CN108926544A - Four generation Couteat of Folic Acid of one kind and preparation method thereof - Google Patents
Four generation Couteat of Folic Acid of one kind and preparation method thereof Download PDFInfo
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- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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Abstract
The present invention provides a kind of four generation Couteat of Folic Acid and preparation method thereof, it includes (6S) -5-methyltetrahydrofolate, glucosamine salt 0.1%~15.0%, diluent 40.0%~94.0%, disintegrating agent 3.0%~42.0%, lubricants 0.2%~12.0%.It uses technique of direct powder compression, by mixing, tabletting and etc. be made.Four generations Couteat of Folic Acid produced by the present invention dissolves out rapidly in the dissolution medium of varying environment, is conducive to discharge in different groups digestive tract environment, and body absorption is fast.
Description
Technical field
The present invention relates to medicine, functional food, and in particular to four generation Couteat of Folic Acid of one kind and preparation method thereof.
Background technique
Folic acid is a kind of water soluble vitamin needed by human, for maintaining cell function and health most important.1939
Year, Bombay,India a doctor had found that yeast extract can be used for treating gravid woman's anemia, and largely effective, this position
Doctor has played being named as " folic acid " it is thought that one group of vitamin；Nineteen forty-one U.S. a doctor has found largely in spinach
" folic acid ", and find that this substance is widely present in green vegetable, so referred to as folic acid.Scientist develops within 1989
5-methyltetrahydrofolate calcium salt becomes the representative of third generation folic acid, and the third generation is folic acid derivatives, can be directly entered human body
Cell, without can be just converted by the metabolism of a series of complex as first generation folic acid or second generation synthesis folic acid
Effective folic acid.Find forth generation folic acid --- (6S) -5-methyltetrahydrofolate glucosamine salt (national health meter finally afterwards
Raw committee No. 8 bulletin in 2017, molecular formula: C32H51N9O16).Foliamin makes in the products such as pregnant and lying-in women, infant, old man
With extensive, existing market circulation is mostly the second generation or third generation foliamin, to provide more outstanding foliamin product,
Four generation Couteat of Folic Acid of one kind and preparation method thereof are provided.
Summary of the invention
An object of the present disclosure is to provide a kind of four generation Couteat of Folic Acid, and second is designed to provide a kind of four generation Couteat of Folic Acid
Preparation for processing.
To achieve the above object, a kind of four generations Couteat of Folic Acid provided by the invention, by (6S) -5-methyltetrahydrofolate, amino
Glucosamine salt, diluent, disintegrating agent, lubricant composition, four generation Couteat of Folic Acid of the invention shine four general rules of Chinese Pharmacopoeia version in 2015
The third method of " 0931 dissolution rate and drug release determination method ", is dissolved out using pH6.8 phosphate buffer 200ml as dissolution medium
Degree test, 37 DEG C of temperature, 50 revs/min of revolving speed, dissolution in vitro is not less than 85% within 15 minutes；
Four generation Couteat of Folic Acid of the invention are according to four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method "
Third method, using pH7.2 phosphate buffer 200ml as dissolution medium carry out Dissolution Rate Testing, 37 DEG C of temperature, 75 turns of revolving speed/
Minute, dissolution in vitro is not less than 80% within 30 minutes；
Four generation Couteat of Folic Acid of the invention are according to four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method "
Third method, using purified water 200ml as dissolution medium carry out Dissolution Rate Testing, 37 DEG C of temperature, 50 revs/min of revolving speed, 15 minutes
Dissolution in vitro is not less than 85%, and dissolution in vitro is not less than 95% within 30 minutes；
Four generation Couteat of Folic Acid of the invention are according to four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method "
Third method, using pH5.5 phosphate buffer 200ml as dissolution medium carry out Dissolution Rate Testing, 37 DEG C of temperature, 100 turns of revolving speed/
Minute, dissolution in vitro is not less than 70% within 30 minutes；
Four generation Couteat of Folic Acid of the invention are according to four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method "
Third method, using the hydrochloric acid solution 200ml of pH1.2 as dissolution medium carry out Dissolution Rate Testing, 100 revs/min of revolving speed, 30 minutes
Dissolution in vitro is not less than 60%；
Four generation Couteat of Folic Acid of the invention include the component of following weight percentage:
The diluent of four generation Couteat of Folic Acid of the invention is selected from pregelatinized starch, microcrystalline cellulose, silicified microcrystalline cellulose, cream
Sugar, cycloheptaamylose, cyclooctaamylose, antierythrite, xylitol, D-mannital, methylcellulose, is total to cyclohexaamylose
It is povidone, calcium monohydrogen phosphate, maltitol, hydroxypropul starch, maltitol, dextrin, ethyl cellulose, soluble starch, anhydrous
The mixture of one or more of calcium monohydrogen phosphate, sucrose, starch, milk powder.
