CN115364056B - Probucol liposome for hypercholesterolemia, preparation and preparation method thereof - Google Patents
Probucol liposome for hypercholesterolemia, preparation and preparation method thereof Download PDFInfo
- Publication number
- CN115364056B CN115364056B CN202211030139.1A CN202211030139A CN115364056B CN 115364056 B CN115364056 B CN 115364056B CN 202211030139 A CN202211030139 A CN 202211030139A CN 115364056 B CN115364056 B CN 115364056B
- Authority
- CN
- China
- Prior art keywords
- probucol
- liposome
- preparation
- drying
- organic solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 title claims abstract description 107
- 229960003912 probucol Drugs 0.000 title claims abstract description 107
- 239000002502 liposome Substances 0.000 title claims abstract description 101
- 238000002360 preparation method Methods 0.000 title claims abstract description 63
- 208000035150 Hypercholesterolemia Diseases 0.000 title abstract description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 46
- 235000012000 cholesterol Nutrition 0.000 claims abstract description 22
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 22
- 229950008882 polysorbate Drugs 0.000 claims abstract description 18
- 229920000136 polysorbate Polymers 0.000 claims abstract description 18
- 239000000463 material Substances 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims description 42
- 238000004108 freeze drying Methods 0.000 claims description 34
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 32
- 238000010438 heat treatment Methods 0.000 claims description 26
- 239000003960 organic solvent Substances 0.000 claims description 26
- 239000007853 buffer solution Substances 0.000 claims description 19
- 238000001125 extrusion Methods 0.000 claims description 18
- 238000004458 analytical method Methods 0.000 claims description 17
- 239000006185 dispersion Substances 0.000 claims description 17
- 238000001035 drying Methods 0.000 claims description 17
- 230000008014 freezing Effects 0.000 claims description 17
- 238000007710 freezing Methods 0.000 claims description 17
- 238000002390 rotary evaporation Methods 0.000 claims description 17
- 238000000859 sublimation Methods 0.000 claims description 17
- 230000008022 sublimation Effects 0.000 claims description 17
- 238000009210 therapy by ultrasound Methods 0.000 claims description 16
- QTYWBJZOZDYCGB-UHFFFAOYSA-L potassium;sodium;2-carboxybenzoate;hydroxide Chemical compound [OH-].[Na+].[K+].OC(=O)C1=CC=CC=C1C([O-])=O QTYWBJZOZDYCGB-UHFFFAOYSA-L 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 5
- 235000003704 aspartic acid Nutrition 0.000 claims description 5
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 5
- 239000000872 buffer Substances 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 5
- CBMPTFJVXNIWHP-UHFFFAOYSA-L disodium;hydrogen phosphate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].OP([O-])([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O CBMPTFJVXNIWHP-UHFFFAOYSA-L 0.000 claims description 4
- 239000007974 sodium acetate buffer Substances 0.000 claims description 4
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 claims description 4
- 239000008187 granular material Substances 0.000 claims description 3
- 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 claims description 2
- 150000003905 phosphatidylinositols Chemical class 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 11
- 239000003814 drug Substances 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 7
- 238000011068 loading method Methods 0.000 abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 6
- 239000007787 solid Substances 0.000 abstract description 5
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 20
- 229940107161 cholesterol Drugs 0.000 description 13
- 229940067631 phospholipid Drugs 0.000 description 13
- 230000000052 comparative effect Effects 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 239000012488 sample solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 238000005538 encapsulation Methods 0.000 description 3
- 239000007962 solid dispersion Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 108010010234 HDL Lipoproteins Proteins 0.000 description 2
- 102000015779 HDL Lipoproteins Human genes 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229960005261 aspartic acid Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- LYRFLYHAGKPMFH-UHFFFAOYSA-N octadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(N)=O LYRFLYHAGKPMFH-UHFFFAOYSA-N 0.000 description 2
- 238000013441 quality evaluation Methods 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 description 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 108010007622 LDL Lipoproteins Proteins 0.000 description 1
- 102000007330 LDL Lipoproteins Human genes 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 239000003741 agents affecting lipid metabolism Substances 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 230000000879 anti-atherosclerotic effect Effects 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- -1 dipalmitoyl choline Chemical compound 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 210000000497 foam cell Anatomy 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 108010022197 lipoprotein cholesterol Proteins 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- FPLYNRPOIZEADP-UHFFFAOYSA-N octylsilane Chemical group CCCCCCCC[SiH3] FPLYNRPOIZEADP-UHFFFAOYSA-N 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229940037312 stearamide Drugs 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Images
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
- A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
- A61K31/10—Sulfides; Sulfoxides; Sulfones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a probucol liposome for hypercholesterolemia, a preparation and a preparation method thereof. The invention utilizes liposome technology, preferably phospholipid, cholesterol and polysorbate liposome materials to carry out entrapment on the probucol, enhances the water solubility of the probucol, improves the drug loading rate and the entrapment rate of the probucol liposome, further utilizes the probucol liposome to prepare a solid preparation, and remarkably improves the dissolution rate of the probucol liposome, thereby increasing the bioavailability of the probucol and reducing the tablet weight of the preparation, and is suitable for clinical use.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a probucol liposome for hypercholesterolemia, a preparation and a preparation method thereof.
