CN105106190A - Central stimulant meclofenoxate hydrochloride composition - Google Patents
Central stimulant meclofenoxate hydrochloride composition Download PDFInfo
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- CN105106190A CN105106190A CN201510645819.8A CN201510645819A CN105106190A CN 105106190 A CN105106190 A CN 105106190A CN 201510645819 A CN201510645819 A CN 201510645819A CN 105106190 A CN105106190 A CN 105106190A
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- meclofenoxate hydrochloride
- meclofenoxate
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Abstract
The invention relates to a central stimulant meclofenoxate hydrochloride composition and belongs to the technical field of medicines. The composition is prepared from meclofenoxate hydrochloride and anhydrous sodium carbonate, wherein the meclofenoxate hydrochloride is crystal and an X-ray powder diffraction pattern obtained through measurement by using Cu-K alpha rays is as shown in picture 1. The new crystal form of the meclofenoxate hydrochloride provided by the invention is different from the crystal form structures in the prior art. As proved by tests, compared with the prior art, the meclofenoxate hydrochloride crystal compound provided by the invention has the advantages that the moisture absorption and flowability are obviously improved, the content of water and impurities is extremely low, the stability is better and convenience is provided for the preparation of preparations. Compared with the prior art, the meclofenoxate hydrochloride crystal compound provided by the invention has higher bioavailability and the side reaction rate is reduced. Compared with the prior art, powder-injection prepared by using the compound of the new crystal form has the advantages of good flowability, extremely low content of water and impurities, better stability, high bioavailability and low side reaction rate.
Description
Technical field
The invention belongs to medical art, relate to a kind of central stimulants meclofenoxate hydrochloride compositions.
Background technology
The chemistry of meclofenoxate hydrochloride is called 2-(dimethylamino) ethyl parachlorophen-oxyacetic acid ester hydrochloride, a kind of central nervous system stimulant and cranial nerve nutrient drug, central nervous system function can be improved, comprise and cause awakening, inspire enthusiasm, excited breathing, improve neural reflex and increase freely activity, it can promote protein assimilation, can be used as the raw material of synthesis choline and acetylcholine in vivo, and then synthesis lecithin, thus change central nervous system nerve mediator content, acetylcholine amount in brain is increased, there is oxygen lack resistant function, promote the redox reaction of brain cell, promote brain energy metabolism, improve study, memory and cognition function, improve cerebral hemodynamic, promote the recovery of Clinical symptom and sign.
The indication of the meclofenoxate hydrochloride preparation of current domestic listing is clinical traumatic stupor, anoxia neonatorum disease, children's send urine disease, disturbance of consciousness, mentally deranged, senile psychosis, senile dementia and alcoholism, carbon monoxide poisoning etc.
Meclofenoxate hydrochloride less stable, and because containing ester bond in molecule, aqueous solution is unstable, facile hydrolysis.Aqueous solution pH raises, and hydrolysis rate is accelerated.In order to address this problem, prior art generally attempts from preparation aspect addressing this problem, the means of use for add adjuvant and adopt comparatively complicated technology to overcome its unstability.Although but the stability that prior art improves meclofenoxate hydrochloride in preparation has certain effect needs to add more adjuvant and needs coordinate the technique of comparatively complexity, but although there is certain effect limited use, limit the application of meclofenoxate hydrochloride, because facile hydrolysis meclofenoxate hydrochloride is unstable in feed stage, need high preservation condition.The prior art also had attempts the meclofenoxate hydrochloride obtaining higher stability from change crystal formation, as: China application CN103214382B, the Meclofenoxate hydrochloride compound that this application provides and drug regimen thereof are compared with prior art, there is better storage stability and mobility, the present inventor finds in test, although the meclofenoxate hydrochloride obtained in this application has good stability under room temperature and acceleration environment, but less stable in the factorial experiments of other influences drug quality, especially still have higher draw moist, make the easy water of hydroscopicity solution of meclofenoxate hydrochloride.China application CN103396328B, this application inventor obtains a kind of Meclofenoxate hydrochloride compound of crystal form unexpectedly in long-term a large amount of research process, and this compound draws moist very low, not easily water of hydroscopicity solution and have high quality stability.The present invention also provides effective ingredient to be composite preparation of Meclofenoxate hydrochloride compound of the present invention and preparation method thereof, according to the preparation that content of the present invention can be prepared into, keep high stability, obviously be better than commercially available kind, substantially increase the safety of meclofenoxate hydrochloride use, effectiveness, but its bioavailability is lower, and rate of side effects is higher.
