CN118236324A - Sulfosamine oral preparation and preparation method thereof - Google Patents
Sulfosamine oral preparation and preparation method thereof Download PDFInfo
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- CN118236324A CN118236324A CN202410384573.2A CN202410384573A CN118236324A CN 118236324 A CN118236324 A CN 118236324A CN 202410384573 A CN202410384573 A CN 202410384573A CN 118236324 A CN118236324 A CN 118236324A
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- sucralfate
- suspension
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- oral
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- 238000002360 preparation method Methods 0.000 title claims abstract description 57
- 229960004291 sucralfate Drugs 0.000 claims abstract description 116
- MNQYNQBOVCBZIQ-JQOFMKNESA-A sucralfate Chemical compound O[Al](O)OS(=O)(=O)O[C@@H]1[C@@H](OS(=O)(=O)O[Al](O)O)[C@H](OS(=O)(=O)O[Al](O)O)[C@@H](COS(=O)(=O)O[Al](O)O)O[C@H]1O[C@@]1(COS(=O)(=O)O[Al](O)O)[C@@H](OS(=O)(=O)O[Al](O)O)[C@H](OS(=O)(=O)O[Al](O)O)[C@@H](OS(=O)(=O)O[Al](O)O)O1 MNQYNQBOVCBZIQ-JQOFMKNESA-A 0.000 claims abstract description 115
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 44
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 44
- 239000010452 phosphate Substances 0.000 claims abstract description 44
- 229940080313 sodium starch Drugs 0.000 claims abstract description 43
- 239000000725 suspension Substances 0.000 claims abstract description 33
- 239000002245 particle Substances 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 15
- 238000003860 storage Methods 0.000 claims abstract description 12
- 230000008569 process Effects 0.000 claims abstract description 11
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 42
- 229960000502 poloxamer Drugs 0.000 claims description 42
- 229920001983 poloxamer Polymers 0.000 claims description 42
- MDYZKJNTKZIUSK-UHFFFAOYSA-N tyloxapol Chemical compound O=C.C1CO1.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 MDYZKJNTKZIUSK-UHFFFAOYSA-N 0.000 claims description 30
- 229960004224 tyloxapol Drugs 0.000 claims description 30
- 229920001664 tyloxapol Polymers 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- 239000002736 nonionic surfactant Substances 0.000 claims description 27
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 18
- 239000004299 sodium benzoate Substances 0.000 claims description 18
- 235000010234 sodium benzoate Nutrition 0.000 claims description 18
- 239000008213 purified water Substances 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 13
- 239000003755 preservative agent Substances 0.000 claims description 13
- 230000002335 preservative effect Effects 0.000 claims description 13
- 229940100692 oral suspension Drugs 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 238000000227 grinding Methods 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 4
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 238000004806 packaging method and process Methods 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 229960004365 benzoic acid Drugs 0.000 claims description 2
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims description 2
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 claims description 2
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 claims description 2
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 2
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 2
- 229960002216 methylparaben Drugs 0.000 claims description 2
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims description 2
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 2
- 229960003415 propylparaben Drugs 0.000 claims description 2
- 229960003885 sodium benzoate Drugs 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 31
- 229940064192 sucralfate oral suspension Drugs 0.000 abstract description 24
- 210000001156 gastric mucosa Anatomy 0.000 abstract description 18
- 238000004062 sedimentation Methods 0.000 abstract description 13
- 229930006000 Sucrose Natural products 0.000 abstract description 11
- 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 abstract description 11
- 239000005720 sucrose Substances 0.000 abstract description 11
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 abstract description 10
- 238000005189 flocculation Methods 0.000 abstract description 10
- 230000016615 flocculation Effects 0.000 abstract description 10
- 150000002500 ions Chemical class 0.000 abstract description 8
- 230000002776 aggregation Effects 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 7
- 238000001179 sorption measurement Methods 0.000 abstract description 7
- 238000005054 agglomeration Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000002131 composite material Substances 0.000 abstract description 4
- 230000000052 comparative effect Effects 0.000 description 42
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 34
- 208000007107 Stomach Ulcer Diseases 0.000 description 33
- 201000005917 gastric ulcer Diseases 0.000 description 30
- 239000002253 acid Substances 0.000 description 21
- 241000700159 Rattus Species 0.000 description 20
- 229960000905 indomethacin Drugs 0.000 description 19
- 239000000463 material Substances 0.000 description 19
- 208000025865 Ulcer Diseases 0.000 description 18
- 231100000397 ulcer Toxicity 0.000 description 18
- 230000002496 gastric effect Effects 0.000 description 12
- 210000002784 stomach Anatomy 0.000 description 10
- 210000004400 mucous membrane Anatomy 0.000 description 9
- 230000002378 acidificating effect Effects 0.000 description 8
- 230000001965 increasing effect Effects 0.000 description 8
- -1 sucralfate compound ions Chemical class 0.000 description 8
- 239000004094 surface-active agent Substances 0.000 description 6
- 230000037396 body weight Effects 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- 208000007882 Gastritis Diseases 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 230000000747 cardiac effect Effects 0.000 description 4
- 239000008098 formaldehyde solution Substances 0.000 description 4
