CN1568953A - Method for preparing mental disease resistant medicine containing succinic acid - Google Patents
Method for preparing mental disease resistant medicine containing succinic acid Download PDFInfo
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- CN1568953A CN1568953A CN 03133219 CN03133219A CN1568953A CN 1568953 A CN1568953 A CN 1568953A CN 03133219 CN03133219 CN 03133219 CN 03133219 A CN03133219 A CN 03133219A CN 1568953 A CN1568953 A CN 1568953A
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- succinic acid
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Abstract
The invention discloses a method for preparing a medicament for treating psychoneurosis such as epilepsy, which comprises succinic acid 50%, lactin 20%, crystalline cellulose 22%, calcium carboxymethylcellulose 2%, waterless silicon acid 2%, carboxyl propionyl cellulose 3%, and magnesium stearate 1%.
Description
Technical field:
The present invention relates to a kind of preparation method of novel anti spirit neurologic agent, specifically a kind of is the preparation method of medicine of the spiritual sacred diseases such as treatment epilepsy of main component with the succinic acid that extracts from natural algae, belongs to natural medicinal plants Application and Development technical field.
Technical background:
Epilepsy is a kind of common nervous system disease.Epidemiological study finds that general population's epilepsy prevalence is 0.5%-1.0%.Epilepsy is the chronic brain dysfunction syndrome that is caused by Different types of etiopathogenises, is sudden, transience functional disorders of brain that brain nervous cell group supersynchronous discharge is repeatedly caused.Because the morbidity and the outbreak mechanism of epilepsy are not illustrated as yet, have influenced prevention and treatment to this disease,,, treat epilepsy at present still based on medicine as operation or ray excision epileptogenic focus though the treatment of epilepsy means improved a lot in recent years.Be control of seizures, many patients need take antiepileptic for a long time, but existing antiepileptic or curative effect are not remarkable, or toxic and side effects is big, have a strong impact on patient's quality of life in the medication treatment, even threat to life.A lot of patients can not adhere to treatment greatly because of poisonous side effect of medicine.Ideal antiepileptic should be that to possess anti-epilepsy spectrum wide, and anti-epilepsy intensity is big, curative effect is high, natural low toxicity, advantage such as cheap.But still do not have a kind of medicine at present and can reach this standard.The objective of the invention is to overcome shortcomings such as the used curative effect of medication of spiritual sacred disease such as existing treatment epilepsy is low, toxic and side effects is big, seek a kind of natural novel antiepileptic of high-efficiency low-toxicity, especially a kind of preparation method that contains the anti-spiritual neurologic agent of succinic acid.
Summary of the invention:
In order to realize the foregoing invention purpose, the present invention adopt the succinic acid that from natural algae, extracts be primary raw material make a kind of prevent and treat epilepsy have health care and the tablet of treatment function and the medicine of two kinds of dosage forms of capsule concurrently.Succinic acid is a natural product, and the source is wide, in being contained in succinum, food plant and some Chinese herbal medicine, also be present in the Sargassum.Succinic acid is the neural lead compound of main natural activity that contains in the Sargassum; its chemical constitution is similar with excitatory neurotransmitter glutamic acid to inhibitory aminoacid neurotransmitter, the taurine of the interior regulation and control of brain epilepsy; this structure activity relationship explanation succinic acid may be the natural antiepileptic endogenous neuroactive substance of a kind of brain, and it has calmness, convulsion and antiepileptic pharmacological action.The contained succinic acid of medicine of the present invention is produced by the following method: add acid after earlier natural algae being pulverized and transfer to acidity, get alcohol extract with alcohol reflux, the extraction of reuse water-saturated n-butanol, n-butyl alcohol partly carries out the low pressure silica gel column chromatography, with the chloroform-methanol gradient elution, at last with ultra-pure water-dehydrated alcohol repeatedly recrystallization get the pure product of succinic acid.Its medicine of making is divided into tablet and two kinds of dosage forms of capsule.
