CN107028950A - A kind of composition of L-5- methyl tetrahydrofolates or its pharmaceutically acceptable salt and pharmaceutic adjuvant and preparation method thereof - Google Patents
A kind of composition of L-5- methyl tetrahydrofolates or its pharmaceutically acceptable salt and pharmaceutic adjuvant and preparation method thereof Download PDFInfo
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- CN107028950A CN107028950A CN201610076722.4A CN201610076722A CN107028950A CN 107028950 A CN107028950 A CN 107028950A CN 201610076722 A CN201610076722 A CN 201610076722A CN 107028950 A CN107028950 A CN 107028950A
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- pharmaceutic adjuvant
- tetrahydrofolates
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- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims description 8
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- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 claims description 6
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- IYKJEILNJZQJPU-UHFFFAOYSA-N acetic acid;butanedioic acid Chemical compound CC(O)=O.OC(=O)CCC(O)=O IYKJEILNJZQJPU-UHFFFAOYSA-N 0.000 claims description 5
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- TZBGSHAFWLGWBO-ABLWVSNPSA-N (2s)-2-[[4-[(2-amino-4-oxo-5,6,7,8-tetrahydro-1h-pteridin-6-yl)methylamino]benzoyl]amino]-5-methoxy-5-oxopentanoic acid Chemical compound C1=CC(C(=O)N[C@@H](CCC(=O)OC)C(O)=O)=CC=C1NCC1NC(C(=O)NC(N)=N2)=C2NC1 TZBGSHAFWLGWBO-ABLWVSNPSA-N 0.000 claims description 3
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- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 claims 1
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- JMNIIIQOMSQWJN-ZEXVLMPOSA-L calcium;(2s)-2-[[4-[[(6s)-2-amino-5-methyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl]methylamino]benzoyl]amino]-5-hydroxy-5-oxopentanoate Chemical compound [Ca+2].C([C@@H]1N(C=2C(=O)NC(N)=NC=2NC1)C)NC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C(O)=O)C=C1.C([C@@H]1N(C=2C(=O)NC(N)=NC=2NC1)C)NC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C(O)=O)C=C1 JMNIIIQOMSQWJN-ZEXVLMPOSA-L 0.000 description 9
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- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 6
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- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 2
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- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 description 2
- 235000013373 food additive Nutrition 0.000 description 2
- 239000002778 food additive Substances 0.000 description 2
- 239000011578 levomefolic acid Substances 0.000 description 2
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- 239000000661 sodium alginate Substances 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 206010002065 Anaemia megaloblastic Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 229910017488 Cu K Inorganic materials 0.000 description 1
- 229910017541 Cu-K Inorganic materials 0.000 description 1
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 208000000682 Megaloblastic Anemia Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 229960003834 dapagliflozin Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000005496 eutectics Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000009878 intermolecular interaction Effects 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- ZNOVTXRBGFNYRX-ABLWVSNPSA-N levomefolic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 ZNOVTXRBGFNYRX-ABLWVSNPSA-N 0.000 description 1
- 235000007635 levomefolic acid Nutrition 0.000 description 1
- 230000036244 malformation Effects 0.000 description 1
- 231100001016 megaloblastic anemia Toxicity 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 201000010193 neural tube defect Diseases 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000001072 progestational effect Effects 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- 150000003195 pteridines Chemical class 0.000 description 1
- 125000001747 pteroyl group Chemical group [H]C1=C([H])C(C(=O)[*])=C([H])C([H])=C1N([H])C([H])([H])C1=C([H])N=C2N([H])C(N([H])[H])=NC(=O)C2=N1 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
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- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A kind of composition and its manufacture method of L-5- methyl tetrahydrofolates or its pharmaceutically acceptable salt and pharmaceutic adjuvant, it includes L-5- methyl tetrahydrofolates or its pharmaceutically acceptable salt and pharmaceutic adjuvant, L-5- methyl tetrahydrofolates or its pharmaceutically acceptable salt are the characteristic peak of the crystal without L-5- methyl tetrahydrofolates or its salt after the background peaks that pharmaceutic adjuvant is deducted in unformed shape, the X-ray powder diffraction spectrum of the composition.The L-5- methyl tetrahydrofolates of the present invention or the composition stability and favorable dispersibility of its pharmaceutically acceptable salt and pharmaceutic adjuvant, add L-5- methyl tetrahydrofolates or the dissolution rate of its salt, it is more beneficial for improving the absorption of the bioavilability and body of pharmaceutical preparation to medicine, under the conditions of accelerated test, good physics and chemical stability can be kept.The preparation method of the unformed composition of the present invention is simple to operate, with low cost, favorable reproducibility, it is easy to accomplish, it is adapted to industrialized production.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to a kind of composition of L-5- methyl tetrahydrofolates or its pharmaceutically acceptable salt and pharmaceutic adjuvant and preparation method thereof.