- 229910052782 aluminium Inorganic materials 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 230000030136 gastric emptying Effects 0.000 description 3
- 235000019640 taste Nutrition 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- 206010070840 Gastrointestinal tract irritation Diseases 0.000 description 2
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 210000000683 abdominal cavity Anatomy 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 210000002318 cardia Anatomy 0.000 description 2
- 239000003729 cation exchange resin Substances 0.000 description 2
- 239000003922 charged colloid Substances 0.000 description 2
- 208000023652 chronic gastritis Diseases 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 208000000718 duodenal ulcer Diseases 0.000 description 2
- 210000000416 exudates and transudate Anatomy 0.000 description 2
- 210000001105 femoral artery Anatomy 0.000 description 2
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 229960002725 isoflurane Drugs 0.000 description 2
- 210000004877 mucosa Anatomy 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 208000000689 peptic esophagitis Diseases 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 230000002633 protecting effect Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 210000001187 pylorus Anatomy 0.000 description 2
- 238000010008 shearing Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 208000018556 stomach disease Diseases 0.000 description 2
- WEPNHBQBLCNOBB-FZJVNAOYSA-N sucrose octasulfate Chemical compound OS(=O)(=O)O[C@@H]1[C@H](OS(O)(=O)=O)[C@H](COS(=O)(=O)O)O[C@]1(COS(O)(=O)=O)O[C@@H]1[C@H](OS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@@H](COS(O)(=O)=O)O1 WEPNHBQBLCNOBB-FZJVNAOYSA-N 0.000 description 2
- 230000008719 thickening Effects 0.000 description 2
- 229910021642 ultra pure water Inorganic materials 0.000 description 2
- 239000012498 ultrapure water Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 208000012895 Gastric disease Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- KVLCHQHEQROXGN-UHFFFAOYSA-N aluminium(1+) Chemical group [Al+] KVLCHQHEQROXGN-UHFFFAOYSA-N 0.000 description 1
- 229940007076 aluminum cation Drugs 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 235000019606 astringent taste Nutrition 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 238000009739 binding Methods 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003232 mucoadhesive effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 235000019629 palatability Nutrition 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000037351 starvation Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229920001285 xanthan gum Polymers 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7016—Disaccharides, e.g. lactose, lactulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
- A61K33/08—Oxides; Hydroxides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
-
- 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
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- 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)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Organic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Biochemistry (AREA)
- Hospice & Palliative Care (AREA)
- Otolaryngology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Dispersion Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses an oral sucralfate suspension and a preparation method thereof. The sucralfate oral suspension disclosed by the invention uses sodium starch phosphate, and can be further adsorbed with the sucrose sulfate composite ions, so that the adsorption effect of the sucrose sulfate composite ions on healthy gastric mucosa is enhanced. The sucralfate oral suspension has uniform particle size of raw materials, high stability, no agglomeration, flocculation, sedimentation and other phenomena no matter in the preparation or storage process, and the preparation process is simple and is suitable for industrial mass production.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a sucralfate oral preparation and a preparation method thereof.
Background
Sucralfate, a complex of sucrose sulfate and aluminum hydroxide, is composed of sucrose octasulfate (Sucrose octasulfate, SOS) with a negative charge and aluminum hydroxide polymer (Polyaluminium complex, PAC) with a positive charge, for the treatment of pathologies associated with gastrointestinal irritation, including those involving lesions of the gastric mucosa and ulcers capable of causing bleeding. Is especially suitable for gastric ulcer, duodenal ulcer, acute gastritis, symptomatic chronic gastritis, gastropathy related to NSAID (non-steroidal anti-inflammatory drug) and reflux esophagitis.
The action mechanism of the sucralfate is that under the acidic environment, the sucralfate compound ions are dissociated, the compound ions are polymerized into insoluble negatively charged colloid, and the insoluble negatively charged colloid can be combined with positively charged protein exudates on the ulcer surface to form a protective film which covers the ulcer surface so as to promote the healing of the ulcer. Although sucralfate has a good barrier effect, its effect is dependent on the acidic environment, and forms a mucosal paste only in the acidic environment and selectively binds to the damaged mucosa. On healthy mucous membrane with pH higher than stomach, sucralfate can not be fully acidified, can only form loose solid aggregate, can not be well adsorbed on gastric mucous membrane surface, and has inferior adsorption effect to non-ulcer surface. At present, the mucoadhesive time of the sucralfate can be increased through multiple administration, but the administration compliance of the sucralfate is affected to a certain extent due to the bitter taste of the sucralfate, and the sucralfate oral suspension prepared by a common preparation method is easy to cause flocculation, particles of the sucralfate are agglomerated, and the particle size is increased, so that a qualified and stable oral liquid dosage form cannot be prepared.
