WO2018236236A1 - Furazidin composition in the form of suspension and method for preparation thereof - Google Patents
Furazidin composition in the form of suspension and method for preparation thereof Download PDFInfo
- Publication number
- WO2018236236A1 WO2018236236A1 PCT/PL2018/050026 PL2018050026W WO2018236236A1 WO 2018236236 A1 WO2018236236 A1 WO 2018236236A1 PL 2018050026 W PL2018050026 W PL 2018050026W WO 2018236236 A1 WO2018236236 A1 WO 2018236236A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- suspension
- agent
- furazidine
- solution
- Prior art date
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- 229960002375 furazidin Drugs 0.000 title claims abstract description 48
- DECBQELQORZLLP-UAIOPKHMSA-N 1-[(e)-[(e)-3-(5-nitrofuran-2-yl)prop-2-enylidene]amino]imidazolidine-2,4-dione Chemical compound O1C([N+](=O)[O-])=CC=C1\C=C\C=N\N1C(=O)NC(=O)C1 DECBQELQORZLLP-UAIOPKHMSA-N 0.000 title claims abstract description 47
- 239000000725 suspension Substances 0.000 title claims abstract description 46
- 238000000034 method Methods 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 239000000203 mixture Substances 0.000 title claims description 34
- 230000003019 stabilising effect Effects 0.000 claims abstract description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000008213 purified water Substances 0.000 claims abstract description 20
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 19
- 239000003381 stabilizer Substances 0.000 claims abstract description 17
- 239000003755 preservative agent Substances 0.000 claims abstract description 14
- 239000004094 surface-active agent Substances 0.000 claims abstract description 12
- 235000019658 bitter taste Nutrition 0.000 claims abstract description 10
- 235000003599 food sweetener Nutrition 0.000 claims abstract description 10
- 239000003765 sweetening agent Substances 0.000 claims abstract description 10
- 239000006068 taste-masking agent Substances 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 4
- 150000002016 disaccharides Chemical class 0.000 claims abstract description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 42
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 24
- 239000000126 substance Substances 0.000 claims description 22
- -1 xanthan gums Chemical class 0.000 claims description 21
- 229930006000 Sucrose Natural products 0.000 claims description 19
- 239000005720 sucrose Substances 0.000 claims description 19
- 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 16
- 239000007968 orange flavor Substances 0.000 claims description 16
- 229920001285 xanthan gum Polymers 0.000 claims description 16
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 15
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 15
- 239000008297 liquid dosage form Substances 0.000 claims description 15
- WBHHMMIMDMUBKC-QJWNTBNXSA-M ricinoleate Chemical compound CCCCCC[C@@H](O)C\C=C/CCCCCCCC([O-])=O WBHHMMIMDMUBKC-QJWNTBNXSA-M 0.000 claims description 15
- 229940066675 ricinoleate Drugs 0.000 claims description 15
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 14
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 14
- 239000000194 fatty acid Substances 0.000 claims description 14
- 229930195729 fatty acid Natural products 0.000 claims description 14
- 235000011187 glycerol Nutrition 0.000 claims description 14
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 12
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 12
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 12
- 229960002216 methylparaben Drugs 0.000 claims description 12
- 239000000230 xanthan gum Substances 0.000 claims description 11
- 235000010493 xanthan gum Nutrition 0.000 claims description 11
- 229940082509 xanthan gum Drugs 0.000 claims description 11
- 125000005274 4-hydroxybenzoic acid group Chemical class 0.000 claims description 9
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 9
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims description 9
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 150000005846 sugar alcohols Polymers 0.000 claims description 9
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 claims description 8
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 150000007513 acids Chemical class 0.000 claims description 8
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 8
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 8
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 8
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 8
- 229960003943 hypromellose Drugs 0.000 claims description 8
- 229920000136 polysorbate Polymers 0.000 claims description 8
- 235000010241 potassium sorbate Nutrition 0.000 claims description 8
- 239000004302 potassium sorbate Substances 0.000 claims description 8
- 229940069338 potassium sorbate Drugs 0.000 claims description 8
- 239000000600 sorbitol Substances 0.000 claims description 8
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 claims description 7
- 239000005711 Benzoic acid Substances 0.000 claims description 7
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 7
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 7
- 235000010233 benzoic acid Nutrition 0.000 claims description 7
- 229960004365 benzoic acid Drugs 0.000 claims description 7
- 229920002678 cellulose Polymers 0.000 claims description 7
- 239000001913 cellulose Substances 0.000 claims description 7
- 235000010980 cellulose Nutrition 0.000 claims description 7
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 7
