CN114159575B - Domperidone sustained release preparation and sustained release carrier - Google Patents
Domperidone sustained release preparation and sustained release carrier Download PDFInfo
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- CN114159575B CN114159575B CN202210022491.4A CN202210022491A CN114159575B CN 114159575 B CN114159575 B CN 114159575B CN 202210022491 A CN202210022491 A CN 202210022491A CN 114159575 B CN114159575 B CN 114159575B
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- domperidone
- sustained release
- sodium
- attapulgite
- preparation
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- FGXWKSZFVQUSTL-UHFFFAOYSA-N domperidone Chemical compound C12=CC=CC=C2NC(=O)N1CCCN(CC1)CCC1N1C2=CC=C(Cl)C=C2NC1=O FGXWKSZFVQUSTL-UHFFFAOYSA-N 0.000 title claims abstract description 93
- 229960001253 domperidone Drugs 0.000 title claims abstract description 93
- 238000013268 sustained release Methods 0.000 title claims abstract description 29
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 29
- 239000003405 delayed action preparation Substances 0.000 title claims abstract description 25
- 229910052625 palygorskite Inorganic materials 0.000 claims abstract description 88
- 229960000892 attapulgite Drugs 0.000 claims abstract description 87
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims abstract description 33
- 239000000463 material Substances 0.000 claims abstract description 21
- 238000002360 preparation method Methods 0.000 claims abstract description 16
- -1 vinyl pyrrolidone modified sodium Chemical class 0.000 claims abstract description 8
- 239000000843 powder Substances 0.000 claims description 37
- 239000002131 composite material Substances 0.000 claims description 24
- 238000002156 mixing Methods 0.000 claims description 23
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 22
- 239000000945 filler Substances 0.000 claims description 17
- 239000000314 lubricant Substances 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 238000009472 formulation Methods 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 12
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 12
- 239000011230 binding agent Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 11
- 239000002245 particle Substances 0.000 claims description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 238000000498 ball milling Methods 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 6
- 229920000881 Modified starch Polymers 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000000853 adhesive Substances 0.000 claims description 6
- 230000001070 adhesive effect Effects 0.000 claims description 6
- 238000005342 ion exchange Methods 0.000 claims description 6
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 6
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 6
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 3
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 3
- 210000004051 gastric juice Anatomy 0.000 claims description 3
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 3
- 229910002012 Aerosil® Inorganic materials 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims 2
- 229920002554 vinyl polymer Polymers 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000011734 sodium Substances 0.000 abstract description 29
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 abstract description 28
- 229910052708 sodium Inorganic materials 0.000 abstract description 28
- 239000003814 drug Substances 0.000 abstract description 16
- 229940079593 drug Drugs 0.000 abstract description 14
- 231100000419 toxicity Toxicity 0.000 abstract description 3
- 230000001988 toxicity Effects 0.000 abstract description 3
- 230000000694 effects Effects 0.000 description 14
- 238000001035 drying Methods 0.000 description 9
- 238000007873 sieving Methods 0.000 description 9
- 229940069328 povidone Drugs 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 239000007939 sustained release tablet Substances 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 230000001186 cumulative effect Effects 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 5
- 239000008367 deionised water Substances 0.000 description 5
- 229910021641 deionized water Inorganic materials 0.000 description 5
- 229960002949 fluorouracil Drugs 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 239000007884 disintegrant Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 230000002496 gastric effect Effects 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000001878 scanning electron micrograph Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 239000004927 clay Substances 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000005176 gastrointestinal motility Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000012844 infrared spectroscopy analysis Methods 0.000 description 2
- 239000002073 nanorod Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 241000282412 Homo Species 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- HZVVJJIYJKGMFL-UHFFFAOYSA-N almasilate Chemical compound O.[Mg+2].[Al+3].[Al+3].O[Si](O)=O.O[Si](O)=O HZVVJJIYJKGMFL-UHFFFAOYSA-N 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000005452 bending Methods 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000002734 clay mineral Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 229910000514 dolomite Inorganic materials 0.000 description 1
- 239000010459 dolomite Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229910021485 fumed silica Inorganic materials 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000009830 intercalation Methods 0.000 description 1
- 230000002687 intercalation Effects 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 239000007777 multifunctional material Substances 0.000 description 1
- KBJFYLLAMSZSOG-UHFFFAOYSA-N n-(3-trimethoxysilylpropyl)aniline Chemical compound CO[Si](OC)(OC)CCCNC1=CC=CC=C1 KBJFYLLAMSZSOG-UHFFFAOYSA-N 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Classifications
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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
- A61K47/02—Inorganic compounds
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Hospice & Palliative Care (AREA)
- Otolaryngology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a sustained release carrier of domperidone, which is sodium attapulgite modified by vinyl pyrrolidone. The invention also discloses a domperidone sustained release preparation which comprises domperidone, vinyl pyrrolidone modified sodium attapulgite serving as a sustained release carrier and pharmaceutically acceptable auxiliary materials. Compared with the prior domperidone preparation, the domperidone sustained-release preparation of the invention not only has good drug sustained-release performance, obviously improves the bioavailability of the domperidone, but also can reduce the toxicity of the drug to cells.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a domperidone sustained release preparation.