Chinese patent CN96191732.6 discloses a preparation of gastric ulcer-relieving (sucralfate) comprising an organic carboxylic acid having two or more carboxyl groups or one or more hydroxyl groups in the molecule and gastric ulcer-relieving agent which can improve the adhesion of the non-acidic mucosal ulcer site.
Patent WO2010031785 discloses a pharmaceutical composition based on an active ingredient selected from sucralfate, al (OH) 3、Mg(OH)2, mgO, magnesium aluminate itself or a mixture thereof, comprising one or more phospholipids, the use of which improves its palatability and counteracts its tongue drying and astringency, for the treatment of gastrointestinal-irritation diseases such as gastric ulcers, duodenal ulcers, acute gastritis, symptomatic chronic gastritis, gastric diseases associated with anti-inflammatory agents, reflux esophagitis.
Chinese patent CN202310269459.0 discloses an oral suspension of sucralfate, which is characterized in that the preparation comprises sucralfate, cation exchange resin, sodium alginate, xanthan gum and preservative, and the cation exchange resin used in the patent is a novel auxiliary material at present and is not popularized and used, and more experimental investigation is still needed although the sucralfate can be effectively released under the conditions of strong acidity and weak acidity.
Because the sucralfate cannot adhere to the healthy mucous membrane of the stomach for a long time due to the dependence of the sucralfate on the strongly acidic environment, the damaged gastric mucous membrane is further damaged by adding the pH regulator, and the discomfort of patients is caused, so that the application range and the field of the sucralfate suspension are limited to a certain extent, and the conventional sucralfate suspension is easy to form particles into clusters and increase in particle size in the long-term storage process, so that flocculation and sedimentation are generated, and the stability is lacking in long-term storage.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide the sucralfate oral suspension and the preparation method thereof, which can be rapidly released into gastric mucosa to form films under different environments, can better adsorb the gastric mucosa especially under weak acid conditions, have better gastrointestinal mucosa adhesiveness, have high long-term storage stability, have no flocculation, sedimentation and other phenomena, and are suitable for large-scale production.
In order to achieve the aim, the invention obtains the following technical scheme by carrying out a great deal of experimental study and improvement on the existing preparation prescription and process: an oral suspension of sucralfate comprises sucralfate, sodium starch phosphate, a nonionic surfactant and a preservative, wherein the nonionic surfactant is a mixture of tyloxapol and poloxamer.
In the invention, the existence of sodium starch phosphate is one of important technical keys for realizing technical effects. The sodium starch phosphate can exchange with part of aluminum cations in sucralfate under the weak acidic condition, so that the sucrose sulfate complex ions are dissociated and combined with protein exudates with positive charges on ulcers, and meanwhile, the generated free starch phosphate can be further adsorbed with the sucrose sulfate complex ions after being adsorbed on gastric mucosa, so that the adsorption effect of the sucrose sulfate complex ions on healthy gastric mucosa is enhanced. In the whole, the sucralfate can be combined with the ulcer surface and the non-ulcer surface of the stomach under the conditions of strong acid and weak acid, thereby playing a role in protecting the gastric mucosa comprehensively. Meanwhile, the sodium starch phosphate has a thickening effect, so that the sucralfate can further form paste on the mucous membrane, and the adsorption effect of the sucralfate is enhanced. In the invention, the dosage of sodium starch phosphate is one of important technical keys for realizing technical effects. The sodium starch phosphate with proper dosage can be better exchanged with aluminum cations in sucralfate to promote the dissociation of the sucrose sulfate complex ions. The sodium starch phosphate is less in dosage, so that the sodium starch phosphate cannot be fully dissociated from the sucrose sulfate composite ions, the hydrolysis balance is broken, the ion exchange and the dissociation of the sucrose sulfate composite ions are inhibited, and the waste of auxiliary materials is caused. When the mass ratio of the sucralfate to the sodium starch phosphate is 1:0.1-0.5, the effect of the aluminum cation exchange in the sodium starch phosphate and the sucralfate is best, the compound ion of the sucrose sulfate is sufficiently dissociated, preferably, the mass ratio of the sucralfate to the sodium starch phosphate is 1:0.2-0.4, and most preferably, the mass ratio of the sucralfate to the sodium starch phosphate is 1:0.3.
In the present invention, the presence of a nonionic surfactant is one of important technical keys for achieving technical effects. Factors affecting the particle size and particle size distribution of sucralfate oral suspensions are: particle size of sucralfate raw material, type of surfactant, dosage ratio of sucralfate and surfactant in raw material liquid medicine. The invention adds the surface active agent at one time in the preparation process, which simplifies the process operation but brings difficulty in controlling the particle size. The invention adopts the specific surfactant and controls the dosage proportion of the sucralfate and the surfactant, so that the problems of abnormal increase of particle size and aggregation of sucralfate raw materials in the mass production process and the storage process are avoided, and the stability and content uniformity of the sucralfate are improved. Preferably, the surfactant is a mixture of the nonionic surfactants tyloxapol and poloxamer. When the mass ratio of the sucralfate to the nonionic surfactant is 1:0.005-0.020, the problems of abnormal increase of particle size and agglomeration of the sucralfate raw material can be effectively avoided in the production process, preferably, the mass ratio of the sucralfate to the nonionic surfactant is 1:0.010-0.015, and most preferably, the mass ratio of the sucralfate to the nonionic surfactant is 1:0.012. when the tyloxapol and the poloxamer are in proper dosage, the sucralfate suspension does not generate sedimentation and flocculation phenomenon in the long-term storage process, the stability is higher, and the mass ratio of the tyloxapol to the poloxamer is 1:0.3-0.8, preferably 1:0.4-0.6, and most preferably 1:0.5.
