CN115444831B - Epalrestat gastric floating tablet and preparation method thereof - Google Patents
Epalrestat gastric floating tablet and preparation method thereof Download PDFInfo
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- CN115444831B CN115444831B CN202211307218.2A CN202211307218A CN115444831B CN 115444831 B CN115444831 B CN 115444831B CN 202211307218 A CN202211307218 A CN 202211307218A CN 115444831 B CN115444831 B CN 115444831B
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- CHNUOJQWGUIOLD-NFZZJPOKSA-N epalrestat Chemical compound C=1C=CC=CC=1\C=C(/C)\C=C1/SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-NFZZJPOKSA-N 0.000 title claims abstract description 59
- 229950010170 epalrestat Drugs 0.000 title claims abstract description 59
- CHNUOJQWGUIOLD-UHFFFAOYSA-N epalrestate Natural products C=1C=CC=CC=1C=C(C)C=C1SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-UHFFFAOYSA-N 0.000 title claims abstract description 59
- 230000002496 gastric effect Effects 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title abstract description 24
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 38
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 38
- 239000000463 material Substances 0.000 claims abstract description 12
- 239000000203 mixture Substances 0.000 claims description 43
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims description 24
- 239000011248 coating agent Substances 0.000 claims description 23
- 238000000576 coating method Methods 0.000 claims description 21
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 20
- 239000003795 chemical substances by application Substances 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 12
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 claims description 12
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 11
- 239000008101 lactose Substances 0.000 claims description 10
- 235000019359 magnesium stearate Nutrition 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 9
- 238000007873 sieving Methods 0.000 claims description 9
- 239000000945 filler Substances 0.000 claims description 8
- 239000000314 lubricant Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 238000004061 bleaching Methods 0.000 claims description 7
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 238000005303 weighing Methods 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 239000007779 soft material Substances 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 3
- 239000012153 distilled water Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical group [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 7
- 238000000338 in vitro Methods 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000007844 bleaching agent Substances 0.000 abstract description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 abstract description 3
- 239000004480 active ingredient Substances 0.000 abstract description 2
- 230000003628 erosive effect Effects 0.000 abstract description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 abstract description 2
- 239000003826 tablet Substances 0.000 description 57
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 230000001186 cumulative effect Effects 0.000 description 6
- 239000007888 film coating Substances 0.000 description 6
- 238000009501 film coating Methods 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 102220487426 Actin-related protein 2/3 complex subunit 3_K15M_mutation Human genes 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 239000008363 phosphate buffer Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 206010012601 diabetes mellitus Diseases 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 210000000653 nervous system Anatomy 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 239000007939 sustained release tablet Substances 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 208000032781 Diabetic cardiomyopathy Diseases 0.000 description 1
- 206010051153 Diabetic gastroparesis Diseases 0.000 description 1
- 206010063547 Diabetic macroangiopathy Diseases 0.000 description 1
- 206010054044 Diabetic microangiopathy Diseases 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 208000003790 Foot Ulcer Diseases 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010040943 Skin Ulcer Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 201000009101 diabetic angiopathy Diseases 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229940075529 glyceryl stearate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229940037627 magnesium lauryl sulfate Drugs 0.000 description 1
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229910021487 silica fume Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
-
- 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
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- 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
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Emergency Medicine (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to epalrestat gastric floating tablets and a preparation method thereof, and the epalrestat gastric floating tablets prepared by the invention have good slow release effect, active ingredients are released slowly at a constant speed, and in-vitro tests show slow release characteristics; the invention adopts an effervescent mechanism, and can quickly float in solution, and the float time is less than 5min; the invention takes the hydroxypropyl methylcellulose as a hydrophilic slow-release framework material, and takes the bleaching agent as an erosion slow-release framework material, thereby effectively controlling the drug rate and achieving slow and constant-speed release.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to epalrestat gastric floating tablets and a preparation method thereof.
Background
Epalrestat (Epalrestat), chemical name 5- [ (1 z,2 e) -2-methyl-3-phenyl-2-propenylidene ] -4-oxo-2-thioxo-3-thiazolidineacetic acid, is the only non-competitive ARIs currently marketed, and is mainly used for the treatment of diabetes mellitus and its complications. Epalrestat has absolute therapeutic effect on diabetes-induced neuropathy. It also has therapeutic effects on diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, diabetic gastroparesis, cataract, foot ulcer, diabetic macroangiopathy, diabetic microangiopathy, hyperglycemia, and complications such as hyperglycosylated hemoglobin level. Epalrestat has been reported to have protective effects on cardiac muscle and nervous system of non-diabetic patients, and also to have therapeutic and controlling effects on non-diabetes-induced nervous system lesions.
Currently, epalrestat is only an immediate release preparation, and needs to be administered 3 times for 1 day. In order to be able to reduce the number of administrations, increase patient compliance, and achieve therapeutic effects with minimal dosages, the dosage form must be modified. In India, zydus Cadila et al developed a sustained release tablet of 150 mg. Patent CN 104940156A is epalrestat enteric sustained-release tablet, the drug release is slow and non-constant, the influence of the gastrointestinal environment of human body on the absorption and release of the drug is large, and certain blood concentration fluctuation exists. Therefore, epalrestat is prepared into a gastric floating preparation which is taken once a day, the treatment compliance of patients is improved, the phenomenon of large fluctuation of blood concentration is reduced, toxic and side effects are reduced, and the safety and the effectiveness of the medicine are improved.
Disclosure of Invention
The invention provides an epalrestat gastric-floating tablet, which comprises the following components in parts by weight: 150 parts of epalrestat, 200 parts of framework material, 150-450 parts of bleaching aid, 90 parts of gas generating agent, 50-60 parts of filler, 0-60 parts of solubilizer and 20 parts of lubricant.
In some embodiments, the epalrestat gastric-floating tablet comprises the following components in parts by weight: 150 parts of epalrestat, 200 parts of framework material, 150-300 parts of bleaching aid, 90 parts of gas generating agent, 50-60 parts of filling agent, 60 parts of solubilizer and 20 parts of lubricant.
In some embodiments, the framework material is selected from one or a combination of several of HPMC K4M, HPMC K15M, HPMC K100 LV; preferably HPMC K4M, HPMC K15M or HPMC K100M in combination with HPMC K100LV, more preferably HPMC K4M in combination with HPMC K100 LV.
In some embodiments, the weight ratio of HPMC K4M, HPMC K15M or HPMC K100M to HPMC K100LV is 1:1 to 1:9, preferably 1:3.
In some embodiments, the bleach aid is selected from one or a combination of several of stearic acid, stearyl alcohol or glyceryl stearate; stearyl alcohol is preferred.
In some embodiments, the gas generating agent is selected from one or a combination of several of sodium bicarbonate, sodium carbonate, calcium carbonate, preferably sodium bicarbonate.
In some embodiments, the filler is selected from one or a combination of several of lactose, microcrystalline cellulose, starch, or dextrin, preferably lactose.
In some embodiments, the epalrestat gastric floating tablet, the solubilizer is selected from one or a combination of several of sodium dodecyl sulfate, tween and poloxamer, preferably sodium dodecyl sulfate.
In some embodiments, the lubricant is selected from one or a combination of several of magnesium lauryl sulfate, magnesium stearate, micro silica gel, talc or hydrogenated vegetable oil, preferably magnesium stearate.
In some embodiments, the epalrestat gastric-floating tablet comprises the following ingredients:
in some embodiments, the epalrestat gastric-floating tablet is prepared by coating epalrestat gastric-floating tablet, and the coating agent is selected from gastric-soluble opadry.
On the other hand, the invention also provides a preparation method of the epalrestat gastric floating tablet, which comprises the following steps:
the preparation method is wet granulation.
Further, the specific preparation process of the preparation method is as follows:
(1) Weighing the components according to the prescription composition of the components in the epalrestat gastric floating tablet;
(2) Sieving the weighed components with a 30-mesh sieve, uniformly mixing epalrestat, a framework material, a bleaching aid, a gas generating agent, a filler and a solubilizer, preparing a soft material by using absolute ethyl alcohol, sieving with a 20-mesh sieve, wet finishing, drying in a baking oven at 40 ℃ for 1.0 hour, and sieving with a 20-mesh sieve to dry finishing;
(3) Adding lubricant and mixing uniformly; stamping and tabletting;
(4) And weighing gastric-soluble film coating agents according to the prescription amount, respectively dissolving the gastric-soluble film coating agents in the distilled water according to the prescription amount, uniformly mixing the gastric-soluble film coating agents to form coating liquid, and coating the plain tablets in a coating pot to obtain the epalrestat gastric-floating tablets.
Preferably, the tabletting die in the step (3) is a round dimple die with the diameter of 12mm, a 17.5×8.5mm oval dimple die or a 20.35×10.85mm oval dimple die.
The invention has the beneficial effects that: the epalrestat gastric floating tablet has good slow release effect, active ingredients are released slowly at a constant speed, and in-vitro tests show that the epalrestat gastric floating tablet has slow release characteristics; the invention adopts an effervescent mechanism, and can quickly float in solution, and the float time is less than 5min; the invention takes the hydroxypropyl methylcellulose as a hydrophilic slow-release framework material, and takes the bleaching agent as an erosion slow-release framework material, thereby effectively controlling the drug rate and achieving slow and constant-speed release.
Drawings
FIG. 1 is a graph of in vitro cumulative percent release versus time for epalrestat gastric-floating tablets of examples 1-3;
FIG. 2 is a graph of in vitro cumulative percent release versus time for the epalrestat gastric-floating tablets of examples 1, 4, and 5;
FIG. 3 is a graph of in vitro cumulative percent release versus time for the epalrestat gastric-floating tablets of examples 1, 6, and 7;
FIG. 4 is a graph of in vitro cumulative percent release versus time for epalrestat gastric floating tablets of examples 1, 8, and 9;
FIG. 5 is a graph of in vitro cumulative percent release versus time for epalrestat gastric-floating tablets of example 1, example 10;
Detailed Description
The present invention will be described in further detail with reference to the following specific embodiments. It should be emphasized that: the following description is merely exemplary in nature and the present invention is not limited to the details of the examples that follow, their implementation may be further modified according to specific requirements.
Method for preparing tablets of examples 1 to 10: sieving the components weighed according to the prescription composition with a 30-mesh sieve, uniformly mixing epalrestat, a framework material, a bleaching aid, a gas generating agent, a filler and a solubilizer, uniformly spraying absolute ethyl alcohol serving as a wetting agent into the mixed powder to prepare a soft material which is agglomerated by hand and is slightly kneaded to be dispersed, sieving the soft material with a 20-mesh sieve, wet granulating, drying in a baking oven at 40 ℃ for 1.0 hour, and sieving the soft material with a 20-mesh sieve to obtain dry granules; adding lubricant and mixing uniformly; circular dimple dies with the diameter of 12mm or 17.5 x 8.5mm elliptical dimple dies or 20.35 x 10.85mm elliptical dimple die tablets; and weighing film coating agents (gastric-soluble type) according to the prescription amount, respectively dissolving the film coating agents in distilled water according to the prescription amount, uniformly mixing the film coating agents to form coating liquid, and placing the plain tablets into a coating pan for coating to obtain the epalrestat gastric-floating tablets.
Method for measuring release degree in examples 1 to 10: according to the fourth rule 0931 dissolution and release measuring method seventh method of Chinese pharmacopoeia 2020 edition, 6 pieces of test sample are placed in 6 reciprocating cylinders, the first 12 hours uses 250mL of pH1.2 hydrochloric acid solution as a release medium, 12 hours-24 hours uses 250mL of pH6.8 phosphoric acid buffer solution as a release medium, the upper screen mesh is 40 meshes, the lower screen mesh is 20 meshes, the reciprocating speed is 10rpm, the temperature is (37+/-0.5), the reciprocating cylinder row numbers are respectively switched between 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours and 24 hours, 20mL of 0.8mol/L sodium phosphate buffer solution is added into the pH1.2 hydrochloric acid release medium to regulate the pH, so that the medicine in the disintegrating fragments in the dissolution cup is dissolved, and the liquid is 10mL. Samples at each sampling point are filtered by a microporous filter membrane with the diameter of 0.45 mu m, the subsequent filtrate is taken to a measuring flask, and phosphate buffer solution with the pH value of 6.8 is used for constant volume and diluted to proper concentration to be used as a test sample solution. Accurately weighing epalrestat raw material medicine 16.67mg to 100ml measuring flask, adding N-N dimethyl amide about 50ml, shaking to dissolve the raw material medicine, fixing volume, and shaking to obtain reference stock solution. Precisely transferring the control stock solution into a measuring flask with volume of 1ml to 50ml, and shaking uniformly by using N-N dimethyl amide to obtain the control solution. The absorbance of the sample solution and the reference solution is measured by ultraviolet spectrophotometry, the detection wavelength is 398nm, and the cumulative release percentage is calculated according to an external standard method.
Example 1
Plain tablet prescription
| Composition of the composition | Dosage (per tablet) |
| Epalrestat | 150mg |
| HPMC K4M | 50mg |
| HPMC K100LV | 150mg |
| Stearyl alcohol | 300mg |
| Sodium bicarbonate | 90mg |
| SDS | 50mg |
| Lactose G200 | 60mg |
| Magnesium stearate | 20mg |
Shading coating film prescription
| Composition of the composition | Dosage (per 100 tablets) |
| Opadry 85G66723-CN brown | 40g |
| Water and its preparation method | 360g |
Example 2
Plain tablet prescription
| Composition of the composition | Dosage (per tablet) |
| Epalrestat | 150mg |
| HPMC K15M | 50mg |
| HPMC K100LV | 150mg |
| Stearyl alcohol | 300mg |
| Sodium bicarbonate | 90mg |
| SDS | 50mg |
| Lactose G200 | 60mg |
| Magnesium stearate | 20mg |
Shading coating film prescription
| Composition of the composition | Dosage (per 100 tablets) |
| Opadry 85G66723-CN brown | 40g |
| Water and its preparation method | 360g |
Example 3
Plain tablet prescription
Shading coating film prescription
| Composition of the composition | Dosage (per 100 tablets) |
| Opadry 85G66723-CN brown | 40g |
| Water and its preparation method | 360g |
Example 4
Plain tablet prescription
| Composition of the composition | Dosage (per tablet) |
| Epalrestat | 150mg |
| HPMC K4M | 100mg |
| HPMC K100LV | 100mg |
| Stearyl alcohol | 300mg |
| Sodium bicarbonate | 90mg |
| SDS | 50mg |
| Lactose G200 | 60mg |
| Magnesium stearate | 20mg |
Shading coating film prescription
| Composition of the composition | Dosage (per 100 tablets) |
| Opadry 85G66723-CN brown | 40g |
| Water and its preparation method | 60g |
Example 5
Plain tablet prescription
Shading coating film prescription
| Composition of the composition | Dosage (per 100 tablets) |
| Opadry 85G66723-CN brown | 40g |
| Water and its preparation method | 360g |
Example 6
Plain tablet prescription
| Composition of the composition | Dosage (per tablet) |
| Epalrestat | 150mg |
| HPMC K4M | 50mg |
| HPMC K100LV | 150mg |
| Stearyl alcohol | 150mg |
| Sodium bicarbonate | 90mg |
| SDS | 50mg |
| Lactose G200 | 60mg |
| Magnesium stearate | 20mg |
Shading coating film prescription
| Composition of the composition | Dosage (per 100 tablets) |
| Opadry 85G66723-CN brown | 40g |
| Water and its preparation method | 360g |
Example 7
Plain tablet prescription
| Composition of the composition | Dosage (per tablet) |
| Epalrestat | 150mg |
| HPMC K4M | 50mg |
| HPMC K100LV | 150mg |
| Stearyl alcohol | 450mg |
| Sodium bicarbonate | 90mg |
| SDS | 50mg |
| Lactose G200 | 60mg |
| Magnesium stearate | 20mg |
Shading coating film prescription
| Composition of the composition | Dosage (per 100 tablets) |
| Opadry 85G66723-CN brown | 40g |
| Water and its preparation method | 360g |
Example 8
Plain tablet prescription
| Composition of the composition | Dosage (per tablet) |
| Epalrestat | 150mg |
| HPMC K4M | 50mg |
| HPMC K100LV | 150mg |
| Stearyl alcohol | 300mg |
| Sodium carbonate | 90mg |
| SDS | 50mg |
| Lactose G200 | 60mg |
| Magnesium stearate | 20mg |
Shading coating film prescription
| Composition of the composition | Dosage (per 100 tablets) |
| Opadry 85G66723-CN brown | 40g |
| Water and its preparation method | 360g |
Example 9
Plain tablet prescription
| Composition of the composition | Dosage (per tablet) |
| Epalrestat | 150mg |
| HPMC K4M | 50mg |
| HPMC K100LV | 150mg |
| Stearyl alcohol | 300mg |
| Calcium carbonate | 90mg |
| SDS | 50mg |
| Lactose G200 | 60mg |
| Magnesium stearate | 20mg |
Shading coating film prescription
| Composition of the composition | Dosage (per 100 tablets) |
| Opadry 85G66723-CN brown | 40g |
| Water and its preparation method | 360g |
Example 10
Plain tablet prescription
Shading coating film prescription
| Composition of the composition | Dosage (per 100 tablets) |
| Opadry 85G66723-CN brown | 40g |
| Water and its preparation method | 360g |
Test example 1: comparative examples 1 to 3
The results show (table 1) that the epalrestat gastric floating tablets respectively adopt different types of hypromellose, have significant influence on the release rate of the preparation, the release rate of the epalrestat gastric floating tablets is obviously slowed down by adopting HPMC K15M, and the release rate of the epalrestat gastric floating tablets is further slowed down by adopting HPMC K100M.
TABLE 1 Release of the formulations of examples 1-3 in phosphate buffer pH1.2-pH6.8
| Time | Example 1 | Example 2 | Example 3 |
| 2h | 9.97％ | 8.62％ | 7.80％ |
| 4h | 20.83％ | 16.53％ | 11.44％ |
| 6h | 33.75％ | 22.08％ | 14.51％ |
| 8h | 42.29％ | 27.49％ | 17.20％ |
| 12h | 57.05％ | 37.27％ | 20.84％ |
| 16h | 75.29％ | 52.58％ | 29.83％ |
| 24h | 94.47％ | 74.41％ | 48.97％ |
Test example 2: comparative examples 1, 4 and 5
The results showed (table 2) that epalrestat gastric-floating tablets used different HPMC K4M: HPMC K100LV ratio has an effect on formulation release rate, HPMC K4M: HPMC k100deg.LV=1: the release rate was faster at 3.
Table 2 release of the formulations of example 1, example 4, example 5 in phosphate buffer at ph1.2-ph6.8
| Time | Example 1 | Example 4 | Example 5 |
| 2h | 9.97％ | 8.77％ | 10.38％ |
| 4h | 20.83％ | 18.33％ | 17.64％ |
| 6h | 33.75％ | 28.26％ | 25.78％ |
| 8h | 42.29％ | 36.40％ | 32.96％ |
| 12h | 57.05％ | 47.78％ | 44.65％ |
| 16h | 75.29％ | 65.13％ | 66.89％ |
| 24h | 94.47％ | 88.58％ | 89.13％ |
Test example 3: comparative examples 1, 6 and 7
The results show (Table 3) that the use of different amounts of stearyl alcohol in the epalrestat gastric-floating tablets has an effect on the release rate of the preparation, and that the use amount of stearyl alcohol increases and the release rate slows down.
TABLE 3 Release of the formulations of example 1, example 6, example 7 in phosphate buffer pH1.2-pH6.8
| Time | Example 1 | Example 6 | Example 7 |
| 2h | 9.97％ | 10.07％ | 8.64％ |
| 4h | 20.83％ | 21.72％ | 16.90％ |
| 6h | 33.75％ | 33.18％ | 26.68％ |
| 8h | 42.29％ | 42.38％ | 35.76％ |
| 12h | 57.05％ | 56.97％ | 45.26％ |
| 16h | 75.29％ | 73.93％ | 58.87％ |
| 24h | 94.47％ | 98.86％ | 83.76％ |
Test example 4: comparative examples 1, 8 and 9
The results show (Table 4) that epalrestat gastric-floating tablets respectively use different types of gas generating agents to influence the release rate of the preparation, and sodium bicarbonate is used as the gas generating agent to release the gas rapidly.
Table 4 release of the formulations of example 1, example 8, example 9 in phosphate buffer at ph1.2-ph6.8
| Time | Example 1 | Example 8 | Example 9 |
| 2h | 9.97％ | 10.80％ | 10.12％ |
| 4h | 20.83％ | 21.88％ | 19.10％ |
| 6h | 33.75％ | 30.55％ | 27.87％ |
| 8h | 42.29％ | 43.13％ | 40.12％ |
| 12h | 57.05％ | 55.01％ | 54.68％ |
| 16h | 75.29％ | 72.54％ | 70.56％ |
| 24h | 94.47％ | 92.46％ | 90.98％ |
Test example 5: comparative examples 1 and 10
The results show (Table 4) that the addition of sodium dodecyl sulfate to epalrestat gastric-floating tablets has a significant effect on the release rate of the preparation, the release rate of sodium dodecyl sulfate is obviously accelerated, and the release end point is obviously improved.
TABLE 5 Release curves of the formulations of example 1, example 10 in phosphate buffers pH1.2-pH6.8
| Time | Example 1 | Example 10 |
| 2h | 9.97％ | 7.79％ |
| 4h | 20.83％ | 14.67％ |
| 6h | 33.75％ | 18.98％ |
| 8h | 42.29％ | 22.65％ |
| 12h | 57.05％ | 30.86％ |
| 16h | 75.29％ | 45.79％ |
| 24h | 94.47％ | 59.99％ |
TABLE 6 float time and hold time in pH1.2 Medium (37.+ -. 0.5 ℃ C.) examples 1 to 10
| Sample of | Time/min of float | Duration of float/h |
| Example 1 | ＜0.5 | ＞12h |
| Example 2 | ＜1.0 | ＞12h |
| Example 3 | ＜1.0 | ＞12h |
| Example 4 | ＜0.5 | ＞12h |
| Example 5 | ＜0.5 | ＞12h |
| Example 6 | ＜0.5 | ＞10h |
| Example 7 | ＜0.5 | ＞12h |
| Example 8 | ＜0.5 | ＞12h |
| Example 9 | ＜0.5 | ＞12h |
| Example 10 | ＜0.5 | ＞12h |
As shown in tables 1-6 and FIGS. 1-5, in examples 1-10, example 1 has a faster float time, a longer hold time, a better slow release effect, and a higher slow release end point than the other examples.
Finally, it is noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solution of the present invention may be modified or equally substituted without departing from the spirit and scope of the technical solution of the present invention, and the scope of the claims of the present invention shall be covered.
Claims (5)
1. The epalrestat gastric floating tablet comprises the following components in parts by weight: 150 parts of epalrestat, 200 parts of framework material, 150-300 parts of bleaching aid, 90 parts of gas generating agent, 50-60 parts of filling agent, 60 parts of solubilizer and 20 parts of lubricant;
wherein the framework material is the combination of HPMC K4M and HPMC K100LV, and the weight ratio of the combination is 1:3;
the bleaching aid is stearyl alcohol;
the gas generating agent is sodium bicarbonate, sodium carbonate or calcium carbonate;
the filler is lactose;
the solubilizer is sodium dodecyl sulfate;
the lubricant is magnesium stearate.
2. Epalrestat gastric-floating tablet according to claim 1, characterized in that epalrestat gastric-floating tablet comprises the following components:
3. epalrestat gastric floating tablet according to any one of claims 1-2, characterized in that the epalrestat gastric floating tablet is prepared by coating epalrestat gastric floating tablet element tablets, and the coating agent is selected from gastric soluble opadry.
4. A process for preparing the epalrestat gastric-floating tablet of claim 3, comprising the steps of:
(1) Weighing the components according to the prescription composition of the components in the epalrestat gastric floating tablet;
(2) Sieving the weighed components with a 30-mesh sieve, uniformly mixing epalrestat, a framework material, a bleaching aid, a gas generating agent, a filler and a solubilizer, preparing a soft material by using absolute ethyl alcohol, sieving with a 20-mesh sieve, wet finishing, drying in a baking oven at 40 ℃ for 1.0 hour, and sieving with a 20-mesh sieve to dry finishing;
(3) Adding lubricant and mixing uniformly; stamping and tabletting;
(4) And weighing gastric-soluble Opadry, respectively dissolving in distilled water of a prescription amount, uniformly mixing to form coating liquid, and coating the plain tablets in a coating pot to obtain the epalrestat gastric floating tablets.
5. The method of claim 4, wherein the tabletting die of step (3) is a round dimple die with a diameter of 12mm, a 17.5 x 8.5mm oval dimple die, or a 20.35 x 10.85mm oval dimple die.
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| CN104940156A (en) * | 2015-06-09 | 2015-09-30 | 扬子江药业集团南京海陵药业有限公司 | Epalrestat enteric-coated and sustained-release tablets and preparation method thereof |
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| CN112137990A (en) * | 2020-11-04 | 2020-12-29 | 南京康川济医药科技有限公司 | Epalrestat sustained-release preparation and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| FR2891459B1 (en) * | 2005-09-30 | 2007-12-28 | Flamel Technologies Sa | MICROPARTICLES WITH MODIFIED RELEASE OF AT LEAST ONE ACTIVE INGREDIENT AND ORAL GALENIC FORM COMPRISING THE SAME |
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| CN1520286A (en) * | 2001-07-04 | 2004-08-11 | ̫��ҽҩ��ҵ����˾ | Gastric retention controlled drug delivery system |
| JP2005132803A (en) * | 2003-10-31 | 2005-05-26 | Ono Pharmaceut Co Ltd | Solid pharmaceutical preparation staying in stomach |
| CN104887641A (en) * | 2015-04-08 | 2015-09-09 | 上海鲁源医药科技有限公司 | Palbociclib gastric-floating tablet and preparation method thereof |
| CN104940156A (en) * | 2015-06-09 | 2015-09-30 | 扬子江药业集团南京海陵药业有限公司 | Epalrestat enteric-coated and sustained-release tablets and preparation method thereof |
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| CN110548014A (en) * | 2019-09-06 | 2019-12-10 | 南京康川济医药科技有限公司 | Epalrestat double-layer osmotic pump controlled release tablet and preparation method thereof |
| CN112137990A (en) * | 2020-11-04 | 2020-12-29 | 南京康川济医药科技有限公司 | Epalrestat sustained-release preparation and preparation method thereof |
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