Background
Domperidone is a gastrointestinal motility regulator, mainly acts on the proximal gastrointestinal tract, can accelerate food digestion, treats nausea and vomiting, and has wide clinical application. Because the prior domperidone tablet has lower bioavailability and shorter half-life period, the development of a slow release preparation is inevitable.
The slow release carrier is one of modes for preparing the slow release preparation, the bonding strength between different slow release carriers and different drug molecules is greatly different and lacks predictability, if the bonding effect is too weak, sudden release is easy to generate, the slow release purpose cannot be achieved, if the bonding effect is too strong, the drug is difficult to release, the dosage is required to be obviously increased in order to achieve the effective concentration of the drug, the potential safety problem is further generated, and most of the drug is not released in vivo and is discharged out of the body along with the carrier, so that the effect of improving the bioavailability of the drug cannot be achieved. Therefore, the qualified sustained release carrier is one of key technologies for developing the domperidone sustained release preparation, and in addition, the good sustained release agent can also reduce the toxicity of the drug to cells.
Attapulgite clay, also known as palygorskite, is a clay mineral of layered chain structure and containing water-containing magnesium aluminosilicate. Attapulgite has a plurality of special performances due to the unique structure. In recent years, the attapulgite is used as a multifunctional material with low price, abundant reserves and biological safety, and has rapid application and development in the field of medicine. For example, "preparation of 5-fluorouracil-loaded modified attapulgite and slow release property study" (Pan Chunyan et al, sichuan journal of chemical industry, volume 24, phase 1, pages 5-9) reports that the 5-fluorouracil-loaded modified attapulgite has better slow release property for the antitumor drug 5-fluorouracil by using hydrochloric acid and trimethoxy [3- (phenylamino) propyl ] silane modified attapulgite as carrier materials, and the cumulative release rate of the 5-fluorouracil-loaded modified attapulgite in simulated gastric fluid for 2.5 hours can be increased to about 7.2% from about 4% of the 5-fluorouracil-loaded unmodified attapulgite. However, too low a release rate for domperidone to act mainly on the gastrointestinal tract to perform gastrointestinal motility regulation does not have the effect of improving its bioavailability.
The "influence of sodium carbonate modification on physical and chemical properties of attapulgite" (Xiong Lian et al, new energy development, volume 6, 2018, pages 533-538) reports that Na is obtained when sodium carbonate is used as a sodium treatment agent for wet sodium treatment of attapulgite + With Al in the attapulgite crystal structure 3+ 、Mg 2+ Ion exchange occurs to form sodium-modified attapulgite.
Disclosure of Invention
Based on the shortcomings of the prior art, the invention aims to provide a domperidone sustained release preparation and a sustained release carrier special for domperidone.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
a sustained release carrier of domperidone, which is characterized in that: the slow release carrier is sodium-modified attapulgite modified by vinyl pyrrolidone.
The preparation method of the slow release carrier comprises the steps of mixing and contacting the sodium modified attapulgite and vinyl pyrrolidone in a solvent, and then separating to obtain the vinyl pyrrolidone modified sodium modified attapulgite.
Preferably, the dosage of the vinyl pyrrolidone is 10-20% of the mass of the sodium-modified attapulgite.
