CN105030779A - (6S)-5-methyl tetrahydrophthalic calcium foliate oral nutrition supplement and method for preparing same - Google Patents
(6S)-5-methyl tetrahydrophthalic calcium foliate oral nutrition supplement and method for preparing same Download PDFInfo
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- CN105030779A CN105030779A CN201510431916.7A CN201510431916A CN105030779A CN 105030779 A CN105030779 A CN 105030779A CN 201510431916 A CN201510431916 A CN 201510431916A CN 105030779 A CN105030779 A CN 105030779A
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- methyltetrahydrofolate calcium
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Abstract
The invention discloses (6S)-5-methyl tetrahydrophthalic calcium foliate oral nutrition supplement and a method for preparing the same. The (6S)-5-methyl tetrahydrophthalic calcium foliate oral nutrition supplement contains (6S)-5-methyl tetrahydrophthalic calcium foliate with the effective dose and water-soluble polymer carriers for dispersing the (6S)-5-methyl tetrahydrophthalic calcium foliate. A mass ratio of the (6S)-5-methyl tetrahydrophthalic calcium foliate to the water-soluble polymer carriers is 1:300-500. The invention further discloses a method for preparing the oral nutrition supplement. The (6S)-5-methyl tetrahydrophthalic calcium foliate oral nutrition supplement and the method have the advantage that the dissolution, the bioavailability and the quality stability of the (6S)-5-methyl tetrahydrophthalic calcium foliate can be improved.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to one (6S)-5-methyltetrahydrofolate calcium oral nutritional supplements, the invention still further relates to the preparation method of said preparation.
Background technology
(6S)-5-methyltetrahydrofolate calcium is the principal mode of tissue or blood folic acid, participates in multiple important biochemical reaction in body.It does not need through loaded down with trivial details enzymatic catalysis in human body, can directly be utilized, avoid taking merely the vitamin B12 that folic acid causes to lose, (6S)-5-methyltetrahydrofolate calcium has the effects such as prevention Foetus neural tube defect, arteriosclerosis, treatment megaloblastic anemia.Below the chemical structural formula of (6S)-5-methyltetrahydrofolate calcium:
(6S) poor stability of-5-methyltetrahydrofolate calcium, preserve easy to change, content under normal temperature condition and obviously decline, catabolite obviously increases, thus causes the bioavailability of preparation on the low side, and drug effect declines, and toxic and side effects even can be caused to increase.In addition, because the content of (6S)-5-methyltetrahydrofolate calcium is on the low side in preparation, during preparation, be difficult to mix homogeneously, cause the uniformity of dosage units in preparation poor, cause quality unstable further.Therefore, researching and developing more stable (the 6S)-5-methyltetrahydrofolate calcium preparation of quality is folic acid supplement field technical barrier urgently to be resolved hurrily.
CN104490887A discloses the stabilizing pharmaceutical composition of one (6S)-5-MTHF calcium salt; it is not oxidized by adding reducing substances protection (6S)-5-MTHF calcium; thus evade due to the drug risk caused of degrading; guarantee discharging fast and reliably of (6S)-5-MTHF calcium, said composition is used for oral contraception simultaneously.
Summary of the invention
The object of the invention is the defect for existing in prior art, a kind of oral nutritional supplements of (6S)-5-methyltetrahydrofolate calcium is provided, to improve the stability of existing preparation, dissolution and bioavailability.
Technical scheme of the present invention is:
A kind of (6S)-5-methyltetrahydrofolate calcium oral nutritional supplements, (6S)-5-methyltetrahydrofolate calcium containing effective dose, also containing the water-soluble polymer carrier for dispersion (6S)-5-methyltetrahydrofolate calcium, the mass ratio of described (6S)-5-methyltetrahydrofolate calcium and water-soluble polymer carrier is 1: 300 ~ 500.
Preferably, described water-soluble polymer carrier is non-ionic celluloses ether, as ethyl cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose etc., and more preferably ethyl cellulose.
Preferably, described oral nutritional supplements is also containing the vitamin and the mineral that meet Chinese DRIs, and described vitamin is one or more in vitamin A, vitamin C, nicotiamide, vitamin E, vitamin B5, beta-carotene, vitamin B6, vitamin B2, vitamin B1, folic acid, biotin, vitamin D, vitamin B12; Described mineral is one or more in magnesium, copper, manganese, ferrum, zinc.
Preferably, described oral nutritional supplements also contains pharmaceutically acceptable excipient, as filler, binding agent, disintegrating agent, lubricant etc.
Described oral nutritional supplements can be the solid dosage forms that any one is applicable to Clinical practice, as granule, tablet, capsule, powder etc., is preferably tablet or capsule.
