CN112006993A - Folic acid solid dispersion, preparation method and application thereof - Google Patents
Folic acid solid dispersion, preparation method and application thereof Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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Abstract
The invention relates to a folic acid solid dispersion, a preparation method and application thereof, wherein the folic acid solid dispersion comprises the following components: folic acid and a carrier; the weight ratio of folic acid to solid carrier is 1: (1-10); the carrier is copovidone or a mixture of hydroxypropyl cellulose and trimethyl chitosan. Also comprises sodium dodecyl sulfate, and the weight ratio of folic acid to sodium dodecyl sulfate is 1: 0.1-5.0. The folic acid solid dispersion can obviously improve the solubility of folic acid, overcomes the defect of low solubility of folic acid, can realize better dissolution after being prepared into a medicinal preparation, and improves the bioavailability of the medicament. Meanwhile, the prepared solid dispersion has the advantages of easy uniform dispersion and good stability, and is easy to realize industrial production.
Description
Technical Field
The invention relates to the technical field of medicaments, in particular to a folic acid solid dispersion and a preparation method thereof.
Background
Folic Acid (Folic Acid) belongs to B vitamins, has a chemical name of N- [4- [ (2-amino-4-oxo-1, 4-dihydro-6-pteridine) methylamino ] benzoyl ] -L-glutamic Acid and has a structural formula shown in the specification
Since this biological factor is found in spinach, it was named folic acid. Folic acid is mainly absorbed in the duodenum and proximal jejunum and excreted out of the body through urine and feces. Folic acid is stable in air, but is decomposed and inactivated by ultraviolet light, is unstable to heat in an acidic solution, and is decomposed into pteridine and sodium aminobenzoylglutamate by irradiation of light after a sodium salt of the folic acid is dissolved in water. The folic acid has extremely low solubility in water, the solubility in water at 25 ℃ is only 0.0016mg/mL (the pH is 4.8-4.8), the folic acid is graded according to the solubility of Chinese pharmacopoeia, and the folic acid belongs to slightly soluble medicines and has low bioavailability, so that the folic acid has important significance in improving the dissolution rate and the bioavailability. Therefore, it is highly necessary for folic acid formulations to have improved stability to light, stability in the gastric acid environment, and bioavailability in the gastrointestinal tract.
A patent document with publication number CN 105395554B applied by Beijing Silian drug industry Co., Ltd describes a folic acid solid dispersion and a preparation method thereof, wherein the solid dispersion comprises folic acid and a hydrophilic carrier, the weight ratio of the folic acid to the hydrophilic carrier is 1: 5-1: 50, and the adopted hydrophilic carrier is one or more of poloxamer, polyethylene glycol, povidone and mannitol. The preparation method is a melting method, and comprises the steps of heating and melting the hydrophilic carrier at 65-80 ℃, then adding folic acid, stirring until the folic acid is completely melted, then rapidly cooling to be completely solidified under the conditions of ice bath and stirring, then freezing at-15 to-30 ℃, heating and drying at 35-45 ℃, crushing and screening to obtain the folic acid solid dispersion. But the temperature variation range of the method is large, and the requirement on equipment is high.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide the folic acid solid dispersion and the preparation method thereof, which can improve the stability and water solubility of folic acid, have simple process and are convenient for industrial mass production.
A folic acid solid dispersion comprising: folic acid and a carrier;
the carrier is copovidone or mixture of hydroxypropyl cellulose and trimethyl chitosan (TMC);
the preferred solid carrier is an equal mass mixture of copovidone and trimethyl chitosan.
The preparation method of trimethyl chitosan refers to the literature, Chinese food journal, 2013, 13, No. 5, P117-123.
The weight ratio of folic acid to solid carrier is 1: (1-10);
preferably, the weight ratio of folic acid to carrier is 1: (3-8), preferably 1: 3. in this ratio, a more preferable solid dispersion form was obtained, and further observed by a microscope, the dispersion form was a mixture of a microcrystalline form and an amorphous form. And better drug loading.
