The above-mentioned suspension of 1mL is pipetted into bag filter (molecular cut off 50000Da), both ends tighten.Bag filter is placed in equipped with 100mL
In the stuffed conical flask of simulated body fluid (10mmol/L phosphate buffer solution, pH=7.4), in 37 DEG C of thermostatic control oscillator vibrations
In, 100r/min back and forth shakes.Respectively at 1,2,4,6,8,12 and for 24 hours, 2,3,4,6,8,10,12 and 14day, take out and all release
Medium is put, while supplementing 100mL dissolution medium.Memantine concentration in dissolution medium is measured, and calculates drug accumulation release percentage
Than drawing drug release patterns in vitro.Drug release patterns in vitro figure such as Fig. 3 institute of 1~embodiment of embodiment 6 and comparative example 2
Show.
The results show that the Memantine mixed suspension injection referring to prepared by 2 method of comparative example is in simulated body fluid environment when 2h,
Accumulation release amount of medicine has reached 90% or more, no showing sustained release effect.And referring to prepared by 1~embodiment of embodiment, 6 method
Memantine difficulty soluble salt it is slow-release injected there is apparent slow releasing function, drug releasing rate is descending successively are as follows: comparative example 2
5 > embodiment of > embodiment 1 > embodiment, 2 > embodiment, 3 > embodiment, 4 > embodiment 6.Memantine-stearate is slow-release injected (real
Apply example 1) and Memantine-palmitate slow-release injected (embodiment 2) can be sustained 7 days, Memantine-oleate is slow-release injected
(embodiment 3) can be sustained 12 days.Using Memantine-prepared by wet laid media polishing, high pressure homogenization method and comminution by gas stream
Embonate slow-release injected (4~embodiment of embodiment 6) can be sustained 14 days or more, wherein embodiment 5 and embodiment 6 by
Larger in partial size, drug releasing rate is slower.
The above results show that compared with Memantine mixed suspension injection, Memantine indissoluble salt is slow-release injected with excellent
Slow releasing function, slow-release time sustainable one week or more.
Embodiment 9:
The slow-release injected rat Internal pharmacokinetics evaluation of Memantine difficulty soluble salt
48 SD rats are taken, male, weight (200 ± 20) g, Southern Yangtze University's Experimental Animal Center provides, and sets experimental situation
After raising 4 days, 8 groups are randomly divided into, every group 6, fasting 12h before testing injects 125mg/kg respectively at Rat Right hind leg muscle
Referring to the preparation of 1 the method for the present embodiment Memantine-stearate is slow-release injected, 125mg/kg is referring to 2 institute of the present embodiment
State method preparation Memantine-palmitate is slow-release injected, 125mg/kg referring to the preparation of 3 the method for the present embodiment U.S. dollar
Just-oleate is slow-release injected, 125mg/kg is infused referring to Memantine-embonate sustained release of 4 the method for embodiment preparation
Penetrate agent, 125mg/kg referring to the preparation of 5 the method for embodiment Memantine-embonate is slow-release injected, 125mg/kg ginseng
According to the preparation of 6 the method for embodiment Memantine-embonate is slow-release injected, 25mg/kg is referring to 1 the method for comparative example
Memantine mixed suspension injection of the memantine solution and 25mg/kg of preparation referring to the preparation of 2 the method for comparative example.Respectively
0.25,0.5,1,2,4,6,8 and 12h, 1,2,3,4,5,6,7,10,14,17,21,25 and 28 are day by quiet after eye socket after administration
Arteries and veins clump takes blood about 0.3mL, sets in the 1.5mL point bottom centrifuge tube of preparatory test tube of hepari, and 4000rpm is centrifuged 10min, draws upper layer blood
It starches to be measured in -80 DEG C of preservations.
Plasma sample processing: precision takes 100 μ L of plasma sample in 7mL centrifuge tube, and 20 μ L inner mark solutions (hydrochloric acid gold is added
Rigid alkanamine) and 200 μ L sodium hydrate aqueous solutions, it is vortexed and mixes, tert-butyl dichloromethane 3mL, vortex 10min, 4000rpm is added
It is centrifuged 10min.Take supernatant into 5mL centrifuge tube, air stream drying is to be measured in -20 DEG C of preservations.200 μ L first are added before measurement
Alcohol, vortex 5min, 12000rpm are centrifuged 10min, supernatant are taken to measure blood concentration using ultra high efficiency liquid chromatography mass spectrometric combined instrument.Respectively
Administration group blood concentration-time curve is as shown in Fig. 4~Fig. 6.
