CN109700816B - Phosphatidyl serine enteric-coated preparation and preparation method thereof - Google Patents
Phosphatidyl serine enteric-coated preparation and preparation method thereof Download PDFInfo
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- CN109700816B CN109700816B CN201811635822.1A CN201811635822A CN109700816B CN 109700816 B CN109700816 B CN 109700816B CN 201811635822 A CN201811635822 A CN 201811635822A CN 109700816 B CN109700816 B CN 109700816B
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- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 title claims abstract description 81
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 title claims abstract description 81
- 238000002360 preparation method Methods 0.000 title claims abstract description 48
- 238000000576 coating method Methods 0.000 claims abstract description 74
- 239000011248 coating agent Substances 0.000 claims abstract description 70
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 14
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 14
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 239000003463 adsorbent Substances 0.000 claims abstract description 7
- 239000000945 filler Substances 0.000 claims abstract description 7
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- 239000003795 chemical substances by application Substances 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims description 34
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 24
- 238000001035 drying Methods 0.000 claims description 24
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 13
- 239000006185 dispersion Substances 0.000 claims description 13
- 238000009472 formulation Methods 0.000 claims description 13
- 238000002156 mixing Methods 0.000 claims description 13
- 239000001069 triethyl citrate Substances 0.000 claims description 13
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 13
- 235000013769 triethyl citrate Nutrition 0.000 claims description 13
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 12
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 12
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 12
- 229940068968 polysorbate 80 Drugs 0.000 claims description 12
- 229920000053 polysorbate 80 Polymers 0.000 claims description 12
- 229920001577 copolymer Polymers 0.000 claims description 11
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 11
- 239000008187 granular material Substances 0.000 claims description 11
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 claims description 6
- 239000004255 Butylated hydroxyanisole Substances 0.000 claims description 6
- 235000019282 butylated hydroxyanisole Nutrition 0.000 claims description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 6
- 235000010388 propyl gallate Nutrition 0.000 claims description 6
- 239000000473 propyl gallate Substances 0.000 claims description 6
- 229940075579 propyl gallate Drugs 0.000 claims description 6
- BGNXCDMCOKJUMV-UHFFFAOYSA-N Tert-Butylhydroquinone Chemical compound CC(C)(C)C1=CC(O)=CC=C1O BGNXCDMCOKJUMV-UHFFFAOYSA-N 0.000 claims description 5
- 239000004250 tert-Butylhydroquinone Substances 0.000 claims description 5
- 235000019281 tert-butylhydroquinone Nutrition 0.000 claims description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 claims description 4
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
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- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- 235000012239 silicon dioxide Nutrition 0.000 claims description 4
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 claims description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 229940043253 butylated hydroxyanisole Drugs 0.000 claims description 3
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 3
- 235000013539 calcium stearate Nutrition 0.000 claims description 3
- 239000008116 calcium stearate Substances 0.000 claims description 3
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 3
- 229960000913 crospovidone Drugs 0.000 claims description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 3
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 3
- 229940049654 glyceryl behenate Drugs 0.000 claims description 3
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 3
- 235000019359 magnesium stearate Nutrition 0.000 claims description 3
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- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 3
- 235000010352 sodium erythorbate Nutrition 0.000 claims description 3
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 3
- 239000008109 sodium starch glycolate Substances 0.000 claims description 3
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 3
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 239000011732 tocopherol Substances 0.000 claims description 3
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- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 239000000853 adhesive Substances 0.000 claims description 2
- 230000001070 adhesive effect Effects 0.000 claims description 2
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 2
- 229940078456 calcium stearate Drugs 0.000 claims description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 2
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 2
- SUPCQIBBMFXVTL-UHFFFAOYSA-N ethyl 2-methylprop-2-enoate Chemical compound CCOC(=O)C(C)=C SUPCQIBBMFXVTL-UHFFFAOYSA-N 0.000 claims description 2
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 claims description 2
- 229940046813 glyceryl palmitostearate Drugs 0.000 claims description 2
- 229940057948 magnesium stearate Drugs 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 239000004320 sodium erythorbate Substances 0.000 claims description 2