- 150000002170 ethers Chemical class 0.000 claims description 7
- 150000002191 fatty alcohols Chemical class 0.000 claims description 7
- 150000004676 glycans Chemical class 0.000 claims description 7
- 150000002334 glycols Chemical class 0.000 claims description 7
- 229920001282 polysaccharide Polymers 0.000 claims description 7
- 239000005017 polysaccharide Substances 0.000 claims description 7
- 229940068965 polysorbates Drugs 0.000 claims description 7
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 7
- 235000010234 sodium benzoate Nutrition 0.000 claims description 7
- 239000004299 sodium benzoate Substances 0.000 claims description 7
- 235000010199 sorbic acid Nutrition 0.000 claims description 7
- 239000004334 sorbic acid Substances 0.000 claims description 7
- 229940075582 sorbic acid Drugs 0.000 claims description 7
- 239000000080 wetting agent Substances 0.000 claims description 7
- 229960003885 sodium benzoate Drugs 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 3
- 230000002335 preservative effect Effects 0.000 claims description 3
- 229960004793 sucrose Drugs 0.000 claims description 3
- 125000000185 sucrose group Chemical group 0.000 claims description 3
- 229960005150 glycerol Drugs 0.000 claims description 2
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 2
- 239000013543 active substance Substances 0.000 description 25
- 239000000243 solution Substances 0.000 description 22
- 239000003814 drug Substances 0.000 description 16
- 229940079593 drug Drugs 0.000 description 15
- 238000012360 testing method Methods 0.000 description 9
- 238000009472 formulation Methods 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000000872 buffer Substances 0.000 description 6
- 238000011109 contamination Methods 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 238000013112 stability test Methods 0.000 description 5
- 235000019640 taste Nutrition 0.000 description 5
- 201000010538 Lactose Intolerance Diseases 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000019634 flavors Nutrition 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 235000019613 sensory perceptions of taste Nutrition 0.000 description 3
- 230000035923 taste sensation Effects 0.000 description 3
- 239000004129 EU approved improving agent Substances 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000000873 masking effect Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 230000009747 swallowing Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-UHFFFAOYSA-N 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 235000016623 Fragaria vesca Nutrition 0.000 description 1
- 240000009088 Fragaria x ananassa Species 0.000 description 1
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 1
- 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 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 235000011034 Rubus glaucus Nutrition 0.000 description 1
- 244000235659 Rubus idaeus Species 0.000 description 1
- 235000009122 Rubus idaeus Nutrition 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000013020 final formulation Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000012395 formulation development Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 238000005549 size reduction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 238000003860 storage Methods 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- 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
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- 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
Definitions
- Furazidin composition in the form of suspension and method for preparation thereof is
- the object of the invention is a furazidine liquid dosage form and the method for the preparation thereof.
- the invention is applicable in medicine.
- Russian patent RU2221575 relates to the administration of antibiotics and furazidine in tablets together with mineral water to small children. This method requires the administration of difficult-to-split solid tablets to small children. Therefore, there is still a need to provide the furazidine liquid dosage form which is also suitable for precise dosing in young patients, with an active substance having high stability, without the necessity to use buffer substances, and which is easy to ingest without any unpleasant taste sensations when swallowing, as well as suitable for lactose-intolerant individuals, and the preparation thereof. Surprisingly, the present invention meets the above mentioned needs.
- the first object of the invention is the furazidine liquid dosage form characterised in that it contains furazidine in the amount from 0.10 g/100 g to 5.04 g/100 g, a sweetening agent selected from a group of disaccharides , a suspension stabilising agent, preservatives, suspension stabilising and viscosity controlling agents, a suspension stabilising and surface-active agent, a bitter taste masking agent and purified water as a solvent.
- the sweetening agent according to the invention is sucrose.
- the suspension stabilising agent is selected from a group comprising polyhydric alcohols or mixtures thereof, preferably, these are glycerol, propylene glycol, sorbitol.
- preservatives according to the invention are substances selected from a group of parahydroxybenzoic acid esters and mixtures thereof, preferably, methyl parahydroxybenzoate, most preferably these are methyl parahydroxybenzoate, propyl parahydroxybenzoate, or acids and salts thereof, most conveniently sorbic acid and potassium sorbate, or benzoic acid and sodium benzoate.