The solid dispersion can obviously improve the solubility of folic acid, and can realize better dissolution after being prepared into a medicinal preparation, improve the bioavailability of the medicament and exert better curative effect. Has better solubility compared with micronization technology
Further research shows that the solubility of the medicine can be further improved by adding the sodium dodecyl sulfate serving as an anionic surfactant.
The lauryl sodium sulfate has a solubilization function, molecules of the lauryl sodium sulfate are in asymmetric structures, and the lauryl sodium sulfate has two groups which are mutually contradictory and are mutually connected, wherein one group is a lipophilic dodecyl chain, and the other group is an ether sulfonic group of a hydrophilic group, and is combined with a folic acid amino part in the process of preparing the solid dispersion by adopting a melting method, so that a synergistic effect can be achieved after the lauryl sodium sulfate is combined with a carrier, and the solubility of the solid dispersion is further improved.
Wherein the weight ratio of the folic acid to the sodium dodecyl sulfate is 1: 0.1-5.0; preferably in a weight ratio of 1: 0.5-2.
The folic acid solid dispersion is prepared by a hot-melt extrusion method, the provided method is convenient, easy and controllable, large-scale production can be realized, the powder flowability and compressibility of the prepared solid dispersion are good, good solubility can be ensured, and the folic acid solid dispersion is favorable for further preparation of pharmaceutical preparations.
The preparation method of the solid dispersion by the hot-melt extrusion method provided by the invention comprises the following steps:
1) mixing folic acid and carrier uniformly to obtain a mixture, heating to 70-135 deg.C for melting, and cooling;
2) the cooled mixture was pulverized and sieved to obtain a solid dispersion.
A pharmaceutical composition comprises folic acid solid dispersion and pharmaceutically acceptable adjuvants. The auxiliary materials comprise a diluent, a disintegrating agent, an adhesive and a lubricant; wherein the diluent is selected from microcrystalline cellulose, lactose, mannitol, pregelatinized starch, calcium hydrogen phosphate, sorbitol, starch, sucrose, calcium sulfate, and calcium carbonate; the disintegrant is selected from croscarmellose sodium, crospovidone, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose; the binder is selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and polyvidone; the lubricant is selected from magnesium stearate, stearic acid, silicon dioxide, and pulvis Talci.
The pharmaceutical composition can be obtained by direct powder compression, dry granulation, wet granulation or filling into capsules.
Drawings
FIG. 1 is a crystal form diagram after preparing a solid dispersion by a melting method. The test result shows that the prepared solid dispersion has obvious change in crystal form, and partial characteristic peaks disappear in the solid dispersion. Further analyzing the crystal form morphology, wherein the crystal form is a mixture of microcrystalline and amorphous. The reason for this analysis may be directly related to the solid carrier copovidone, trimethyl chitosan. Trimethyl chitosan can be used for preparing nano-grade materials, folic acid raw materials are combined with copovidone, and the trimethyl chitosan is combined, so that the crystal form size is changed, and smaller and finer microcrystals are formed. The solubility test and photostability results further indicate that the presence of a microcrystalline and amorphous mixture facilitates the dissolution and release of the drug while increasing the stability of the folic acid crystals.
Detailed Description
The technical solution of the present invention will be described below with specific examples.
EXAMPLE 1 Effect of different Carriers on folate solubility
Mixing folic acid: selecting different carriers according to a carrier weight ratio of 1:3, mixing folic acid with carrier materials, heating for melting, cooling, crushing, sieving with a 60-mesh sieve to obtain folic acid solid dispersions, respectively measuring the solubility of the folic acid solid dispersions, respectively adding the obtained samples into a dissolution instrument, taking 500ml of water as a dissolution medium, performing a solubility test by a paddle method, sampling at 1 hour as a test solution, measuring by HPLC, and calculating the saturation solubility, wherein the specific data are shown in Table 1:
TABLE 1
Under the condition that the weight ratio of folic acid to a carrier is the same, the solubility of folic acid is obviously improved by selecting the solid dispersion prepared from the copovidone or the mixture of hydroxypropyl cellulose and trimethyl chitosan (TMC), and when the mixture with the same mass of the copovidone and the trimethyl chitosan is adopted, the solid dispersion prepared by the hot-melt extrusion method can obtain better solubility, and the dissolution rate is increased after SDS is added.