Preferably, the solvent is water.
Preferably, the sodium-modified attapulgite is prepared by a method comprising the steps of: and carrying out ion exchange on the attapulgite and sodium carbonate in water to obtain the sodium-modified attapulgite.
A domperidone sustained release preparation, which is characterized in that: the domperidone sustained release preparation comprises domperidone, a sustained release carrier as described above and pharmaceutically acceptable auxiliary materials.
Preferably, the mass ratio of the domperidone to the slow release carrier is 5-15:10.
More preferably, in the domperidone sustained release preparation, the mass percentage content of the domperidone is 5-15%.
Preferably, the domperidone sustained release formulation is a tablet.
Preferably, the pharmaceutically acceptable auxiliary materials are fillers, disintegrants, lubricants and binders.
More preferably, the mass ratio of the filler, the disintegrating agent, the lubricant and the binder is 60-80:1-10:1-5:0.01-0.5.
More preferably, the filler is pregelatinized starch or lactose.
More preferably, the disintegrating agent is one or more of microcrystalline cellulose, low-substituted hydroxypropyl cellulose and croscarmellose sodium.
More preferably, the lubricant is one or more of aerosil, magnesium stearate and talcum powder.
More preferably, the binder is polyvinylpyrrolidone.
Preferably, in the artificial gastric juice, the cumulative release rate of domperidone in the domperidone sustained release preparation for 1 hour is 25-35%, and the cumulative release rate for 8 hours is 70-80%.
The preparation method of the domperidone sustained release preparation comprises the following steps:
firstly, mixing domperidone with a slow-release carrier, and ball milling to obtain composite powder;
and mixing the composite powder with pharmaceutically acceptable auxiliary materials.
When the preparation is a tablet, the compound powder and pharmaceutically acceptable auxiliary materials are uniformly mixed and then tabletting is carried out, thus obtaining the domperidone sustained-release tablet.
Preferably, the particle size of the composite powder is not less than 75 microns.
Advantageous effects
Compared with the prior domperidone preparation, the invention adopts the sodium attapulgite modified by the vinyl pyrrolidone as the drug sustained-release carrier of the domperidone, and the prepared domperidone sustained-release preparation not only has good drug sustained-release performance, obviously improves the bioavailability of the domperidone, but also can reduce the toxicity of the drug to cells.
Drawings
FIG. 1 is a graph showing the cumulative release profile of the domperidone sustained release formulation of the present invention in artificial simulated gastric fluid.
FIG. 2 is an infrared spectrum of the M-ATP/DOM composite powder of the present invention.
FIG. 3 is an XRD curve of the M-ATP/DOM composite powder of the present invention.
FIG. 4 is a scanning electron micrograph of the M-ATP/DOM composite powder of the present invention.
FIG. 5 shows the results of an activity test of the M-ATP/DOM composite powder of the present invention on human gastric mucosal epithelial cells.
Detailed Description
The technical scheme of the invention is further described in detail below with reference to the attached drawings and the preferred embodiments.
The domperidone sustained release preparation of the invention mainly comprises the following components: domperidone, a slow release carrier and pharmaceutically acceptable auxiliary materials, wherein the slow release carrier adopts vinyl pyrrolidone modified sodium attapulgite.
In the domperidone sustained release preparation, the mass ratio of domperidone to a sustained release carrier can be controlled to be 5-15:10.
In some embodiments of the invention, the mass ratio of domperidone to sustained release carrier is 5:10, 6:10, 7:10, 8:10, 9:10, 10:10, 11:10, 12:10, 13:10, 14:10, or 15:10.
In the domperidone sustained release preparation, the mass percentage of the domperidone can be controlled to be 5-15%.
In some embodiments of the present invention, the mass percentage of domperidone in the domperidone sustained release formulation is 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15%.
The formulation of the domperidone sustained release preparation is not particularly limited in the present invention.
In some embodiments of the invention, the sustained release formulation of domperidone is a tablet.
The preparation process of the domperidone sustained release preparation comprises the following steps:
(1) Firstly, mixing domperidone with a slow-release carrier, and ball milling to obtain composite powder;
(2) And mixing the composite powder with pharmaceutically acceptable auxiliary materials for molding.