- suspension stabilising and viscosity controlling agents are selected from a group of natural polysaccharides, comprising xanthan gums, and/or from a group of cellulose derivatives, preferably these are hydroxypropyl celluloses, hypromellose .
- the suspension stabilising and surface-active agent according to the invention is selected from a group comprising ethers of higher fatty alcohols with polyoxyethylated glycols, including macrogolglycerol ricinoleate, or from a group of polyoxyethylene sorbitan and higher fatty acids esters, or from a group of sorbitan and higher fatty acids esters, preferably these are polysorbates .
- the bitter taste masking agent is a natural orange flavour.
- the form according to the invention contains furazidine, sucrose, glycerol, methyl parahydroxybenzoate, propyl parahydroxybenzoate, macrogolglycerol ricinoleate, hydroxypropylcellulose, xanthan gum, natural orange flavour, and purified water.
- the second object of the invention is a method for the preparation of furazidine fluid dosage form characterised in that it includes: a) preparing a solution containing suspension stabilising and viscosity controlling agents are selected from a group of natural polysaccharides and/or from a group of cellulose derivatives ;
- the method according to the invention is characterised by that the suspension stabilising and viscosity controlling agent is xanthan gum, hydroxypropyl celluloses or hypromellose .
- the sweetening agent is sucrose
- the preservative are parahydroxybenzoic acid esters, preferably methyl parahydroxybenzoate and propyl parahydroxybenzoate, most preferably sorbic acid and potassium sorbate, benzoic acid and salts thereof.
- the method according to the invention is characterised by that the wetting agent is selected from a group of polyhydric alcohols, glycerol, propylene glycol, sorbitol, suspension stabilising and surface-active agents from a group of ethers of higher fatty alcohols with polyoxyethylated glycols, preferably macrogolglycerol ricinoleate, or from a group of polyoxyethylene sorbitan and higher fatty acids esters, or from a group of sorbitan and higher fatty acids esters, preferably polysorbates .
- the wetting agent is selected from a group of polyhydric alcohols, glycerol, propylene glycol, sorbitol, suspension stabilising and surface-active agents from a group of ethers of higher fatty alcohols with polyoxyethylated glycols, preferably macrogolglycerol ricinoleate, or from a group of polyoxyethylene sorbitan and higher fatty acids esters, or from a group of
- furazidine liquid dosage form which is characterised by high stability, is suitable for precise dose measurement, causes no unpleasant taste sensations, and can be ingested by lactose- intolerant individuals, and during the preparation thereof there is no need to use buffer substances which unfavourably affect the stability of the active substance.
- Example 1 The method for preparing the suspension according to the invention
- the suspension stabilising and viscosity controlling agents from a group of natural polysaccharides, e.g. xanthan gums, and/or from a group of cellulose derivatives, e.g. hydroxypropyl celluloses, hypromellose;
- sucrose and preservatives selected from a group of parahydroxybenzoic acid esters and mixtures thereof, e.g. methyl parahydroxybenzoate and propyl parahydroxybenzoate, or acids and salts thereof, e.g. sorbic acid and potassium sorbate, benzoic acid and sodium benzoate, dissolved in heated purified water, and cooling the solution;
- the wetting agent from a group of polyhydric alcohols or mixtures thereof, e.g. glycerol, propylene glycol, sorbitol, suspension stabilising and surface-active agents from a group of ethers of higher fatty alcohols with polyoxyethylated glycols, e.g. macrogolglycerol ricinoleate, or from a group of polyoxyethylene sorbitan and higher fatty acids esters, or from a group of sorbitan and higher fatty acids esters, e.g. polysorbates, natural orange flavour and furazidine with purified water;
- a group of polyhydric alcohols or mixtures thereof e.g. glycerol, propylene glycol, sorbitol
- suspension stabilising and surface-active agents from a group of ethers of higher fatty alcohols with polyoxyethylated glycols, e.g. macrogolglycerol ricinoleate, or from a group of polyoxy
- sorbic acid and potassium sorbate benzoic acid and sodium benzoate, dissolved in heated purified water, mixing the wetting agent from a group of polyhydric alcohols or mixtures thereof, e.g. glycerol, propylene glycol, sorbitol, suspension stabilising and surface-active agents from a group of ethers of higher fatty alcohols with polyoxyethylated glycols, e.g. macrogolglycerol ricinoleate, or from a group of polyoxyethylene sorbitan and higher fatty acids esters, or from a group of sorbitan and higher fatty acids esters, e.g.