- RBWSWDPRDBEWCR-RKJRWTFHSA-N sodium;(2r)-2-[(2r)-3,4-dihydroxy-5-oxo-2h-furan-2-yl]-2-hydroxyethanolate Chemical compound [Na+].[O-]C[C@@H](O)[C@H]1OC(=O)C(O)=C1O RBWSWDPRDBEWCR-RKJRWTFHSA-N 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 229960004274 stearic acid Drugs 0.000 claims description 2
- 235000010384 tocopherol Nutrition 0.000 claims description 2
- 229960001295 tocopherol Drugs 0.000 claims description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 2
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims 1
- 239000002702 enteric coating Substances 0.000 abstract description 8
- 238000009505 enteric coating Methods 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 7
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- 210000004211 gastric acid Anatomy 0.000 abstract description 6
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- 235000013305 food Nutrition 0.000 description 11
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- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
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- 102000057297 Pepsin A Human genes 0.000 description 2
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- 102000011420 Phospholipase D Human genes 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
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- 230000002378 acidificating effect Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229940009868 aluminum magnesium silicate Drugs 0.000 description 1
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 1
- 235000013405 beer Nutrition 0.000 description 1
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- 235000013611 frozen food Nutrition 0.000 description 1
- 235000019990 fruit wine Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
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- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
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- 238000011160 research Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
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- 210000002345 respiratory system Anatomy 0.000 description 1
- 235000012045 salad Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium erythorbate Chemical compound [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
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- 239000008107 starch Substances 0.000 description 1
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- 238000005728 strengthening Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 235000013616 tea Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 235000019149 tocopherols Nutrition 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000008939 whole milk Nutrition 0.000 description 1
- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention provides a phosphatidylserine enteric coating preparation and a preparation method thereof, wherein the phosphatidylserine enteric coating preparation consists of a core and a coating layer; wherein the core comprises the following raw material components in parts by weight: 45-95 parts of phosphatidylserine, 0.1-1 part of antioxidant, 4-12 parts of disintegrating agent, 0.5-10 parts of adsorbent, 0.5-3 parts of lubricant and 0-20 parts of bonding filler. The phosphatidylserine enteric coating preparation can be dissolved in the intestinal tract at a fixed point, avoids the damage of enzymes and gastric acid in the stomach to the phosphatidylserine, and can be released and absorbed in the intestinal tract continuously at a higher concentration; meanwhile, the preparation method takes the active substance phosphatidyl serine which plays a role in medicine as a core to carry out coating, so that the activity of the active substance phosphatidyl serine is not lost.
Description
Technical Field
The invention relates to a phosphatidylserine preparation and a preparation method thereof, in particular to a phosphatidylserine enteric-coated preparation and a preparation method thereof.
Background
Phosphatidylserine (PS), a phospholipid nutrient, is active in cell membranes and is the major acidic phospholipid component in brain cell membranes. PS plays a critical role in many membrane-associated neuronal processes. The primary purpose of PS is to help maintain proper membrane fluidity, a property that is closely related to most membrane functions. PS has been the subject of many human clinical trials related to memory loss, mood, cognitive behavior and learning ability. Many studies have shown that PS can be helpful in those subjects with age-related memory impairment. In addition, PS can even contribute to cognitive optimization in subjects without cognitive impairment.
Dietary PS is efficiently and rapidly absorbed in the intestine into the blood and readily crosses the blood-brain barrier to reach nerve cells within the brain. PS can be extracted from bovine brain, plants, or can be produced from soybean phospholipids using biocatalytic techniques. Modification of the phospholipid head group can be easily performed by transphosphatidylation (transphosphatidylation) reaction using phospholipase D (PLDs). Thus, phosphatidylserine can be produced from phosphatidylcholine or any other phospholipid mixture with serine by PLD catalysis.
Phosphatidylserine (PS) is used as a raw material of medicines and health care products, and is widely used in various brain-strengthening foods, nutriments and the like at present. However, the phosphatidylserine monomer in the prior art is used as a raw material to prepare medicines or health care products, the phosphatidylserine is easy to oxidize and absorb moisture during storage, and enzymes in the stomach and gastric acid are easy to damage the phosphatidylserine during taking.