The disintegrating agent of four generation Couteat of Folic Acid of the invention is selected from hydroxypropylcellulose, sodium carboxymethyl starch, crospovidone, crosslinking carboxylic
The mixture of one or more of sodium carboxymethylcellulose pyce, low-substituted hydroxypropyl cellulose.
The lubricant of four generation Couteat of Folic Acid of the invention is selected from talcum powder, silica, polyethylene glycol, stearic acid, palm wax, hard
Fatty acid magnesium, Compritol 888 ATO, sodium stearyl fumarate.
Four generation Couteat of Folic Acid of the invention are according to four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method "
Third method, using pH6.8 phosphate buffer 200ml as dissolution medium carry out Dissolution Rate Testing, 37 DEG C of temperature, 50 turns of revolving speed/
Minute, dissolution in vitro is not less than 85% within 15 minutes；The four generations Couteat of Folic Acid shines four general rules " 0931 of Chinese Pharmacopoeia version in 2015
The third method of dissolution rate and drug release determination method " carries out dissolution rate examination by dissolution medium of pH7.2 phosphate buffer 200ml
It tests, 37 DEG C of temperature, 75 revs/min of revolving speed, dissolution in vitro is not less than 81% within 30 minutes；The four generations Couteat of Folic Acid shines Chinese Pharmacopoeia
The third method of four general rules of version in 2015 " 0931 dissolution rate and drug release determination method ", using purified water 200ml as dissolution medium into
Row Dissolution Rate Testing, 37 DEG C of temperature, 50 revs/min of revolving speed, dissolution in vitro is not less than 86% within 15 minutes, 30 minutes In Vitro Dissolutions
Degree is not less than 95%；The four generations Couteat of Folic Acid shines Chinese Pharmacopoeia version in 2015 four general rules " 0931 dissolution rate and drug release determinations
The third method of method ", using pH5.5 phosphate buffer 200ml as dissolution medium progress Dissolution Rate Testing, 37 DEG C of temperature, revolving speed 100
Rev/min, dissolution in vitro is not less than 70% within 30 minutes；The four generations Couteat of Folic Acid shines four general rules of Chinese Pharmacopoeia version in 2015
The third method of " 0931 dissolution rate and drug release determination method " carries out dissolution rate by dissolution medium of the hydrochloric acid solution 200ml of pH1.2
Test, 100 revs/min of revolving speed, dissolution in vitro is not less than 60% within 30 minutes；The four generations Couteat of Folic Acid includes: (6S) -5- methyl
Tetrahydrofolic acid, glucosamine salt 0.4g, pregelatinized starch 20.0g, microcrystalline cellulose 60.0g, calcium monohydrogen phosphate 6.0g, carboxymethyl
Sodium starch 4.0g, crospovidone 4.0g, low-substituted hydroxypropyl cellulose 4.0g, silica 1 .0g, polyethylene glycol 0.6g.
Four generation Couteat of Folic Acid of the invention are according to four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method "
Third method, using pH6.8 phosphate buffer 200ml as dissolution medium carry out Dissolution Rate Testing, 37 DEG C of temperature, 50 turns of revolving speed/
Minute, dissolution in vitro is not less than 85% within 15 minutes；The four generations Couteat of Folic Acid shines four general rules " 0931 of Chinese Pharmacopoeia version in 2015
The third method of dissolution rate and drug release determination method " carries out dissolution rate examination by dissolution medium of pH7.2 phosphate buffer 200ml
It tests, 37 DEG C of temperature, 75 revs/min of revolving speed, dissolution in vitro is not less than 81% within 30 minutes；The four generations Couteat of Folic Acid shines Chinese Pharmacopoeia
The third method of four general rules of version in 2015 " 0931 dissolution rate and drug release determination method ", using purified water 200ml as dissolution medium into
Row Dissolution Rate Testing, 37 DEG C of temperature, 50 revs/min of revolving speed, dissolution in vitro is not less than 86% within 15 minutes, 30 minutes In Vitro Dissolutions
Degree is not less than 95%；The four generations Couteat of Folic Acid shines Chinese Pharmacopoeia version in 2015 four general rules " 0931 dissolution rate and drug release determinations
The third method of method ", using pH5.5 phosphate buffer 200ml as dissolution medium progress Dissolution Rate Testing, 37 DEG C of temperature, revolving speed 100
Rev/min, dissolution in vitro is not less than 71% within 30 minutes；The four generations Couteat of Folic Acid shines four general rules of Chinese Pharmacopoeia version in 2015
The third method of " 0931 dissolution rate and drug release determination method " carries out dissolution rate by dissolution medium of the hydrochloric acid solution 200ml of pH1.2
Test, 100 revs/min of revolving speed, dissolution in vitro is not less than 62% within 30 minutes；The four generations Couteat of Folic Acid includes: (6S) -5- methyl
Tetrahydrofolic acid, glucosamine salt 0.9g, microcrystalline cellulose 80.0g, sodium carboxymethyl starch 7.0g, crospovidone 11.0g, two
Silica 1.1g.