- polyhydric alcohols or mixtures thereof e.g. glycerol, propylene glycol, sorbitol
- suspension stabilising and surface-active agents from a group of ethers of higher fatty alcohols with polyoxyethylated glycols, e.g. macrogolglycerol ricinoleate, or
- polysorbates natural orange flavour and furazidine; preparing the suspension by combining the solution I, filtered solution II; or dissolving sucrose and preservatives: from a group of parahydroxybenzoic acid esters and mixtures thereof, e.g. methyl parahydroxybenzoate and propyl parahydroxybenzoate, or acids and salts thereof, e.g. sorbic acid and potassium sorbate, benzoic acid and sodium benzoate, in heated purified water, mixing the wetting agent from a group of polyhydric alcohols or mixtures thereof, e.g.
- suspension stabilising and viscosity controlling agents from a group of natural polysaccharides, e.g. xanthan gums, and/or from a group of cellulose derivatives, e.g
- Example 2 A stable furazidine liquid dosage form was obtained (Example 2) which is suitable for precise dosing also in young patients, easy to ingest without any unpleasant taste sensations when swallowing (Example 3), suitable for lactose- intolerant individuals, the unique composition of all components of which (active substance and auxiliary substances) provides optimal pH for the stability of the active substance: furazidine, without using any pH control agents/pH buffer systems (Example 4) .
- Example 2 Physical stability of the liquid dosage form depending on the auxiliary substances used in stability tests
- composition of the invention provides the best stability for the liquid dosage form in stability tests due to optimal dispersion of the active substance, adequate size reduction of active substance particles, and proper viscosity of the dispersing phase, thereby lowering the tendency of the active substance to settle.
- the disclosed composition according to the invention provides an acceptable taste of the liquid form of the drug.
- the main idea behind this part of experimental testing was to introduce as few artificial taste improving agents as possible.
- the sucrose was used which mainly functions as a density regulator as well as taste regulator, and because of that the masking of the active substance bitter taste it gives is insufficient to enable the use of the formulation (Sample 5) as a final drug form.
- Tests with the variant use of different flavours were conducted. Exemplary formulations from this testing step are shown in Table No. 3.
- Example 4 Providing proper environment for the stability of the active substance in liquid dosage form
- Prior art formulations with furazidine available on the market contain no liquid auxiliary substances.
- aqueous environment has an undesirable effect on the stability of therapeutic substances and it is necessary to provide suitable conditions, mainly pH, for the chemical stability of the active substance.
- the developmental work in this step was started with the determination in what pH range furazidine in aqueous environment is chemically stable. To achieve that, furazidine was combined with aqueous solutions of different pH and contaminations resulting from the active substance degradation were tested (Table 4).
- furazidine in combination with water shows the best stability in a pH range of 1-2 which is too low for the final drug form.
- the liquid drug form for which the main solvent is water, has the final pH in a range of 1-2 which renders the oral application of such a dosage form impossible due to the risk of irreversible lesions in upper alimentary organs during the application.
- Example 4a Determining the amount of active substance in a liquid drug form containing furazidine
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Abstract
The object of the invention is furazidine in the form of suspension characterized in that it contains furazidine in the amount from 0.1 g/100 g to 5.04 g /100 g, a sweetening agent selected from a group of disaccharides, a suspension stabilising agent, preservatives, suspension stabilising and viscosity controlling agent, a suspension stabilising and surface-active agent, a bitter taste masking agent and purified water as a solvent, and the method for the preparation thereof.
Description
Furazidin composition in the form of suspension and method for preparation thereof
The object of the invention is a furazidine liquid dosage form and the method for the preparation thereof. The invention is applicable in medicine.
Solid dosage forms containing furazidine in the form of a tablet containing lactose, potato starch, sucrose, stearic acid and polysorbate (Teva, US Pharmacia) , or potato starch, sucrose, colloidal silicon dioxide, stearic acid (Adamed) , or lactose monohydrate, silicified microcrystalline cellulose with the following composition: 98% of microcrystalline cellulose and 2% colloidal anhydrous silica, magnesium stearate, colloidal anhydrous silica, sodium carboxymethyl starch type A (Adamed) as auxiliary substances are known. None of the above tablets are suitable for precise dose measurement, especially of paediatric doses. Some of the above are not suitable for lactose-intolerant individuals. Russian patent RU2221575 relates to the administration of antibiotics and furazidine in tablets together with mineral water to small children. This method requires the administration of difficult-to-split solid tablets to small children. Therefore, there is still a need to provide the furazidine liquid dosage form which is also suitable for precise dosing in young patients, with an active substance having high stability, without the necessity to use buffer substances, and which is easy to ingest without any unpleasant taste sensations when swallowing, as well as suitable for lactose-intolerant individuals, and the preparation thereof. Surprisingly, the present invention meets the above mentioned needs.