The tablet that the present invention makes is grouped into by following several one-tenth: succinic acid 50%, lactose 20%, microcrystalline Cellulose 22%, carboxymethylcellulose calcium 2%, anhydrous silicic acid 2%, carboxyl propionyl cellulose 3%, magnesium stearate 1%.Wherein, succinic acid extracts from natural algae and makes, and all the other components are buied by commercially available.The method that the present invention prepares tablet is: weigh above-mentioned various component in proportion respectively, succinic acid, lactose, carboxymethylcellulose calcium and anhydrous silicic acid homogeneous are mixed, then with isopropyl alcohol dissolving carboxyl propionyl cellulose, above-mentioned 5 kinds of compositions are mixed, granulate with damp process, make two kinds of tablets that contain 250mg and 500mg succinic acid after the granule made and magnesium stearate are mixed.
The capsule that the present invention makes is grouped into by following several one-tenth: succinic acid 50%, medical starch 49%, magnesium stearate 1%.Medical starch, magnesium stearate can be buied by commercially available.The method that the present invention prepares capsule is: weigh above-mentioned various component in proportion respectively, and mix homogeneously, filled capsules is made two kinds of capsules that contain 250mg and 500mg succinic acid.
Medicine of the present invention use from algae natural antiepileptic activity material---succinic acid is as main component, its aboundresources, chemical constitution is clear and definite, have no side effect, effect is lasting, and is evident in efficacy, solved spiritual neurologic agent weak curative effect such as existing treatment epilepsy, outstanding shortcoming that toxic and side effects is big, its advantage is that the synthetic antiepileptic of present clinical chemistry is not available, has great development and application values.
Embodiment:
Embodiment 1: the preparation process of this novel anti spirit neurologic agent (tablet) is as follows:
The first step, the preparation of natural amber acid and purification.Natural algae is ground into coarse powder for 1000 kilograms, adds acid and transfer to pH value to 3-4, with 75% alcohol reflux 3 times, merge, reclaim solvent, extractum 85kg.After alcohol extractum is soluble in water, with water-saturated n-butanol extraction 4 times, n-butanol layer gets 27kg after reclaiming solvent, n-butyl alcohol partly carries out the low pressure silica gel column chromatography, mixes sample with silica gel H, and dry column-packing, column chromatogram chromatography is carried out in pressurization, with chloroform-methanol (20: 1-1: 1) gradient eluting successively, 10: 1 eluting parts are carried out the low-pressure column chromatography chromatography once more, natural amber acid 31g.The natural amber acid that obtains is dissolved in ultra-pure water-dehydrated alcohol (1: 8) solvent, slowly 50-80 ℃ of extremely dissolving of heating on magnetic stirrer, cooling gradually then, promptly obtain colourless crystallization, the elimination supernatant carries out the recrystallization operation as stated above repeatedly, flings to ethanol, drying, it is standby that mistake 80 mesh sieves are made the succinic acid powder.The natural amber acid purity that operation according to said method obtains can reach more than 99%.
Second step: patent medicine preparation.Weighing natural amber acid 25g separately, lactose 10g, microcrystalline Cellulose 11g, carboxylic formaldehyde cellulose calcium 1g, anhydrous silicic acid 1g, carboxyl propionyl cellulose 1.5g, magnesium stearate 0.5g.With succinic acid, lactose, carboxylic formaldehyde cellulose calcium and anhydrous silicic acid mix homogeneously, then with isopropyl alcohol dissolving carboxyl propionyl cellulose, above-mentioned several compositions are mixed, granulate with damp process, granule and the magnesium stearate made are mixed, make every tablet of two kinds of tablets that contain 250mg, the acid of 500mg natural amber.
Low dosage 500mg/ day, higher dosage 750-1500mg/ day was as clinical treatment epilepsy consumption as clinical prevention epilepsy dosage.Instructions of taking: prevention and treatment epilepsy can be used everyone 500-2000mg every day of tablet.