A kind of preparation method of four generations Couteat of Folic Acid, the preparation method include the following steps:
(1) percentage composition weighs following components by weight:
It is spare；
(2) (6S) -5-methyltetrahydrofolate, glucosamine salt and diluent, disintegrating agent are set in mixing machine, mixing 5
~90 minutes, add mix lubricant 3~60 minutes, it is spare；
(3) material in (2) is set in tablet press machine, tabletting, control tablet hardness is 80~200N, is coated or is not coated, i.e.,
Obtain four generations Couteat of Folic Acid of the invention.
The invention has the following advantages: four generation Couteat of Folic Acid of the invention dissolved out in the dissolution medium of varying environment it is fast
Speed is conducive to discharge in different groups digestive tract environment, and body absorption is fast, can alleviate promotion lacrimal secretion, alleviates dry eyes
Disease.
Specific embodiment
The present invention, raw material used in following embodiments, test example, examination are further illustrated below by specific embodiment
Agent material etc. buys commercial product unless otherwise specified.Following embodiment is merely to illustrate the present invention, wherein the reality
Proved recipe method is conventional method such as without specifically defined.
Preparation of reagents method:
The hydrochloric acid solution of pH1.2: taking 7.65mL hydrochloric acid, be diluted with water to 1000mL, shake up to get；
0.2mol/L potassium dihydrogen phosphate: 27.22g potassium dihydrogen phosphate is taken, is dissolved with water and is diluted to 1000mL；
0.2mol/L sodium hydroxide solution: 8.00g sodium hydroxide is taken, is dissolved with water and is diluted to 1000mL；
Phosphate buffer (pH5.5): 250mL 0.2mol/L potassium dihydrogen phosphate and 9.0mL0.2mol/L hydrogen-oxygen are taken
Change sodium solution mixing after, add water and be diluted to 1000mL, shake up to get；
Phosphate buffer (PH 6.8): 250mL 0.2mol/L potassium dihydrogen phosphate and 112.0mL0.2mol/L are taken
Sodium hydroxide solution mixing after, add water and be diluted to 1000mL, shake up to get；
Phosphate buffer (PH 7.2): 250mL 0.2mol/L potassium dihydrogen phosphate and 173.5mL0.2mol/L are taken
Sodium hydroxide solution mixing after, add water and be diluted to 1000mL, shake up to get.
Dissolution in vitro test method:
(1) test solution:
Sample under each embodiment is taken, according to four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method "
Third method, using pH6.8 phosphate buffer 200ml as dissolution medium carry out Dissolution Rate Testing, 37 DEG C of temperature, 50 turns of revolving speed/
Minute, 15 minutes whens, sample 10mL, 0.45 μm of filter membrane are crossed, as test solution；
Sample under each embodiment is taken, according to four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method "
Third method, using pH7.2 phosphate buffer 200ml as dissolution medium carry out Dissolution Rate Testing, 37 DEG C of temperature, 75 turns of revolving speed/
Minute, 30 minutes whens, sample 10mL, 0.45 μm of filter membrane are crossed, as test solution；
Sample under each embodiment is taken, according to four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method "
Third method, using purified water 200ml as dissolution medium carry out Dissolution Rate Testing, 37 DEG C of temperature, 50 revs/min of revolving speed, 15 minutes
When sample 10mL, cross 0.45 μm of filter membrane, as test solution, be supplemented 10mL purified water, 30 minutes whens, sample 10mL again,
0.45 μm of filter membrane is crossed, as test solution；
Sample under each embodiment is taken, according to four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method "
Third method, using pH5.5 phosphate buffer 200ml as dissolution medium carry out Dissolution Rate Testing, 37 DEG C of temperature, 100 turns of revolving speed/
Minute, 30 minutes whens, sample 10mL, 0.45 μm of filter membrane are crossed, as test solution；
Sample under each embodiment is taken, the four generations Couteat of Folic Acid shines four general rule " 0931 dissolution rates of Chinese Pharmacopoeia version in 2015
With drug release determination method " third method, using the hydrochloric acid solution 200ml of pH1.2 as dissolution medium carry out Dissolution Rate Testing, revolving speed
10mL is sampled at 100 revs/min, 30 minutes, 0.45 μm of filter membrane is crossed, as test solution.
(2) reference substance solution:
It weighs a certain amount of (6S) -5-methyltetrahydrofolate calcium salt standard items and (is equivalent to 0.020g (6S) -5- methyl tetrahydro
Folic acid), it is accurately weighed, it is placed in 100mL volumetric flask, adds purified water to dissolve and be diluted to scale, low temperature ultrasonic 2min shakes up,
0.45 μm of filter membrane is crossed, as reference substance solution.