Compared with the simultaneous mixing, the domperidone is firstly ball-milled and compounded with the slow release carrier, and then is mixed with other auxiliary materials, so that the domperidone and the vinyl pyrrolidone modified sodium attapulgite serving as the slow release carrier can generate a mechanochemical effect, the domperidone is firmly combined on the surface of the slow release carrier, the occupation of other auxiliary materials on the surface of the slow release carrier is reduced, and the stable release of the domperidone medicine is provided.
Taking the tablets as the class, uniformly mixing the composite powder with pharmaceutically acceptable auxiliary materials, and tabletting to obtain the domperidone sustained-release tablet.
The particle size of the composite powder used for tabletting is not less than 75 microns.
In some embodiments of the invention, the pharmaceutically acceptable excipients selected for the tablet include fillers, disintegrants, lubricants and binders.
In some embodiments of the invention, the filler is selected from pregelatinized starch or lactose.
In some embodiments of the invention, the disintegrant is selected from one or more of microcrystalline cellulose, low substituted hydroxypropyl cellulose, croscarmellose sodium.
In some embodiments of the invention, the lubricant is selected from one or more of fumed silica, magnesium stearate, and talc.
In some embodiments of the invention, the binder is selected from povidone.
In some embodiments of the present invention, the mass ratio of filler, disintegrant, lubricant and binder is 60-80:1-10:1-5:0.01-0.5.
In some embodiments of the invention, povidone is mixed with the composite powder as a povidone solution having a concentration of 1% to 5% by mass.
In the invention, the preparation process of the vinyl pyrrolidone modified sodium attapulgite comprises the following steps:
(1) Sodium modification of attapulgite to obtain sodium modified attapulgite;
(2) And (3) fully mixing and contacting the sodium attapulgite with the vinyl pyrrolidone in a solvent, and then separating to obtain the vinyl pyrrolidone modified sodium attapulgite.
In some embodiments of the invention, the sodium treatment of attapulgite is performed by wet sodium treatment, and the specific process comprises: and (3) carrying out sufficient ion exchange on the attapulgite and sodium carbonate in water to obtain the sodium-modified attapulgite.
The mass ratio of the attapulgite to the sodium carbonate can be controlled to be 100:1-10.
In some embodiments of the invention, the mass ratio of attapulgite to sodium carbonate is 100:1, 100:2, 100:3, 100:4, 100:5, 100:6, 100:7, 100:8, 100:9, 100:10.
When the wet sodium treatment is carried out, the concentration of the attapulgite in the system can be controlled to be 1-10wt%.
In some embodiments of the present invention, the concentration of attapulgite in the system upon wet sodium modification is 1wt%, 2wt%, 3wt%, 4wt%, 5wt%, 6wt%, 7wt%, 8wt%, 9wt%, 10wt%.
During ion exchange, the stirring speed can be controlled to be 400-550 r.min -1 The time is controlled to be 4-6 hours.
In some embodiments of the invention, the mixing contact is performed according to the amount of the vinyl pyrrolidone which is 10-20% of the mass of the sodium-modified attapulgite.
In some embodiments of the invention, the solvent may be water, and the mixing time may be controlled to 1-5 h after dissolving the vinyl pyrrolidone in water and then fully mixing with the sodium-modified attapulgite.
The term english abbreviations:
PVP: povidone (also known as polyvinylpyrrolidone)
ATP: attapulgite
Na-ATP: sodium modified attapulgite
M-ATP: vinyl pyrrolidone modified sodium attapulgite
DOM: domperidone
NVP: vinyl pyrrolidone (also known as 1-vinyl-2-pyrrolidone).
1. In vitro Release Properties
Fig. 1 is a cumulative release profile of the domperidone sustained release formulation of the present invention in artificial gastric juice. As can be seen from the graph, the cumulative release rates of the drug at 1h, 2 h, 6h and 12 h were 29%,54%,72% and 78%, respectively. The M-ATP is used as a carrier material to effectively control the release rate of domperidone, the release time can reach 12 hours, and the sustained-release effect is good.