The first object of the invention is the furazidine liquid dosage form characterised in that it contains furazidine in
the amount from 0.10 g/100 g to 5.04 g/100 g, a sweetening agent selected from a group of disaccharides , a suspension stabilising agent, preservatives, suspension stabilising and viscosity controlling agents, a suspension stabilising and surface-active agent, a bitter taste masking agent and purified water as a solvent. Preferably, the sweetening agent according to the invention is sucrose. Still preferably, the suspension stabilising agent is selected from a group comprising polyhydric alcohols or mixtures thereof, preferably, these are glycerol, propylene glycol, sorbitol. More preferably, preservatives according to the invention are substances selected from a group of parahydroxybenzoic acid esters and mixtures thereof, preferably, methyl parahydroxybenzoate, most preferably these are methyl parahydroxybenzoate, propyl parahydroxybenzoate, or acids and salts thereof, most conveniently sorbic acid and potassium sorbate, or benzoic acid and sodium benzoate. In another preferred embodiment of the invention, suspension stabilising and viscosity controlling agents are selected from a group of natural polysaccharides, comprising xanthan gums, and/or from a group of cellulose derivatives, preferably these are hydroxypropyl celluloses, hypromellose . Still it is preferable that the suspension stabilising and surface-active agent according to the invention is selected from a group comprising ethers of higher fatty alcohols with polyoxyethylated glycols, including macrogolglycerol ricinoleate, or from a group of polyoxyethylene sorbitan and higher fatty acids esters, or from a group of sorbitan and higher fatty acids esters, preferably these are polysorbates . In further equally convenient embodiment of the invention, the bitter taste masking agent is a natural orange flavour. Most preferably, the form according to the invention contains furazidine, sucrose, glycerol, methyl parahydroxybenzoate, propyl parahydroxybenzoate, macrogolglycerol ricinoleate,
hydroxypropylcellulose, xanthan gum, natural orange flavour, and purified water.
The second object of the invention is a method for the preparation of furazidine fluid dosage form characterised in that it includes: a) preparing a solution containing suspension stabilising and viscosity controlling agents are selected from a group of natural polysaccharides and/or from a group of cellulose derivatives ;
b) preparing a solution containing the sweetening agent and preservatives selected from a group of parahydroxybenzoic acid esters and mixtures thereof, or acids and salts thereof, dissolved in heated purified water, preferably subsequently cooling the prepared solution; c) preparing a solution by mixing a wetting agent from a group of polyhydric alcohols or mixtures thereof, suspension stabilising and surface-active agents, bitter taste masking agents, preferably a natural orange flavour, and furazidine with purified water, and, subsequently, preparing a suspension by combining the solution from step a) , the filtered solution from step b) and the solution from step c) , wherein more preferably the suspension is formed by mixing the solution from step a) and a solution of mixed substances from steps b) and c) , most preferably the suspension is formed by mixing the substances from steps a) , b) , and c) .
Preferably, the method according to the invention is characterised by that the suspension stabilising and viscosity controlling agent is xanthan gum, hydroxypropyl celluloses or hypromellose . In another preferred embodiment of the invention, the sweetening agent is sucrose, and the preservative are parahydroxybenzoic acid esters, preferably methyl parahydroxybenzoate and propyl parahydroxybenzoate, most preferably sorbic acid and potassium sorbate, benzoic acid and salts thereof. Most preferably, the method according to the invention is characterised by that the wetting agent is selected from a group of polyhydric alcohols, glycerol, propylene glycol, sorbitol, suspension stabilising and surface-active agents from a group of ethers of higher fatty alcohols with polyoxyethylated glycols, preferably macrogolglycerol ricinoleate, or from a group of polyoxyethylene sorbitan and higher fatty acids esters, or from a group of sorbitan and higher fatty acids esters, preferably polysorbates .
Owing to the present invention, it is possible to obtain furazidine liquid dosage form which is characterised by high stability, is suitable for precise dose measurement, causes no unpleasant taste sensations, and can be ingested by lactose- intolerant individuals, and during the preparation thereof there is no need to use buffer substances which unfavourably affect the stability of the active substance.