In the invention, the particle size of the sucralfate is one of the keys for realizing the technical effect. According to the invention, the particle size of the sucralfate bulk drug is controlled to be D90-10 mu m, so that the particle size distribution span is smaller, the narrow particle size distribution of the bulk drug in the sucralfate suspension is ensured, the quality control of the particle size of the product is further improved, and meanwhile, the sucralfate suspension is ensured to be easy to be uniform and the administration dosage is accurate in the storage and use processes. Meanwhile, under the particle size, the sodium starch phosphate is matched, so that the taste of the sucralfate suspension is improved, and the suspension is fine and smooth and has no gritty feel. Preferably, the particle size of the sucralfate is 5 μm or less and D90. Ltoreq.10 μm or less.
In the sucralfate oral suspension, the preservative is one or a mixture of more than two of methylparaben, ethylparaben, propylparaben, benzoic acid and sodium benzoate, and the mass ratio of the preservative to the sucralfate is 1:30-50, preferably 1:40.
Specifically, the invention provides an oral sucralfate suspension, which comprises sucralfate, sodium starch phosphate, a nonionic surfactant and a preservative, wherein the nonionic surfactant is a mixture of tyloxapol and poloxamer, the mass ratio of the sucralfate to the sodium starch phosphate is 1:0.3, and the mass ratio of the sucralfate to the nonionic surfactant is 1:0.012, wherein the mass ratio of tyloxapol to poloxamer is 1:0.5, the particle size of sucralfate is more than or equal to 5 mu m and less than or equal to D90 and less than or equal to 10 mu m, the preservative is sodium benzoate, and the mass ratio of the preservative to the sucralfate is 1:40.
Specifically, the invention also provides a sucralfate oral suspension, which comprises the following components:
| Name of the name | Content g |
| Sulfosamine (grain diameter is not less than 5 mu m and not more than 10 mu m D90) | 200.00 |
| Sodium starch phosphate | 60.00 |
| Tyloxapol | 1.60 |
| Poloxamer (poloxamer) | 0.80 |
| Sodium benzoate | 5.00 |
| Water and its preparation method | Purified water was added to 2000ml |
The invention also provides a preparation process of the sucralfate oral suspension, the sucralfate oral suspension prepared by the process has high long-term storage stability, no flocculation, sedimentation and other phenomena, the process has simple steps, and the feasibility of production amplification is ensured, and the process comprises the following steps:
1) Dissolving sodium benzoate under heating at 60-80deg.C, adding sucralfate, circularly homogenizing under 1000bar pressure for 2 hr, and heating to 90deg.C for 5 min.
2) Adding the grinding liquid medicine into a storage tank, cooling to below 65 ℃, continuously adding sodium starch phosphate, poloxamer and tyloxapol, adding purified water to fix the volume, stirring, and sub-packaging to obtain the sucralfate suspension.
Compared with the prior art, the invention has the following outstanding advantages and beneficial effects:
(1) The sucralfate can only form a pasty mucous membrane in an acidic environment and can be selectively combined with a damaged mucous membrane, and on a healthy mucous membrane with the pH higher than that of the stomach, the sucralfate can not be fully acidified and can only form loose solid aggregates.
(2) The sodium starch phosphate used in the invention has a certain thickening effect, so that the sucralfate can further form paste on the mucous membrane, and the adsorption effect of the sucralfate is enhanced.
(3) The nonionic surfactant tyloxapol and poloxamer mixture used in the invention has uniform particle size of raw materials, high stability, no agglomeration, flocculation, sedimentation and other phenomena no matter in the preparation or storage process, fine taste, no gravel feel, simple preparation process and suitability for industrial mass production.
Drawings
Fig. 1: indomethacin under strong acid causes gastric ulcer of rats, and blank auxiliary materials are used for 12h group of gastric pictures.
Fig. 2: indomethacin under strong acid causes gastric ulcers in rats, example 1 sets 12h gastric pictures.
Fig. 3: indomethacin under weak acid causes gastric ulcer of rats, and blank auxiliary materials are used for 12h group of gastric pictures.
Fig. 4: indomethacin induced gastric ulcers in rats under weak acids, example 1, 12h group gastric pictures.
Detailed Description
The present invention will be described in further detail with reference to examples, but embodiments of the invention are not limited thereto.