The present inventor starts with from the research of meclofenoxate hydrochloride solid chemical material existence, has prepared a kind of new meclofenoxate hydrochloride crystalline compounds through a large amount of tests.Comparatively prior art compares hygroscopicity to meclofenoxate hydrochloride crystal-form compound provided by the present invention, mobility is significantly improved, and moisture and impurity content are extremely low, and stability is better, and the preparation for preparation provides conveniently.Meclofenoxate hydrochloride crystalline compounds provided by the invention is compared compared with prior art has higher bioavailability, and side reaction rate reduces.Utilize the injectable powder that this crystal compound is obtained, comparatively prior art contrast, good fluidity, moisture and impurity content are extremely low, and stability is better, and bioavailability is high, and side reaction rate is low.
Summary of the invention
Goal of the invention of the present invention is to provide a kind of central stimulants meclofenoxate hydrochloride compositions.
In order to complete object of the present invention, the technical scheme of employing is:
A kind of central stimulants meclofenoxate hydrochloride of the present invention compositions, consisting of of described compositions: meclofenoxate hydrochloride 1 weight portion, natrium carbonicum calcinatum 0.1-0.3 weight portion; Described meclofenoxate hydrochloride is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
First optimal technical scheme of the present invention is consisting of of described compositions: meclofenoxate hydrochloride 1 weight portion, natrium carbonicum calcinatum 0.15-0.25 weight portion.
Second optimal technical scheme of the present invention is consisting of of described compositions: meclofenoxate hydrochloride 1 weight portion, natrium carbonicum calcinatum 0.2 weight portion.
3rd optimal technical scheme of the present invention is the dosage form of described compositions is injection, and the preparation method of described injection comprises the following steps:
(1) take meclofenoxate hydrochloride crystal and natrium carbonicum calcinatum in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
The preparation method of the meclofenoxate hydrochloride crystal in the present composition comprises the following steps:
(1) meclofenoxate hydrochloride crude product is ground, cross 90 mesh sieves, join in the N-methyl vinyl amine aqueous solution of 45%, warming while stirring to 30 DEG C; Meclofenoxate hydrochloride crude product and 45% the weight ratio of N-methyl vinyl amine aqueous solution be 1:10; Mixing speed is 180 revs/min; Add active carbon, stir aseptic filtration after 50 minutes;
(2) add ether while stirring, be cooled to-5 DEG C simultaneously; Mixing speed is 240 revs/min; The weight of ether is 7 times of mixed solution weight of meclofenoxate hydrochloride, 45%N-methyl vinyl amine aqueous solution, and adding speed is 95 ml/min; Cooling rate is 10 DEG C/h;
(3), after mixed solvent adds, after obtaining crystal, crystallize is left standstill; Filter, washing, vacuum drying, obtains Meclofenoxate hydrochloride compound.
The polymorphism of solid chemical is the natural phenomena that a kind of general material exists, this phenomenon refers to that a kind of solid chemical can exist 2 kinds or two or more crystal form state, be also called the polymorphic state of material, the polymorphic state of material is also referred to as " allomorphism " phenomenon.Although its chemical nature of allomorphous solid matter is identical, its physicochemical property may be different.For " allomorphism medicine " that physicochemical property is different, also can show the curative effect of different disease preventing and treating clinically, directly affect application and the clinical effectiveness of medicine.
The present inventor starts with from the research of meclofenoxate hydrochloride solid chemical material existence, has prepared a kind of new meclofenoxate hydrochloride crystalline compounds through a large amount of tests.Comparatively prior art compares hygroscopicity to meclofenoxate hydrochloride crystal-form compound provided by the present invention, mobility is significantly improved, and moisture and impurity content are extremely low, and stability is better, and the preparation for preparation provides conveniently.Meclofenoxate hydrochloride crystalline compounds provided by the invention is compared compared with prior art has higher bioavailability, and side reaction rate reduces.Utilize the injectable powder that this crystal compound is obtained, comparatively prior art contrast, good fluidity, moisture and impurity content are extremely low, and stability is better, and bioavailability is high, and side reaction rate is low.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction that the meclofenoxate hydrochloride crystal of the embodiment of the present invention 1 preparation uses the measurement of Cu-K alpha ray to obtain.
Detailed description of the invention
Below by specific embodiment, summary of the invention of the present invention is described in further detail, but does not therefore limit content of the present invention.
embodiment 1:the preparation of meclofenoxate hydrochloride crystal
(1) meclofenoxate hydrochloride crude product is ground, cross 90 mesh sieves, join in the N-methyl vinyl amine aqueous solution of 45%, warming while stirring to 30 DEG C; Meclofenoxate hydrochloride crude product and 45% the weight ratio of N-methyl vinyl amine aqueous solution be 1:10; Mixing speed is 180 revs/min; Add active carbon, stir aseptic filtration after 50 minutes;
(2) add ether while stirring, be cooled to-5 DEG C simultaneously; Mixing speed is 240 revs/min; The weight of ether is 7 times of mixed solution weight of meclofenoxate hydrochloride, 45%N-methyl vinyl amine aqueous solution, and adding speed is 95 ml/min; Cooling rate is 10 DEG C/h;
(3), after mixed solvent adds, after obtaining crystal, crystallize is left standstill; Filter, washing, vacuum drying, obtains Meclofenoxate hydrochloride compound.