2. Infrared spectroscopic analysis
FIG. 2 is an infrared spectrum of M-ATP, DOM,5% M-ATP/DOM and 10% M-ATP/DOM. As seen from the infrared spectrum of DOM, the absorption bands were 3127cm respectively -1 (N-H stretching vibration peak), 1695cm -1 (C=O stretching vibration peak), 1623cm -1 (N-H bending vibration peak), 1487cm -1 (C=C stretching vibration peak), 1270cm -1 (C-N asymmetric stretching vibration peak), 1066cm -1 (C-N symmetrical stretching vibration peak), in contrast, the absorption band of N-H in the infrared spectrum of M-ATP/DOM is from 3127cm -1 Transfer to 3138 cm -1 This indicates that in the composite powder M-ATP/DOM, there is a hydrogen bond interaction between the organic groups on the surface of M-ATP and N-H in the DOM molecule.
3. XRD profiling
FIG. 3 is an XRD plot of ATP, M-ATP, DOM,5% M-ATP/DOM, and 10% M-ATP/DOM. As can be seen from the XRD profile of ATP, the characteristic peaks at 2θ=8.48 °, 19.83 °, 20.86 °, 27.94 ° and 35.12 ° correspond to the characteristic reflections of the 110, 040, 121, 400 and 161 crystal planes of attapulgite. In addition, the characteristic peaks at 2θ= 26.64 ° and 30.88 ° belong to the characteristic reflections of quartz and dolomite crystal planes. The XRD pattern of the M-ATP sample was essentially the same as that of ATP, indicating that the modification treatment of sodium carbonate and vinylpyrrolidone had no effect on the crystal structure of ATP. Further analysis, the XRD pattern of the M-ATP/DOM sample was substantially the same as that of M-ATP, indicating that the loading of domperidone did not affect the crystal structure of attapulgite, as the drug molecules were only bound on the surface of attapulgite without intercalation.
In the above infrared spectroscopy analysis and XRD analysis, a tablet having 5% M-ATP/DOM of 5% by weight and 10% of DOM by weight, and a tablet having 10% M-ATP/DOM of 10% by weight and 10% of DOM by weight were prepared in the same manner as in example 1.
4. Microstructure analysis
Fig. 4 (a) is an SEM image of ATP, from which it can be seen that the ATP rod-like crystals tend to exist in parallel aggregates or clusters due to the effects of van der waals forces and hydrogen bonding on their surfaces. Fig. 4 (b) is an SEM image of M-ATP/DOM, and it can be seen that after the ATP modified with sodium carbonate and vinylpyrrolidone is loaded with domperidone, the ATP nanorods are covered with a plurality of spherical domperidone particles, and the domperidone particles are firmly fixed on the ATP nanorod surface and uniformly distributed.
5. In vitro cytotoxicity assay
FIG. 5 is a graph showing the activity of DOM, M-ATP and M-ATP/DOM powder on human gastric mucosal epithelial cells. From the graph, the concentration of DOM and M-ATP is in the range of 20-100 mug/mL, good cell compatibility is shown, and the cell activity does not change significantly with the increase of the concentration. This reveals that attapulgite is a biologically safe clay that is not harmful to humans. The measured cell activity of the M-ATP/DOM powder is obviously increased, which shows that the sustained release tablet not only has excellent cell compatibility, but also has the effect of promoting cell growth.
Example 1
Step 1: 100g of attapulgite and 5g of sodium carbonate are added into 1.9L of deionized water together, and the stirring speed is 400-550 r min -1 Stirring for 4-6 h to make sodium carbonate and attapulgite undergo the processes of ion exchange, then making the mixed solution undergo the processes of centrifugation, washing, drying, pulverizing and sieving so as to obtain the invented sodium-modified attapulgite, and marking it as Na-ATP.
Step 2: dissolving a certain amount of vinyl pyrrolidone (NVP) in water, adding sodium attapulgite, wherein the concentration of the sodium attapulgite is 10wt%, the dosage of the vinyl pyrrolidone is 10% of the mass of the sodium attapulgite, oscillating for 3 hours at constant temperature, and then sequentially filtering, washing with deionized water, drying, crushing and sieving the mixed solution to obtain the organic attapulgite, wherein the organic attapulgite is marked as M-ATP.