(3) measuring method
Chromatographic condition
System suitability tailing factor is less than or equal to 2, and theoretical cam curve is more than or equal to 20000.
Measuring method shines above-mentioned chromatographic condition, by water (being free of solute) injection, runs chromatograph according to the above-mentioned time, right respectively
Test solution and control solution analysis, records reference substance solution and test solution chromatographic peak, calculates dissolution rate (%).
Embodiment 1
Formula:
| (6S) -5-methyltetrahydrofolate, glucosamine salt | 0.1% | 0.1g |
| Diluent | 94.0% | Silicified microcrystalline cellulose 94.0g |
| Disintegrating agent | 3.0% | Crospovidone 3.0g |
| Lubricant | 2.9% | Polyethylene glycol 2.9g |
Preparation method: percentage composition weighs following components by weight:
It is spare；
(2) (6S) -5-methyltetrahydrofolate, glucosamine salt and diluent, disintegrating agent are set in mixing machine, mixing 5
Minute, add mix lubricant 3 minutes, it is spare；
(3) material in (2) is set in tablet press machine, tabletting, control tablet hardness is 80N, is not coated to get four generations of the invention
Couteat of Folic Acid.
Dissolution in vitro result:
| Dissolution medium | Dissolution in vitro |
| PH6.8 phosphate buffer | 15 minutes: 89.3% |
| PH7.2 phosphate buffer | 30 minutes: 95.1% |
| Purified water | 15 minutes: 88.5%, 30 minutes: 98.9% |
| PH5.5 phosphate buffer | 30 minutes: 85.2% |
| The hydrochloric acid solution of pH1.2 | 30 minutes: 81.0% |
Embodiment 2
Formula:
| (6S) -5-methyltetrahydrofolate, glucosamine salt | 15.0% | 15.0g |
| Diluent | 40.0% | Pregelatinized starch 20g, microcrystalline cellulose 20.0g |
| Disintegrating agent | 42.0% | Hydroxypropylcellulose 2.0g, sodium carboxymethyl starch 40.0g |
| Lubricant | 3.0% | Talcum powder 0.5g, silica 2.5g |
Preparation method:
(1) percentage composition weighs following components by weight:
It is spare；
(2) (6S) -5-methyltetrahydrofolate, glucosamine salt and diluent, disintegrating agent are set in mixing machine, mixing 90
Minute, add mix lubricant 60 minutes, it is spare；
(3) material in (2) is set in tablet press machine, tabletting, control tablet hardness is 200N, is not coated to get the present invention four
For Couteat of Folic Acid.
Dissolution in vitro result:
| Dissolution medium | Dissolution in vitro |
| PH6.8 phosphate buffer | 15 minutes: 87.8% |
| PH7.2 phosphate buffer | 30 minutes: 97.4% |
| Purified water | 15 minutes: 89.2%, 30 minutes: 99.6% |
| PH5.5 phosphate buffer | 30 minutes: 90.1% |
| The hydrochloric acid solution of pH1.2 | 30 minutes: 89.7% |
Embodiment 3
Formula:
Preparation method: (1) percentage composition weighs following components by weight:
It is spare；
(2) (6S) -5-methyltetrahydrofolate, glucosamine salt and diluent, disintegrating agent are set in mixing machine, mixing 48
Minute, add mix lubricant 33 minutes, it is spare；
(3) material in (2) is set in tablet press machine, tabletting, control tablet hardness is 140N, is not coated to get the present invention four
For Couteat of Folic Acid.
Dissolution in vitro result:
| Dissolution medium | Dissolution in vitro |
| PH6.8 phosphate buffer | 15 minutes: 90.2% |
| PH7.2 phosphate buffer | 30 minutes: 97.2% |
| Purified water | 15 minutes: 90.5%, 30 minutes: 100.2% |
| PH5.5 phosphate buffer | 30 minutes: 87.4% |
| The hydrochloric acid solution of pH1.2 | 30 minutes: 89.0% |
Embodiment 4
Formula:
Preparation method: (1) percentage composition weighs following components by weight:
It is spare；
(2) (6S) -5-methyltetrahydrofolate, glucosamine salt and diluent, disintegrating agent are set in mixing machine, mixing 5
Minute, add mix lubricant 3 minutes, it is spare；
(3) material in (2) is set in tablet press machine, tabletting, control tablet hardness is 140N, film coating, coating weight gain
2% to get four generation Couteat of Folic Acid of the invention.
Dissolution in vitro result:
| Dissolution medium | Dissolution in vitro |
| PH6.8 phosphate buffer | 15 minutes: 90.4% |
| PH7.2 phosphate buffer | 30 minutes: 93.5% |
| Purified water | 15 minutes: 90.7%, 30 minutes: 99.7% |
| PH5.5 phosphate buffer | 30 minutes: 88.7% |
| The hydrochloric acid solution of pH1.2 | 30 minutes: 84.2% |
Embodiment 5
Formula:
Preparation method: (1) percentage composition weighs following components by weight:
It is spare；
(2) (6S) -5-methyltetrahydrofolate, glucosamine salt and diluent, disintegrating agent are set in mixing machine, mixing 90
Minute, add mix lubricant 60 minutes, it is spare；
(3) material in (2) is set in tablet press machine, tabletting, control tablet hardness be 80N, film coating, coating weight gain 6%,
Up to four generation Couteat of Folic Acid of the invention.