Example 1. The method for preparing the suspension according to the invention
The product being the object of the invention, the preferred embodiment of which is presented in Table 1, was prepared according to the following production technology which involves :
- preparing the solution I containing the suspension stabilising and viscosity controlling agents: from a group of natural polysaccharides, e.g. xanthan gums, and/or from a group of cellulose derivatives, e.g. hydroxypropyl celluloses, hypromellose;
- preparing the solution II containing: sucrose and preservatives selected from a group of parahydroxybenzoic acid esters and mixtures thereof, e.g. methyl parahydroxybenzoate and propyl parahydroxybenzoate, or acids and salts thereof, e.g. sorbic acid and potassium sorbate, benzoic acid and sodium benzoate, dissolved in heated purified water, and cooling the solution;
- preparing the solution III by mixing the wetting agent from a group of polyhydric alcohols or mixtures thereof, e.g. glycerol, propylene glycol, sorbitol, suspension stabilising and surface-active agents from a group of ethers of higher fatty alcohols with polyoxyethylated glycols, e.g. macrogolglycerol ricinoleate, or from a group of polyoxyethylene sorbitan and higher fatty acids esters, or from a group of sorbitan and higher fatty acids esters, e.g. polysorbates, natural orange flavour and furazidine with purified water;
- preparing the suspension by combining the solution I, filtered solution II, and solution III; or preparing the solution · I containing the suspension stabilising and viscosity control 1ing agents: from a group of
natural polysaccharides, e.g. xanthan gums, and/or from a group of cellulose derivatives, e.g. hydroxypropyl celluloses, hypromellose; preparing the solution II containing: sucrose and preservatives: from a group of parahydroxybenzoic acid esters and mixtures thereof, e.g. methyl parahydroxybenzoate and propyl parahydroxybenzoate, or acids and salts thereof, e.g. sorbic acid and potassium sorbate, benzoic acid and sodium benzoate, dissolved in heated purified water, mixing the wetting agent from a group of polyhydric alcohols or mixtures thereof, e.g. glycerol, propylene glycol, sorbitol, suspension stabilising and surface-active agents from a group of ethers of higher fatty alcohols with polyoxyethylated glycols, e.g. macrogolglycerol ricinoleate, or from a group of polyoxyethylene sorbitan and higher fatty acids esters, or from a group of sorbitan and higher fatty acids esters, e.g. polysorbates, natural orange flavour and furazidine; preparing the suspension by combining the solution I, filtered solution II; or dissolving sucrose and preservatives: from a group of parahydroxybenzoic acid esters and mixtures thereof, e.g. methyl parahydroxybenzoate and propyl parahydroxybenzoate, or acids and salts thereof, e.g. sorbic acid and potassium sorbate, benzoic acid and sodium benzoate, in heated purified water, mixing the wetting agent from a group of polyhydric alcohols or mixtures thereof, e.g. glycerol, propylene glycol, sorbitol, suspension stabilising and surface-active agents from a group of ethers of higher fatty alcohols with polyoxyethylated glycols, e.g. macrogolglycerol ricinoleate, or from a group of polyoxyethylene sorbitan and higher fatty acids esters, or from a group of sorbitan and higher fatty
acids esters, e.g. polysorbates, natural orange flavour and furazidine and solubilising ( suspension stabilising and viscosity controlling agents: from a group of natural polysaccharides, e.g. xanthan gums, and/or from a group of cellulose derivatives, e.g. hydroxypropyl celluloses, hypromellose) .
Requirements concerning the size of furazidine were as follows: 10÷150 μπι
Table 1 - Composition of the product being the object of the invention
Or
Starting material Amount [g]
Solution I
Xanthan gum 0.34
Hypromellose 0.20
Purified water q.s.
Solution II
Sucrose 40.0
Potassium sorbate 0.20
Sorbitol 5.0
Polysorbate 80 0.10
Furazidine 0.84
Natural orange flavour 0.55
Purified water Ad 100 or
Starting material Amount [g]
Xanthan gum 0.34
Hydroxypropyl cellulose 0.20
Sucrose 40.0
Sodium benzoate 0.20
Propylene glycol 5.0
Macrogolglycerol ricinoleate 0.10
Furazidine 0.84
Natural orange flavour 0.55
Purified water Ad 100
A stable furazidine liquid dosage form was obtained (Example 2) which is suitable for precise dosing also in young patients, easy to ingest without any unpleasant taste sensations when swallowing (Example 3), suitable for lactose- intolerant individuals, the unique composition of all components of which (active substance and auxiliary substances) provides optimal pH for the stability of the active substance: furazidine, without using any pH control agents/pH buffer systems (Example 4) .