Step 3: uniformly mixing the organized attapulgite and domperidone in the step 2 in a mass ratio of 5:10, performing ball milling, drying and sieving treatment to obtain composite powder of the organized attapulgite and the domperidone, and marking M-ATP/DOM. The particle size of the powder used for final tabletting is not less than 75 and um.
Step 4: and 3, uniformly mixing the composite powder in the step 3 with other auxiliary materials by a powder direct tabletting method, and tabletting to obtain the domperidone sustained release tablet. Wherein, other auxiliary materials are as follows: the filler adopts pregelatinized starch, the disintegrating agent adopts microcrystalline cellulose, the lubricant adopts micro-powder silica gel, the binder adopts povidone solution with the mass percent concentration of 2%, and the mass ratio of the filler, the disintegrating agent, the lubricant, the binder and domperidone is 80:1:1:10:10.
Example 2
Step 1: the preparation of sodium attapulgite was the same as in example 1.
Step 2: dissolving a certain amount of vinyl pyrrolidone in water, adding sodium attapulgite, wherein the concentration of the sodium attapulgite is 10wt%, the dosage of the vinyl pyrrolidone is 15% of the mass of the sodium attapulgite, oscillating for 3 hours at constant temperature, and then sequentially filtering, washing with deionized water, drying, crushing and sieving the mixed solution to obtain the organic attapulgite, wherein the organic attapulgite is marked as M-ATP.
Step 3: uniformly mixing the organized attapulgite and domperidone in the step 2 in a mass ratio of 10:10, ball milling, drying and sieving to obtain the composite powder of the organized attapulgite and the domperidone, and marking M-ATP/DOM. The particle size of the powder used for final tabletting is not less than 75 and um.
Step 4: and 3, uniformly mixing the composite powder in the step 3 with other auxiliary materials by a powder direct tabletting method, and tabletting to obtain the domperidone sustained release tablet. Wherein, other auxiliary materials are as follows: lactose is adopted as the filler, microcrystalline cellulose is adopted as the disintegrating agent, micro powder silica gel is adopted as the lubricant, 5% povidone solution is adopted as the binder, and the mass ratio of the filler, the disintegrating agent, the lubricant, the binder and domperidone is 60:10:5:10:10.
Example 3
Step 1: the preparation of sodium attapulgite was the same as in example 1.
Step 2: dissolving a certain amount of vinyl pyrrolidone in water, adding sodium attapulgite, wherein the concentration of the sodium attapulgite is 10wt%, the dosage of the vinyl pyrrolidone is 15% of the mass of the sodium attapulgite, oscillating for 5 hours at constant temperature, and then sequentially filtering, washing with deionized water, drying, crushing and sieving the mixed solution to obtain the organic attapulgite, wherein the mark is M-ATP.
Step 3: uniformly mixing the organized attapulgite and domperidone in the step 2 in a mass ratio of 15:10, performing ball milling, drying and sieving treatment to obtain composite powder of the organized attapulgite and the domperidone, and marking M-ATP/DOM. The particle size of the powder used for final tabletting is not less than 75 and um.
Step 4: and 3, uniformly mixing the composite powder in the step 3 with other auxiliary materials by a powder direct tabletting method, and tabletting to obtain the domperidone sustained release tablet. Wherein, other auxiliary materials are as follows: the filler adopts pregelatinized starch, the disintegrating agent adopts crosslinked sodium carboxymethyl cellulose, the lubricant adopts magnesium stearate, the adhesive adopts povidone solution with the mass percentage concentration of 1%, and the mass ratio of the filler, the disintegrating agent, the lubricant, the adhesive and domperidone is 70:3:2:1:10.
Example 4
Step 1: the preparation of sodium attapulgite was the same as in example 1.
Step 2: dissolving a certain amount of vinyl pyrrolidone in water, adding sodium attapulgite, wherein the concentration of the sodium attapulgite is 10wt%, the dosage of the vinyl pyrrolidone is 20% of the mass of the sodium attapulgite, oscillating for 1h at constant temperature, and then sequentially filtering, washing with deionized water, drying, crushing and sieving the mixed solution to obtain the organic attapulgite, wherein the mark is M-ATP.