Embodiment 2: the preparation process of this novel anti spirit neurologic agent (capsule) is as follows:
The first step, the preparation of natural amber acid and purification.With embodiment 1 first step.
Second step: patent medicine preparation.Weighing natural amber acid 25g separately, medical starch 24.5g, magnesium stearate 0.5g mix homogeneously, filled capsules is made two kinds of capsules that each contains 250mg, the acid of 500mg natural amber.Instructions of taking is identical with consumption and tablet.
Using above-mentioned tablet that makes or capsule treats 20 example trouble epilepsy volunteers.Experimental group 10 people and matched group 10 people relatively show that curative effect of medication of the present invention is better.The all conventional oral antiepileptic of matched group 10 people, valproic acid 4 examples wherein, carbamazepine 2 examples, phenytoin Sodium 2 examples, appropriate safe 1 example, all effect is undesirable.Experimental group 10 human oral succinic acid tablet of the present invention or capsule 250mg, a twice-daily or three times.Cure 4 examples, epilepsy is controlled fully, and is not having recurrence more than 6 months; Effective 5 examples, attack times reduces more than 50%; Invalid 1 example, attack times do not have minimizing or reduce number of times below 50%.Total effective rate reaches 90%, and effect is better.
Acute toxicity testing records oral medicine mice LD of the present invention
50For 5.0g/kg (95% credibility interval 4.5-5.0g/kg), illustrate that its toxicity is lower.Long term toxicity (6 months) is not seen pathological change in 22 kinds of tissues of mice and internal organs, the blood test routine is not seen yet ANOMALOUS VARIATIONS.
Light antiepileptic action and the mechanism of action thereof that research succinic acid medicine of the present invention on the epilepsy model is lighted in corpus amygdaloideum electricity irritation at the comparatively ideal PTZ of internationally recognized research epilepsy (pentylenetetrazole, i.e. Pentylenetetrazole) chemistry, the result is as follows:
1, succinic acid medicine of the present invention influence that PTZ is lighted.Succinic acid 100-400mgkg
-1But the outbreak that ip dose-dependent inhibition PTZ chemical is lighted reduces by 6 grades of outbreak percentage rate (p＜0.01) of Europe Neng Shi (Ono ' s) classification and Europe Neng Shi (Ono ' s).
Table 1 succinic acid medicine of the present invention is to the inhibitory action of PTZ kindled rats
6 grades of attack rate of dosage Europe Neng Shi classification (%)
(mgkg
-1) before the administration after the administration before the administration after the administration
50 6 5.3±1.0
a 100.0 66.7
a
100 6 4.6±1.1
b 100.0 25.0
b
200 6 3.0±1.3
c 100.0 12.5
c
400 6 3.3±1.4
c 100.0 16.7
c
With comparison before the administration
aP＞0.05
bP＜0.05,
cP＜0.01. x ± s, n=9
2, succinic acid medicine of the present invention is to the influence ° succinic acid 100-400mgkg of corpus amygdaloideum KE
-1But amygdala-kindled seizure under the ip dose-dependent inhibition threshold stimulus, rising onset threshold (ADT) reduces auspicious Sen Shi (Racine ' s) outbreak classification and auspicious Sen Shi (Racine ' s) V level outbreak percentage rate (p＜0.01).
Table 2 succinic acid medicine of the present invention is to the influence of the various outbreak indexs of corpus amygdaloideum kindled rats
The auspicious Sen Shi classification of dosage ADT (V)
(mgkg
-1) before the administration after the administration before the administration after the administration
50 3.4±1.0 3.4±1.1
a 5.0 4.2±1.6
a
100 3.4±1.2 3.8±1.0
b 5.0 3.1±1.5
b
200 3.4±1.1 3.8±1.0
b 5.0 1.9±1.2
c
400 3.4±1.0 3.9±1.1
c 5.0 1.5±0.8
c
Compare with matched group before the administration
aP＞0.05,
bP＜0.05,
cP＜0.01. x ± s, n=9
3, succinic acid medicine of the present invention is to the influence of mice picrotoxin convulsions model.At the experiment of mice picrotoxin convulsions, succinic acid 200-400mgkg
-1The incubation period of ip significant prolongation picrotoxin convulsions mice.