Disclosure of Invention
The purpose of the invention is as follows: the first object of the present invention is to provide an enteric coated formulation for sustained release absorption of phosphatidylserine in the intestinal tract at a higher concentration; it is a second object of the invention to provide a method for the preparation of such formulations.
The technical scheme is as follows: the invention provides a phosphatidylserine enteric-coated preparation which consists of a core and a coating layer; wherein the core comprises the following raw material components in parts by weight: 45-95 parts of phosphatidylserine, 0.1-1 part of antioxidant, 4-12 parts of disintegrating agent, 0.5-10 parts of adsorbent, 0.5-3 parts of lubricant and 0-20 parts of bonding filler.
Further, the coating accounts for 10-30% by mass. When the coating mass ratio accounts for 10-30% of the total preparation, the release amount in acid for 2 hours is 3.0% of the marked amount at the lowest, and the release amount in buffer solution is 97.5% at the highest, thus meeting the pharmacopoeia requirements.
Preferably, the antioxidant is one of butylated hydroxyanisole, dibutyl hydroxytoluene, propyl gallate, tert-butyl hydroquinone, tocopherol and sodium erythorbate.
Among them, butyl hydroxy anisole is stable to heat and is not easy to be destroyed under weak alkaline condition, so it is a good antioxidant;
the dibutyl hydroxy toluene is a fat-soluble antioxidant, and the application of the dibutyl hydroxy toluene in food is basically the same as that of BHA, but the dibutyl hydroxy toluene is not as good as that of BHA in antioxidant capacity;
propyl gallate is used as a fat-soluble antioxidant and can be applied to food, but the stability of propyl gallate is poor, the propyl gallate is not high-temperature resistant and is not suitable for baking;
the antioxidant effect of the tert-butyl hydroquinone is 5-7 times stronger than that of BHA, BHT and PG, the tert-butyl hydroquinone is suitable for animal and vegetable fat and fat-rich food, is particularly suitable for vegetable oil, is a preferred antioxidant for salad oil, blend oil and high cooking oil, can effectively delay the oxidation of grease, improves the stability of food, and obviously prolongs the shelf life of the grease and the fat-rich food;
tocopherols are natural oil-soluble antioxidants currently produced in large quantities. The product has wide application in whole milk powder, butter or artificial butter, meat products, aquatic products, dehydrated vegetables, fruit juice beverages, frozen foods, instant foods and the like;
sodium isoascorbate is an important antioxidant preservative in the food industry, can maintain the color and luster and natural flavor of food, prolongs the shelf life, has no toxic or side effect, and is mainly used for meat products, fruits, vegetables, cans, jam, beer, soda water, fruit tea, fruit juice, wine and the like in the food industry.
Preferably, the disintegrant is one of croscarmellose sodium, sodium starch glycolate, crospovidone, and low-substituted hydroxypropyl cellulose; the adsorbent is silicon dioxide and/or magnesium aluminum silicate; the lubricant is one of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate and glyceryl palmitostearate; the bonding filler is one of microcrystalline cellulose, mannitol and anhydrous calcium hydrogen phosphate.
Preferably, the coating consists of triethyl citrate, glyceryl monostearate, polysorbate 80 and a copolymer of methacrylic acid ethyl acrylate.
Wherein, the triethyl citrate has strong dissolving capacity and good compatibility with a plurality of resins, and the product plasticized by the triethyl citrate has good oil resistance, light resistance and mildew resistance, and can be absorbed by human bodies through ways of delighting alimentary tracts, respiratory tracts, skins and the like;
the glyceryl monostearate can form a stable hydrated dispersoid in water, has good surface activity, can play roles in emulsification, foaming, dispersion, defoaming, starch aging resistance and the like, and is an emulsifier which is widely applied in foods and cosmetics;
the polysorbate 80 improves hydrophobicity and allows the coating to maintain proper hardness and appearance.
Preferably, the methacrylic acid-ethyl acrylate copolymer is a 1:1 copolymer of ethyl methacrylate, which is a commonly used aqueous coating material.