Background
Probucol is a lipid-regulating agent and has an anti-atherosclerosis effect. The lipid-lowering effect is to lower blood cholesterol and low density lipoprotein by lowering cholesterol synthesis and promoting cholesterol decomposition, and also to change the property and function of the high density lipoprotein subtype, so that the high density lipoprotein has remarkable antioxidant effect, can inhibit the formation of foam cells, delay the formation of atherosclerosis plaques, and resolve the formed atherosclerosis plaques.
Probucol is white crystalline powder, insoluble in water, soluble in ethanol and petroleum ether, and easily soluble in chloroform and propanol. The biggest problem of probucol in clinical application is that the oral bioavailability is small, only about 10%, and the absorption is affected by food, and the individual difference is large, so the dosage of probucol is large. Probucol is a water-insoluble drug, and has a small dissolution rate in the gastrointestinal tract, so that probucol is difficult to absorb. Chinese patent CN102475688 discloses an oral nano solid preparation of probucol and its preparation method, and the dissolution of the existing probucol tablet in the dissolution medium (water) for 30 minutes is only 3%. From this, it is known that the improvement of the dissolution rate of probucol is a key to the improvement of the oral absorption thereof.
Methods such as microcapsule, inclusion compound, self-emulsifying drug, self-assembled nanoparticle, solid dispersion and the like are reported to be capable of improving the dissolution rate of probucol. Chinese patent CN1138537 discloses a probucol inclusion capsule, chinese patent CN1559385 discloses a probucol solid dispersion, in order to increase the water solubility of probucol and improve the bioavailability thereof. However, due to the large dose of probucol, the specification of one tablet reaches 125mg or 250mg, a large amount of carrier material is needed for preparing the probucol into inclusion compound, solid dispersion or microemulsion, the drug loading rate of the probucol is low, and finally the weight of one tablet containing 125mg or 250mg of the probucol solid preparation is as high as 1g or even 2g. Obviously, the traditional Chinese medicine composition is beyond the normal weight range and is not suitable for practical clinic.
Therefore, it is necessary to design an oral solid preparation containing probucol, which can not only increase the bioavailability of the probucol, but also be suitable for clinical use.
Disclosure of Invention
The invention provides a probucol liposome and a preparation method thereof, which solve the problem of low drug loading rate of a probucol preparation and overcome the problem of poor water solubility and low dissolution rate of the probucol by optimizing liposome wrapping materials.
Specifically, the technical scheme of the invention is as follows:
the first object of the present invention is to provide a method for preparing a first probucol liposome, comprising the following steps:
(1) Dissolving phospholipid, cholesterol, polysorbate and probucol in a proper amount of organic solvent, removing the organic solvent by reduced pressure rotary evaporation to form a film, adding a buffer solution for dispersion and shaking;
(2) Carrying out ultrasonic treatment on the product obtained in the step (1), and forming 30-80nm liposome by using a French extrusion method;
(3) Freeze-drying the liposome obtained in the step (2);
the freeze-drying procedure was:
a. pre-freezing: the temperature is between minus 30 ℃ and minus 40 ℃ and the time is between 1.5 and 3 hours;
b. sublimation: vacuum 10-30Pa, and heating to-5-5deg.C;
c. and (5) analysis and drying: raising the temperature to 15-25 ℃ and keeping for 4-6h.
Further, the pH of the buffer is=4.5-5.5, preferably ph=5.2.
Further, the probucol liposome comprises 1 part by weight of probucol, 0.5-1.5 parts by weight of phospholipid, 0.1-0.5 part by weight of cholesterol and 0.05-0.2 part by weight of polysorbate.
