CN105213361A - A kind of medicine meclofenoxate hydrochloride compositions for the treatment of infantile enuresis - Google Patents
A kind of medicine meclofenoxate hydrochloride compositions for the treatment of infantile enuresis Download PDFInfo
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- CN105213361A CN105213361A CN201510632860.1A CN201510632860A CN105213361A CN 105213361 A CN105213361 A CN 105213361A CN 201510632860 A CN201510632860 A CN 201510632860A CN 105213361 A CN105213361 A CN 105213361A
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Abstract
The invention discloses a kind of medicine meclofenoxate hydrochloride compositions for the treatment of infantile enuresis, belong to medical art.Said composition is made up of meclofenoxate hydrochloride and sodium chloride, and 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.The novel crystal forms of meclofenoxate hydrochloride provided by the present invention is different from the crystalline structure of prior art, verification experimental verification, meclofenoxate hydrochloride crystal-form compound provided by the present invention comparatively prior art hygroscopicity, mobility is significantly improved, moisture and impurity content are extremely low, stability is better, and the preparation for preparation provides conveniently.And meclofenoxate hydrochloride crystalline compounds provided by the invention has higher bioavailability compared with prior art, side reaction rate reduces.Utilize the injectable powder that this crystal compound is obtained, good fluidity, moisture and impurity content are extremely low, and stability is better, and bioavailability is high, and side reaction rate is low.
Description
Technical field
The invention belongs to medical art, relate to a kind of medicine meclofenoxate hydrochloride compositions for the treatment of infantile enuresis.
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 be clinically be used for 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, and the means of use, for adding adjuvant and adopting comparatively complicated technology, 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, this 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, this compound draws moist very low, not easily water of hydroscopicity solution and there is high quality stability, but its bioavailability is lower, and rate of side effects is higher.
Summary of the invention
Goal of the invention of the present invention is to provide a kind of medicine meclofenoxate hydrochloride compositions for the treatment of infantile enuresis.
In order to complete object of the present invention, the technical scheme of employing is:
Treat a medicine meclofenoxate hydrochloride compositions for infantile enuresis, consisting of of described compositions: meclofenoxate hydrochloride 1 weight portion, sodium chloride 0.6-1.0 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.
Preferably, consisting of of described compositions: meclofenoxate hydrochloride 1 weight portion, sodium chloride 0.7-0.9 weight portion.
Preferably, consisting of of described compositions: meclofenoxate hydrochloride 1 weight portion, sodium chloride 0.8 weight portion.
Preferably, 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 sodium chloride 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 above-mentioned composition comprises the following steps:
(1) be dissolved in by meclofenoxate hydrochloride in the mixed solvent of acetone and water, the solvent load that needs of every gram of meclofenoxate hydrochloride is 80ml, and the volume ratio of acetone and water is 1:5;
(2), after being heated to 35 DEG C of dissolvings, after cool to room temperature, crystal seed is added;
(3) be cooled to less than 0 DEG C, stirring and crystallizing, the temperature of crystallize is-10 DEG C, filters, dry, collects crystal and namely obtains meclofenoxate hydrochloride crystal.
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 has higher bioavailability compared with prior art, 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) be dissolved in by meclofenoxate hydrochloride in the mixed solvent of acetone and water, the solvent load that needs of every gram of meclofenoxate hydrochloride is 80ml, and the volume ratio of acetone and water is 1:5;
(2), after being heated to 35 DEG C of dissolvings, after cool to room temperature, crystal seed is added;
(3) be cooled to less than 0 DEG C, stirring and crystallizing, the temperature of crystallize is-10 DEG C, filters, dry, collects crystal and namely obtains meclofenoxate hydrochloride crystal.
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, sodium chloride 0.6 weight portion.
Preparation method is:
(1) take meclofenoxate hydrochloride crystal and sodium chloride 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, sodium chloride 0.7 weight portion.
Preparation method is:
(1) take meclofenoxate hydrochloride crystal and sodium chloride 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, sodium chloride 0.8 weight portion.
Preparation method is:
(1) take meclofenoxate hydrochloride crystal and sodium chloride 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, sodium chloride 0.9 weight portion.
Preparation method is:
(1) take meclofenoxate hydrochloride crystal and sodium chloride 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, sodium chloride 1.0 weight portion.
Preparation method is:
(1) take meclofenoxate hydrochloride crystal and sodium chloride in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
to the test example research of meclofenoxate hydrochloride prepared by the present invention
Comparative example 1
:according to Meclofenoxate hydrochloride compound prepared by patent CN103214382B embodiment 1;
Comparative example 2: the Meclofenoxate hydrochloride compound prepared according to 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 in 6 months 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 is better than contrasting the meclofenoxate hydrochloride crystal formation of medicine, 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. treat a medicine meclofenoxate hydrochloride compositions for infantile enuresis, it is characterized in that, consisting of of described compositions: meclofenoxate hydrochloride 1 weight portion, sodium chloride 0.6-1.0 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. the medicine meclofenoxate hydrochloride compositions for the treatment of infantile enuresis according to claim 1, is characterized in that, consisting of of described compositions: meclofenoxate hydrochloride 1 weight portion, sodium chloride 0.7-0.9 weight portion.
3. the medicine meclofenoxate hydrochloride compositions for the treatment of infantile enuresis according to claim 2, is characterized in that, consisting of of described compositions: meclofenoxate hydrochloride 1 weight portion, sodium chloride 0.8 weight portion.
4. the medicine meclofenoxate hydrochloride compositions of the treatment infantile enuresis 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 sodium chloride in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
5. the medicine meclofenoxate hydrochloride compositions for the treatment of infantile enuresis according to claim 1, is characterized in that, the crystal preparation method of described meclofenoxate hydrochloride is:
(1) be dissolved in by meclofenoxate hydrochloride in the mixed solvent of acetone and water, the solvent load that needs of every gram of meclofenoxate hydrochloride is 80ml, and the volume ratio of acetone and water is 1:5;
(2), after being heated to 35 DEG C of dissolvings, after cool to room temperature, crystal seed is added;
(3) be cooled to less than 0 DEG C, stirring and crystallizing, the temperature of crystallize is-10 DEG C, filters, dry, collects crystal and namely obtains meclofenoxate hydrochloride crystal.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510632860.1A CN105213361A (en) | 2015-09-30 | 2015-09-30 | A kind of medicine meclofenoxate hydrochloride compositions for the treatment of infantile enuresis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510632860.1A CN105213361A (en) | 2015-09-30 | 2015-09-30 | A kind of medicine meclofenoxate hydrochloride compositions for the treatment of infantile enuresis |
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| Publication Number | Publication Date |
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| CN105213361A true CN105213361A (en) | 2016-01-06 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510632860.1A Withdrawn CN105213361A (en) | 2015-09-30 | 2015-09-30 | A kind of medicine meclofenoxate hydrochloride compositions for the treatment of infantile enuresis |
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| CN (1) | CN105213361A (en) |
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Application publication date: 20160106 |
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| WW01 | Invention patent application withdrawn after publication |