Preferably, the mass ratio of the triethyl citrate, the glyceryl monostearate, the polysorbate 80 and the methacrylic acid-ethyl acrylate copolymer is 1:1:1: 1.
The invention also provides a preparation method of the phosphatidylserine enteric-coated preparation, which comprises the following steps:
(1) mixing phosphatidyl serine, an antioxidant, a disintegrating agent, an adsorbent, a lubricant and an adhesive filler according to parts by weight to obtain a mixture;
(2) dry granulating the mixture to obtain mixture granules;
(3) dispersing triethyl citrate, glyceryl monostearate, polysorbate 80 and a copolymer of methacrylic acid-ethyl acrylate in water, and mixing and stirring to obtain a coating dispersion; filtering the coating dispersion and then coating;
(4) and heating and drying after coating to obtain the phosphatidylserine enteric coated preparation.
Preferably, the dry granulation in step (2) is to obtain dry extract powder by spray drying, to be pressed into slices by a dry extrusion granulator, and to be crushed into granules.
Preferably, when the coating temperature in the step (3) is 50-55 ℃, and the coating temperature is 50-55 ℃, the quality of the phosphatidylserine enteric-coated preparation is excellent, and the release amount of phosphatidylserine is low; when the coating temperature is lower than 50 ℃ or higher than 55 ℃, the quality of the phosphatidylserine enteric-coated preparation is poor; the release amount of phosphatidylserine is high.
Preferably, the mixing and stirring of step (3) is high shear homogenizer shear mixing for 30 minutes, and the filtering is 60 mesh sieve.
Preferably, the mass ratio of the triethyl citrate, the glyceryl monostearate, the polysorbate 80 and the methacrylic acid-ethyl acrylate copolymer in the step (3) is 1:1:1: 1.
Preferably, the weight part of the water in the step (3) is the sum of the weight parts of triethyl citrate, glyceryl monostearate, polysorbate 80 and the methacrylic acid-ethyl acrylate copolymer.
Preferably, the temperature for heating and drying in the step (4) is 60-70 ℃, and when the drying temperature after coating is 60-70 ℃, the quality of the phosphatidylserine enteric-coated preparation is excellent; the release amount of phosphatidylserine is low; when the drying temperature is less than 60 ℃ or more than 70 ℃, the quality of the phosphatidylserine enteric-coated preparation is poor; the release amount of phosphatidylserine is high.
Further, the drying time in the step (4) is 20-30 minutes.
Has the advantages that: compared with the prior art, the invention has the following advantages: the phosphatidylserine enteric coating preparation can be dissolved in the intestinal tract at a fixed point, avoids the damage of enzymes and gastric acid in the stomach to the phosphatidylserine, and can be released and absorbed in the intestinal tract continuously at a higher concentration; meanwhile, the preparation method takes the active substance phosphatidyl serine which plays a role in medicine as a core to carry out coating, so that the activity of the active substance phosphatidyl serine is not lost.
Detailed Description
The following describes in detail embodiments of the present invention.
Example 1
Step 1: mixing 450g of phosphatidylserine, 1g of butylated hydroxyanisole, 40g of croscarmellose sodium, 5g of silicon dioxide and 5g of magnesium stearate to obtain a mixture;
step 2: and (3) spray-drying the mixture to obtain dry extract powder, pressing the dry extract powder into slices by using a dry extrusion granulator, and crushing the slices into granules to obtain mixture granules.
And step 3: dispersing 110g triethyl citrate, 110g glyceryl monostearate, 110g polysorbate 80 and 110g 1:1 copolymer of methacrylic acid ethyl acrylate in 440g water followed by shear mixing for 30 minutes with a high shear homogenizer to give a coating dispersion; sieving the coating dispersion with a 60-mesh sieve, filtering, and performing fluidized bed coating;
and 4, step 4: heating and drying after coating, wherein the drying temperature is 60 ℃, and the drying time is 20 minutes; obtaining the phosphatidyl serine enteric-coated preparation.