Background technology
The chemical name of L-5- methyl tetrahydrofolates is (S) -5 of N- (5- methyl) -6,6,7,8,-tetrahydro pteroyl base-Pidolidone, referred to as (6S) -5-MTHF, and structural formula is as follows：
L-5- methyl tetrahydrofolates are the forms of folic acid most bioactivity and function, are the unique channels that folic acid participates in physiological metabolism, also occur from the unique forms that animal blood plasma and cell free folic acid are present.It is mainly used in active constituents of medicine and food additives, has prevention Foetus neural tube defect, artery sclerosis, treat megaloblastic anemia, strengthen the therapeutic effect of fluorinated pyrimidine, treat the autoimmune disease of such as psoriasis and rheumatic arthritis.The application of progestational hormone and 5-methyltetrahydrofolate drug combination in terms for the treatment of endometriosis simultaneously mitigates treatment side effect and reduces the risk in congenital malformation of period of gestation simultaneously.
Although the curative effect of L-5- methyl tetrahydrofolates has been widely recognized as, but still there are some defects.L-5- methyl tetrahydrofolates and its salt are highly unstable, it is especially extremely sensitive to oxidation [to see A.1.Fiitzhugh, pteridine (Pteridines) 4 (4), 187-191 (1993)], it is therefore necessary to a kind of solid forms of stabilization are developed for use as active constituents of medicine and food additives.Patent CN1154648C discloses the calcium salt that L-5- methyl tetrahydrofolates are handled in the solution higher than 60 DEG C, calcium salt is crystallized from polar solvent, obtains the crystal formation of the L-5- methyl tetrahydrofolate calcium of four kinds of excellent stabilities.Although these four crystal formations are thermodynamically stable crystal formations, stable type is good, and solubility of these four crystal formations in water is extremely low, and the medicine is insoluble drug, and its extremely low water solubility has had a strong impact on the bioavilability of medicine.Patent CN1154648C also discloses that the unformed of L-5- methyl tetrahydrofolate calcium simultaneously, although have preferable solubility, but the L-5- methyl tetrahydrofolate salt chemical stabilities of amorphous state are excessively poor, it is difficult to reach medicinal and edible requirement.
The solid forms of medicine directly affect stability, rate of dissolution, the dissolution rate of preparation and the bioavilability of bulk drug; in order to improve stability, the bioavilability of medicine; reduce consumption, reduction toxic side effect; the new solid forms of medicine would generally be developed; because not enough and unformed medicine stability of the crystal formation L-5- methyl tetrahydrofolate salt in terms of bioavilability is not enough, finds solid dispersions of unformed L-5- methyl tetrahydrofolates newly and its salt and preparation method thereof and just seem very necessary.
The content of the invention
It is an object of the invention to provide composition of a kind of L-5- methyl tetrahydrofolates or its pharmaceutically acceptable salt and pharmaceutic adjuvant and preparation method thereof, obtain the L-5- methyl tetrahydrofolates of the unformed shape of stability and favorable dispersibility or the composition of its pharmaceutically acceptable salt and pharmaceutic adjuvant, add L-5- methyl tetrahydrofolates or the dissolution rate of its salt, the preparation method is not limited by drying process, also do not limited by solvent species and quantity of solvent, it is easy to operate, it is with low cost, it is easily achieved, industrialized production can be achieved.
In order to achieve the above object, technical scheme is as follows：
A kind of composition of L-5- methyl tetrahydrofolates or its pharmaceutically acceptable salt and pharmaceutic adjuvant, said composition includes L-5- methyl tetrahydrofolates or its pharmaceutically acceptable salt and pharmaceutic adjuvant, and both weight ratios are 1:0.1~100, wherein, during described L-5- methyl tetrahydrofolates or its pharmaceutically acceptable salt are unformed shape, the X-ray powder diffraction spectrum of the composition, the characteristic peak of the crystal without L-5- methyl tetrahydrofolates or its salt after the background peaks of pharmaceutic adjuvant is deducted.
Further, the pharmaceutic adjuvant is selected from least one of diluent, lubricant, adhesive, disintegrant, surfactant, filmogen, coating material and capsule material.
Preferably, described pharmaceutic adjuvant is selected from HPMC, hydroxypropyl cellulose, PVP, polyethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethylethylcellulose, carboxymethyl cellulose phthalic acid ester, hydroxypropyl methylcellulose phthalate, HPMC acetate succinate, polyacrylic resin, carbopol, alginates, carragheen, caprolactone, natural gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, PEO, chitosan, at least one of chitosan and collagen.
The invention provides the preparation method of a kind of L-5- methyl tetrahydrofolates or the composition of its pharmaceutically acceptable salt and pharmaceutic adjuvant, comprise the following steps：
1) L-5- methyl tetrahydrofolates or its pharmaceutically acceptable salt and pharmaceutic adjuvant are mixed in a solvent, mixing temperature is -50~150 DEG C, form the solution or suspension of methyl tetrahydrofolate containing L-5- or its salt and pharmaceutic adjuvant, wherein, the weight ratio of L-5- methyl tetrahydrofolates or its pharmaceutically acceptable salt and solvent is 0.001~100:The weight ratio of 1, L-5- methyl tetrahydrofolate or its pharmaceutically acceptable salt and pharmaceutic adjuvant is 1:0.1~100；
2) removing step 1) solvent in obtained solution or suspension, obtain the L-5- methyl tetrahydrofolates of unformed shape or the composition of its pharmaceutically acceptable salt and pharmaceutic adjuvant.