EXAMPLE 1 preparation of sucralfate oral suspension
| Name of the name | Content g |
| Sulfosamine (grain diameter is not less than 5 mu m and not more than 10 mu m D90) | 200.00 |
| Sodium starch phosphate | 60.00 |
| Tyloxapol | 1.60 |
| Poloxamer (poloxamer) | 0.80 |
| Sodium benzoate | 5.00 |
| Water and its preparation method | Purified water was added to 2000ml |
The preparation method comprises the following steps:
1) Dissolving sodium benzoate under heating at 60-80deg.C, adding sucralfate, circularly homogenizing under 1000bar pressure for 2 hr, and heating to 90deg.C for 5 min.
2) Adding the grinding liquid medicine into a storage tank, cooling to below 65 ℃, continuously adding sodium starch phosphate, poloxamer and tyloxapol, adding purified water to fix the volume, stirring, and sub-packaging to obtain the sucralfate suspension.
EXAMPLE 2 preparation of sucralfate oral suspension
| Name of the name | Content g |
| Sulfosamine (grain diameter is not less than 5 mu m and not more than 10 mu m D90) | 200.00 |
| Sodium starch phosphate | 100.00 |
| Tyloxapol | 2.22 |
| Poloxamer (poloxamer) | 1.78 |
| Sodium benzoate | 6.70 |
| Water and its preparation method | Purified water was added to 2000ml |
The preparation is as in example 1.
EXAMPLE 3 preparation of sucralfate oral suspension
| Name of the name | Content g |
| Sulfosamine (grain diameter is not less than 5 mu m and not more than 10 mu m D90) | 200.00 |
| Sodium starch phosphate | 20.00 |
| Tyloxapol | 0.77 |
| Poloxamer (poloxamer) | 0.23 |
| Sodium benzoate | 4.00 |
| Water and its preparation method | Purified water was added to 2000ml |
The preparation is as in example 1.
EXAMPLE 4 preparation of sucralfate oral suspension
| Name of the name | Content g |
| Sulfosamine (grain diameter D90 is less than or equal to 2 μm and less than or equal to 5 μm) | 200.00 |
| Sodium starch phosphate | 80.00 |
| Tyloxapol | 1.88 |
| Poloxamer (poloxamer) | 1.13 |
| Hydroxy-benzoic acid methyl ester | 5.70 |
| Water and its preparation method | Purified water was added to 2000ml |
The preparation is as in example 1.
EXAMPLE 5 preparation of sucralfate oral suspension
| Name of the name | Content g |
| Sulfosamine (grain diameter D90 is less than or equal to 2 μm and less than or equal to 5 μm) | 200.00 |
| Sodium starch phosphate | 40.00 |
| Tyloxapol | 1.43 |
| Poloxamer (poloxamer) | 0.57 |
| Hydroxy-phenyl ethyl ester | 4.40 |
| Water and its preparation method | Purified water was added to 2000ml |
The preparation is as in example 1.
Comparative example 1 preparation of sucralfate oral suspension
| Name of the name | Content g |
| Sulfosamine (grain diameter is not less than 5 mu m and not more than 10 mu m D90) | 200.00 |
| Sodium starch phosphate | 120.00 |
| Tyloxapol | 2.50 |
| Poloxamer (poloxamer) | 2.50 |
| Sodium benzoate | 10.00 |
| Water and its preparation method | Purified water was added to 2000ml |
Preparation method as in example 1, comparative example 1 is more sodium starch phosphate than example 1, more nonionic surfactant is used, and more poloxamer is used in the nonionic surfactant and more sodium benzoate is used in the nonionic surfactant.
Comparative example 2 preparation of sucralfate oral suspension
Preparation method as in example 1, comparative example 2 has less sodium starch phosphate and less nonionic surfactant than example 1, and has less poloxamer and less sodium benzoate in the nonionic surfactant.
Comparative example 3 preparation of sucralfate oral suspension
| Name of the name | Content g |
| Sulfosamine (grain diameter is not less than 5 mu m and not more than 10 mu m D90) | 200.00 |
| Tyloxapol | 1.60 |
| Poloxamer (poloxamer) | 0.80 |
| Sodium benzoate | 5.00 |
| Water and its preparation method | Purified water was added to 2000ml |
Preparation method as in example 1, comparative example 3 uses no sodium starch phosphate compared to example 1.
Comparative example 4 preparation of sucralfate oral suspension
| Name of the name | Content g |
| Sulfosamine (grain diameter is not less than 5 mu m and not more than 10 mu m D90) | 200.00 |
| Sodium starch phosphate | 60.00 |
| Poloxamer (poloxamer) | 2.40 |
| Sodium benzoate | 5.00 |
| Water and its preparation method | Purified water was added to 2000ml |
Preparation method as in example 1, comparative example 4 does not use tyloxapol compared to example 1.
Comparative example 5 preparation of sucralfate oral suspension
Preparation method as in example 1, comparative example 5 does not use poloxamer compared to example 1.