The X-ray powder diffraction pattern that the meclofenoxate hydrochloride crystal prepared uses the measurement of Cu-K alpha ray to obtain as shown in Figure 1.
embodiment 2:the preparation of meclofenoxate hydrochloride compositions
Consist of: meclofenoxate hydrochloride crystal 1 weight portion prepared by the present invention, natrium carbonicum calcinatum 0.1 weight portion.
Preparation method is:
(1) take meclofenoxate hydrochloride crystal and natrium carbonicum calcinatum in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
embodiment 3:the preparation of meclofenoxate hydrochloride compositions
Consist of: meclofenoxate hydrochloride crystal 1 weight portion prepared by the present invention, natrium carbonicum calcinatum 0.15 weight portion.
Preparation method is:
(1) take meclofenoxate hydrochloride crystal and natrium carbonicum calcinatum in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
embodiment 4:the preparation of meclofenoxate hydrochloride compositions
Consist of: meclofenoxate hydrochloride crystal 1 weight portion prepared by the present invention, natrium carbonicum calcinatum 0.2 weight portion.
Preparation method is:
(1) take meclofenoxate hydrochloride crystal and natrium carbonicum calcinatum in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
embodiment 5:the preparation of meclofenoxate hydrochloride compositions
Consist of: meclofenoxate hydrochloride crystal 1 weight portion prepared by the present invention, natrium carbonicum calcinatum 0.25 weight portion.
Preparation method is:
(1) take meclofenoxate hydrochloride crystal and natrium carbonicum calcinatum in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
embodiment 6:the preparation of meclofenoxate hydrochloride compositions
Consist of: meclofenoxate hydrochloride crystal 1 weight portion prepared by the present invention, natrium carbonicum calcinatum 0.3 weight portion.
Preparation method is:
(1) take meclofenoxate hydrochloride crystal and natrium carbonicum calcinatum in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
comparative example 1:according to Meclofenoxate hydrochloride compound prepared by patent CN103214382B embodiment 1
comparative example 2:according to Meclofenoxate hydrochloride compound prepared by patent CN103396328B embodiment 1
test example 1:hygroscopicity is investigated
This test example is respectively under the condition of humidity 80% and 90%, and each sample thief 1g is placed on electronic balance, and time recording weight, to detect moisture absorption degree, the results are shown in Table 1.
Table 1 hygroscopicity testing result
Can be found out by result of the test, compared with prior art, meclofenoxate hydrochloride crystal not easily moisture absorption prepared by the present invention, good stability.
test example 2:fluidity test
Method: sample respectively, adopt fixed funnel method, funnel is placed in the suitable height on graph paper, meclofenoxate hydrochloride is freely flowed down from bell mouth, until the cone top formed contacts with bell mouth, measure hypotenuse and the horizontal angle (θ angle of repose) of meclofenoxate hydrochloride accumulation horizon, the results are shown in Table shown in 2.
The fluidity test result of table 2 meclofenoxate hydrochloride
Can be found out by result of the test, compared with prior art, meclofenoxate hydrochloride crystal mobility prepared by the present invention is obviously improved.
test example 3:stability test
The Meclofenoxate hydrochloride compound prepare the embodiment of the present invention 1 and comparative example 1, comparative example 2 carry out accelerated stability investigation (40 DEG C ± 2 DEG C, RH75% ± 5%) by commercially available back, the results are shown in Table 3.
Table 3 Meclofenoxate hydrochloride compound accelerated test result
Can be found out by result of the test, compared with prior art, meclofenoxate hydrochloride crystal moisture prepared by the present invention obviously reduces, and always the assorted content of assorted and list is low, good stability.
24 months long term tests have been carried out to the embodiment of the present invention 1 and documents 1, documents 2, found that meclofenoxate hydrochloride crystal moisture prepared by the present invention controls within 0.10, be starkly lower than prior art, always the assorted content of assorted and list is low, good stability.
test example 4:clinical adverse monitoring test
The meclofenoxate hydrochloride provided the embodiment of the present invention 1, comparative example 1, comparative example 2 is example, carry out clinical trial, result display embodiment side reaction rate 4%, comparative example 1 side reaction rate 89%, comparative example 2 side reaction rate is 78%, show to present invention significantly reduces side reaction rate, improve the safety of clinical application.