The fluidized bed coating adopts a GLATT mini coating machine, and the coating process is controlled according to the following parameters.
| Device | GLATT mini-coating machine |
| Amount of charge | 500g |
| Coating temperature | 50℃ |
| Temperature of outlet air | 30℃ |
| Air inlet flow | 1.1m3/min |
| Spray feed rate | 4.5-5.0g/min |
| Atomization air pressure | 100kpa |
| Diameter of nozzle | 0.8mm |
Example 2
Step 1: mixing 95g of phosphatidylserine, 1g of dibutyl hydroxy toluene, 12g of sodium starch glycolate, 10g of magnesium aluminum silicate, 3g of calcium stearate and 20g of microcrystalline cellulose to obtain a mixture;
step 2: and (3) spray-drying the mixture to obtain dry extract powder, pressing the dry extract powder into slices by using a dry extrusion granulator, and crushing the slices into granules to obtain mixture granules.
And step 3: dispersing 40g of triethyl citrate, 40g of glyceryl monostearate, 40g of polysorbate 80 and 40g of 1:1 copolymer of methacrylic acid-ethyl acrylate in 160g of water respectively and then shear-mixing with a high shear homogenizer for 30 minutes to obtain a coating dispersion; sieving the coating dispersion with a 60-mesh sieve, filtering, and performing fluidized bed coating;
and 4, step 4: heating and drying after coating, wherein the drying temperature is 70 ℃, and the drying time is 30 minutes; obtaining the phosphatidyl serine enteric-coated preparation.
The fluidized bed coating adopts a GLATT mini coating machine, and the coating process is controlled according to the following parameters.
| Device | GLATT mini-coating machine |
| Amount of charge | 140g |
| Coating temperature | 55℃ |
| Temperature of outlet air | 30℃ |
| Air inlet flow | 1.1m3/min |
| Spray feed rate | 4.5-5.0g/min |
| Atomization air pressure | 100kpa |
| Diameter of nozzle | 0.8mm |
Example 3
Step 1: mixing 500g of phosphatidylserine, 0.7g of propyl gallate, 10g of crospovidone, 5g of a 1:1 mixture of silicon dioxide and aluminum magnesium silicate, 2.5g of sodium stearyl fumarate and 10g of mannitol to obtain a mixture;
step 2: and (3) spray-drying the mixture to obtain dry extract powder, pressing the dry extract powder into slices by using a dry extrusion granulator, and crushing the slices into granules to obtain mixture granules.
And step 3: after dispersing 132.5g of triethyl citrate, 132.5g of glycerol monostearate, 132.5g of polysorbate 80 and 132.5g of a 1:1 copolymer of methacrylic acid-ethyl acrylate in 530g of water, each was shear-mixed for 30 minutes by a high shear homogenizer to obtain a coating dispersion; sieving the coating dispersion with a 60-mesh sieve, filtering, and performing fluidized bed coating;
and 4, step 4: heating and drying after coating, wherein the drying temperature is 70 ℃, and the drying time is 30 minutes; obtaining the phosphatidyl serine enteric-coated preparation.
The fluidized bed coating adopts a GLATT mini coating machine, and the coating process is controlled according to the following parameters.
| Device | GLATT mini-coating machine |
| Amount of charge | 530g |
| Coating temperature | 55℃ |
| Temperature of outlet air | 30℃ |
| Air inlet flow | 1.1m3/min |
| Spray feed rate | 4.5-5.0g/min |
| Atomization air pressure | 100kpa |
| Diameter of nozzle | 0.8mm |
Example 4
Step 1: mixing 80g of phosphatidylserine, 1g of tert-butylhydroquinone, 10g of low-substituted hydroxypropyl cellulose, 3.5g of magnesium aluminum silicate, 1g of glyceryl behenate and 10g of mannitol to obtain a mixture;
step 2: and (3) spray-drying the mixture to obtain dry extract powder, pressing the dry extract powder into slices by using a dry extrusion granulator, and crushing the slices into granules to obtain mixture granules.