Comparative example 6 preparation of sucralfate oral suspension
| Name of the name | Content g |
| Sulfosamine (grain diameter is not less than 5 mu m and not more than 10 mu m D90) | 200.00 |
| Sodium starch phosphate | 60.00 |
| Tyloxapol | 1.60 |
| Polysorbate 80 | 0.80 |
| Sodium benzoate | 5.00 |
| Water and its preparation method | Purified water was added to 2000ml |
Preparation method as in example 1, comparative example 6 uses no poloxamer and the nonionic surfactant uses tyloxapol and polysorbate 80 compared to example 1.
Comparative example 7 preparation of sucralfate oral suspension
| Name of the name | Content g |
| Sulfosamine (particle size D90 > 10 μm) | 200.00 |
| Sodium starch phosphate | 60.00 |
| Tyloxapol | 1.60 |
| Poloxamer (poloxamer) | 0.80 |
| Sodium benzoate | 5.00 |
| Water and its preparation method | Purified water was added to 2000ml |
Preparation is as in example 1, and the particle size of the sucralfate in comparative example 7 is more than 10 μm compared with that in example 1.
Example 6
The sucralfate suspensions of examples 1 to 5 and comparative examples 1 to 7 were subjected to tests for sedimentation volume ratio, particle diameter, viscosity, redispersion, etc., and the results are shown in tables 1 and 2
Table 1 examples 1-5 test of properties related to sucralfate suspensions
Table 2 comparative examples 1-7 sucralfate suspension related Performance test
As can be seen from the test results in tables 1 and 2, the sucralfate suspensions prepared in examples 1 to 5 and comparative examples 1 and 3 were uniformly dispersed, were excellent in redispersibility, were uniform in particle size of the raw materials, were high in stability, and were free from aggregation, flocculation, sedimentation and the like. The sucralfate suspension prepared in comparative example 2 has higher viscosity, lower sedimentation volume and poorer dispersibility, and the analysis is caused by the imbalance of the system due to the lower dosage of the nonionic surfactants tyloxapol and poloxamer. The sucralfate suspensions prepared in comparative examples 4, 5 and 6 also had problems of higher viscosity, lower sedimentation volume and poor dispersibility, and were analyzed because the nonionic surfactant contained only tyloxapol, lacked poloxamer, or only poloxamer, lacked tyloxapol, or nonionic surfactants other than tyloxapol and poloxamer were added, and the system could not reach the most balanced effect. The system does not reach an equilibrium state, which leads to rough surfaces of sucralfate or leads to more 'tentacles' on the surfaces of sucralfate, leading to binding, agglomeration, flocculation, increased viscosity, low sedimentation volume ratio, instability and difficult redispersion. In comparative example 7, although the viscosity was lower than that of comparative examples 2 and 4, the viscosity was also higher, the sedimentation volume was lower, and the dispersibility was poor, and it was found by analysis that the sucralfate had a larger particle size, which was not easily dispersed in the present system, and the larger particle size had a tendency to aggregate easily, resulting in uneven particle size and gritty mouthfeel. Examples 1 to 5 are preferred in the present embodiment, and various parameters in example 1, including the types and proportions of auxiliary materials, are most preferred, such as sucralfate, sodium starch phosphate, nonionic surfactant, etc. are in a proper proportion, and the sucralfate with proper particle size is matched, so that the sucralfate suspension has uniform particle size, high stability, no agglomeration, flocculation, sedimentation, etc., better dispersibility, fine taste, and no gritty feel.
EXAMPLE 7 Indometacin-induced gastric ulcer model in rats under strong acid
The purpose is as follows: the gastric mucosa protection effect of the oral sucralfate suspension test preparation and the commercial oral sucralfate suspension in the presence of strong acid is examined by comparing the therapeutic effect on gastric ulcer by using a rat gastric ulcer model caused by indomethacin.
The method comprises the following steps:
SPF-grade male SD rats were randomly divided into 16 groups by body weight: model group, blank auxiliary material 0.5h group, blank auxiliary material 4h group and blank auxiliary material 12h group; control 0.5h group, control 4h group, control 12h group; group example 1, 0.5h, group example 1, 4h, group example 1, 12 h; comparative example 1, 0.5h group, comparative example 1, 4h group, comparative example 1, 12h group; comparative example 3, 0.5h group, comparative example 3, 4h group, comparative example 3, 12h group.
The experimental animals were fasted preoperatively without water withdrawal for 48 hours, wherein 100mg/kg of indomethacin solution was administered after the model group had been filled with ultra pure water at 10 ml/kg. Blank auxiliary material 0.5h group, blank auxiliary material 4h group, blank auxiliary material 12h group; control 0.5h group, control 4h group, control 12h group; group example 1, 0.5h, group example 1, 4h, group example 1, 12 h; comparative example 1, 0.5h group, comparative example 1, 4h group, comparative example 1, 12h group; comparative example 30.5h group, comparative example 34 h group, and comparative example 312 h group, 100mg/kg indomethacin was administered by gavage after administration for 0.5h, 4h, and 12h, respectively, according to Table 3, to prepare a gastric ulcer model. Indomethacin was given and returned to the feeder cage with fasted water. After 6 hours, the rats were anesthetized with isoflurane (1% -3%), the abdominal cavity was opened, the pylorus ligated, the cardia ligated, and the femoral artery exsanguinated to kill the rats. Taking 10ml of 2% formaldehyde solution, adding the 10ml into the stomach from the cardiac, ligating the cardiac again, placing the mixture into the 2% formaldehyde solution for 30min, shearing along the greater curvature of the stomach, flattening, washing with normal saline, observing gastric mucosa injury condition by naked eyes, photographing, detecting gastric ulcer area and total gastric area by using imageJ image analysis software, and calculating gastric ulcer coefficients.