Dissolution in vitro result:
| Dissolution medium | Dissolution in vitro |
| PH6.8 phosphate buffer | 15 minutes: 89.6% |
| PH7.2 phosphate buffer | 30 minutes: 92.9% |
| Purified water | 15 minutes: 89.7%, 30 minutes: 100.4% |
| PH5.5 phosphate buffer | 30 minutes: 89.8% |
| The hydrochloric acid solution of pH1.2 | 30 minutes: 87.0% |
Embodiment 6
Formula:
Preparation method: (1) percentage composition weighs following components by weight:
It is spare；
(2) (6S) -5-methyltetrahydrofolate, glucosamine salt and diluent, disintegrating agent are set in mixing machine, mixing 48
Minute, add mix lubricant 30 minutes, it is spare；
(3) material in (2) is set in tablet press machine, tabletting, control tablet hardness is 200N, film coating, coating weight gain
4% to get four generation Couteat of Folic Acid of the invention.
Dissolution in vitro result:
| Dissolution medium | Dissolution in vitro |
| PH6.8 phosphate buffer | 15 minutes: 89.2% |
| PH7.2 phosphate buffer | 30 minutes: 94.3% |
| Purified water | 15 minutes: 89.9%, 30 minutes: 99.8% |
| PH5.5 phosphate buffer | 30 minutes: 88.7% |
| The hydrochloric acid solution of pH1.2 | 30 minutes: 86.4% |
Embodiment 7
Formula:
Preparation method: (1) percentage composition weighs following components by weight:
It is spare；
(2) (6S) -5-methyltetrahydrofolate, glucosamine salt and diluent, disintegrating agent are set in mixing machine, mixing 15
Minute, add mix lubricant 15 minutes, it is spare；
(3) material in (2) is set in tablet press machine, tabletting, control tablet hardness is 100N, film coating, coating weight gain
3% to get four generation Couteat of Folic Acid of the invention.
Dissolution in vitro result:
| Dissolution medium | Dissolution in vitro |
| PH6.8 phosphate buffer | 15 minutes: 89.1% |
| PH7.2 phosphate buffer | 30 minutes: 93.8% |
| Purified water | 15 minutes: 89.6%, 30 minutes: 100.2% |
| PH5.5 phosphate buffer | 30 minutes: 87.9% |
| The hydrochloric acid solution of pH1.2 | 30 minutes: 86.7% |
Embodiment 8
Formula:
Preparation method: (1) percentage composition weighs following components by weight:
It is spare；
(2) (6S) -5-methyltetrahydrofolate, glucosamine salt and diluent, disintegrating agent are set in mixing machine, mixing 10
Minute, add mix lubricant 20 minutes, it is spare；
(3) material in (2) is set in tablet press machine, tabletting, control tablet hardness is 100N, is not coated to get the present invention four
For Couteat of Folic Acid.
Dissolution in vitro result:
| Dissolution medium | Dissolution in vitro |
| PH6.8 phosphate buffer | 15 minutes: 89.9% |
| PH7.2 phosphate buffer | 30 minutes: 94.7% |
| Purified water | 15 minutes: 90.3%, 30 minutes: 99.9% |
| PH5.5 phosphate buffer | 30 minutes: 89.2% |
| The hydrochloric acid solution of pH1.2 | 30 minutes: 86.7% |
Embodiment 9
Formula:
Preparation method: (1) percentage composition weighs following components by weight:
It is spare；
(2) (6S) -5-methyltetrahydrofolate, glucosamine salt and diluent, disintegrating agent are set in mixing machine, mixing 15
Minute, add mix lubricant 30 minutes, it is spare；
(3) material in (2) is set in tablet press machine, tabletting, control tablet hardness is 100N, is not coated to get the present invention four
For Couteat of Folic Acid.
Dissolution in vitro result:
| Dissolution medium | Dissolution in vitro |
| PH6.8 phosphate buffer | 15 minutes: 89.8% |
| PH7.2 phosphate buffer | 30 minutes: 94.7% |
| Purified water | 15 minutes: 89.9%, 30 minutes: 100.1% |
| PH5.5 phosphate buffer | 30 minutes: 88.6% |
| The hydrochloric acid solution of pH1.2 | 30 minutes: 86.9% |
Embodiment 10
Formula:
| (6S) -5-methyltetrahydrofolate, glucosamine salt | 0.4% | 0.4g |
| Diluent | 84.6% | Calcium monohydrogen phosphate 84.6g |
| Disintegrating agent | 2.0% | Sodium carboxymethyl starch 2.0g |
| Lubricant | 13% | Magnesium stearate 12.0g, polyethylene glycol 1.0g |
Preparation method: (1) percentage composition weighs following components by weight:
It is spare；
(2) (6S) -5-methyltetrahydrofolate, glucosamine salt and diluent, disintegrating agent are set in mixing machine, mixing 15
Minute, add mix lubricant 30 minutes, it is spare；
(3) material in (2) is set in tablet press machine, tabletting, control tablet hardness is 100N, is not coated to get the present invention four
For Couteat of Folic Acid.