Fig. 4 shows, the memantine injection referring to the preparation of 1 the method for comparative example and the side referring to described in comparative example 2
The Memantine mixed suspension injection of method preparation is given in rat 6 hours through intramuscular injection, and blood concentration is all remarkably higher than referring to implementation
The Memantine difficulty soluble salt of 1~embodiment of example, 6 the method preparation is slow-release injected；At 4 hours, 2 groups of blood of comparative example 1 and comparative example
Concentration is up to 18000ng/mL~29000ng/mL, and 1~embodiment of embodiment, 6 groups of blood concentrations are below 1000ng/mL,
Only 280ng/mL~1000ng/mL about reduces 18~103 times；After 24 hours, 2 groups of blood concentrations of comparative example 1 and comparative example
Be below 25ng/mL, no showing sustained release effect, and 1~embodiment of embodiment, 6 groups of blood concentrations be still maintained at 250ng/mL~
Within the scope of 800ng/mL.The above results show that compared with memantine injection and Memantine mixed suspension injection, Memantine is difficult
Dissolved salt is slow-release injected to have apparent slow releasing function in rat body.
Fig. 5 and Fig. 6 show, is administered initial stage (in 2 days), and each group blood concentration is from high to low successively are as follows: 1 (U.S. dollar of embodiment
Just-stearate is slow-release injected) > embodiment 2 (Memantine-palmitate is slow-release injected) (Memantine-oleic acid of > embodiment 3
Salt is slow-release injected) > embodiment 4 (Memantine-embonate is slow-release injected) (Memantine-embonate of > embodiment 5
It is slow-release injected) > embodiment 6 (Memantine-embonate is slow-release injected).Wherein prepared referring to 1 the method for embodiment
Memantine-stearate slow-release injected be sustained 5 days；Referring to Memantine-palmitate of 2 the method for embodiment preparation
Slow-release injected and referring to the preparation of 3 the method for embodiment Memantine-oleate is slow-release injected to be sustained 7 days；Referring to real
Memantine-the embonate for applying the preparation of 4 the method for example slow-release injected is sustained 21 days；Referring to embodiment 5 and embodiment 6
Memantine-embonate prepared by the method is slow-release injected to be sustained 28 days.
It should be noted that the above examples are only used to illustrate the technical scheme of the present invention and are not limiting, although referring to preferable
Embodiment describes the invention in detail, those skilled in the art should understand that, it can be to technology of the invention
Scheme is modified or replaced equivalently, and without departing from the spirit and scope of the technical solution of the present invention, should all be covered in this hair
In bright scope of the claims.
Claims (10)
1. a kind of Memantine difficulty soluble salt is slow-release injected, it is characterised in that: be calculated in mass percent, including as active constituent
Memantine difficulty soluble salt 1%~30%, stabilizer 0.1%~10%, pH adjusting agent 0%~1%, isotonic regulator 0.1%~5%
With water for injection 60%~98%；The Memantine difficulty soluble salt includes Memantine-oleate, Memantine-linoleate, U.S. dollar
Just-linolenate, Memantine-arachidonate, Memantine-stearate, Memantine-laruate, Memantine-tannic acid
One of salt, Memantine-palmitate, Memantine-embonate, Memantine-furan type hydrochlorate.
2. Memantine difficulty soluble salt as described in claim 1 is slow-release injected, it is characterised in that: further include, with mass percent
Meter, 0.1%~15% freeze drying protectant, the freeze drying protectant includes trehalose, lactose, glucose, mannitol, sweet
One of oil, sorbierite, polyethylene glycol, sodium carboxymethylcellulose, povidone, amino acid, ascorbic acid, albumin are several
Kind.
3. Memantine difficulty soluble salt as claimed in claim 1 or 2 is slow-release injected, it is characterised in that: the stabilizer includes sea
Mosanom, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polysorbate, Bo Luosha
Nurse, phosphatide, polyethylene glycol, povidone, polyethylene glycol-polylactic acid block copolymer, polyethylene glycol-polylactic acid glycolic acid block
One of copolymer or more than one.