TABLE 3 Indometacin gastric ulcer model dose and dosing volume table
Results:
The results of the gastric ulcer coefficients of the rat gastric ulcer model caused by indomethacin are shown in table 4, fig. 1 and fig. 2, and compared with the model group, the gastric ulcer coefficients of animals in the blank auxiliary material group (0.5 h,4h and 12 h) are not obviously different in statistics (p > 0.05), the gastric ulcer coefficients of animals in the control group (0.5 h,4h and 12 h) and the animal gastric ulcer coefficients in the example 1 group (0.5 h,4h and 12 h) are obviously reduced (p < 0.05). The control groups increased in ulcer coefficient over time, indicating a decrease in gastric mucosal protection due to decreased gastric emptying and decreased sucralfate adhesion. The increase in ulcer coefficients was slower with time for each of the groups of example 1, indicating that the adhesion was enhanced and the effect of gastric emptying was reduced due to the contributions of the components of the prescription, and the ulcer coefficients were lower for the 0.5h of the group of example 1 compared to the 0.5h of the control group, indicating that the sucralfate oral suspension of the group of example 1 had a faster film formation time and was immediately available after administration. The sodium starch phosphate in each group of comparative example 1 is used in a large amount, and the sodium starch phosphate reacts with acid directly under the condition of strong acid to affect the decomposition of sucralfate, so that the gastric mucosa protection effect of the sodium starch phosphate is reduced, and the sucralfate in each group of comparative example 3 is decomposed into the octasulfuric acid sucrose with negative charges under the condition of strong acid, so that the sodium starch phosphate can take effect rapidly. Thus, the method is applicable to a variety of applications. The results show that the sucralfate oral suspension prepared in example 1 has a faster film formation time and a longer adhesion time after administration.
Table 4, the rate of gastric ulcer model ulcer caused by rat indomethacin
Example 8 Indometacin-induced gastric ulcer model in rats under weak acid
The purpose is as follows: the gastric mucosa protection effect of the oral sucralfate suspension test preparation and the commercial oral sucralfate suspension in weak acid is examined by comparing the gastric ulcer treatment effect with the indomethacin-induced rat gastric ulcer model.
The method comprises the following steps:
SPF-grade male SD rats were randomly divided into 13 groups by body weight: model group, blank auxiliary material 0.5h group, blank auxiliary material 4h group and blank auxiliary material 12h group; control 0.5h group, control 4h group, control 12h group; group example 1, 0.5h, group example 1, 4h, group example 1, 12 h; comparative example 3, 0.5h group, comparative example 3, 4h group, comparative example 3, 12h group.
The experimental animals were fasted preoperatively without water withdrawal for 48 hours, wherein the model group was perfused with 10ml/kg of gastric ultra-pure water 6 hours after administration of 100mg/kg of indomethacin solution. After 100mg/kg indomethacin was administered by stomach infusion for 6 hours, fasted water was used to prepare a gastric ulcer model, and the following experimental groups were formed by administering for 0.5 hours, 4 hours and 12 hours according to Table 5, respectively: blank auxiliary material 0.5h group, blank auxiliary material 4h group, blank auxiliary material 12h group; control 0.5h group, control 4h group, control 12h group; group example 1, 0.5h, group example 1, 4h, group example 1, 12 h; comparative example 3, 0.5h group, comparative example 3, 4h group, comparative example 3, 12h group. Isoflurane (1% -3%) anesthetized rats, the abdominal cavity was opened, pylorus, cardia were ligated, femoral artery exsanguinated and the rats were sacrificed. Taking 10ml of 2% formaldehyde solution, adding the 10ml into the stomach from the cardiac, ligating the cardiac again, placing the mixture into the 2% formaldehyde solution for 30min, shearing along the greater curvature of the stomach, flattening, washing with normal saline, observing gastric mucosa injury condition by naked eyes, photographing, detecting gastric ulcer area and total gastric area by using imageJ image analysis software, and calculating gastric ulcer coefficients.