And step 3: dispersing 21.3g of triethyl citrate, 21.3g of glyceryl monostearate, 21.3g of polysorbate 80 and 21.3g of a 1:1 copolymer of methacrylic acid ethyl acrylate in 85g of water followed by shear mixing for 30 minutes with a high shear homogenizer to give a coating dispersion; sieving the coating dispersion with a 60-mesh sieve, filtering, and performing fluidized bed coating;
and 4, step 4: heating and drying after coating, wherein the drying temperature is 65 ℃, and the drying time is 25 minutes; obtaining the phosphatidyl serine enteric-coated preparation.
The fluidized bed coating adopts a GLATT mini coating machine, and the coating process is controlled according to the following parameters.
| Device | GLATT mini-coating machine |
| Amount of charge | 106g |
| Coating temperature | 55℃ |
| Temperature of outlet air | 30℃ |
| Air inlet flow | 1.1m3/min |
| Spray feed rate | 4.5-5.0g/min |
| Atomization air pressure | 100kpa |
| Diameter of nozzle | 0.8mm |
The applicant finds that the phosphatidylserine monomer in the prior art is easy to oxidize and absorb moisture in storage of medicines or health care products prepared by taking the phosphatidylserine monomer as a raw material, and enzymes in the stomach and gastric acid are easy to damage the phosphatidylserine in taking the medicines or the health care products. For this reason, it is considered to overcome the problems of the prior art by coating, but the existing coating conditions are not tried out, and thus further research on relevant parameters is required.
Comparative example 1
Design 5 sets of parallel experiments, design coating temperatures of 45, 50, 53, 55, 60 ℃ respectively, the rest of the raw materials and preparation steps were the same as in example 1, and a disintegration tester was used to immerse 5g of the granular formulation with different enteric coating ratios into USP simulated gastric acid, PH1.2, not containing pepsin, for 1 hour, the quality and release amount of the phosphatidylserine enteric coated formulation are shown in table 1:
TABLE 1 Effect of coating temperature on the quality of phosphatidylserine enteric coated formulations
As can be seen from the above table, in the preparation of the phosphatidylserine enteric coating preparation, when the coating temperature is 50-55 ℃,
the quality of the phosphatidylserine enteric coating preparation is excellent, and the release amount of phosphatidylserine is low; when the coating temperature is lower than 50 ℃ or higher than 55 ℃, the quality of the phosphatidylserine enteric-coated preparation is poor; the release amount of phosphatidylserine is high.
Comparative example 2
Design 4 sets of parallel experiments, design drying temperatures after coating as 55, 60, 65, 70, 75 ℃, and the rest raw materials and preparation steps are the same as in example 1, and a disintegration tester is used to immerse 5g of granular formulations with different enteric coating ratios into PH1.2 for 1 hour in USP simulated gastric acid without pepsin, and the quality and the release amount of phosphatidylserine enteric coated formulations are shown in table 2:
TABLE 2 Effect of drying temperature after coating on the quality of phosphatidylserine enteric coated formulations
As can be seen from the above table, in the preparation of the phosphatidylserine enteric-coated preparation, when the drying temperature after coating is 60-70 ℃, the quality of the phosphatidylserine enteric-coated preparation is excellent; the release amount of phosphatidylserine is low; when the drying temperature is less than 60 ℃ or more than 70 ℃, the quality of the phosphatidylserine enteric-coated preparation is poor; the release amount of phosphatidylserine is high.
Comparative example 3
The release rate of the phosphatidylserine enteric-coated preparation with different coating ratios is measured, and the measuring method refers to a second method (for enteric-coated preparations) in the second appendix X.D release rate measuring method of the 2010 version of Chinese pharmacopoeia. The results of testing the release amount of the phosphatidylserine enteric-coated preparation in acid for 2 hours and the release amount in buffer for 20 minutes are shown in the following table, and the results obtained in this example are 3.1% of the labeled amount, and 92.2%, which meet the pharmacopoeia requirements, and the experimental results are shown in table 3.