Further, the pharmaceutic adjuvant is selected from least one of diluent, lubricant, adhesive, disintegrant, surfactant, filmogen, coating material and capsule material.
Preferably, step 1) described in pharmaceutic adjuvant be selected from HPMC, hydroxypropyl cellulose, PVP, polyethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethylethylcellulose, carboxymethyl cellulose phthalic acid ester, hydroxypropyl methylcellulose phthalate, HPMC acetate succinate, polyacrylic resin, carbopol, alginates, carragheen, caprolactone, natural gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, PEO, chitosan, at least one of chitosan and collagen.
Also, step 1) solvent is selected from least one of alcohols, phenols, ethers, halogenated hydrocarbons, ketone, aldehydes, nitrile, acid amides, sulfone, sulfoxide, carboxylic acid and water containing less than 12 carbon atoms, step 2) method that removes solvent includes：Evaporation, vacuum evaporation, spray drying, freeze-drying, hot-melt extruded, filtering, centrifugation or agitated thin film.
Composition in the present invention refers to mixture, compound, copolymer, co-precipitate, eutectic, solid dispersions, solvate and hydrate.
The L-5- methyl tetrahydrofolates of the present invention or the composition of its pharmaceutically acceptable salt and pharmaceutic adjuvant, radiated using Cu-K α, to spend in the X-ray powder diffraction spectrum that 2 θ are represented characteristic peak of the background peaks without L-5- methyl tetrahydrofolate crystalline states for deducting pharmaceutic adjuvant, it is unformed state to show L-5- methyl tetrahydrofolates or its pharmaceutically acceptable salt.The general crystalline state using L-5- methyl tetrahydrofolates, has no the report of its unformed shape in the prior art.Normally due to the orderly and periodic arrangement of amorphous material molecule, reduce the energy of intermolecular interaction, energy is relatively low, and the L-5- methyl tetrahydrofolates or its pharmaceutically acceptable salt of the present invention is unformed shape, molecule is in height disordered state, and the surface free energy of material is bigger, molecule in solid matter has higher energy compared with the molecule in crystalline solid material, easily disperse, increase its dissolution rate, improve L-5- methyl tetrahydrofolates or the bioavilability of its salt.
After L-5- methyl tetrahydrofolates or its pharmaceutically acceptable salt and pharmaceutic adjuvant are well mixed by the present invention, " solid dispersion " method of use, drug molecule is obstructed by the polymer network structure of pharmaceutic adjuvant, suppresses the generation of crystallization, it is kept scattered and unformed state.Present invention use is widely used, the pharmaceutic adjuvant that cheap, dissolubility is good, these pharmaceutic adjuvants are mixed with L-5- methyl tetrahydrofolates or its pharmaceutically acceptable salt, coordinate the technologies such as evaporation, spray drying, freeze-drying and hot-melt extruded to obtain L-5- methyl tetrahydrofolates or the amorphous forms of its pharmaceutically acceptable salt.
The present invention selects pharmaceutically widely used, cheap auxiliary material, obtain the composition of L-5- methyl tetrahydrofolates or its pharmaceutically acceptable salt and pharmaceutic adjuvant, stability and favorable dispersibility, it is easy to develop pharmaceutical formulation, preparation method of the invention is not limited by drying process, also do not limited by solvent species and quantity of solvent, it is easy to operate, it is with low cost, it is easy to accomplish, industrialized production can be achieved.
Compared with prior art, the beneficial effects of the invention are as follows：
1) the unformed L-5- methyl tetrahydrofolates or the composition of its salt and pharmaceutic adjuvant that prepared by the present invention have high dispersion and stability, after solid pharmaceutical preparation is made, by disintegration can make drug particle degree of scatter more preferably, disperse and dissolution rate faster, be conducive to the absorption of medicine.Therefore, the dissolution rate of unformed state medicine substantially increases, and is more beneficial for absorption of the body to medicine, improves the bioavilability of medicine, allows medicament to preferably play clinical disease treatment effect.
2) preparation method of the composition of the L-5- methyl tetrahydrofolates of unformed state of the invention or its pharmaceutically acceptable salt and pharmaceutic adjuvant is not limited by drying process, also do not limited by solvent species and quantity of solvent, it is easy to operate, it is with low cost, it is easily achieved, industrialized production can be achieved.
3) (40 ± 2 DEG C, humidity 75% ± 5%) can keep good physical stability and chemical stability to the L-5- methyl tetrahydrofolates of unformed state or the composition of its salt and pharmaceutic adjuvant that prepared by the present invention under the conditions of accelerated test.Therefore, the present invention will have broad application prospects.
Brief description of the drawings
Fig. 1 for the embodiment of the present invention 1 unformed L-5- methyl tetrahydrofolates and PVP K30 composition X-ray powder diffraction figure.