Specifically, the preparation method of the probucol liposome comprises the following steps:
(1) Dissolving 0.5-1.5 parts by weight of phospholipid, 0.1-0.5 part by weight of cholesterol, 0.05-0.2 part by weight of polysorbate and 1 part by weight of probucol in a proper amount of organic solvent, removing the organic solvent by reduced pressure rotary evaporation to form a film, adding a buffer solution with pH of 4.5-5.5 for dispersion and shaking;
(2) Carrying out ultrasonic treatment on the product obtained in the step (1), and forming 30-80nm liposome by using a French extrusion method;
(3) And (3) freeze-drying the liposome obtained in the step (2) to obtain the liposome.
The freeze-drying procedure was:
a. pre-freezing: the temperature is between minus 30 ℃ and minus 40 ℃ and the time is between 1.5 and 3 hours;
b. sublimation: vacuum 10-30Pa, and heating to-5-5deg.C;
c. and (5) analysis and drying: raising the temperature to 15-25 ℃ and keeping for 4-6h.
Further, the organic solvent is at least one of chloroform, ethanol, isopropanol and methanol, preferably chloroform.
Further, the buffer solution is one of disodium hydrogen phosphate-citric acid buffer solution, acetic acid-sodium acetate buffer solution and potassium hydrogen phthalate-sodium hydroxide buffer solution, and is preferably potassium hydrogen phthalate-sodium hydroxide buffer solution.
Further, the phospholipid is at least one of phosphatidylcholine, sphingomyelin, phosphatidylethanolamine, dipalmitoyl choline, distearoyl choline, phosphatidylglycerol, phosphatidylinositol, phosphatidic acid, and stearamide, preferably sphingomyelin.
A second object of the present invention is to provide a second method for preparing the probucol liposome, wherein 0.05-0.1 parts by weight of aspartic acid can be added in the step (1).
The preparation method of the probucol liposome comprises the following steps:
(1) Dissolving 0.5-1.5 parts by weight of phospholipid, 0.1-0.5 part by weight of cholesterol, 0.05-0.2 part by weight of polysorbate, 1 part by weight of probucol and 0.05-0.1 part by weight of aspartic acid in a proper amount of organic solvent, performing reduced pressure rotary evaporation to remove the organic solvent, forming a film, adding a buffer solution with pH of 4.5-5.5 for dispersion and shaking;
(2) Carrying out ultrasonic treatment on the product obtained in the step (1), and forming 30-80nm liposome by using a French extrusion method;
(3) And (3) freeze-drying the liposome obtained in the step (2) to obtain the liposome.
The freeze-drying procedure was:
a. pre-freezing: the temperature is between minus 30 ℃ and minus 40 ℃ and the time is between 1.5 and 3 hours;
b. sublimation: vacuum 10-30Pa, and heating to-5-5deg.C;
c. and (5) analysis and drying: raising the temperature to 15-25 ℃ and keeping for 4-6h.
The purpose of the ultrasonic wave is to improve the permeability of the liposome membrane and the encapsulation rate, and moreover, the ultrasonic wave is utilized to lead the liposome particles to generate a severe interaction, so that the purpose of stirring is achieved, the follow-up extrusion of the liposome crude product into liposome particles with uniform particle size is facilitated, and the uniformity is further improved.
The third object of the present invention is to provide a probucol liposome, which is characterized by being prepared by the first method.
The fourth object of the present invention is to provide a probucol liposome, which is characterized by being prepared by the second method.
A fifth object of the present invention is to provide a preparation of two probucol liposomes, which comprises the probucol liposome prepared by the first method or the probucol liposome prepared by the first method, and pharmaceutically acceptable excipients.
Further, the formulations include, but are not limited to, tablets, granules, capsules.
Compared with the prior art, the invention has the beneficial effects that:
(1) The invention encapsulates the probucol by using liposome technology, improves the water solubility of the probucol, and further prepares a solid preparation by using the probucol liposome, improves the dissolution of the probucol, thereby increasing the bioavailability of the probucol.
(2) The invention selects proper liposome material to carry out entrapment on the probucol, optimizes the preparation method, improves the drug-loading capacity and entrapment rate of the probucol liposome, reduces the tablet weight of the preparation, is suitable for clinical use, reduces the content of related substances and improves the stability of the preparation.
Drawings
Fig. 1: examples 8-13, comparative example 7 probucol formulation dissolution curves
Detailed Description
The present invention will be further described with reference to examples for the purpose of making the objects and technical aspects of the present invention more apparent, but the scope of the present invention is not limited to these examples, which are only for explaining the present invention. It will be understood by those skilled in the art that variations or equivalent substitutions that do not depart from the spirit of the invention are intended to be included within the scope of the invention.