Dissolution in vitro result:
| Dissolution medium | Dissolution in vitro |
| PH6.8 phosphate buffer | 15 minutes: 59.3% |
| PH7.2 phosphate buffer | 30 minutes: 62.2% |
| Purified water | 15 minutes: 49.4%, 30 minutes: 70.3% |
| PH5.5 phosphate buffer | 30 minutes: 48.1% |
| The hydrochloric acid solution of pH1.2 | 30 minutes: 42.8% |
Embodiment 11
Formula:
Preparation method: (1) percentage composition weighs following components by weight:
It is spare；
(2) (6S) -5-methyltetrahydrofolate, glucosamine salt and diluent, disintegrating agent are set in mixing machine, mixing 10
Minute, add mix lubricant 20 minutes, it is spare；
(3) material in (2) is set in tablet press machine, tabletting, control tablet hardness is 100N, is not coated to get the present invention four
For Couteat of Folic Acid.
Dissolution in vitro result:
| Dissolution medium | Dissolution in vitro |
| PH6.8 phosphate buffer | 15 minutes: 57.2% |
| PH7.2 phosphate buffer | 30 minutes: 58.1% |
| Purified water | 15 minutes: 36.7%, 30 minutes: 65.4% |
| PH5.5 phosphate buffer | 30 minutes: 46.7% |
| The hydrochloric acid solution of pH1.2 | 30 minutes: 38.2% |
Embodiment 12
Formula:
| (6S) -5-methyltetrahydrofolate, glucosamine salt | 0.4% | 0.4g |
| Diluent | 95.0% | Dextrin 95.0g |
| Disintegrating agent | 4.0% | Sodium carboxymethyl starch 4.0g |
| Lubricant | 0.6% | Silica 0.6g |
Preparation method: (1) percentage composition weighs following components by weight:
It is spare；
(2) (6S) -5-methyltetrahydrofolate, glucosamine salt and diluent, disintegrating agent are set in mixing machine, mixing 15
Minute, add mix lubricant 30 minutes, it is spare；
(3) material in (2) is set in tablet press machine, tabletting, control tablet hardness is 100N, is not coated to get the present invention four
For Couteat of Folic Acid.
Dissolution in vitro result:
| Dissolution medium | Dissolution in vitro |
| PH6.8 phosphate buffer | 15 minutes: 49.8% |
| PH7.2 phosphate buffer | 30 minutes: 52.3% |
| Purified water | 15 minutes: 33.5%, 30 minutes: 62.7% |
| PH5.5 phosphate buffer | 30 minutes: 41.5% |
| The hydrochloric acid solution of pH1.2 | 30 minutes: 35.2% |
Observation of the test example 1 to dry eyes nude mice lacrimal secretion
1. sample source: 9 sample of Example, 11 sample of embodiment and commercially available Couteat of Folic Acid.
2. test method: taking nude mice 50, be randomly divided into blank group, model group, 9 groups of embodiment, 11 city Zu Ji of embodiment
Sell sample controls group.
With no treatment, normal feed is given once daily in blank group, until experiment terminates；
Model group with 1.5% the daily eye drip of atropine sulfate ophthalmic solution three times, it is each primary in the morning, afternoon and evening, be given once daily normal
Feed, until experiment terminate；
9 groups of embodiment with 1.5% the daily eye drip of atropine sulfate ophthalmic solution three times, it is each primary in the morning, afternoon and evening, opened in the 7th day
Addition 9 sample of embodiment (being equivalent to 100 μ g of (6S) -5-methyltetrahydrofolate) in feed is started from, until experiment terminates；
11 groups of embodiment with 1.5% the daily eye drip of atropine sulfate ophthalmic solution three times, it is each primary in the morning, afternoon and evening, in the 7th day
Start from adding 11 sample of embodiment (being equivalent to 100 μ g of (6S) -5-methyltetrahydrofolate) in feed, until experiment terminates；
Commercial samples control group with 1.5% the daily eye drip of atropine sulfate ophthalmic solution three times, it is each primary in the morning, afternoon and evening, in the
Start within 7 days adding commercial samples sample (being equivalent to 100 μ g of folic acid) in feed, until experiment terminates.