A kind of preparation method of (6S)-5-methyltetrahydrofolate calcium oral nutritional supplements, it comprises the following steps:
1) by water-soluble polymer carrier solubilizes in water or ethanol water, obtain the water-soluble polymer carrier solution that mass concentration is 15 ~ 30%;
2) (6S)-5-methyltetrahydrofolate calcium is scattered in water-soluble polymer carrier solution, the mass ratio of (6S)-5-methyltetrahydrofolate calcium and water-soluble polymer carrier is made to be 1: 300 ~ 500, carry out spraying dry after stirring, homogenizing, obtain (6S)-5-methyltetrahydrofolate calcium dispersion;
3) in (6S)-5-methyltetrahydrofolate calcium dispersion, meet Chinese DRIs vitamin and mineral is added, and pharmaceutically acceptable excipient, make tablet or capsule.
Preferably, described water-soluble polymer carrier is ethyl cellulose, and the mass concentration of described water-soluble polymer carrier solution is 20 ~ 25%.
Preferably, described spray-dired process conditions are: inlet temperature is 130-160 DEG C, and leaving air temp is 50-70 DEG C, and charging rate is 10-20mL/min, and spray pressure is 0.1-0.5MPa.
The invention has the beneficial effects as follows:
1) effectively improve the dissolution of (6S)-5-methyltetrahydrofolate calcium in preparation, thus improve the bioavailability of (6S)-5-methyltetrahydrofolate calcium.
2) (6S)-5-methyltetrahydrofolate calcium is not easily degraded, is oxidized, thus improves quality stability and the safety of preparation.
3) under (6S)-5-methyltetrahydrofolate calcium is diluted 300-500 prerequisite doubly, improve (6S)-5-methyltetrahydrofolate calcium dispersed homogeneous degree in the formulation, thus make product quality more controlled, technique is simpler.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in detail, but should not be understood as the restriction that scope is carried out.
Embodiment 1
1) get ethyl cellulose respectively, to be dissolved in 640g concentration be in the ethanol water of 50% for methylcellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, each 160g of sodium carboxymethyl cellulose, obtains the water-soluble polymer carrier solution that concentration is 20%;
2) getting 0.4g (6S)-5-methyltetrahydrofolate calcium is respectively scattered in above-mentioned five kinds of water-soluble polymer carrier solutions, spraying dry is carried out after stirring, homogenizing, controlling inlet temperature is 150 DEG C, leaving air temp is 60 DEG C, charging rate is 10mL/min, spray pressure is 0.3MPa, obtains (6S)-5-methyltetrahydrofolate calcium dispersion powder;
3) five kinds of (6S)-5-methyltetrahydrofolate calcium dispersion powders are mixed with 80g microcrystalline Cellulose, 115g lactose respectively, with ethanol soft material, granulate, after drying, add 4g cross-linking sodium carboxymethyl cellulose and 1g magnesium stearate, tabletting after mixing.
1. dissolution determination:
Get each 6 of above-mentioned tablet, by Chinese Pharmacopoeia version in 2010 two annex dissolution methods, adopt paddle method, 50 revs/min, with the hydrochloric acid solution of pH1.0 as dissolution medium, operate in accordance with the law, extract solution 5ml when 10min, 20mim, 30min, 45min, 60min and filter, get subsequent filtrate 20 μ l injection liquid chromatography and detect dissolution.Preparation is simultaneously following contrasts tablet: get 0.4g (6S)-5-methyltetrahydrofolate calcium, mix with 80g microcrystalline Cellulose, 275g lactose, with ethanol soft material, granulate, 4g cross-linking sodium carboxymethyl cellulose and 1g magnesium stearate is added, tabletting after mixing after drying.
Table 1 dissolution determination result (%)
| Type of polymer | 10min | 20min | 30min | 45min | 60min |
| Ethyl cellulose | 61.5 | 83.5 | 98.4 | 98.5 | 99.5 |
| Methylcellulose | 63.2 | 81.2 | 92.4 | 94.5 | 99.2 |
| Hydroxypropyl cellulose | 57.8 | 78.8 | 87.5 | 92.4 | 96.8 |
| Hydroxypropyl emthylcellulose | 53.8 | 75.4 | 86.3 | 90.1 | 94.4 |
| Sodium carboxymethyl cellulose | 58.9 | 79.8 | 90.2 | 93.4 | 96.7 |
| Nothing | 21.8 | 33.8 | 37.5 | 52.4 | 56.8 |
As can be seen from the above results, the stripping of tablet (6S)-5-methyltetrahydrofolate calcium prepared by embodiment 1 is obviously fast than comparison film agent, and the stripping of ethyl cellulose is the fastest.