1. Preparation of probucol liposome
EXAMPLE 1 preparation of probucol liposomes
The formula comprises the following components:
the preparation method comprises the following steps:
(1) Dissolving phospholipid, cholesterol, polysorbate and probucol in a proper amount of chloroform, removing an organic solvent by reduced pressure rotary evaporation to form a film, adding a potassium hydrogen phthalate-sodium hydroxide buffer solution with pH of=5.2 for dispersion and shaking;
(2) Carrying out ultrasonic treatment on the product obtained in the step (1), and forming 30-80nm liposome by using a French extrusion method;
(3) And (3) freeze-drying the liposome obtained in the step (2) to obtain the liposome.
The freeze-drying procedure was:
a. pre-freezing: the temperature is minus 35 ℃ and the time is 2 hours;
b. sublimation: vacuum 20Pa, and heating to 2 ℃;
c. and (5) analysis and drying: heating to 20deg.C, and maintaining for 5 hr.
EXAMPLE 2 preparation of probucol liposomes
The formula comprises the following components:
the preparation method comprises the following steps:
(1) Dissolving phospholipid, cholesterol, polysorbate and probucol in a proper amount of chloroform, removing an organic solvent by reduced pressure rotary evaporation to form a film, adding a potassium hydrogen phthalate-sodium hydroxide buffer solution with pH of 4.5 for dispersion and shaking;
(2) Carrying out ultrasonic treatment on the product obtained in the step (1), and forming 30-80nm liposome by using a French extrusion method;
(3) And (3) freeze-drying the liposome obtained in the step (2) to obtain the liposome.
The freeze-drying procedure was:
a. pre-freezing: the temperature is minus 35 ℃ and the time is 2 hours;
b. sublimation: vacuum 20Pa, and heating to 2 ℃;
c. and (5) analysis and drying: the temperature was raised to 20℃and maintained for 5h.
EXAMPLE 3 preparation of probucol liposomes
The formula comprises the following components:
the preparation method comprises the following steps:
(1) Dissolving phospholipid, cholesterol, polysorbate and probucol in a proper amount of chloroform, removing an organic solvent by reduced pressure rotary evaporation to form a film, adding a potassium hydrogen phthalate-sodium hydroxide buffer solution with pH of=5.5 for dispersion and shaking;
(2) Carrying out ultrasonic treatment on the product obtained in the step (1), and forming 30-80nm liposome by using a French extrusion method;
(3) And (3) freeze-drying the liposome obtained in the step (2) to obtain the liposome.
The freeze-drying procedure was:
a. pre-freezing: the temperature is minus 35 ℃ and the time is 2 hours;
b. sublimation: vacuum 20Pa, and heating to 2 ℃;
c. and (5) analysis and drying: heating to 20deg.C, and maintaining for 5 hr.
EXAMPLE 4 preparation of probucol liposomes
The formula comprises the following components:
the preparation method comprises the following steps:
(1) Dissolving phospholipid, cholesterol, polysorbate and probucol in a proper amount of ethanol, removing an organic solvent by reduced pressure rotary evaporation to form a film, adding disodium hydrogen phosphate-citric acid buffer solution with pH of=5.0 for dispersion and shaking;
(2) Carrying out ultrasonic treatment on the product obtained in the step (1), and forming 30-80nm liposome by using a French extrusion method;
(3) And (3) freeze-drying the liposome obtained in the step (2) to obtain the liposome.
The freeze-drying procedure was:
a. pre-freezing: the temperature is-30 ℃ and the time is 3 hours;
b. sublimation: vacuum 10Pa, and heating to-5deg.C;
c. and (5) analysis and drying: the temperature was raised to 15C and held for 4h.
EXAMPLE 5 preparation of probucol liposomes
The formula comprises the following components:
the preparation method comprises the following steps:
(1) Dissolving phospholipid, cholesterol, polysorbate and probucol in proper amount of isopropanol, removing the organic solvent by reduced pressure rotary evaporation to form a film, adding acetic acid-sodium acetate buffer solution with pH of 4.8 for dispersion and shaking;
(2) Carrying out ultrasonic treatment on the product obtained in the step (1), and forming 30-80nm liposome by using a French extrusion method;
(3) And (3) freeze-drying the liposome obtained in the step (2) to obtain the liposome.
The freeze-drying procedure was:
a. pre-freezing: the temperature is-40 ℃ and the time is 1.5h;
b. sublimation: vacuum 30Pa, and heating to 5 ℃;
c. and (5) analysis and drying: the temperature was raised to 25℃and maintained for 6h.