Example 2 Effect of different Carrier dosages on the solubility of folic acid
Mixing the medicine and the carrier, heating and melting, cooling, crushing, sieving by a 60-mesh sieve to obtain folic acid solid dispersoids, and respectively measuring the solubility of the folic acid solid dispersoids, wherein the measuring method comprises the following steps of: respectively adding the obtained samples into a dissolution instrument, taking 500ml of water as a dissolution medium, performing a solubility test by a paddle method, sampling at 1.5 hours to be used as a test solution, performing HPLC (high performance liquid chromatography) determination, calculating saturated solubility, and inspecting the weight ratio of different drugs and carriers, wherein the specific data are shown in a table 2:
TABLE 2
As can be seen from table 2, the solubility of the obtained folic acid solid dispersion in the dissolution medium is significantly increased, and the solubility of the obtained folic acid solid dispersion is better within the range of the ratio of folic acid to carrier of 1:1-10, and exceeds 1: 10, no greater increase in dissolution, but less than 1:1, the increase in dissolution rate is not significant enough. The solubility obtained is optimal in the range of a folic acid to carrier ratio of 1: 2-5. In addition, under the condition that the carrier is the mixture of hydroxypropyl cellulose and TMC or the blending of copovidone and TMC, the obtained solid dispersion has better solubility.
Example 3 application
Solid dispersions were prepared by melt processing as set forth in group 6 of example 1, and then pharmaceutical compositions were prepared in the proportions shown in Table 3.
TABLE 3
| Components | Dosage of |
| Folic acid solid dispersion | 20mg |
| Croscarmellose sodium | 77mg |
| Silicon dioxide | 2.5mg |
| Magnesium stearate | 0.5mg |
The preparation process comprises the following steps:
mixing solid dispersion 20mg, silicon dioxide 2.5mg and magnesium stearate 0.5mg, mixing with croscarmellose sodium 77mg, and making into capsule or tablet.
Example 4
Solid dispersions were prepared by melt processing as set forth in group 6 of example 1, and then pharmaceutical compositions were prepared in the proportions shown in Table 4.
TABLE 4
| Name (R) | Dosage of |
| Folic acid solid dispersion | 20mg |
| Microcrystalline cellulose | 67mg |
| Croscarmellose sodium | 10mg |
| Silicon dioxide | 2.5mg |
| Magnesium stearate | 0.5mg |
The preparation process comprises the following steps:
mixing solid dispersion 20mg, microcrystalline cellulose 67mg and croscarmellose sodium 10mg to obtain a mixture, adding silicon dioxide 2.5mg and magnesium stearate 0.5mg, mixing, and tabletting.
The finished pharmaceutical preparations prepared in examples 3 and 4 were subjected to a photostability study with a folic acid tablet reference preparation published by SFDA (specification: 5 mg).
Stability test conditions: performing intense light irradiation (4500Lx) test according to the appendix XIXC of the second part of the year edition of the Chinese pharmacopoeia 2015, and performing sampling detection on 0 day, 10 days and 30 days respectively, wherein the detection items are related substances. And the bulk drug and a reference preparation published by SFDA (specification: 5mg) were used for comparison.