test example 5:bioavailability study
Document " the bioequivalence Journal of Sex Research of meclofenoxate hydrochloride capsules in healthy human body " (China Dispensary the 22nd volume the 18th phase in the 2011) method of employing, by DASVer2.0 computed in software main pharmacokinetic parameters, the bioavailability of Evaluation operation example 1, comparative example 1, comparative example 2.The C of embodiment 1, comparative example 1, comparative example 2
max, AUC carries out variance analysis after Logarithm conversion, and adopts Doubled haploid population and (1-2 α) confidence interval method to evaluate further, t
maxadopt non parametric tests method.Result shows: the C of meclofenoxate hydrochloride crystal formation of the present invention
max, AUC value be better than now contrast medicine 1 and contrast medicine 2 meclofenoxate hydrochloride crystal formation, the elimination half-life t of medicine of the present invention in blood plasma
l/2be greater than comparative example 1, comparative example 2.Show that meclofenoxate hydrochloride crystal formation of the present invention has better absorption characteristic and bioavailability.
Claims (5)
1. a central stimulants meclofenoxate hydrochloride compositions, is characterized in that, consisting of of described compositions: meclofenoxate hydrochloride 1 weight portion, natrium carbonicum calcinatum 0.1-0.3 weight portion; Described meclofenoxate hydrochloride is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
2. central stimulants meclofenoxate hydrochloride compositions according to claim 1, is characterized in that, consisting of of described compositions: meclofenoxate hydrochloride 1 weight portion, natrium carbonicum calcinatum 0.15-0.25 weight portion.
3. central stimulants meclofenoxate hydrochloride compositions according to claim 2, is characterized in that, consisting of of described compositions: meclofenoxate hydrochloride 1 weight portion, natrium carbonicum calcinatum 0.2 weight portion.
4. the central stimulants meclofenoxate hydrochloride compositions according to any one of claim 1-3, is characterized in that, the dosage form of described compositions is injection, and the preparation method of described injection comprises the following steps:
(1) take meclofenoxate hydrochloride crystal and natrium carbonicum calcinatum in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
5. central stimulants meclofenoxate hydrochloride compositions according to claim 1, is characterized in that, the crystal preparation method of described meclofenoxate hydrochloride is:
(1) meclofenoxate hydrochloride crude product is ground, cross 90 mesh sieves, join in the N-methyl vinyl amine aqueous solution of 45%, warming while stirring to 30 DEG C; Meclofenoxate hydrochloride crude product and 45% the weight ratio of N-methyl vinyl amine aqueous solution be 1:10; Mixing speed is 180 revs/min; Add active carbon, stir aseptic filtration after 50 minutes;
(2) add ether while stirring, be cooled to-5 DEG C simultaneously; Mixing speed is 240 revs/min; The weight of ether is 7 times of mixed solution weight of meclofenoxate hydrochloride, 45%N-methyl vinyl amine aqueous solution, and adding speed is 95 ml/min; Cooling rate is 10 DEG C/h;
(3), after mixed solvent adds, after obtaining crystal, crystallize is left standstill; Filter, washing, vacuum drying, obtains Meclofenoxate hydrochloride compound.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510645819.8A CN105106190A (en) | 2015-10-09 | 2015-10-09 | Central stimulant meclofenoxate hydrochloride composition |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510645819.8A CN105106190A (en) | 2015-10-09 | 2015-10-09 | Central stimulant meclofenoxate hydrochloride composition |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61171460A (en) * | 1985-01-23 | 1986-08-02 | Dainippon Pharmaceut Co Ltd | Production of i-type crystal of meclofenoxate hydrochloride |
| WO1999000358A1 (en) * | 1997-06-30 | 1999-01-07 | Societatea Comerciala Sintofarm S.A. | Procedure to prepare n,n-dimethylaminoethanol 2-chlor-4-dimethyl-amidosulfonyl-fenoxyacetate hydrochloride |
| CN103396328A (en) * | 2013-08-21 | 2013-11-20 | 湖北美林药业有限公司 | Meclofenoxate hydrochloride compound and pharmaceutical composition thereof |
-
2015
- 2015-10-09 CN CN201510645819.8A patent/CN105106190A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61171460A (en) * | 1985-01-23 | 1986-08-02 | Dainippon Pharmaceut Co Ltd | Production of i-type crystal of meclofenoxate hydrochloride |
| WO1999000358A1 (en) * | 1997-06-30 | 1999-01-07 | Societatea Comerciala Sintofarm S.A. | Procedure to prepare n,n-dimethylaminoethanol 2-chlor-4-dimethyl-amidosulfonyl-fenoxyacetate hydrochloride |
| CN103396328A (en) * | 2013-08-21 | 2013-11-20 | 湖北美林药业有限公司 | Meclofenoxate hydrochloride compound and pharmaceutical composition thereof |
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Application publication date: 20151202 |