EXAMPLE 6 preparation of probucol liposomes
The formula comprises the following components:
the preparation method comprises the following steps:
(1) Dissolving phospholipid, cholesterol, polysorbate, probucol and aspartic acid in a proper amount of mixed organic solvent of chloroform and methanol (volume ratio is 3:1), removing the organic solvent by reduced pressure rotary evaporation to form a film, adding potassium hydrogen phthalate-sodium hydroxide with pH=5.2 for dispersion and shaking;
(2) Carrying out ultrasonic treatment on the product obtained in the step (1), and forming 30-80nm liposome by using a French extrusion method;
(3) And (3) freeze-drying the liposome obtained in the step (2) to obtain the liposome.
The freeze-drying procedure was:
a. pre-freezing: the temperature is minus 35 ℃ and the time is 2 hours;
b. sublimation: vacuum 20Pa, and heating to 2 ℃;
c. and (5) analysis and drying: heating to 20deg.C, and maintaining for 5 hr.
EXAMPLE 7 preparation of probucol liposomes
The formula comprises the following components:
the preparation method comprises the following steps:
(1) Dissolving phospholipid, cholesterol, polysorbate, probucol and aspartic acid in a proper amount of mixed organic solvent of chloroform and isopropanol (volume ratio is 2:1), removing the organic solvent by reduced pressure rotary evaporation to form a film, adding potassium hydrogen phthalate-sodium hydroxide with pH=5.2 for dispersion and shaking;
(2) Carrying out ultrasonic treatment on the product obtained in the step (1), and forming 30-80nm liposome by using a French extrusion method;
(3) And (3) freeze-drying the liposome obtained in the step (2) to obtain the liposome.
The freeze-drying procedure was:
a. pre-freezing: the temperature is minus 35 ℃ and the time is 2 hours;
b. sublimation: vacuum 20Pa, and heating to 2 ℃;
c. and (5) analysis and drying: heating to 20deg.C, and maintaining for 5 hr.
Comparative example 1 preparation of probucol liposomes
The formula comprises the following components:
the preparation method comprises the following steps:
(1) Dissolving phospholipid, cholesterol, polysorbate and probucol in a proper amount of chloroform, removing an organic solvent by reduced pressure rotary evaporation to form a film, adding a potassium hydrogen phthalate-sodium hydroxide buffer solution with pH of=5.2 for dispersion and shaking;
(2) Carrying out ultrasonic treatment on the product obtained in the step (1), and forming 30-80nm liposome by using a French extrusion method;
(3) And (3) freeze-drying the liposome obtained in the step (2) to obtain the liposome.
The freeze-drying procedure was:
a. pre-freezing: the temperature is minus 35 ℃ and the time is 2 hours;
b. sublimation: vacuum 20Pa, and heating to 2 ℃;
c. and (5) analysis and drying: heating to 20deg.C, and maintaining for 5 hr.
Comparative example 2 preparation of probucol liposomes
The formula comprises the following components:
the preparation method comprises the following steps:
(1) Dissolving phospholipid, cholesterol, polysorbate and probucol in a proper amount of chloroform, removing an organic solvent by reduced pressure rotary evaporation to form a film, adding disodium hydrogen phosphate-citric acid buffer solution with pH of 6.5 for dispersion and shaking;
(2) Carrying out ultrasonic treatment on the product obtained in the step (1), and forming 30-80nm liposome by using a French extrusion method;
(3) And (3) freeze-drying the liposome obtained in the step (2) to obtain the liposome.
The freeze-drying procedure was:
a. pre-freezing: the temperature is minus 35 ℃ and the time is 2 hours;
b. sublimation: vacuum 20Pa, and heating to 2 ℃;
c. and (5) analysis and drying: heating to 20deg.C, and maintaining for 5 hr.
Comparative example 3 preparation of probucol liposomes
The formula comprises the following components:
the preparation method comprises the following steps:
(1) Dissolving phospholipid, cholesterol, polysorbate and probucol in a proper amount of chloroform, removing an organic solvent by reduced pressure rotary evaporation to form a film, adding an acetic acid-sodium acetate buffer solution with pH of=5.2 for dispersion and shaking;
(2) Forming 30-80nm liposome by using the product obtained in the step (1) through a French extrusion method;
(3) And (3) freeze-drying the liposome obtained in the step (2) to obtain the liposome.
The freeze-drying procedure was:
a. pre-freezing: the temperature is minus 35 ℃ and the time is 2 hours;
b. sublimation: vacuum 20Pa, and heating to 2 ℃;
c. and (5) analysis and drying: heating to 20deg.C, and maintaining for 5 hr.