Step 3: uniformly mixing the organized attapulgite and domperidone in the step 2 in a mass ratio of 10:10, ball milling, drying and sieving to obtain the composite powder of the organized attapulgite and the domperidone, and marking M-ATP/DOM. The particle size of the powder used for final tabletting is not less than 75 and um.
Step 4: and 3, uniformly mixing the composite powder in the step 3 with other auxiliary materials by a powder direct tabletting method, and tabletting to obtain the domperidone sustained release tablet. Wherein, other auxiliary materials are as follows: the filler adopts pregelatinized starch, the disintegrating agent adopts microcrystalline cellulose, the lubricant adopts talcum powder, the adhesive adopts povidone solution with the mass percent concentration of 3%, and the mass ratio of the filler, the disintegrating agent, the lubricant, the adhesive and domperidone is 70:5:5:5:10.
Finally, it should be noted that: the foregoing description is only a preferred embodiment of the present invention, and the present invention is not limited thereto, but it is to be understood that modifications and equivalents of some of the technical features described in the foregoing embodiments may be made by those skilled in the art, although the present invention has been described in detail with reference to the foregoing embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (14)
1. A sustained release carrier of domperidone, which is characterized in that: the slow release carrier is vinyl pyrrolidone modified sodium attapulgite;
the slow release carrier is prepared by the following method:
comprises the steps of mixing and contacting sodium-modified attapulgite with vinyl pyrrolidone in a solvent, and then separating to obtain vinyl pyrrolidone-modified sodium-modified attapulgite;
the dosage of the vinyl pyrrolidone is 10-20% of the mass of the sodium-modified attapulgite.
2. The method for preparing the sustained-release carrier according to claim 1, wherein: comprises the steps of mixing and contacting sodium-modified attapulgite with vinyl pyrrolidone in a solvent, and then separating to obtain vinyl pyrrolidone-modified sodium-modified attapulgite; the dosage of the vinyl pyrrolidone is 10-20% of the mass of the sodium-modified attapulgite.
3. The preparation method according to claim 2, characterized in that: the solvent is water.
4. The preparation method according to claim 2, characterized in that: the sodium-modified attapulgite is prepared by a method comprising the following steps: and carrying out ion exchange on the attapulgite and sodium carbonate in water to obtain the sodium-modified attapulgite.
5. A domperidone sustained release preparation, which is characterized in that: the domperidone sustained release preparation comprises domperidone, a sustained release carrier as claimed in claim 1 and pharmaceutically acceptable auxiliary materials.
6. The domperidone sustained release formulation according to claim 5, wherein: the mass ratio of the domperidone to the slow release carrier is 5-15:10.
7. The domperidone sustained release formulation according to claim 6, wherein: in the domperidone sustained release preparation, the mass percentage content of the domperidone is 5-15%.
8. The domperidone sustained release formulation according to claim 5, wherein: the domperidone sustained release preparation is a tablet.
9. The domperidone sustained release formulation of claim 8, wherein: the pharmaceutically acceptable auxiliary materials comprise a filler, a disintegrating agent, a lubricant and an adhesive.
10. The domperidone sustained release formulation according to claim 9, wherein: the mass ratio of the filler to the disintegrating agent to the lubricant to the binder is 60-80:1-10:1-5:0.01-0.5.
11. The domperidone sustained release formulation according to claim 9, wherein:
the filler is pregelatinized starch or lactose;
the disintegrating agent is one or more of microcrystalline cellulose, low-substituted hydroxypropyl cellulose and croscarmellose sodium;
the lubricant is one or more of aerosil, magnesium stearate and talcum powder;
the adhesive is polyvinylpyrrolidone.
12. The domperidone sustained release preparation according to any one of claims 5 to 11, characterized in that: the domperidone sustained release preparation is characterized in that in artificial gastric juice, the accumulated release rate of domperidone in 1 hour is 25-35%, and the accumulated release rate in 8 hours is 70-80%.
13. The preparation method of the domperidone sustained release preparation according to any one of claims 5 to 12, comprising:
firstly, mixing domperidone with a slow-release carrier, and ball milling to obtain composite powder;
and mixing the composite powder with pharmaceutically acceptable auxiliary materials.
14. The method of manufacturing according to claim 13, wherein: the particle size of the composite powder is not less than 75 microns.
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