Fig. 2 for the embodiment of the present invention 12 unformed L-5- methyl tetrahydrofolates and Eudragit L 100 composition X-ray powder diffraction figure.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described, but protection scope of the present invention is not limited by the following examples.
X-ray powder diffraction figure of the present invention is gathered on Ultima IV x-ray diffractometers.The method parameter of X-ray powder diffraction of the present invention is as follows：
X-ray powder parameter：Cu-Kα
Kα：1.5418
Voltage：40 kilovolts
Electric current：40 milliamperes
Divergent slit：Automatically
Scan pattern：Continuously
Scanning range：From 2.0 to 60.0 degree
Sampling step length：0.0200 degree
Sweep speed：60 degrees/min
Embodiment 1
L-5- methyl tetrahydrofolates calcium salt (50 milligrams) and PVP K30 (500 milligrams) are dissolved in water (10 milliliters), 60 DEG C of stirring dissolved clarifications are heated to.Above-mentioned solution is freeze-dried, obtain the composition of unformed L-5- methyl tetrahydrofolates calcium salt and PVP K30, the X-ray powder diffraction figure of said composition is as shown in figure 1, deduct the characteristic peak without L-5- methyl tetrahydrofolate calcium salt crystal formations after the background peaks of pharmaceutic adjuvant in X-ray powder diffraction figure.
Embodiment 2
L-5- methyl tetrahydrofolates (50 milligrams) and PVP K30 (500 milligrams) are dissolved in water (2 milliliters), 60 DEG C of stirring dissolved clarifications are heated to.Above-mentioned solution is freeze-dried, obtain in the composition of unformed L-5- methyl tetrahydrofolates and PVP K30, the X-ray powder diffraction figure of said composition deduct pharmaceutic adjuvant background peaks after the characteristic peak without L-5- methyl tetrahydrofolate crystal formations.
Embodiment 3
(10 grams) of L-5- methyl tetrahydrofolates glucosamine salt (0.1 gram) and PEG 8000 are added in water (300 milliliters), 60 DEG C of stirring dissolved clarifications are heated to.Above-mentioned solution is dried with JISL mini spray dryers LSD-48, maintain 60 DEG C of inlet temperature, 50 DEG C of outlet temperature, collect outlet material, obtain white solid, further vacuum drying obtains the composition of unformed L-5- methyl tetrahydrofolates glucosamine salt and PEG 8000, in the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate glucosamine salt crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 4
L-5- methyl tetrahydrofolates calcium salt (0.1 gram) and HPMC E50 (2 grams) are added in water (10 milliliters), 40 DEG C of stirring dissolved clarifications are heated to.Above-mentioned solution is freeze-dried, obtain white solid, in the composition of i.e. unformed L-5- methyl tetrahydrofolates calcium salt and HPMC E50, the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate calcium salt crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 5
L-5- methyl tetrahydrofolates (1 gram), PEG 8000 (20 grams) and ethanol (20 grams) are heated to be quickly cooled to room temperature under 80 DEG C, stirring, white solid is obtained.Above-mentioned solid is crushed, obtain white powdery solids, in the composition of i.e. unformed L-5- methyl tetrahydrofolates and PEG 8000, the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 6
By L-5- methyl tetrahydrofolates (0.1 gram), PEG20000 (1 gram) and mannitol (10 grams), it is well mixed at 100 DEG C, is quickly cooled to room temperature, obtains white solid.Above-mentioned solid is crushed, obtain white powdery solids, in i.e. unformed L-5- methyl tetrahydrofolates and mannitol and the composition of PEG20000, the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 7
The mixture of L-5- methyl tetrahydrofolates (1 gram), methanol (10 grams), water (20 grams) and liposome (4 grams) is heated to 90 DEG C, stirring, it is well mixed, it is evaporated in vacuo and removes solvent, it is cooled to room temperature and obtains white solid, in the composition of i.e. unformed L-5- methyl tetrahydrofolates and liposome, the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 8
The mixture of L-5- methyl tetrahydrofolates calcium salt (0.2 gram), water (20 grams) and methacrylic acid copolymer A types (4 grams) is heated to 50 DEG C, stirring, it is evaporated in vacuo and removes solvent, it is cooled to room temperature and obtains white solid, the composition of i.e. unformed L-5- methyl tetrahydrofolates calcium salt and methacrylic acid copolymer A types, in the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate calcium salt crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 9
The mixture of L-5- methyl tetrahydrofolates (1 gram), water (10 grams) and ethyl cellulose (2 grams) is heated to 30 DEG C, stirring, it is well mixed, it is evaporated in vacuo and removes solvent, it is cooled to room temperature and obtains white solid, in the composition of i.e. unformed L-5- methyl tetrahydrofolates and ethyl cellulose, the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 10
The mixture of L-5- methyl tetrahydrofolates calcium salt (0.2 gram), water (20 grams) and hydroxypropyl cellulose SSL (4 grams) is heated to 30 DEG C, stir dissolved clarification, it is evaporated in vacuo and removes solvent, it is cooled to room temperature and obtains white solid, the composition of i.e. unformed L-5- methyl tetrahydrofolates calcium and hydroxypropyl cellulose SSL, in the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate calcium salt crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 11
The mixture of L-5- methyl tetrahydrofolates calcium salt (0.2 gram), methanol (20 grams), water (10 grams) and polyvinyl acetate (4 grams) is heated to 30 DEG C, stir dissolved clarification, it is evaporated in vacuo and removes solvent, it is cooled to room temperature and obtains white solid, the composition of i.e. unformed L-5- methyl tetrahydrofolates and polyvinyl acetate, in the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate isethionate crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 12
L-5- methyl tetrahydrofolates (50 milligrams) and polyacrylic resin Eudragit L100 (100 milligrams) are added to methanol (750 microlitres), stirred and evenly mixed at room temperature.Above-mentioned solution is slowly concentrated to dryness in a rotary evaporator, obtain white solid, the composition of i.e. unformed L-5- methyl tetrahydrofolates and polyacrylic resin Eudragit L100, the X-ray powder diffraction figure of said composition is as shown in Fig. 2 deduct the characteristic peak without L-5- methyl tetrahydrofolate crystal formations after the background peaks of pharmaceutic adjuvant in X-ray powder diffraction figure.