2. Determination of Content Uniformity
Detect the uniformity of dosage units of above-mentioned sample, the results are shown in Table 2.
Table 2 uniformity of dosage units testing result
| Type of polymer | A+1.8S | Result |
| Ethyl cellulose | 12 | A+1.8S < 15 uniformity of dosage units conforms with the regulations |
| Methylcellulose | 10 | A+1.8S < 15 uniformity of dosage units conforms with the regulations |
| Hydroxypropyl cellulose | 11 | A+1.8S < 15 uniformity of dosage units conforms with the regulations |
| Hydroxypropyl emthylcellulose | 11 | A+1.8S < 15 uniformity of dosage units conforms with the regulations |
| Sodium carboxymethyl cellulose | 12 | A+1.8S < 15 uniformity of dosage units conforms with the regulations |
| Nothing | 76 | A+1.8S > 15 uniformity of dosage units is against regulation |
3. the stable content of related substance detects
Above-mentioned sample is placed in respectively 60 DEG C of baking ovens to place 10 days, adopts HPLC method to detect, investigate the situation of change of related substance, the results are shown in Table 3.
The stable content testing result (%) of table 3 related substance
| Type of polymer | 0 day | 10 days |
| Ethyl cellulose | 0.11 | 0.13 |
| Methylcellulose | 0.12 | 0.17 |
| Hydroxypropyl cellulose | 0.12 | 0.16 |
| Hydroxypropyl emthylcellulose | 0.13 | 0.20 |
| Sodium carboxymethyl cellulose | 0.10 | 0.16 |
| Nothing | 0.11 | 0.75 |
Result shows, tablet prepared by embodiment 1 is starkly lower than contrast tablet at the content of placement related substance after 10 days, illustrates that the stability of (6S)-5-methyltetrahydrofolate calcium in embodiment 1 is better.
Embodiment 2
A kind of preparation method of (6S)-5-methyltetrahydrofolate calcium oral nutritional supplements, its step is as follows:
1) ethyl cellulose 125g being dissolved in 375g concentration is in the ethanol water of 70%, obtains the ethyl cellulose solution that concentration is 25%;
2) 416mg (6S)-5-methyltetrahydrofolate calcium is scattered in ethyl cellulose solution, spraying dry is carried out after stirring, homogenizing, controlling inlet temperature is 130 DEG C, leaving air temp is 50 DEG C, charging rate is 10mL/min, spray pressure is 0.1MPa, obtains dry (6S)-5-methyltetrahydrofolate calcium dispersion;
3) in (6S)-5-methyltetrahydrofolate calcium dispersion, 3g vitamin A is added, 180g vitamin C, 20g nicotiamide, 12g vitamin E, 10g vitamin B5, 2.2g vitamin B6, 1.6g vitamin B2, 1.5g vitamin B1, 10mg vitamin D, 2.7mg vitamin B12 and 70g magnesium, 28g ferrum, 15g zinc, 1g copper mine material, adopt the method mixing of equal increments, and then with 260g microcrystalline Cellulose (filler), 240g lactose (filler) mixes, ethanol water with 75% stirs makes soft material, then crushed 20 eye mesh screens make granule, and in fluid bed, carry out drying obtain dry granule.In dry granule, add 12g Explotab (disintegrating agent), 6g magnesium stearate (lubricant), be pressed into 1000 after mixing, make tablet.
The every sheet of this product is containing (6S)-5-methyltetrahydrofolate calcium 416 μ g.Each serving with 1 ~ 2.
Embodiment 3
A kind of preparation method of (6S)-5-methyltetrahydrofolate calcium oral nutritional supplements, its step is as follows:
1) ethyl cellulose 200g is dissolved in the water, obtains the ethyl cellulose solution that concentration is 15%;
2) 416mg (6S)-5-methyltetrahydrofolate calcium is scattered in ethyl cellulose solution, spraying dry is carried out after stirring, homogenizing, inlet temperature is 160 DEG C, leaving air temp is 70 DEG C, charging rate is 20mL/min, spray pressure is-0.5MPa, obtains dry (6S)-5-methyltetrahydrofolate calcium dispersion;
3) in (6S)-5-methyltetrahydrofolate calcium dispersion, add 20mg vitamin D and 10g zinc, adopt the method mixing of equal increments, and then mix with 350g starch, granulate, with capsule-filling, make capsule.
This product every containing (6S)-5-methyltetrahydrofolate calcium 208 μ g, each serving with 1 ~ 3.