In progress Schirmer I test in the 1st day, 7 days and 30 days: tears detecting filter strip one end folded and puts in people's lower eyelid
In 1/3 conjunctival sac, filter paper is taken out after 5min, measures its wetted length from folding place.
3. evaluation result: the present invention can promote dry eyes nude mice lacrimal secretion.Concrete outcome is shown in Table 1.
1 tear amount evaluation result (x ± s, mm) of table
The test of 2 rat body absorption of test example
1. sample source: 2 sample of Example, 8 sample of embodiment, 10 sample of embodiment and commercially available Couteat of Folic Acid.
2. test method: taking nude mice 24, be randomly divided into 2 groups of embodiment, 8 groups of embodiment, 10 groups of embodiment and commercially available sample
Product control group.2 groups of embodiment, 8 groups of embodiment, 10 groups of gastric infusions of embodiment (0.1mg/kg (6S) -5-methyltetrahydrofolate),
Commercial samples control group gastric infusion (0.1mg/kg folic acid), fasting after administration, not water restriction.
It takes a blood sample point: 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h and for 24 hours after 0h and administration before being administered.From the big rathole of SD
Vena orbitalis posterior clump adopts whole blood sample.Using commercially available rat folic acid ELISA kit to each sampling time point of each tested group of animal
Sample carries out folate content detection, and calculates the mean value of each assessment item of each tested group of rat.It is right and before sample analysis detection
Precision, accuracy, specificity, detection limit of method etc. carry out methodology validation, the results showed that this method is accurate and reliable.3.
Evaluation result: faster, the Tmax time is shorter for infiltration rate of the present invention.Concrete outcome is shown in Table 2.
2 rat body absorption evaluation result of table
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Made any modifications, equivalent replacements, and improvements etc., should all be included in the protection scope of the present invention within mind and principle.
Claims (7)
1. a kind of four generation Couteat of Folic Acid, by (6S) -5-methyltetrahydrofolate, glucosamine salt, diluent, disintegrating agent, lubricant
Composition, which is characterized in that the four generations Couteat of Folic Acid according to four general rules of Chinese Pharmacopoeia version in 2015 " survey by 0931 dissolution rate and release
Determine method " third method, using pH6.8 phosphate buffer 200ml as dissolution medium carry out Dissolution Rate Testing, 37 DEG C of temperature, revolving speed
50 revs/min, dissolution in vitro is not less than 85% within 15 minutes；
Third of the four generations Couteat of Folic Acid according to four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method "
Method, using pH7.2 phosphate buffer 200ml as dissolution medium progress Dissolution Rate Testing, 37 DEG C of temperature, 75 revs/min of revolving speed, 30
Minute dissolution in vitro is not less than 80%；
Third of the four generations Couteat of Folic Acid according to four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method "
Method carries out Dissolution Rate Testing by dissolution medium of purified water 200ml, and 37 DEG C of temperature, 50 revs/min of revolving speed, 15 minutes external molten
Out-degree is not less than 85%, and dissolution in vitro is not less than 95% within 30 minutes；
Third of the four generations Couteat of Folic Acid according to four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method "
Method, using pH5.5 phosphate buffer 200ml as dissolution medium progress Dissolution Rate Testing, 37 DEG C of temperature, 100 revs/min of revolving speed,
Dissolution in vitro is not less than 70% within 30 minutes；
Third of the four generations Couteat of Folic Acid according to four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method "
Method carries out Dissolution Rate Testing by dissolution medium of the hydrochloric acid solution 200ml of pH1.2, and 100 revs/min of revolving speed, 30 minutes external molten
Out-degree is not less than 60%；
The four generations Couteat of Folic Acid includes the component of following weight percentage:
2. four generations Couteat of Folic Acid as described in claim 1, which is characterized in that diluent described in it is selected from pregelatinized starch, micro-
Crystalline cellulose, silicified microcrystalline cellulose, lactose, cyclohexaamylose, cycloheptaamylose, cyclooctaamylose, antierythrite, xylose
Alcohol, D-mannital, methylcellulose, copolyvidone, calcium monohydrogen phosphate, maltitol, hydroxypropul starch, maltitol, dextrin,
The mixture of one or more of ethyl cellulose, soluble starch, calcium phosphate dibasic anhydrous, sucrose, starch, milk powder.
3. four generations Couteat of Folic Acid as described in claim 1, which is characterized in that the disintegrating agent described in it is selected from hydroxypropylcellulose, carboxylic
One or more of methyl starch sodium, crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose
Mixture.
4. four generations Couteat of Folic Acid as described in claim 1, which is characterized in that the lubricant described in it is selected from talcum powder, titanium dioxide
Silicon, polyethylene glycol, stearic acid, palm wax, magnesium stearate, Compritol 888 ATO, sodium stearyl fumarate.