Example 2. Physical stability of the liquid dosage form depending on the auxiliary substances used in stability tests
The disclosed composition of the invention provides the best stability for the liquid dosage form in stability tests due to optimal dispersion of the active substance, adequate size reduction of active substance particles, and proper viscosity of the dispersing phase, thereby lowering the tendency of the active substance to settle.
Mixtures of the active substance and auxiliary substances were prepared with compositions presented in Table 2.
Table 2 - Selection of auxiliary substances
Surprisingly, it has been found that only the use of as many as four auxiliary substances: hydroxypropyl cellulose, xanthan gum, macrogolglycerol ricinoleate, glycerol, in properly
experimentally determined concentrations, resulted in the proper stability of the obtained suspension (Sample 5) . Also, only in this case the satisfactory viscosity of the drug liquid dosage form as well as the suitable redispersion time for the active substance were obtained.
Example 3. Providing an acceptable taste of the liquid dosage form containing furazidine
The disclosed composition according to the invention provides an acceptable taste of the liquid form of the drug. Considering the fact that said drug will be intended mainly for children and the elderly, the main idea behind this part of experimental testing was to introduce as few artificial taste improving agents as possible. In the earlier steps of the formulation development, the sucrose was used which mainly functions as a density regulator as well as taste regulator, and because of that the masking of the active substance bitter taste it gives is insufficient to enable the use of the formulation (Sample 5) as a final drug form. Tests with the variant use of different flavours were conducted. Exemplary formulations from this testing step are shown in Table No. 3.
Table 3 - Bitter taste masking, technological trials
No. Amount [g]
Starting material
Sample 6 Sample 7 Sample 8
1. Furazidine 0.84 0.84 0.84
2. Sucrose 40.0 40.0 40.0
3. Glycerol 5.0 5.0 5.0
4. Macrogolglycerol ricinoleate
0.10 0.10 0.10
5. Xanthan gum
0.34 0.34 0.34
6. Hydroxypropyl cellulose
0.20 0.20 0.20
raspberry 0.55 - -
7. Flavour: strawberry - 0.55 - orange - - 0.55
8. Purified water
ad. 100 ad. 100 ad 100
Surprisingly, it has been found that the use of natural orange flavour only in combination with sucrose already present in the formulation masked the bitter taste of the active substances without the necessity to use additional sweeteners and other taste improving agents. It is worth highlighting that other flavours were unsuccessful; moreover, the addition of natural orange flavour to the formulation had no negative effect on the stability of the suspension which was the object of earlier series of experiments.
Example 4. Providing proper environment for the stability of the active substance in liquid dosage form
Prior art formulations with furazidine available on the market contain no liquid auxiliary substances. As it is known, aqueous environment has an undesirable effect on the stability of therapeutic substances and it is necessary to provide suitable conditions, mainly pH, for the chemical stability of the active substance. The developmental work in this step was started with the determination in what pH range furazidine in aqueous environment is chemically stable. To achieve that, furazidine was combined with aqueous solutions of different pH and contaminations resulting from the active substance degradation were tested (Table 4).
Table No. 4 - Stability of furazidine in aqueous environment depending on pH
It has been found that furazidine in combination with water shows the best stability in a pH range of 1-2 which is too low for the final drug form. Based on the data presented above, the liquid drug form, for which the main solvent is water, has the final pH in a range of 1-2 which renders the oral application of such a dosage form impossible due to the risk of irreversible lesions in upper alimentary organs during the application. Nevertheless, it was decided to verify whether it is possible to determine a composition of auxiliary substances such that the furazidine stability is ensured at a different, more neutral pH, which would allowed the use of such a drug form in therapeutic practice.
In order to confirm the above observations, the product was made with different pH and contaminations resulting from the active substance degradation were tested in the final product. In Table 5, the results for the obtained product are presented :
Table 5. The effect of product pH on the active substance stability
Based on the conducted experiments, no increase in the contamination level was observed at the tested pH range (2.0 - 6.5) of the product.