Claims (9)
1. (6S)-5-methyltetrahydrofolate calcium oral nutritional supplements, (6S)-5-methyltetrahydrofolate calcium containing effective dose, it is characterized in that: also containing the water-soluble polymer carrier for dispersion (6S)-5-methyltetrahydrofolate calcium, the mass ratio of described (6S)-5-methyltetrahydrofolate calcium and water-soluble polymer carrier is 1: 300 ~ 500.
2. (6S)-5-methyltetrahydrofolate calcium oral nutritional supplements as claimed in claim 1, is characterized in that: described water-soluble polymer carrier is non-ionic celluloses ether.
3. (6S)-5-methyltetrahydrofolate calcium oral nutritional supplements as claimed in claim 2, is characterized in that: described non-ionic celluloses ether is ethyl cellulose.
4. (6S)-5-methyltetrahydrofolate calcium oral nutritional supplements as claimed in claim 1, is characterized in that: also containing the vitamin and the mineral that meet Chinese DRIs.
5. (6S)-5-methyltetrahydrofolate calcium oral nutritional supplements as claimed in claim 1, is characterized in that: also containing pharmaceutically acceptable excipient.
6. (6S)-5-methyltetrahydrofolate calcium oral nutritional supplements as claimed in claim 1, is characterized in that: described oral formulations is tablet or capsule.
7. a preparation method for (6S)-5-methyltetrahydrofolate calcium oral nutritional supplements, is characterized in that comprising the following steps:
1) by water-soluble polymer carrier solubilizes in water or ethanol water, obtain the water-soluble polymer carrier solution that mass concentration is 15 ~ 30%;
2) (6S)-5-methyltetrahydrofolate calcium is scattered in water-soluble polymer carrier solution, the mass ratio of (6S)-5-methyltetrahydrofolate calcium and water-soluble polymer carrier is made to be 1: 300 ~ 500, carry out spraying dry after stirring, homogenizing, obtain (6S)-5-methyltetrahydrofolate calcium dispersion;
3) in (6S)-5-methyltetrahydrofolate calcium dispersion, meet Chinese DRIs vitamin and mineral is added, and pharmaceutically acceptable excipient, make tablet or capsule.
8. the preparation method of (6S)-5-methyltetrahydrofolate calcium oral nutritional supplements as claimed in claim 7, it is characterized in that: described water-soluble polymer carrier is ethyl cellulose, the mass concentration of described water-soluble polymer carrier solution is 20 ~ 25%.
9. the preparation method of (6S)-5-methyltetrahydrofolate calcium oral nutritional supplements as claimed in claim 7, it is characterized in that: described spray-dired process conditions are: inlet temperature is 130-160 DEG C, leaving air temp is 50-70 DEG C, charging rate is 10-20mL/min, and spray pressure is 0.1-0.5MPa.
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Cited By (4)
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| CN105748503A (en) * | 2016-03-14 | 2016-07-13 | 福格森（武汉）生物科技股份有限公司 | Multivitamin pellet containing 5-methyltetrahydrofolate |
| CN108926544A (en) * | 2018-08-19 | 2018-12-04 | 张奉明 | Four generation Couteat of Folic Acid of one kind and preparation method thereof |
| CN109456330A (en) * | 2018-11-26 | 2019-03-12 | 连云港德洋化工有限公司 | Folic acid class stable compound and preparation method thereof |
| CN110237046A (en) * | 2019-03-29 | 2019-09-17 | 福格森（武汉）生物科技股份有限公司 | A kind of preparation method of L-5- methyl tetrahydrofolate micro-capsule |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105748503A (en) * | 2016-03-14 | 2016-07-13 | 福格森（武汉）生物科技股份有限公司 | Multivitamin pellet containing 5-methyltetrahydrofolate |
| CN105748503B (en) * | 2016-03-14 | 2018-10-23 | 福格森（武汉）生物科技股份有限公司 | A kind of multi-vitamins pellet containing 5-methyltetrahydrofolate |
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| CN108926544B (en) * | 2018-08-19 | 2021-08-06 | 张奉明 | Tetrafolic acid tablet and preparation method thereof |
| CN109456330A (en) * | 2018-11-26 | 2019-03-12 | 连云港德洋化工有限公司 | Folic acid class stable compound and preparation method thereof |
| CN110237046A (en) * | 2019-03-29 | 2019-09-17 | 福格森（武汉）生物科技股份有限公司 | A kind of preparation method of L-5- methyl tetrahydrofolate micro-capsule |
| CN110237046B (en) * | 2019-03-29 | 2021-07-30 | 福格森（武汉）生物科技股份有限公司 | Preparation method of L-5-methyltetrahydrofolic acid microcapsules |
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