Embodiment 13
L-5- methyl tetrahydrofolates (50 milligrams) and polyacrylic resin Eudragit S100 (5 milligrams) are added at methanol (4 milliliters) and ethyl acetate (1 milliliter), 30 DEG C and stirred and evenly mixed.Above-mentioned solution is slowly concentrated to dryness in a rotary evaporator, obtain white solid, stirring is lower to separate out white solid, the composition of i.e. unformed L-5- methyl tetrahydrofolates and polyacrylic resin Eudragit S100, in the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 14
L-5- methyl tetrahydrofolates (50 milligrams) and carbopol Carbomer 940 (50 milligrams) are added at methanol (4 milliliters) and tetrahydrofuran (1 milliliter), -30 DEG C and are uniformly mixed.Above-mentioned solution is slowly concentrated to dryness in a rotary evaporator, obtain white solid, stirring is lower to separate out white solid, the composition of i.e. unformed L-5- methyl tetrahydrofolates and carbopol Carbomer 940, in the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 15
L-5- methyl tetrahydrofolates (50 milligrams) and pregelatinized starch Pharma-Gel (100 milligrams) are added to methanol (4 milliliters) and water (1 milliliter), are well mixed at room temperature.Above-mentioned solution is slowly concentrated to dryness in a rotary evaporator, obtain white solid, stirring is lower to separate out white solid, the composition of i.e. unformed L-5- methyl tetrahydrofolates and Pharma-Gel pregelatinized starch, in the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 16
L-5- methyl tetrahydrofolates (50 milligrams) and high side chain crosslinked starch (50 milligrams) are added to methanol (4 milliliters) and water (1 milliliter), stir and evenly mix at room temperature, above-mentioned solution is slowly concentrated to dryness in a rotary evaporator, obtain white solid, stirring is lower to separate out white solid, the composition of i.e. unformed Dapagliflozin and high side chain crosslinked starch, in the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 17
L-5- methyl tetrahydrofolates (50 milligrams) and sodium carboxymethylcellulose SCMC (500 milligrams) are added to dimethyl sulfoxide (DMSO) (5 milliliters), stirred and evenly mixed at room temperature.Above-mentioned solution is slowly concentrated to dryness in a rotary evaporator, obtain white solid, the composition of i.e. unformed L-5- methyl tetrahydrofolates and sodium carboxymethylcellulose SCMC, in the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 18
L-5- methyl tetrahydrofolates (50 milligrams) and chitosan (500 milligrams) are added to ethanol (5 milliliters), stir and evenly mix at room temperature, above-mentioned solution is slowly concentrated to dryness in a rotary evaporator, obtain white solid, the composition of i.e. unformed L-5- methyl tetrahydrofolates and chitosan, in the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 19
L-5- methyl tetrahydrofolates (50 milligrams) and sodium carboxymethyl starch Explotab (500 milligrams) are added to ethanol (5 milliliters), it is uniformly mixed at room temperature, above-mentioned solution is slowly concentrated to dryness in a rotary evaporator, obtain white solid, the composition of i.e. unformed L-5- methyl tetrahydrofolates and sodium carboxymethyl starch Explotab, in the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 20
L-5- methyl tetrahydrofolates (50 milligrams) and alginates E401 (500 milligrams) are added to ethanol (5 milliliters), are uniformly mixed at room temperature.Above-mentioned solution is slowly concentrated to dryness in a rotary evaporator, obtain white solid, in the composition of i.e. unformed L-5- methyl tetrahydrofolates and alginates E401, the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 21
L-5- methyl tetrahydrofolates (50 milligrams) and carboxymethyl cellulose phthalic acid ester Agucoat CPD (5 grams) are suspended in methanol (30 milliliters), 50 DEG C is heated to and is uniformly mixed.By above-mentioned solution, slowly concentration removes most of solvent in a rotary evaporator, filtering, dry, obtain white solid, the composition of i.e. unformed L-5- methyl tetrahydrofolates and carboxymethyl cellulose phthalic acid ester Agucoat CPD, in the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 22
L-5- methyl tetrahydrofolates (50 milligrams) and carragheen E407 (500 milligrams) are suspended in methanol (30 milliliters), 50 DEG C are heated to be uniformly mixed, by above-mentioned solution, slowly concentration removes most of solvent in a rotary evaporator, filtering, dry, obtain white solid, the composition of i.e. unformed L-5- methyl tetrahydrofolates and carragheen E407, in the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 23
L-5- methyl tetrahydrofolates (50 milligrams) and chitosan (5 grams) are suspended in methanol (50 milliliters), 50 DEG C is heated to and is uniformly mixed.By above-mentioned solution, slowly concentration removes most of solvent in a rotary evaporator, filtering, dry, obtain white solid, the composition of i.e. unformed L-5- methyl tetrahydrofolates and chitosan, in the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 24