4. Memantine difficulty soluble salt as claimed in claim 1 or 2 is slow-release injected, it is characterised in that: the pH adjusting agent includes
Hydrochloric acid, sodium hydroxide, sodium bicarbonate, glutamic acid, lactic acid, phosphate, acetic acid and its salt, citric acid and its salt, tartaric acid and its
One of salt or more than one；The isotonic regulator is selected from glucose, sodium chloride, glycerol, sodium sulphate, sodium alginate, sweet
Reveal one of alcohol or more than one.
5. Memantine difficulty soluble salt as claimed in claim 1 or 2 is slow-release injected, it is characterised in that: the Memantine difficulty soluble salt
It is slow-release injected that powder-type injection and the storage of dilution two parts can be stored or be divided into liquid suspension form；Its
In, the powder-type injection can be the Memantine indissoluble salt powder comprising one or more kinds of auxiliary materials, or not include
The Memantine indissoluble salt powder of any auxiliary material, the dilution can be the solution comprising one or more kinds of auxiliary materials, can also be with
It is the water for injection not comprising auxiliary material.
6. the slow-release injected preparation method of any Memantine difficulty soluble salt of Claims 1 to 5, it is characterised in that: including,
It prepares Memantine difficulty soluble salt: memantine and hydrochlorate is dissolved in water, it is under agitation, hydrochlorate is water-soluble
Liquid adds in memantine aqueous solution, and filter cake, as Memantine difficulty soluble salt are collected in filtering, carries out to Memantine difficulty soluble salt pure
Change；
Memantine difficulty soluble salt is slow-release injected: dispersing the Memantine difficulty soluble salt in the aqueous solution containing auxiliary material, stirring makes
It is uniformly dispersed, and is ground using wet laid media grinder, and Memantine difficulty soluble salt suspension is obtained；Or by Memantine difficulty soluble salt
It is scattered in the aqueous solution containing auxiliary material liquid at the beginning of obtaining the suspension of Memantine difficulty soluble salt and obtains beauty using high-pressure homogeneous carry out homogeneous
Buddha's warrior attendant difficulty soluble salt suspension；Or Memantine difficulty soluble salt is transferred in airslide disintegrating mill and is crushed, Memantine hardly possible must be micronized
Dissolved salt powder.
7. the slow-release injected preparation method of Memantine difficulty soluble salt as claimed in claim 6, it is characterised in that: the preparation beauty
Buddha's warrior attendant difficulty soluble salt, including, memantine and hydrochlorate are dissolved in water, at 75 DEG C, concentration, which is respectively configured, is
The solution of 0.1mol/L under agitation adds to acid salt aqueous solution in memantine aqueous solution, 10000r/min centrifugation
10min is filtered, and collects precipitating, and hot water washs three times, for 24 hours by 40 DEG C of gained filter cake vacuum drying.
8. the slow-release injected preparation method of Memantine difficulty soluble salt as claimed in claim 6, it is characterised in that: further include, it will
1%~15% freeze drying protectant is added in the Memantine difficulty soluble salt suspension, is freeze-dried, obtains powder-type Memantine
Difficulty soluble salt is slow-release injected；Or it disperses the micronization Memantine indissoluble salt powder in and is lyophilized containing auxiliary material and 1%~15%
It in protectant aqueous solution, then dispenses and is freeze-dried, it is slow-release injected to obtain powder-type Memantine difficulty soluble salt.
9. the slow-release injected preparation method of Memantine difficulty soluble salt as claimed in claim 6, it is characterised in that: the wet process is situated between
Matter grinding, abrasive media includes one of polystyrene bead, zirconium oxide bead, zirconium silicate pearl.
10. the slow-release injected preparation method of Memantine difficulty soluble salt as described in claim 7~9 is any, it is characterised in that: institute
Stating the slow-release injected average grain diameter of Memantine difficulty soluble salt is 0.2 μm~10 μm.
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| CN113861039A (en) * | 2021-09-30 | 2021-12-31 | 江南大学 | Memantine pamoate crystal and preparation method and application thereof |
| CN114014763A (en) * | 2021-09-30 | 2022-02-08 | 天津大学 | Memantine pamoate crystal and preparation method and application thereof |
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Application publication date: 20181211 |