Comparative example 4 preparation of probucol liposomes
The formula comprises the following components:
probucol 10g
Sphingomyelin 10g
Cholesterol 2g
The preparation method comprises the following steps:
(1) Dissolving phospholipid, cholesterol and probucol in a proper amount of chloroform, removing an organic solvent by reduced pressure rotary evaporation to form a film, adding a potassium hydrogen phthalate-sodium hydroxide buffer solution with pH=5.2 for dispersion and shaking;
(2) Carrying out ultrasonic treatment on the product obtained in the step (1), and forming 30-80nm liposome by using a French extrusion method;
(3) And (3) freeze-drying the liposome obtained in the step (2) to obtain the liposome.
The freeze-drying procedure was:
a. pre-freezing: the temperature is minus 35 ℃ and the time is 2 hours;
b. sublimation: vacuum 20Pa, and heating to 2 ℃;
c. and (5) analysis and drying: heating to 20deg.C, and maintaining for 5 hr.
Comparative example 5 preparation of probucol liposomes
The formula comprises the following components:
the preparation method comprises the following steps:
(1) Dissolving phospholipid, cholesterol, polysorbate and probucol in a proper amount of chloroform, removing an organic solvent by reduced pressure rotary evaporation to form a film, adding a potassium hydrogen phthalate-sodium hydroxide buffer solution with pH of=5.2 for dispersion and shaking;
(2) Carrying out ultrasonic treatment on the product obtained in the step (1), and forming 30-80nm liposome by using a French extrusion method;
(3) And (3) freeze-drying the liposome obtained in the step (2) to obtain the liposome.
The freeze-drying procedure was:
a. pre-freezing: the temperature is-20 ℃ and the time is 2 hours;
b. sublimation: vacuum 20Pa, and heating to 2 ℃;
c. and (5) analysis and drying: raising the temperature to 30 ℃ and keeping for 5 hours to obtain the product.
Comparative example 6 preparation of probucol liposomes
The formula comprises the following components:
the preparation method comprises the following steps:
(1) Dissolving phospholipid, cholesterol, polysorbate, probucol and glycine in a proper amount of chloroform, removing an organic solvent by reduced pressure rotary evaporation to form a film, adding a potassium hydrogen phthalate-sodium hydroxide buffer solution with pH of=5.2 for dispersion and shaking;
(2) Carrying out ultrasonic treatment on the product obtained in the step (1), and forming 30-80nm liposome by using a French extrusion method;
(3) And (3) freeze-drying the liposome obtained in the step (2) to obtain the liposome.
The freeze-drying procedure was:
a. pre-freezing: the temperature is minus 35 ℃ and the time is 2 hours;
b. sublimation: vacuum 20Pa, and heating to 2 ℃;
c. and (5) analysis and drying: heating to 20deg.C, and maintaining for 5 hr.
2. Preparation of probucol preparation
Example 8 probucol tablet (100 tablets)
The formula comprises the following components:
the preparation method comprises the following steps: according to the formula, the tablet is prepared by adopting a direct tabletting method.
EXAMPLE 9 probucol tablet (100 tablets)
The formula comprises the following components:
the preparation method comprises the following steps: according to the formula, the tablet is prepared by adopting a direct tabletting method.
EXAMPLE 10 probucol tablet (100 tablets)
The formula comprises the following components:
the preparation method comprises the following steps: according to the formula, the tablet is prepared by adopting a direct tabletting method.
EXAMPLE 11 probucol tablet (100 tablets)
The formula comprises the following components:
the preparation method comprises the following steps: according to the formula, the tablet is prepared by adopting a direct tabletting method.
EXAMPLE 12 probucol Capsule
The preparation method comprises the following steps: granulating according to the formula by wet method, and making into capsule.
EXAMPLE 13 probucol particles
The preparation method comprises the following steps: granulating according to the formula by wet method, and making into granule.
Comparative example 7: probucol tablet (le)
Verification embodiment
1. Quality evaluation of probucol liposome
1. Drug-loading rate and encapsulation rate research of probucol liposome
Table 1 examples and examples probucol liposomes drug loading and encapsulation efficiency
2. Leakage rate study of probucol liposomes
Each of the examples and comparative examples was stored at 0 ℃, 4 ℃, 25 ℃ and tested for drug leakage at 0d, 30d, 60d, 90d, 180d, respectively.