L-5- methyl tetrahydrofolates (30 milligrams) and polyacrylic resin Eudragit E100 (30 milligrams) are dissolved in n-butanol (600 microlitres), methyl phenyl ethers anisole (900 microlitres) and N, in dinethylformamide (600 microlitres), it is heated to 50 DEG C of stirring dissolved clarifications, above-mentioned solution is cooled to 10 DEG C, separate out white solid, filtering, dry, obtain the composition of unformed L-5- methyl tetrahydrofolates and polyacrylic resin Eudragit E100, in the X-ray powder diffraction figure of said composition, deduct the characteristic peak without L-5- methyl tetrahydrofolate crystal formations after the background peaks of pharmaceutic adjuvant.
Embodiment 25
L-5- methyl tetrahydrofolates (30 milligrams) and collagen Peptan (300 milligrams) are dissolved in n-butanol (600 microlitres), methyl phenyl ethers anisole (900 microlitres) and acetonitrile (600 microlitres), 50 DEG C of stirring dissolved clarifications are heated to.Above-mentioned solution is cooled to 10 DEG C, white solid, filtering is separated out, dry, obtain in the composition of unformed L-5- methyl tetrahydrofolates and collagen Peptan, the X-ray powder diffraction figure of said composition, deduct the characteristic peak without L-5- methyl tetrahydrofolate crystal formations after the background peaks of pharmaceutic adjuvant.
Embodiment 26
L-5- methyl tetrahydrofolates (30 milligrams) and natural gum Galactosol (300 milligrams) are dissolved in n-butanol (600 microlitres), methyl phenyl ethers anisole (900 microlitres) and methanol (600 microlitres), 50 DEG C of stirring dissolved clarifications are heated to.Above-mentioned solution is cooled to 10 DEG C, white solid, filtering is separated out, dry, obtain in the composition of unformed L-5- methyl tetrahydrofolates and natural gum Galactosol, the X- ray powder diffraction patterns of said composition, deduct the characteristic peak without L-5- methyl tetrahydrofolate crystal formations after the background peaks of pharmaceutic adjuvant.
Embodiment 27
L-5- methyl tetrahydrofolates calcium salt (30 milligrams) and hydroxypropyl methylcellulose phthalate HPMCP (300 milligrams) are added to ethanol (750 microlitres) and water (1500 microlitres), 80 DEG C is heated to and is uniformly mixed.By above-mentioned solution, slowly concentration removes solvent in a rotary evaporator, obtain white solid, the composition of i.e. unformed L-5- methyl tetrahydrofolates calcium salt and hydroxypropyl methylcellulose phthalate HPMCP, in the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate calcium salt crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 28
L-5- methyl tetrahydrofolates (30 milligrams) and caprolactone (300 milligrams) are added to ethanol (750 microlitres) and water (750 microlitres), 80 DEG C is heated to and is uniformly mixed.By above-mentioned solution, slowly concentration removes solvent in a rotary evaporator, obtain brown solid, the composition of i.e. unformed L-5- methyl tetrahydrofolates and caprolactone, in the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 29
L-5- methyl tetrahydrofolates (30 milligrams) and dextrin Maltrin M100 (300 milligrams) are added to ethanol (750 microlitres) and water (750 microlitres), 80 DEG C is heated to and is uniformly mixed.By above-mentioned solution, slowly concentration removes solvent in a rotary evaporator, obtain brown solid, the composition of i.e. unformed L-5- methyl tetrahydrofolates and dextrin Maltrin M100, in the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 30
L-5- methyl tetrahydrofolates calcium salt (30 milligrams) and sodium carboxymethylcellulose SCMS (3 milligrams) are added to water (30 milliliters), 100 DEG C is heated to and is uniformly mixed.By above-mentioned solution, slowly concentration removes solvent in a rotary evaporator, obtain white solid, the composition of i.e. unformed L-5- methyl tetrahydrofolates calcium salt and sodium carboxymethylcellulose SCMC, in the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate calcium salt crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 31
L-5- methyl tetrahydrofolates calcium salt (30 milligrams) and beta-schardinger dextrin (30 milligrams) are added to methanol (300 microlitres) and water (300 microlitres), dissolved clarification is stirred at room temperature.By above-mentioned solution, slowly concentration removes solvent in a rotary evaporator, obtain white solid, the composition of i.e. unformed L-5- methyl tetrahydrofolates calcium salt and beta-schardinger dextrin, in the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate calcium salt crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 32