TABLE 3 Effect of coating ratio on the Release degree of phosphatidylserine enteric-coated formulations
| Coating proportion | Release amount in acid liquor | Release amount in buffer solution |
| 8％ | 25.6％ | —— |
| 10％ | 4.1％ | 97.5％ |
| 18％ | 3.8％ | 95.5％ |
| 25％ | 3.4％ | 93.2％ |
| 30％ | 3.0％ | 92.8％ |
| 33％ | 3.0％ | 85.3％ |
| 35％ | 2.9％ | 81.5％ |
As can be seen from the above table, when the coating mass ratio accounts for 8% of the total preparation, the release amount of the phosphatidylserine enteric-coated preparation in acid for 2 hours is more than 25% of the labeled amount; when the coating mass ratio accounts for 10-30% of the total preparation, the release amount in acid for 2 hours is 3.0% of the marked amount at the lowest, and the release amount in buffer solution is 97.5% at the highest, so that the requirements of pharmacopoeia are met; however, when the coating mass ratio was more than 30% of the total formulation, the release amount in the buffer was only 81.5% and 85.3%.
Claims (5)
1. The phosphatidyl serine enteric-coated preparation is characterized by comprising a core and a coating, wherein the coating accounts for 10-30% by mass; the core is prepared from the following raw materials in parts by weight: 45-95 parts of phosphatidylserine, 0.1-1 part of antioxidant, 4-12 parts of disintegrating agent, 0.5-10 parts of adsorbent, 0.5-3 parts of lubricant and 0-20 parts of bonding filler; the coating consists of triethyl citrate, glyceryl monostearate, polysorbate 80 and a methacrylic acid-ethyl acrylate copolymer in a mass ratio of 1:1:1:1, wherein the methacrylic acid-ethyl acrylate copolymer is a 1:1 copolymer of ethyl methacrylate; the temperature during coating is 50-55 ℃, and the temperature for heating and drying after coating is finished is 60-70 ℃.
2. The enteric coated formulation of phosphatidylserine of claim 1, wherein: the antioxidant is one of butylated hydroxyanisole, dibutyl hydroxy toluene, propyl gallate, tert-butyl hydroquinone, tocopherol and sodium erythorbate.
3. The enteric coated formulation of phosphatidylserine of claim 1, wherein: the disintegrating agent is one of croscarmellose sodium, sodium starch glycolate, crospovidone and low-substituted hydroxypropyl cellulose; the adsorbent is silicon dioxide and/or magnesium aluminum silicate; the lubricant is one of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate and glyceryl palmitostearate; the bonding filler is one of microcrystalline cellulose, mannitol and anhydrous calcium hydrogen phosphate.
4. A method for preparing the enteric coated formulation of phosphatidylserine of claim 1, comprising the steps of:
(1) mixing phosphatidyl serine, an antioxidant, a disintegrating agent, an adsorbent, a lubricant and an adhesive filler according to parts by weight to obtain a mixture;
(2) dry granulating the mixture to obtain mixture granules;
(3) dispersing triethyl citrate, glyceryl monostearate, polysorbate 80 and a copolymer of methacrylic acid and ethyl acrylate in water, mixing and stirring to obtain a coating dispersion, and filtering the coating dispersion to coat;
(4) and heating and drying after coating to obtain the phosphatidylserine enteric coated preparation.
5. The method for preparing a phosphatidylserine enteric coated preparation according to claim 4, wherein: and (4) drying for 20-30 minutes.
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| CN101410095A (en) * | 2006-03-06 | 2009-04-15 | 波曾公司 | Dosage forms for administering combinations of drugs |
| CN102844034A (en) * | 2010-05-14 | 2012-12-26 | 长濑化成株式会社 | Composition containing stabilized phosphatidylserine |
| CN102908336A (en) * | 2011-08-05 | 2013-02-06 | 深圳市华正实业有限公司 | Stable preparation of phosphatidylserine and preparation method, application as well as application product of stable preparation |
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| CN101410095A (en) * | 2006-03-06 | 2009-04-15 | 波曾公司 | Dosage forms for administering combinations of drugs |
| CN102844034A (en) * | 2010-05-14 | 2012-12-26 | 长濑化成株式会社 | Composition containing stabilized phosphatidylserine |
| CN102908336A (en) * | 2011-08-05 | 2013-02-06 | 深圳市华正实业有限公司 | Stable preparation of phosphatidylserine and preparation method, application as well as application product of stable preparation |
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