TABLE 5 Indometacin gastric ulcer model dose and dosing volume table
Results:
The results of the gastric ulcer coefficients of the rat gastric ulcer model caused by indomethacin are shown in Table 6, FIG. 3 and FIG. 4, and compared with the model group, the blank auxiliary material group (0.5 h,4h and 12 h) has no obvious statistical difference (p > 0.05), the control group (0.5 h,4h and 12 h) has no obvious effect although the ulcer coefficients are reduced, the analysis shows that the gastric mucosa adhesion effect of the sucralfate is weaker under the weak acid environment caused by gastric ulcer, the film cannot be formed fully, and the ulcer coefficients of the control group are increased along with the time, so that the gastric mucosa protection effect is reduced due to the reduced gastric emptying effect and the reduced adhesion effect of the sucralfate. The animals in the group of example 1 (0.5 h,4h12 h) had significantly lower gastric ulcer coefficients (p < 0.05), increased with time, and the ulcer coefficients increased more slowly, indicating that the sucralfate had increased adhesion due to the contributions of the components of the formulation, and the group of example 1, 0.5h, had lower ulcer coefficients than the control group, indicating that the sucralfate oral suspension of the group of example 1 had a faster film-forming time, a better film-forming effect, and a rapid onset of action after administration, under weak acid conditions. Comparative example 3 groups each lack sodium starch phosphate and thus sucralfate is not completely released under weakly acidic conditions, resulting in a decrease in gastric mucosa protecting effect. The results show that the sucralfate oral suspension prepared in example 1 has a faster film formation time and a longer adhesion time after administration.
Table 6, rate of gastric ulcer model ulcer caused by rat indomethacin
From the results of example 7 and example 8, it is clear that the sucralfate suspension prepared in example 1 has better gastric mucosa adsorption effect and more comprehensive protection effect under strong acid and weak acid conditions. The inventors subsequently conducted experiments on the sucralfate suspensions prepared in examples 2 to 5 according to examples 7 and 8, and as a result, similar effects to those in example 1 were obtained. The aluminum sucralfate suspension prepared by the technical scheme of the application has better gastric mucosa adsorption effect under strong acid and weak acid conditions, and the gastric mucosa adhesion time is longer, so that the protection is more comprehensive.
The inventors subsequently used rats with a body weight of 200-300g, and after 24 hours of starvation of the rats, the sucralfate suspension prepared in example 1 was taken at a body weight of 20mL/kg and the commercially available sucralfate suspension was taken at a body weight of 10mL/kg, and the sucralfate suspension prepared in example 1 was measured to have a higher retention in the stomach at 12 hours and 24 hours, indicating a better gastric mucoadhesion.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (9)
1. An oral sucralfate suspension is characterized in that the preparation comprises sucralfate, sodium starch phosphate, a nonionic surfactant and a preservative, wherein the nonionic surfactant is a mixture of tyloxapol and poloxamer.
2. An oral suspension of sucralfate according to claim 1, wherein the mass ratio of sucralfate to sodium starch phosphate is 1:0.1-0.5, preferably 1:0.2-0.4, most preferably 1:0.3.
3. An oral sucralfate suspension according to claim 1, wherein the mass ratio of sucralfate to nonionic surfactant is 1:0.005-0.020, preferably 1:0.010-0.015, most preferably 1:0.012.
4. An oral suspension of sucralfate according to claim 1, wherein the mass ratio of tyloxapol to poloxamer is 1:0.3-0.8, preferably 1:0.4-0.6, most preferably 1:0.5.
5. An oral suspension of sucralfate according to claim 1, wherein the sucralfate has a particle size d90.ltoreq.10 μm, preferably the sucralfate has a particle size d90.ltoreq.10 μm of 5 μm.
6. An oral suspension of sucralfate according to claim 1, wherein the preservative is one or a mixture of more than two of methylparaben, ethylparaben, propylparaben, benzoic acid, sodium benzoate, and the mass ratio of the preservative to the sucralfate is 1:30-50, preferably 1:40.
7. The oral suspension of sucralfate in claim 1, wherein the formulation comprises sucralfate, sodium starch phosphate, a nonionic surfactant, and a preservative, wherein the nonionic surfactant is a mixture of tyloxapol and poloxamer, the mass ratio of sucralfate to sodium starch phosphate is 1:0.3, and the mass ratio of sucralfate to nonionic surfactant is 1:0.012, wherein the mass ratio of tyloxapol to poloxamer is 1:0.5, the particle size of sucralfate is more than or equal to 5 mu m and less than or equal to D90 and less than or equal to 10 mu m, the preservative is sodium benzoate, and the mass ratio of the preservative to sucralfate is 1:40.
8. An oral sucralfate suspension characterized by comprising the following components:
the grain diameter of the sucralfate is more than or equal to 5 mu m and less than or equal to 10 mu m, and D90 is less than or equal to 10 mu m.
9. A process for the preparation of an oral suspension of sucralfate according to any of the claims 1 to 8,
The method comprises the following steps:
1) Heating sodium benzoate at 60-80deg.C for dissolving, adding sucralfate, circularly homogenizing and grinding for 2 hr under 1000bar pressure by homogenizing and grinding machine, heating the medicinal liquid to 90deg.C for 5min,
2) Adding the grinding liquid medicine into a storage tank, cooling to below 65 ℃, continuously adding sodium starch phosphate, poloxamer and tyloxapol, adding purified water to fix the volume, stirring, and sub-packaging to obtain the sucralfate suspension.
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