L-5- methyl tetrahydrofolates (30 milligrams) and sodium carboxymethylcellulose SCMC (30 milligrams) are added at methanol (300 microlitres) and water (60 microlitres), 60 DEG C and are uniformly mixed.By above-mentioned solution, slowly concentration removes solvent in a rotary evaporator, obtain white solid, the composition of i.e. unformed L-5- methyl tetrahydrofolates and sodium carboxymethylcellulose SCMC, in the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 33
L-5- methyl tetrahydrofolates (5 milligrams) and PEO Polyox WSR301 (60 milligrams) are added at methanol (300 microlitres) and water (60 microlitres), 60 DEG C and are uniformly mixed.By above-mentioned solution, slowly concentration removes solvent in a rotary evaporator, obtain white solid, the composition of i.e. unformed L-5- methyl tetrahydrofolates and PEO Polyox WSR301, in the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 34
L-5- methyl tetrahydrofolates (30 milligrams) and polyvinyl alcohol EG-40 (60 milligrams) are added to methanol (300 microlitres) and water (60 microlitres), dissolved clarification is stirred at 60 DEG C, by above-mentioned solution, slowly concentration removes solvent in a rotary evaporator, obtain white solid, the composition of i.e. unformed L-5- methyl tetrahydrofolates and polyvinyl alcohol EG-40, in the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 35
L-5- methyl tetrahydrofolates (50 milligrams) and HPMC acetate succinate Agoat MG (2 grams) are added to ethanol (10 milliliters) and water (2 milliliters), it is uniformly mixed at 80 DEG C, above-mentioned solution is slowly concentrated to dryness in a rotary evaporator, obtain white solid, the composition of i.e. unformed L-5- methyl tetrahydrofolates and HPMC acetate succinate Agoat MG, in the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 36
L-5- methyl tetrahydrofolates (50 milligrams) and carboxymethylethylcellulose (2 grams) are added to ethanol (10 milliliters) and water (1 milliliter), it is uniformly mixed at 80 DEG C, above-mentioned solution is slowly concentrated to dryness in a rotary evaporator, obtain white solid, the composition of i.e. unformed L-5- methyl tetrahydrofolates and carboxymethylethylcellulose, in the X-ray powder diffraction figure of said composition, the characteristic peak without L-5- methyl tetrahydrofolate crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 37：The influence factor of unformed L-5- methyl tetrahydrofolates calcium salt and PVP K30 composition is tested
Material：The composition of the unformed L-5- methyl tetrahydrofolates calcium salt of the gained of embodiment 1 and PVP K30
Table 1：
Table 1 illustrates：Unformed L-5- methyl tetrahydrofolates calcium salt under high temperature, super-humid conditions, is placed 10 days with PVP K30 composition, and relevant material is without significantly changing, and no L-5- methyl tetrahydrofolates calcium salt crystallization is separated out.
Embodiment 38：The influence factor of unformed L-5- methyl tetrahydrofolates calcium salt and PVP K30 composition is tested
Material：The composition of the unformed L-5- methyl tetrahydrofolates calcium salt of the gained of embodiment 1 and PVP K30
Experiment condition：40 DEG C ± 2 DEG C of temperature, humidity 75% ± 5%
Table 2：
Table 2 illustrates：Unformed L-5- methyl tetrahydrofolates calcium salt under the conditions of accelerated test, is placed 6 months with PVP K30 composition, and relevant material is without significantly changing, and no L-5- methyl tetrahydrofolates calcium salt crystallization is separated out.
The L-5- methyl tetrahydrofolates of the present invention or the unformed composition of its pharmaceutically acceptable salt and pharmaceutic adjuvant, its dissolution rate substantially increases, it is more beneficial for improving the bioavilability of medicine, allow medicament to preferably play clinical disease treatment effect, the amorphous article is (40 ± 2 DEG C under the conditions of accelerated test, humidity 75% ± 5%), good physical stability and chemical stability can be kept.
Claims (9)
1. the composition of a kind of L-5- methyl tetrahydrofolates or its pharmaceutically acceptable salt and pharmaceutic adjuvant, its
Be characterised by, the composition comprising L-5- methyl tetrahydrofolates or its pharmaceutically acceptable salt with
Pharmaceutic adjuvant, both weight ratios are 1:0.1~100, wherein, described L-5- methyl tetrahydrochysene leaves
Acid or its pharmaceutically acceptable salt are unformed shape, the X-ray powder diffraction of the composition
In spectrum, the spy without L-5- methyl tetrahydrofolates or its salt crystal after the background peaks of pharmaceutic adjuvant is deducted
Levy peak.
2. L-5- methyl tetrahydrofolates according to claim 1 or its pharmaceutically acceptable salt with it is medicinal
The composition of auxiliary material, it is characterised in that the pharmaceutic adjuvant is selected from diluent, lubricant, bonding
At least one in agent, disintegrant, surfactant, filmogen, coating material and capsule material
Kind.