Table 2 examples and comparative examples probucol liposome leakage rate (%)
2. Quality evaluation of probucol preparation
1. Dissolution study of probucol formulations
Taking the probucol preparation of examples 8-13 and comparative example 7, measuring according to a second method of a four-part rule 0931 dissolution and release degree measuring method of Chinese pharmacopoeia 2020 edition, taking 900mL of phosphate buffer solution with pH=5.0 as a dissolution medium, adding 0.5% sodium dodecyl sulfate, 75r/min per minute by a paddle method, and taking the solution according to sampling time of 5min, 10min, 15min, 30min, 45min and 60min for measuring.
2. Stability investigation-content and related substance investigation
2.1 content determination is determined according to high performance liquid chromatography (general rule 0512) of Chinese pharmacopoeia 2020.
Test solution: taking about 25mg of the product, precisely weighing, placing into a 50ml measuring flask, adding mobile phase to dissolve and dilute to scale, shaking uniformly, precisely weighing 3ml, placing into a 10ml measuring flask, diluting to scale with mobile phase, and shaking uniformly.
Control solution: taking a proper amount of probucol reference substance, precisely weighing, adding a mobile phase for dissolution, and quantitatively diluting to prepare a solution containing about 0.15mg per 1 ml.
Chromatographic conditions: using octyl silane bonded silica gel as a filler; acetonitrile-water (85:15) as mobile phase; the detection wavelength is 242nm; the sample volume was 20. Mu.l.
System applicability requirements: the theoretical plate number is not lower than 2500 calculated according to probucol peaks.
Assay: precisely measuring the sample solution and the reference substance solution, respectively injecting into a liquid chromatograph, and recording the chromatograms. Calculated as peak area according to the external standard method.
2.2 related substances are measured according to high performance liquid chromatography (general rule 0512) of Chinese pharmacopoeia 2020.
Test solution: the product is taken, dissolved by adding a mobile phase and diluted to prepare a solution containing about 1mg of the product in each 1 ml.
Control solution: precisely measuring 1ml of the sample solution, placing in a 100ml measuring flask, diluting to scale with mobile phase, and shaking.
Chromatographic conditions: silica gel is used as a filler; absolute ethyl alcohol-n-hexane (1:4000) is used as a mobile phase; the detection wavelength is 242nm; the sample volume was 20. Mu.l.
System applicability requirements: the theoretical plate number is not less than 4000 calculated according to the probucol peak.
Assay: precisely measuring the sample solution and the control solution, respectively injecting into a liquid chromatograph, and recording the chromatogram till the retention time of the main component peak is 2 times.
Limit: the chromatogram of the sample solution has impurity peaks, and the sum of the areas of the impurity peaks is not greater than the main peak area (1.0%) of the control solution.
Acceleration test: and (3) packaging the materials on the market, standing the materials for 6 months at the temperature of 40+/-2 ℃ and the relative humidity of 75+/-5%, and respectively sampling the materials at the 1 st month, 2 months, 3 months and 6 months during the test period, and measuring the content of the related substances and the content of the probucol.
TABLE 3 stability investigation of the probucol formulations of examples 8-13, comparative example 7
Claims (10)
1. A method for preparing probucol liposome, which is characterized by comprising the following steps:
(1) Dissolving 0.5-1.5 parts by weight of phospholipid, 0.1-0.5 part by weight of cholesterol, 0.05-0.2 part by weight of polysorbate and 1 part by weight of probucol in a proper amount of organic solvent, removing the organic solvent by reduced pressure rotary evaporation to form a film, adding a buffer solution with pH of 4.5-5.5 for dispersion and shaking;
(2) Carrying out ultrasonic treatment on the product obtained in the step (1), and forming 30-80nm liposome by using a French extrusion method;
(3) Freeze-drying the liposome obtained in the step (2) to obtain the liposome;
the freeze-drying procedure was:
a. pre-freezing: the temperature is minus 30 to minus 40 ℃ and the time is 1.5 to 3 hours;
b. sublimation: vacuum 10-30Pa, and heating to-5-5deg.C;
c. and (5) analysis and drying: raising the temperature to 15-25 ℃ and keeping for 4-6h;
the phospholipid is at least one of phosphatidylcholine, sphingomyelin and phosphatidylinositol.
2. The method of claim 1, wherein the pH of the buffer is = 5.2.
3. The method of claim 1, wherein the organic solvent is at least one of chloroform, ethanol, isopropanol, and methanol.
4. A method according to claim 3, wherein the organic solvent is chloroform.
5. The method of claim 1, wherein the buffer solution is one of disodium hydrogen phosphate-citric acid buffer, acetic acid-sodium acetate buffer, potassium hydrogen phthalate-sodium hydroxide buffer.