Table 3 succinic acid medicine of the present invention brings out the influence of mice convulsion to γ-An Jidingsuan A receptor antagonist picrotoxin
Group dosage (mgkg
-1) number of animals convulsions number of animals incubation period (min)
Normal saline 10 10 8.9 ± 3.4
a
Succinic acid 200 10 9 14.0 ± 5.4
b
400 10 8 17.3±3.2
c
Compare with the normal saline matched group
aP＞0.05,
bP＜0.05,
cP＜0.01, x ± s, n=10
Claims (4)
1, a kind of preparation method that contains the anti-spiritual neurologic agent of succinic acid, it is characterized in that with the succinic acid that extracts be primary raw material from natural algae, make two kinds of dosage forms of tablet and capsule, add acid after earlier natural algae being pulverized and transfer to acidity, get alcohol extract with alcohol reflux, the extraction of reuse water-saturated n-butanol, n-butyl alcohol partly carries out the low pressure silica gel column chromatography, with the chloroform-methanol gradient elution, at last with ultra-pure water-dehydrated alcohol repeatedly recrystallization get the pure product of succinic acid, tablet is grouped into by following several one-tenth: succinic acid 50%, lactose 20%, microcrystalline Cellulose 22%, carboxymethylcellulose calcium 2%, anhydrous silicic acid 2%, carboxyl propionyl cellulose 3%, magnesium stearate 1%, weigh above-mentioned various component in proportion respectively, with succinic acid, lactose, carboxymethylcellulose calcium and anhydrous silicic acid homogeneous mix, then with isopropyl alcohol dissolving carboxyl propionyl cellulose, above-mentioned 5 kinds of compositions are mixed, granulate, make two kinds of tablets that contain 250mg and 500mg succinic acid after the granule made and magnesium stearate are mixed with damp process; Capsule is grouped into by following several one-tenth: succinic acid 50%, and medical starch 49%, magnesium stearate 1% weighs above-mentioned various component in proportion respectively, mix homogeneously, filled capsules is made two kinds of capsules that contain 250mg and 500mg succinic acid.
2, a kind of preparation method that contains the anti-spiritual neurologic agent of succinic acid according to claim 1 when it is characterized in that extracting succinic acid, transfers to pH value to 3-4 with adding acid after the natural algae pulverizing.
3, a kind of preparation method that contains the anti-spiritual neurologic agent of succinic acid according to claim 1, when it is characterized in that extracting succinic acid, n-butyl alcohol partly carries out the low pressure silica gel column chromatography, mixes sample with silica gel H, and dry column-packing, and column chromatogram chromatography is carried out in pressurization.
4, a kind of preparation method that contains the anti-spiritual neurologic agent of succinic acid according to claim 1, when it is characterized in that extracting succinic acid and carrying out the recrystallization purification operations, after being dissolved in natural amber acid in ultra-pure water-dehydrated alcohol (1: 8) solvent, slowly 50-80 ℃ of extremely dissolving of heating on magnetic stirrer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03133219 CN1568953A (en) | 2003-07-21 | 2003-07-21 | Method for preparing mental disease resistant medicine containing succinic acid |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03133219 CN1568953A (en) | 2003-07-21 | 2003-07-21 | Method for preparing mental disease resistant medicine containing succinic acid |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101269057B (en) * | 2008-02-22 | 2011-11-30 | 青岛大学 | Use of succinic acid as metal disease resistant medicament synergistic agent |
-
2003
- 2003-07-21 CN CN 03133219 patent/CN1568953A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101269057B (en) * | 2008-02-22 | 2011-11-30 | 青岛大学 | Use of succinic acid as metal disease resistant medicament synergistic agent |
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