3. L-5- methyl tetrahydrofolates according to claim 1 or its pharmaceutically acceptable salt with it is medicinal
The composition of auxiliary material, it is characterised in that the pharmaceutic adjuvant is selected from HPMC, hydroxypropyl
Base cellulose, PVP, polyethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer
Thing, polyvinyl acetate, carboxymethylethylcellulose, carboxymethyl cellulose phthalic acid ester, hydroxyl
Third methyl cellulose phthalate ester, HPMC acetate succinate, polypropylene
Acid resin, carbopol, alginates, carragheen, caprolactone, natural gum, polyvinyl alcohol,
Pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, PEO, chitosan,
At least one of chitosan and collagen.
4. the composition of a kind of L-5- methyl tetrahydrofolates or its pharmaceutically acceptable salt and pharmaceutic adjuvant
Preparation method, comprises the following steps：
1) L-5- methyl tetrahydrofolates or its pharmaceutically acceptable salt and pharmaceutic adjuvant are mixed in a solvent
Close, mixing temperature is -50~150 DEG C, form methyl tetrahydrofolate containing L-5- or it pharmaceutically may be used
The salt of receiving and the solution of pharmaceutic adjuvant or suspension, wherein, L-5- methyl tetrahydrofolates or
The weight ratio of its pharmaceutically acceptable salt and solvent is 0.001~100:1, L-5- methyl tetrahydrochysene
The weight ratio of folic acid or its pharmaceutically acceptable salt and pharmaceutic adjuvant is 1:0.1~100；
2) removing step 1) solvent in obtained solution or suspension, obtain the L-5- of unformed shape
The composition of methyl tetrahydrofolate or its pharmaceutically acceptable salt and pharmaceutic adjuvant.
5. L-5- methyl tetrahydrofolates according to claim 7 or its pharmaceutically acceptable salt with it is medicinal
The preparation method of the composition of auxiliary material, it is characterised in that the pharmaceutic adjuvant is selected from diluent, profit
Lubrication prescription, adhesive, disintegrant, surfactant, filmogen, coating material and capsule material
At least one of.
6. L-5- methyl tetrahydrofolates according to claim 7 or its pharmaceutically acceptable salt with it is medicinal
The preparation method of the composition of auxiliary material, it is characterised in that described pharmaceutic adjuvant is selected from hydroxypropyl
Cellulose, hydroxypropyl cellulose, PVP, polyethylene glycol, ethyl cellulose, liposome, first
The adjacent benzene of base acrylic copolymer, polyvinyl acetate, carboxymethylethylcellulose, carboxymethyl cellulose
Dicarboxylic acid esters, hydroxypropyl methylcellulose phthalate, HPMC acetate amber
Acid esters, polyacrylic resin, carbopol, alginates, carragheen, caprolactone, tree
Glue, polyvinyl alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polycyclic oxygen
At least one of ethane, chitosan, chitosan and collagen.
7. L-5- methyl tetrahydrofolates according to claim 7 or its pharmaceutically acceptable salt with it is medicinal
The preparation method of the composition of auxiliary material, it is characterised in that step 1) solvent be selected from contain 12
The alcohols of following carbon atom, phenols, ethers, halogenated hydrocarbons, ketone, aldehydes, nitrile, acid amides,
At least one of sulfone, sulfoxide, carboxylic acid and water；Step 2) remove solvent method include：Steam
Hair, vacuum evaporation, spray drying, freeze-drying, hot-melt extruded, filtering, centrifuge or stir thin
Film is dried.
8. purposes of the solid dispersions described in claims 1 to 3 in food and vitamin products is prepared.
9. solid dispersions described in claims 1 to 3 prepare the pharmaceutical preparation of regulation homocysteine level,
In the pharmaceutical preparation for preventing and treating angiocardiopathy and the pharmaceutical preparation for preventing neurotrophy deficiency disease
Purposes.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108926544A (en) * | 2018-08-19 | 2018-12-04 | 张奉明 | Four generation Couteat of Folic Acid of one kind and preparation method thereof |
| CN117771389A (en) * | 2023-12-28 | 2024-03-29 | 浙江圣达生物药业股份有限公司 | L-5-methyltetrahydrofolate calcium-gamma-cyclodextrin inclusion compound and preparation method thereof |
-
2016
- 2016-02-03 CN CN201610076722.4A patent/CN107028950A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108926544A (en) * | 2018-08-19 | 2018-12-04 | 张奉明 | Four generation Couteat of Folic Acid of one kind and preparation method thereof |
| CN108926544B (en) * | 2018-08-19 | 2021-08-06 | 张奉明 | Tetrafolic acid tablet and preparation method thereof |
| CN117771389A (en) * | 2023-12-28 | 2024-03-29 | 浙江圣达生物药业股份有限公司 | L-5-methyltetrahydrofolate calcium-gamma-cyclodextrin inclusion compound and preparation method thereof |
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Application publication date: 20170811 |