5. the four generation Couteat of Folic Acid as described in Claims 1-4 is any, which is characterized in that the four generations Couteat of Folic Acid shines Chinese Pharmacopoeia
The third method of four general rules of version in 2015 " 0931 dissolution rate and drug release determination method " is with pH6.8 phosphate buffer 200ml
Dissolution medium carries out Dissolution Rate Testing, and 37 DEG C of temperature, 50 revs/min of revolving speed, dissolution in vitro is not less than 85% within 15 minutes；
Third of the four generations Couteat of Folic Acid according to four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method "
Method, using pH7.2 phosphate buffer 200ml as dissolution medium progress Dissolution Rate Testing, 37 DEG C of temperature, 75 revs/min of revolving speed, 30
Minute dissolution in vitro is not less than 81%；
Third of the four generations Couteat of Folic Acid according to four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method "
Method carries out Dissolution Rate Testing by dissolution medium of purified water 200ml, and 37 DEG C of temperature, 50 revs/min of revolving speed, 15 minutes external molten
Out-degree is not less than 86%, and dissolution in vitro is not less than 95% within 30 minutes；
Third of the four generations Couteat of Folic Acid according to four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method "
Method, using pH5.5 phosphate buffer 200ml as dissolution medium progress Dissolution Rate Testing, 37 DEG C of temperature, 100 revs/min of revolving speed,
Dissolution in vitro is not less than 70% within 30 minutes；
Third of the four generations Couteat of Folic Acid according to four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method "
Method carries out Dissolution Rate Testing by dissolution medium of the hydrochloric acid solution 200ml of pH1.2, and 100 revs/min of revolving speed, 30 minutes external molten
Out-degree is not less than 60%；
The four generations Couteat of Folic Acid includes: (6S) -5-methyltetrahydrofolate, glucosamine salt 0.4g, pregelatinized starch 20.0g,
Microcrystalline cellulose 60.0g, calcium monohydrogen phosphate 6.0g, sodium carboxymethyl starch 4.0g, crospovidone 4.0g, low substituted hydroxy-propyl fiber
Plain 4.0g, silica 1 .0g, polyethylene glycol 0.6g.
6. the four generation Couteat of Folic Acid as described in Claims 1-4 is any, which is characterized in that the four generations Couteat of Folic Acid shines Chinese Pharmacopoeia
The third method of four general rules of version in 2015 " 0931 dissolution rate and drug release determination method " is with pH6.8 phosphate buffer 200ml
Dissolution medium carries out Dissolution Rate Testing, and 37 DEG C of temperature, 50 revs/min of revolving speed, dissolution in vitro is not less than 85% within 15 minutes；
Third of the four generations Couteat of Folic Acid according to four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method "
Method, using pH7.2 phosphate buffer 200ml as dissolution medium progress Dissolution Rate Testing, 37 DEG C of temperature, 75 revs/min of revolving speed, 30
Minute dissolution in vitro is not less than 81%；
Third of the four generations Couteat of Folic Acid according to four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method "
Method carries out Dissolution Rate Testing by dissolution medium of purified water 200ml, and 37 DEG C of temperature, 50 revs/min of revolving speed, 15 minutes external molten
Out-degree is not less than 86%, and dissolution in vitro is not less than 95% within 30 minutes；
Third of the four generations Couteat of Folic Acid according to four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method "
Method, using pH5.5 phosphate buffer 200ml as dissolution medium progress Dissolution Rate Testing, 37 DEG C of temperature, 100 revs/min of revolving speed,
Dissolution in vitro is not less than 71% within 30 minutes；
Third of the four generations Couteat of Folic Acid according to four general rules of Chinese Pharmacopoeia version in 2015 " 0931 dissolution rate and drug release determination method "
Method carries out Dissolution Rate Testing by dissolution medium of the hydrochloric acid solution 200ml of pH1.2, and 100 revs/min of revolving speed, 30 minutes external molten
Out-degree is not less than 62%；
The four generations Couteat of Folic Acid includes: (6S) -5-methyltetrahydrofolate, glucosamine salt 0.9g, microcrystalline cellulose 80.0g,
Sodium carboxymethyl starch 7.0g, crospovidone 11.0g, silica 1 .1g.
7. a kind of preparation method of four generations Couteat of Folic Acid according to any one of claims 1 to 6, the preparation method include as follows
Step:
(1) percentage composition weighs following components by weight:
It is spare；
(2) (6S) -5-methyltetrahydrofolate, glucosamine salt and diluent, disintegrating agent are set in mixing machine, mixing 5~90
Minute, add mix lubricant 3~60 minutes, it is spare；
(3) material in (2) is set in tablet press machine, tabletting, control tablet hardness is 80~200N, is coated or is not coated to get this
Invent four generation Couteat of Folic Acid.
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| WO2022268167A1 (en) * | 2021-06-24 | 2022-12-29 | 连云港金康和信药业有限公司 | Application of folic acid derivatives in preparation of drugs for treating contact lens discomfort and xerophthalmia |
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