Detection of related substances
Detecting according to related substances of folic acid tablets recorded in Chinese pharmacopoeia. The specific test operations were as follows:
and (4) avoiding light. Taking about 100mg of the product, placing into a 100ml measuring flask, adding about 1ml of ammonia test solution to dissolve, diluting with mobile phase to scale, and shaking to obtain test solution. Precisely measure 1ml, place in a 100ml measuring flask, dilute to the scale with mobile phase, shake well, as control solution. Taking 10mg of pteroic acid, placing the pteroic acid in a 100ml measuring flask, adding 5ml of 0.lmol/L sodium carbonate solution and 10ml of test solution, adding mobile phase for dissolving and diluting to a scale, shaking up, taking L0ul according to the chromatographic conditions under the content determination item, injecting into a liquid chromatograph, and recording the chromatogram, wherein the separation degree of the pteroic acid peak and the folic acid peak is more than 4.0. Precisely measuring each l0ul of the test solution and the reference solution, respectively injecting into a liquid chromatograph, and recording the retention time of chromatogram to main component peak to be 3 times. In the chromatogram of the test solution, the peak areas of the pteroic acid and other single impurities are not more than 0.6 times (0.6%) of the main peak area of the control solution, and the sum of the peak areas of the impurities except the pteroic acid peak is not more than 2 times (2.0%) of the main peak area of the control solution. The peaks in the chromatogram of the test solution, which are smaller than 0.05 times the area of the main peak of the control solution, are ignored.
HPLC test conditions: the instrument comprises the following steps: dalia UltiMate 3000; a chromatographic column: shim-pack VP-ODS5 μm 250L × 4.6; a detector: VWD-3100, detection wavelength: 256 nm; the mobile phase is methanol-water-glacial acetic acid (30:70: 0.4); a flow rate; 1.0mL/min, column temperature: at 30 ℃.
The test results are shown in table 5:
TABLE 5
Remarking: according to the requirements of Chinese pharmacopoeia, the total impurities do not include pteroic acid impurities.
The results in table 5 show that: after the folic acid is prepared into the solid dispersion, the dissolution is increased by 3-4 times, meanwhile, the folic acid solid dispersion is adopted to further prepare the pharmaceutical preparation, and the total impurities exceed the standard after 30-day illumination acceleration test under the illumination condition.
Claims (7)
1. A folic acid solid dispersion, comprising: folic acid and a carrier; the weight ratio of folic acid to carrier is 1: (1-10); the carrier is copovidone or a mixture of hydroxypropyl cellulose and trimethyl chitosan.
2. The folic acid solid dispersion according to claim 1, characterized in that the carrier is an equal mass mixture of copovidone and trimethyl chitosan; the weight ratio of folic acid to carrier is 1: (3-8).
3. The folic acid solid dispersion according to claim 1, characterized in that the weight ratio of folic acid to carrier is 1: 3.
4. the folic acid solid dispersion according to any one of claims 1 to 3, further comprising sodium lauryl sulfate, wherein the weight ratio of folic acid to sodium lauryl sulfate is 1: 0.1-5.0.
5. The folic acid solid dispersion according to claim 4, characterized in that the weight ratio of folic acid to sodium lauryl sulfate is 1: 0.5-2.
6. The method for preparing the folic acid solid dispersion of claim 1, which is prepared by a hot-melt extrusion method, comprising the following steps:
1) mixing folic acid and carrier uniformly to obtain a mixture, heating to 70-135 ℃ for melting, and cooling;
2) the cooled mixture was pulverized and sieved to obtain a solid dispersion.
7. A pharmaceutical composition comprising the folic acid solid dispersion of claim 1 and a pharmaceutically acceptable excipient.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105796567A (en) * | 2014-12-29 | 2016-07-27 | 北京万生药业有限责任公司 | Cetilistat solid dispersion and medicinal preparation prepared from the solid dispersion |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105796567A (en) * | 2014-12-29 | 2016-07-27 | 北京万生药业有限责任公司 | Cetilistat solid dispersion and medicinal preparation prepared from the solid dispersion |
Non-Patent Citations (1)
| Title |
|---|
| 冯年平: "《中药经皮给药与功效性化妆品》", 31 May 2019, 中国医药科技出版社 * |
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