6. The method of claim 5, wherein the buffer solution is potassium hydrogen phthalate-sodium hydroxide buffer.
7. The method of claim 1, wherein the phospholipid is sphingomyelin.
8. The method according to claim 1, wherein 0.05 to 0.1 parts by weight of aspartic acid is further added in the step (1).
9. A probucol liposome prepared by the method of claim 1 or claim 8.
10. A preparation containing the probucol liposome according to claim 9, characterized in that the preparation contains pharmaceutically acceptable auxiliary materials, and the preparation is a tablet, a granule or a capsule.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211030139.1A CN115364056B (en) | 2022-08-26 | 2022-08-26 | Probucol liposome for hypercholesterolemia, preparation and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211030139.1A CN115364056B (en) | 2022-08-26 | 2022-08-26 | Probucol liposome for hypercholesterolemia, preparation and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115364056A CN115364056A (en) | 2022-11-22 |
| CN115364056B true CN115364056B (en) | 2023-07-11 |
Family
ID=84067412
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211030139.1A Active CN115364056B (en) | 2022-08-26 | 2022-08-26 | Probucol liposome for hypercholesterolemia, preparation and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115364056B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2711369A1 (en) * | 2012-09-20 | 2014-03-26 | Bernina Plus GmbH | Liposomes containing tetraether lipid derivatives |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6773719B2 (en) * | 1994-03-04 | 2004-08-10 | Esperion Luv Development, Inc. | Liposomal compositions, and methods of using liposomal compositions to treat dislipidemias |
-
2022
- 2022-08-26 CN CN202211030139.1A patent/CN115364056B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2711369A1 (en) * | 2012-09-20 | 2014-03-26 | Bernina Plus GmbH | Liposomes containing tetraether lipid derivatives |
Non-Patent Citations (1)
| Title |
|---|
| 脂质体制备方法的选择;孙庆雪 等;中成药;第32卷(第08期);第1397-1401页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115364056A (en) | 2022-11-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103705485B (en) | Composite for treating myelodysplastic syndrome and preparation method thereof | |
| CN102232937A (en) | Nanometer preparation and preparation method thereof | |
| CN109662950B (en) | Pharmaceutical composition containing dapoxetine hydrochloride | |
| CN105125545A (en) | Medicine composition containing pitavastatin calcium and preparing method thereof | |
| CN101766578B (en) | Tablet containing Rosuvastatin calcium and preparation process thereof | |
| CN104586804A (en) | Preparation method for letrozole tablets with good stability | |
| CN115364056B (en) | Probucol liposome for hypercholesterolemia, preparation and preparation method thereof | |
| CN101020060A (en) | Cyclodextrin clathrate of entecavir and its prepn proces and medicinal application | |
| CN105732517A (en) | Medicine preparation containing 5-fluorouracil drug eutectic with nicotinamide as precursor and preparation method of medicine preparation | |
| CN106309395A (en) | Tacrolimus sustained-release tablets and preparation method thereof | |
| CN102600149B (en) | Pharmaceutical composition for treating diabetes | |
| CN103356495B (en) | A kind of Letrozole tablet and preparation method thereof | |
| CN106860408B (en) | Glimepiride tablet | |
| CN109381431B (en) | Huperzine A sustained-release pellet and preparation method thereof | |
| CN103385863B (en) | Sodium azulene sulfonate sustained-release preparation | |
| CN114767633B (en) | Solid dispersion containing anti-breast cancer medicament tamoxifen, preparation method and preparation | |
| CN115040482B (en) | Irbesartan liposome for treating hypertension, preparation and preparation method thereof | |
| CN103709329B (en) | A kind of dispersive tablets of Fuyankang for gynecological inflammation pharmaceutical excipient compound and preparation method thereof and application | |
| CN113133977B (en) | Afatinib maleate tablet and preparation method thereof | |
| CN100484515C (en) | Guacetisal dry-mixing suspending agents and method of preparing the same | |
| CN116211868B (en) | Cefixime antibiotic tablet and preparation method thereof | |
| CN113368066B (en) | Icariin tablet and preparation method thereof | |
| CN115177591A (en) | Candesartan cilexetil-containing liposome, composition and preparation method of composition | |
| CN102038663B (en) | Carbazole sulfonamide antineoplastic agent capsules and preparation method | |
| CN106667916A (en) | Sorafenib tosylate-mesoporous silica solid dispersion and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |