CN116492308A - Furosemide solid preparation and preparation method thereof - Google Patents
Furosemide solid preparation and preparation method thereof Download PDFInfo
- Publication number
- CN116492308A CN116492308A CN202310599389.5A CN202310599389A CN116492308A CN 116492308 A CN116492308 A CN 116492308A CN 202310599389 A CN202310599389 A CN 202310599389A CN 116492308 A CN116492308 A CN 116492308A
- Authority
- CN
- China
- Prior art keywords
- parts
- furosemide
- regulator
- mixture
- preparation
- 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.)
- Pending
Links
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 title claims abstract description 76
- 229960003883 furosemide Drugs 0.000 title claims abstract description 76
- 238000002360 preparation method Methods 0.000 title claims abstract description 64
- 239000007787 solid Substances 0.000 title claims abstract description 20
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 29
- 239000000314 lubricant Substances 0.000 claims abstract description 27
- 239000003085 diluting agent Substances 0.000 claims abstract description 26
- 229910002024 Aerosil® 200 Pharma Inorganic materials 0.000 claims abstract description 21
- 239000002245 particle Substances 0.000 claims abstract description 19
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical group [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 63
- 238000002156 mixing Methods 0.000 claims description 43
- 238000007873 sieving Methods 0.000 claims description 41
- 238000005303 weighing Methods 0.000 claims description 31
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 30
- 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 20
- 239000008101 lactose Substances 0.000 claims description 20
- 229920000881 Modified starch Polymers 0.000 claims description 15
- 235000019359 magnesium stearate Nutrition 0.000 claims description 15
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 12
- 229920002472 Starch Polymers 0.000 claims description 10
- 239000008107 starch Substances 0.000 claims description 10
- 235000019698 starch Nutrition 0.000 claims description 10
- 238000009472 formulation Methods 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000007908 dry granulation Methods 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 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
- 238000003825 pressing Methods 0.000 claims description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000007884 disintegrant Substances 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 239000000454 talc Substances 0.000 claims description 2
- 229910052623 talc Inorganic materials 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims 1
- 229930195725 Mannitol Natural products 0.000 claims 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims 1
- 239000000594 mannitol Substances 0.000 claims 1
- 235000010355 mannitol Nutrition 0.000 claims 1
- 239000008108 microcrystalline cellulose Substances 0.000 claims 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims 1
- 229940016286 microcrystalline cellulose Drugs 0.000 claims 1
- 238000009702 powder compression Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 22
- 229940079593 drug Drugs 0.000 abstract description 19
- 238000004090 dissolution Methods 0.000 abstract description 15
- 230000001105 regulatory effect Effects 0.000 abstract description 4
- 239000012047 saturated solution Substances 0.000 abstract description 4
- 239000003826 tablet Substances 0.000 description 33
- 230000000052 comparative effect Effects 0.000 description 22
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 238000007907 direct compression Methods 0.000 description 13
- 239000000843 powder Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 11
- 238000012360 testing method Methods 0.000 description 10
- 230000000291 postprandial effect Effects 0.000 description 9
- 239000000463 material Substances 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 5
- 239000006187 pill Substances 0.000 description 5
- 239000006191 orally-disintegrating tablet Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 229910001868 water Inorganic materials 0.000 description 4
- 239000012738 dissolution medium Substances 0.000 description 3
- 230000001882 diuretic effect Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 208000004880 Polyuria Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 230000000916 dilatatory effect Effects 0.000 description 2
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 2
- 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 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000002934 diuretic Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- -1 furophenone Chemical compound 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 206010048962 Brain oedema Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 101100391172 Dictyostelium discoideum forA gene Proteins 0.000 description 1
- 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 description 1
- 206010024119 Left ventricular failure Diseases 0.000 description 1
- 239000005434 MCC/mannitol excipient Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010030124 Oedema peripheral Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 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
- 230000017531 blood circulation Effects 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000004856 capillary permeability Effects 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification 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
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000008327 renal blood flow Effects 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- 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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- 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
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- 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)
- 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)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a furosemide solid preparation and a preparation method thereof, and relates to the technical field of medicines. The solid preparation provided by the invention comprises the following components: the pharmaceutical composition comprises furosemide, a microenvironment pH regulator, a preparation porosity regulator, a diluent, a disintegrating agent and a lubricant, wherein the microenvironment pH regulator is sodium bicarbonate, and the preparation porosity regulator is hydrophilic AEROSIL200 Pharma. According to the invention, porous AEROSIL200Pharma is adopted to adsorb furosemide, and the pH value of the saturated solution around the drug particles is regulated by using the micro-environment pH regulator sodium bicarbonate, so that the solubility of the drug can be improved, and the drug dissolution can be increased.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a furosemide solid preparation and a preparation method thereof.
Background
Furosemide is a quick-acting and high-efficiency diuretic, also called as tachyuria (alias-diuretic sulfanilamide, furophenone, proline, etc.). Furosemide can inhibit the absorption function of renal tubules and promote the excretion of water, sodium, chlorine, potassium, calcium, magnesium, phosphorus and the like. Furosemide inhibits prostaglandin E activity and causes prostaglandin E to be present 2 The content is increased, thereby having the function of dilating blood vessels. Dilating renal blood vessel, reducing renal vascular resistance, and increasing renal blood flow, especially deep blood flow of renal cortex. Furosemide can dilate pulmonary capacity veins, reduce pulmonary capillary permeability, reduce the amount of blood returned to the heart by adding its diuretic effect, reduce the end-diastole pressure of the left ventricle, and is helpful for the treatment of acute left heart failure. The dosage forms include tablets, granules, sustained release tablets and injections. Has the characteristics of quick and short diuretic effect, high curative effect, wide application range and small side effect, and can be widely used for treating various diseases such as edema, dysfunction caused by heart, kidney and liver diseases or peripheral edema and cerebral edema caused by vascular wall disorder.
Furosemide, a furananilic acid compound, with chemical name of 2- [ (2-furanmethyl) amino group]]-5- (sulfamoyl) -4-chlorobenzoic acid of formula C 12 H 11 ClN 2 O 5 S, the structural formula is as follows.
Patent CN 1682709A provides a furosemide orally disintegrating tablet and a preparation method thereof, the orally disintegrating tablet does not need to drink water, the burden of a patient is lightened, and the orally disintegrating tablet successfully solves the problems that the dosage of auxiliary materials is large, the auxiliary materials are insoluble in water and insoluble substances remain after disintegration by adopting a pretreatment method before tabletting. The orally disintegrating tablet comprises 5-40% of furosemide, a diluent, a disintegrating agent and a lubricant; 30-80% of a diluent; 5-25% of disintegrating agent; 0.1-5% of lubricant.
Patent CN 1771933A discloses a furosemide drop pill and a preparation process thereof, wherein the furosemide drop pill is prepared from furosemide and a drop pill matrix. The weight ratio of the furosemide to the dripping pill matrix is 1:1-1:10. the dripping pill matrix is one or more of polyethylene glycol, sodium carboxymethyl starch, poloxamer, sodium carboxymethyl cellulose, stearic acid, sodium stearate and polyoxyethylene monostearate, and the content of each compatible component is not equal to zero.
Furosemide is very slightly soluble in water, and the solubility is 0.01 mg.mL -1 Belongs to weak acid, has pKa value of 3.9, logP value of 0.74 and CLogP value of 1.9. Belongs to the class of BCS IV with low solubility and low permeability, and the drug dissolution rate is the speed limiting step of drug absorption.
Furosemide is a weak acidic drug with increased solubility with increasing pH, the release of the drug has pH dependence, rather than ideal non-pH dependent release characteristics, food also changes the pH of the gastrointestinal tract, eating slows down absorption, and there is a large difference in gastrointestinal pH from patient to patient, as well as differences in absorption rate and extent. Thus, strategies need to be developed to overcome the effects of pH in dissolution subjects to increase the rate and/or extent of drug absorption (Cmax and/or AUC) and reduce inter-individual variability.
Based on the above problems, the present invention provides a furosemide solid preparation, which aims to overcome the problem that the rate and/or degree of drug absorption of different patients are different due to the influence of the pH value in the furosemide Mi Rongjie. To be used forAs a reference preparation, the furosemide tablet and the reference preparation have bioequivalence through experimental study on human bioequivalence, and the individual difference is smaller than that of the reference preparation.
Disclosure of Invention
The invention aims at the problems and provides a furosemide solid preparation and a preparation method thereof, so as toAs a reference preparation, the furosemide tablet prepared by the invention has bioequivalence with the reference preparation through experimental study on bioequivalence of human body, and the individual difference is smaller than that of the reference preparation.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
in one aspect, the invention provides a furosemide solid preparation, which comprises the following components: the pharmaceutical composition comprises furosemide, a microenvironment pH regulator, a preparation porosity regulator, a diluent, a disintegrating agent and a lubricant, wherein the microenvironment pH regulator is sodium bicarbonate, and the preparation porosity regulator is hydrophilic AEROSIL200 Pharma.
Preferably, the components in parts by weight may be: 18-23 parts of furosemide, 12-18 parts of micro-environment pH regulator, 3-7 parts of preparation porosity regulator, 45-54 parts of diluent, 5-11 parts of disintegrating agent and 0.1-3 parts of lubricant.
Further preferably, the components may be: 19-21 parts of furosemide, 14-16 parts of micro-environment pH regulator, 4-6 parts of preparation porosity regulator, 18-52 parts of diluent, 6-9 parts of disintegrating agent and 0.5-2 parts of lubricant.
More preferably, the components may be: 20 parts of furosemide, 15 parts of a micro-environment pH regulator, 5 parts of a preparation porosity regulator, 50.5 parts of a diluent, 8 parts of a disintegrating agent and 1.5 parts of a lubricant.
More preferably, the components may be: 20 parts of furosemide, 15 parts of a micro-environment pH regulator, 5 parts of a preparation porosity regulator, 51 parts of a diluent, 8 parts of a disintegrating agent and 1 part of a lubricant.
Preferably, the diluent comprises at least one of sucrose, lactose, starch, microcrystalline cellulose and mannitol, and further preferably, the diluent can be lactose.
Preferably, the disintegrating agent comprises at least one of croscarmellose sodium, sodium carboxymethyl starch and pregelatinized starch; further preferably, the disintegrant may be pregelatinized starch.
Preferably, the lubricant comprises at least one of magnesium stearate, silicon dioxide and talcum powder; further preferably, the lubricant comprises at least one of magnesium stearate and talc.
On the other hand, the above-mentioned solid preparation method comprises at least one of powder direct compression and dry granulation, and preferably, powder direct compression.
The invention provides a powder direct-compression preparation method of a furosemide solid preparation, which comprises the following steps:
1) Mixing the prescription dose of furosemide and the micro-environment pH regulator for 3-8min, and sieving to obtain a mixture 1;
2) Weighing AEROSIL200Pharma with prescription amount, mixing with mixture 1 for 3-8min, sieving, mixing for 5-10min, and sieving to obtain mixture 2;
3) Sieving diluent and disintegrating agent, weighing according to prescription, mixing with mixture 2 for 3-8min to obtain mixture 3;
4) Sieving lubricant, weighing according to prescription, and mixing with mixture 3 for 3-8min to obtain mixture 4;
5) Tabletting, and tabletting the mixture obtained in the step 4) by using a tabletting machine according to 100mg tablets to obtain the furosemide tablets.
The invention provides a dry granulation preparation method of a furosemide solid preparation, which comprises the following steps:
1) Mixing the prescription dose of furosemide and the micro-environment pH regulator for 3-8min, and sieving to obtain a mixture 1;
2) Weighing AEROSIL200Pharma with prescription amount, mixing with mixture 1 for 3-8min, sieving, mixing for 5-10min, and sieving to obtain mixture 2;
3) Sieving diluent and disintegrating agent, weighing according to prescription, mixing with mixture 2 for 3-8min to obtain mixture 3;
4) Sieving lubricant, weighing according to prescription, and mixing with mixture 3 for 3-8min to obtain mixture 4;
5) The mixture 4 is dried and crushed by a dry granulator, sieved and then mixed with 0.5-1.5g of sieved lubricant for 5-10min to obtain intermediate granules.
6) Tabletting, and tabletting the intermediate particles obtained in the step 5) by a tabletting machine according to 100mg tablets to obtain the furosemide tablets.
Preferably, the pH of the aqueous solution of mixture 1 obtained in step 1) of the two preparation methods described above may be between 5.8 and 8.0; further preferably, the pH of the aqueous solution of mixture 1 obtained in step 1) may be from 6.8 to 7.2.
Compared with the prior art, the invention has the following beneficial effects:
the porous AEROSIL200Pharma has high loading capacity, the porous AEROSIL200Pharma is adopted to adsorb furosemide, and the pH value of a saturated solution around drug particles is regulated by using a micro-environment pH regulator sodium bicarbonate, so that the solubility of the drug can be improved, and the dissolution of the drug can be increased.
Detailed Description
In order to make the technical means, the creation features, the achievement of the purpose and the effect of the present invention easy to understand, the present invention will be further elucidated with reference to the specific embodiments, but the following embodiments are only preferred embodiments of the present invention, not all of them. Based on the examples in the embodiments, those skilled in the art can obtain other examples without making any inventive effort, which fall within the scope of the invention. It is to be noted that the raw materials used in the present invention are all common commercial products, and the sources thereof are not particularly limited. Technical and scientific terms used in the examples have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
Example 1
Preparing the furosemide tablet by a powder direct compression process:
the prescription composition is as follows (1000 tablets are prepared in total):
| raw and auxiliary materials | Weight is%g) | Function of |
| Furosemide | 20 | Active ingredient |
| Sodium bicarbonate | 15 | Micro-environment pH regulator |
| AEROSIL 200Pharma | 5 | Porosity regulator |
| Lactose and lactose | 51 | Diluent agent |
| Pregelatinized starch | 8 | Disintegrating agent |
| Magnesium stearate | 1 | Lubricant |
The preparation process comprises the following steps:
1) Weighing 20g of furosemide and 15g of sodium bicarbonate serving as a micro-environment pH regulator, mixing for 5 nins, and sieving with a 80-mesh sieve for later use;
2) Weighing 5g of AEROSIL200Pharma, mixing with the mixture obtained in step 1) for 5min, sieving with 80 mesh sieve, mixing for 5min, sieving with 80 mesh sieve again, and keeping;
3) Sieving lactose and pregelatinized starch with a 60-mesh sieve, weighing 51g and 8g respectively, and mixing with the mixture obtained in step 2) for 5min for later use;
4) Sieving magnesium stearate with 20 mesh sieve, weighing 1g, and mixing with the mixture obtained in 3) for 5min to obtain uniformly mixed intermediate particles;
5) And (3) tabletting the intermediate particles obtained in the step (4) by a tabletting machine according to 100mg tablets to obtain the powder direct compression furosemide tablet, wherein the pH value of the solution is 7.0.
Example 2
Preparation of furosemide tablets by dry granulation process:
the prescription composition is as follows (1000 tablets are prepared in total):
the preparation process comprises the following steps:
1) Weighing 20g of furosemide and 15g of sodium bicarbonate serving as a micro-environment pH regulator, mixing for 5 nins, and sieving with a 80-mesh sieve for later use;
2) Weighing 5g of AEROSIL200Pharma, mixing with the mixture obtained in step 1) for 5min, sieving with 80 mesh sieve, mixing for 5min, sieving with 80 mesh sieve again, and keeping;
3) Sieving lactose and pregelatinized starch with a 60-mesh sieve, weighing 50.5g and 8g respectively, and mixing with the mixture obtained in step 2) for 5min for later use;
4) Sieving talcum powder with a 20-mesh sieve, weighing 0.5g, and mixing with the mixture obtained in step 3) for 5min for later use;
5) Dry-pressing and crushing the material obtained in the step 4) by a dry-method granulator, sieving by a 20-mesh sieve, and then mixing with 1g of magnesium stearate which is sieved by the 20-mesh sieve for 5 minutes to obtain evenly mixed intermediate particles;
6) Tabletting the intermediate particles obtained in the step 5) by a tabletting machine according to 100mg tablets, thus obtaining dry granulating furosemide tablets, wherein the pH value of the solution is 7.0.
Comparative example 1
Preparation of powder direct-compression furosemide tablet:
the prescription composition is as follows (1000 tablets are prepared in total):
| raw and auxiliary materials | Weight (g) | Function of |
| Furosemide | 20 | Active ingredient |
| Starch | 15 | Diluent agent |
| AEROSIL 200Pharma | 5 | Porosity regulator |
| Lactose and lactose | 51 | Diluent agent |
| Pregelatinized starch | 8 | Disintegrating agent |
| Magnesium stearate | 1 | Lubricant |
The preparation process comprises the following steps:
1) Weighing 20g of furosemide and 5g of AEROSIL200Pharma, mixing for 5n, and sieving with a 80-mesh sieve for later use;
2) Sieving lactose, starch and pregelatinized starch with 60 mesh sieve, weighing 51g, 15g and 8g respectively, and mixing with the mixture obtained in 1) for 5min for use;
3) Sieving magnesium stearate with a 20-mesh sieve, weighing 1g, and mixing with the mixture obtained in the step 2) for 5min to obtain uniformly mixed intermediate particles;
4) And (3) tabletting the intermediate particles obtained in the step (3) by a tabletting machine according to 100mg tablets, thus obtaining the powder direct compression furosemide tablet, wherein the pH value of the solution is 4.5.
Comparative example 2
Preparing the furosemide tablet by a powder direct compression process:
the prescription composition is as follows (1000 tablets are prepared in total):
| raw and auxiliary materials | Weight (g) | Function of |
| Furosemide | 20 | Active ingredient |
| Sodium bicarbonate | 15 | Micro-environment pH regulator |
| Lactose and lactose | 56 | Diluent agent |
| Pregelatinized starch | 8 | Disintegrating agent |
| Magnesium stearate | 1 | Lubricant |
The preparation process comprises the following steps:
1) Weighing 20g of furosemide and 15g of sodium bicarbonate serving as a micro-environment pH regulator, mixing for 5 nins, and sieving with a 80-mesh sieve for later use;
2) Sieving lactose and pregelatinized starch with 60 mesh sieve, weighing 56g and 8g respectively, and mixing with the mixture obtained in step 1) for 5min for use;
3) Sieving magnesium stearate with a 20-mesh sieve, weighing 1g, and mixing with the mixture obtained in the step 2) for 5min to obtain uniformly mixed intermediate particles;
4) And (3) tabletting the intermediate particles obtained in the step (3) by a tabletting machine according to 100mg tablets, thus obtaining the powder direct compression furosemide tablet, wherein the pH value of the solution is 7.0.
Comparative example 3
Preparing the furosemide tablet by a powder direct compression process:
the prescription composition is as follows (1000 tablets are prepared in total):
| raw and auxiliary materials | Weight (g) | Function of |
| Furosemide | 20 | Active ingredient |
| Starch | 15 | Diluent agent |
| Lactose and lactose | 56 | Diluent agent |
| Pregelatinized starch | 8 | Disintegrating agent |
| Magnesium stearate | 1 | Lubricant |
The preparation process comprises the following steps:
1) Screening furosemide with 80 mesh sieve, screening starch, lactose and pregelatinized starch with 60 mesh sieve, and screening magnesium stearate with 20 mesh sieve for use;
2) Weighing 20g of furosemide, 15g of starch, 56g of lactose and 8g of pregelatinized starch in the step 1), and mixing for 10min for later use;
3) Weighing 1g of magnesium stearate in the step 1), and mixing with the mixture obtained in the step 2) for 5min to obtain evenly mixed intermediate particles;
4) And (3) tabletting the intermediate particles obtained in the step (3) by a tabletting machine according to 100mg tablets, thus obtaining the powder direct compression furosemide tablet, wherein the pH value of the solution is 4.5.
Comparative example 4
Preparing the furosemide tablet by a powder direct compression process:
the prescription composition is as follows (1000 tablets are prepared in total):
| raw and auxiliary materials | Weight (g) | Function of |
| Furosemide | 20 | Active ingredient |
| Sodium bicarbonate | 15 | Micro-environment pH regulator |
| Lactose and lactose | 54 | Diluent agent |
| Pregelatinized starch | 8 | Disintegrating agent |
| Magnesium stearate | 1 | Lubricant |
| AEROSIL 200Pharma | 2 | Glidant |
The preparation process comprises the following steps:
1) Weighing 20g of furosemide and 15g of sodium bicarbonate serving as a micro-environment pH regulator, mixing for 5 nins, and sieving with a 80-mesh sieve for later use;
2) Sieving lactose and pregelatinized starch with 60 mesh sieve, weighing 54g and 8g respectively, and mixing with the mixture obtained in step 1) for 5min for use;
3) Sieving magnesium stearate and AEROSIL200Pharma with 20 mesh sieve, weighing 1g and 2g, and mixing with the mixture obtained in 2) for 5min to obtain uniformly mixed intermediate particles;
4) And (3) tabletting the intermediate particles obtained in the step (3) by a tabletting machine according to 100mg tablets, thus obtaining the powder direct compression furosemide tablet, wherein the pH value of the solution is 7.0.
Test example 1
Dissolution measurement
Taking the product, taking 5mL of solution according to a dissolution rate measurement method (second method of the fourth rule 0931 of the year edition 2020 of Chinese pharmacopoeia), taking 900mL of acetate buffer with pH of 4.0 as a dissolution medium, operating at 50 revolutions per minute according to the law, taking 5mL of solution respectively after 5, 10, 15, 20, 30, 45, 60, 90 and 120 minutes, immediately supplementing the dissolution medium with the same temperature and the same volume, filtering, and taking the subsequent filtrate as a sample solution after 5, 10 and 15 minutes; 20. at 30, 45, 60, 90 and 120 minutes, 2mL of the subsequent filtrate was measured precisely, placed in a 5mL measuring flask, diluted to scale with dissolution medium, and shaken well to obtain a sample solution. Absorbance was measured at 274nm by ultraviolet-visible spectrophotometry (chinese pharmacopoeia 2020 edition, fourth edition, general rule 0401), respectively.
Samples of examples 1-2, comparative examples 1-4 and reference formulations were assayedThe results of the experiment are as follows:
dissolution factor F of examples 1-2 and comparative examples 1-4 2
| Examples | F 2 |
| Example 1 | 62.26 |
| Example 2 | 60.84 |
| Comparative example 1 | 40.06 |
| Comparative example 2 | 46.68 |
| Comparative example 3 | 36.98 |
| Comparative example 4 | 47.07 |
From the analysis of the results in the above table, it can be seen that: the porous AEROSIL200Pharma adsorption furosemide provided by the invention can improve the solubility of the medicine and increase the dissolution of the medicine by regulating the pH value of a saturated solution around the medicine particles by using the micro-environment pH regulator sodium bicarbonate, and F of the samples of the example 1 and the example 2 and the reference preparation 2 The dissolution curves were consistent with the reference formulation, 62.26 and 60.84, respectively. In comparative example 1, only the porosity adjuster AEROSIL200Pharma was added, and the effect of improving the solubility of the drug could not be achieved without adding the micro-environmental pH adjuster, and dissolution was slower than that of the reference preparation, F 2 40.06; in comparative example 2, only sodium bicarbonate, a micro-environmental pH regulator, was added, no porosity regulator was added, the dissolution was slightly faster than comparative example 1, but still significantly slower than the reference formulation, and the dissolution was still incomplete in 2 hours, F 2 46.68; in comparative example 3, no porosity and micro-environmental pH regulator were added, and the dissolution was significantly slower than that of the reference formulation, F 2 Only 36.98; in comparative example 4, AEROSIL200Pharma was added as a lubricant and did not increase drug dissolutionThe dissolution is still significantly slower than that of the reference preparation, F 2 47.07.
Test example 2
Postprandial bioequivalence experiments with reference formulations
Reference preparationThe samples prepared in examples 1-2 and comparative examples 1-4 were subjected to postprandial bioequivalence experiments as C max And AUC as main pharmacokinetic index, examine whether it is bioequivalent with reference preparation, the experimental result is as follows:
PK parameter data after postprandial test subjects dosed with reference formulations
Post-prandial test subjects take PK parameter data from example 1
Post-prandial test subjects take PK parameter data from example 2
Post-prandial test subjects take comparative example 1 PK parameter data
Post-prandial test subjects taking comparative example 2 PK parameter data
Post-prandial test subjects take comparative example 3 PK parameter data
Post-prandial test subjects take comparative example 4 PK parameter data
Pharmacokinetic index in furosemide tablet after meal administration
/>
From the above bioequivalence test results, it can be seen that: the 90% confidence interval for comparative examples 1-4 is not in the range of 80% -125% of FDA requirement for bioequivalence; the relative bioavailability is not in the required range of 80-120%, and is low. It was further demonstrated that comparative examples 1-4 released slower than the reference formulation in vivo, resulting in bioequivalence. The 90% confidence intervals of the embodiment 1 and the embodiment 2 are in the range of 80% -125%, the relative bioavailability is in the required range of 80% -120%, the relative bioavailability is bioequivalent to the reference preparation, and the SD value of each PK parameter data of 12 subjects is smaller than that of the reference preparation, which indicates that the porous AEROSIL200Pharma is adopted to adsorb furosemide, and the pH value of the saturated solution around the drug particles is regulated by the micro-environment pH regulator sodium bicarbonate, so that the prepared furosemide tablet can not only increase the release and absorption of the drug in vivo, but also overcome the influence of the pH value difference of different patients on the dissolution of the drug, and reduce the difference among individuals.
Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.
Claims (10)
1. The furosemide solid preparation is characterized by comprising the following components: the pharmaceutical composition comprises furosemide, a microenvironment pH regulator, a preparation porosity regulator, a diluent, a disintegrating agent and a lubricant, wherein the microenvironment pH regulator is sodium bicarbonate, and the preparation porosity regulator is hydrophilic AEROSIL200 Pharma.
2. The solid preparation according to claim 1, wherein the components are in parts by weight: 18-23 parts of furosemide, 12-18 parts of micro-environment pH regulator, 3-7 parts of preparation porosity regulator, 45-54 parts of diluent, 5-11 parts of disintegrating agent and 0.1-3 parts of lubricant.
3. The solid preparation according to claim 2, wherein the components are in parts by weight: 19-21 parts of furosemide, 14-16 parts of micro-environment pH regulator, 4-6 parts of preparation porosity regulator, 18-52 parts of diluent, 6-9 parts of disintegrating agent and 0.5-2 parts of lubricant.
4. The solid preparation according to claim 3, wherein the components are in parts by weight: 20 parts of furosemide, 15 parts of a micro-environment pH regulator, 5 parts of a preparation porosity regulator, 51 parts of a diluent, 8 parts of a disintegrating agent and 1 part of a lubricant.
5. The solid preparation according to claim 1, wherein the diluent comprises at least one of sucrose, lactose, starch, microcrystalline cellulose, mannitol.
6. The solid formulation of claim 1, wherein the disintegrant comprises at least one of croscarmellose sodium, sodium carboxymethyl starch, and pregelatinized starch.
7. The solid formulation of claim 1, wherein the lubricant comprises at least one of magnesium stearate, silica, talc.
8. The dry granulation preparation method of the furosemide solid preparation is characterized by comprising the following steps of:
1) Mixing the prescription dose of furosemide and the micro-environment pH regulator for 3-8min, and sieving to obtain a mixture 1;
2) Weighing AEROSIL200Pharma with prescription amount, mixing with mixture 1 for 3-8min, sieving, mixing for 5-10min, and sieving to obtain mixture 2;
3) Sieving diluent and disintegrating agent, weighing according to prescription, mixing with mixture 2 for 3-8min to obtain mixture 3;
4) Sieving lubricant, weighing according to prescription, and mixing with mixture 3 for 3-8min to obtain mixture 4;
5) Dry-pressing the mixture 4 by a dry granulator, crushing, sieving, and mixing with 0.5-1.5g of sieved lubricant for 5-10min to obtain intermediate particles;
6) Tabletting, and tabletting the intermediate particles obtained in the step 5) by a tabletting machine according to 100mg tablets to obtain the furosemide tablets.
9. The direct powder compression preparation method of the furosemide solid preparation is characterized by comprising the following steps of:
1) Mixing the prescription dose of furosemide and the micro-environment pH regulator for 3-8min, and sieving to obtain a mixture 1;
2) Weighing AEROSIL200Pharma with prescription amount, mixing with mixture 1 for 3-8min, sieving, mixing for 5-10min, and sieving to obtain mixture 2;
3) Sieving diluent and disintegrating agent, weighing according to prescription, mixing with mixture 2 for 3-8min to obtain mixture 3;
4) Sieving lubricant, weighing according to prescription, and mixing with mixture 3 for 3-8min to obtain mixture 4;
5) And (3) pressing the mixture obtained in the step 4) into tablets according to the weight of 100mg by using a tablet press to obtain the furosemide tablets.
10. The process according to claims 8-9, wherein the pH of the mixture 1 obtained in step 1) is between 5.8 and 8.0.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310599389.5A CN116492308A (en) | 2023-05-25 | 2023-05-25 | Furosemide solid preparation and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310599389.5A CN116492308A (en) | 2023-05-25 | 2023-05-25 | Furosemide solid preparation and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116492308A true CN116492308A (en) | 2023-07-28 |
Family
ID=87328401
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310599389.5A Pending CN116492308A (en) | 2023-05-25 | 2023-05-25 | Furosemide solid preparation and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116492308A (en) |
-
2023
- 2023-05-25 CN CN202310599389.5A patent/CN116492308A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2783682B1 (en) | Pharmaceutical composition comprising pimobendan | |
| KR100493836B1 (en) | Pharmaceutical Compositions Comprising Oxcarbazepine | |
| KR100762847B1 (en) | Multiple unit type sustained release oral formulation and process for the preparation thereof | |
| CN100473382C (en) | Oral dosage form for propiverine or pharmaceutically acceptable salts thereof with an extended release of the active ingredient | |
| RU2600797C2 (en) | Solid pharmaceutical preparation of matrix type | |
| RU2616516C2 (en) | Pharmaceutical composition containing olmesartan medoxomil and rosuvastatin or its salt | |
| MX2007014872A (en) | Pharmaceutical composition. | |
| US9724374B2 (en) | Capsule containing total flavonoids of desmodium styracifolium, method for preparing the same and use | |
| CN107669683B (en) | Pharmaceutical composition containing sitagliptin and metformin | |
| US20060240101A1 (en) | Orally disintegrating pharmaceutical tablet formulations of olanzapine | |
| CN103127022B (en) | A kind of compound medicine-releasing system of Allopurinol and preparation method thereof | |
| CN105853386B (en) | Tablet containing dapagliflozin propylene glycol hydrate and preparation method thereof | |
| CN109157527B (en) | Irbesartan capsule and preparation method thereof | |
| WO2020090970A1 (en) | Pharmaceutical composition containing antitumor agent | |
| CN116492308A (en) | Furosemide solid preparation and preparation method thereof | |
| CN107441051B (en) | Propafenone hydrochloride micro-tablet and preparation method thereof | |
| CN108888602A (en) | A kind of montelukast preparation of sodium and preparation method thereof | |
| CN112245402A (en) | Indapamide tablet and preparation method thereof | |
| KR102409102B1 (en) | pharmaceutical composition | |
| CN104546778A (en) | Medical composition of Gliclazide sustained release preparation and preparation method of medical composition | |
| WO2020090971A1 (en) | Tablet containing antitumor agent | |
| KR102584268B1 (en) | Formulation comprising pirfenidone with improved drug safety and stability and method for the preparing the same | |
| CN108379235A (en) | It being capable of quickly disintegrated tacrolimus sustained-release tablet composition | |
| CN103191071B (en) | Irbesartan dispersible tablet and preparation method thereof | |
| Revathi et al. | Formulation and evaluation of bilayer tablets of diabetis drugs |
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 |