Subsequently, the furazidine stability in the product was verified with pH control agents/buffer systems typically used in such types of a drug form. To achieve that a series of technological samples was prepared, some of which are shown in Table 6
Table 6 - Furazidine stability in a liquid drug form depending on the pH control agent/buffer system used
Starting material Sample 9 Sample 10
Furazidine 0.84 0.84
Sucrose 40.0 40.0
Glycerol 5.0 5.0
0.18 0.18
Methyl parahydroxybenzoate
Propyl 0.02 0.02 parahydroxybenzoate
Macrogolglycerol ricinoleate 0.10 0.10
Hydroxypropyl cellulose 0.34 0.34
Xanthan gum 0.20 0.20
Citric acid 0.5 -
Sodium citrate 1.73 -
Sodium hydrogen phosphate - 4.37
Sodium dihydrogen phosphate - 0.5
Natural orange flavour 0.55 0.55
Purified water ad 100 ad 100
5.08 5.12 start
pH
5.04 5.05
60°C 5 days
0.007 0.005 start
ACRO
0.09 <LOD
60°C 5 days
0.238 0.046 start
Cont. 1
0.141 0.330
60°C 5 days
<LOQ <LOQ start
Cont. 2
0.037 <LOQ
60°C 5 days
<LOQ <LOQ start
Cont. 3
<LOQ 0.136
60°C 5 days
start <LOQ <LOQ
Cont. 4
<LOQ 0.112
60°C 5 days
start 0.245 0.051
TOTAL
0.273 0.577
60°C 5 days
Prepared formulations were tested in terms of the formation of contaminations resulting from the active substance degradation. Tests were performed immediately after the sample preparation and after the storage of samples in stress conditions (60°C, 5 days).
The test results show that the introduction of pH control agents/buffer systems to the composition of liquid drug form containing furazidine generates the increase in contaminations. Surprisingly, it has been found that in samples developed for the purpose of testing for the effectiveness of preservatives, in which no pH control agent/buffer system was used yet (it was not used, because simultaneously there were works on the selection of optimal pH regulators), Table 7, the contamination level during stress tests was in most cases below the detection level (LOQ) , indicating the furazidine was stable at pH between 4 - 6.5 despite the lack of pH stabilising substances.
Table 7 - Selection of a preservative
Starting material Sample 22
Furazidine 0.84
Sucrose 40.0
Glycerol 5.0
Methyl 0.18 parahydroxybenzoate
Propyl 0.02 parahydroxybenzoate
Macrogolglycerol ricinoleate 0.10
Hydroxypropyl cellulose 0.34
Xanthan gum 0.20
Natural orange flavour 0.55
Purified water ad 100
6.25 start
PH
5.40
60°C 5 days
<LOD start
ACRO
0.067
60°C 5 days
start <LOQ
Cont. 1
60°C 5 days <LOQ
<LOQ start
Cont. 2
0.135
60°C 5 days
<LOQ start
Cont. 3
<LOQ
60°C 5 days
<LOQ start
Cont. 4
<LOQ
60°C 5 days
<LOQ start
TOTAL
0.202
60°C 5 days
Also, during the stability tests performed on the final drug form it has been found that, despite the lack of pH control agents/buffer systems, the active substance shows chemical stability and product pH does not go beyond set limits of deviations for the final drug form of 4 - 6.5. The results of stability tests on the liquid drug form are shown in Table 8.
Table 8 - Stability tests on the oral liquid drug form of the composition disclosed in the invention
Surprisingly, it has been found that in this case experimentally determined final formulation of auxiliary substances used has ensured the stability of the active substance despite the lack of pH control agents/buffer systems and, what is equally surprising, the chemical stability of furazidine has been obtained in a different more neutral pH range, enabling the formation of said liquid dosage form in contrast to conclusions drawn based on the pre-formulation
tests in which the furazidine stability in combination with water at different pH was verified.
Example 4a. Determining the amount of active substance in a liquid drug form containing furazidine
According to the description of preparing the liquid dosage form containing furazidine disclosed in the essence of description, formulations were prepared with varying content of active substance, while other components were used in the amounts described in the essence of the invention. Limit amounts of active substance which give satisfactory results in terms of active substance stability are shown in Table 9.
Table 9 - Limit amounts of furazidine in the presented liquid dosage form
No. Amount [g]
Starting material
Sample 31 Sample 32 Sample 33
1. Furazidine 0.10 0.84 5.04
2. Sucrose 40.0 40.0 40.0
3. Glycerol 5.0 5.0 5.0
4. Macrogolglycerol ricinoleate
0.10 0.10 0.10
5. Xanthan gum 0.34 0.34 0.34
6. Hydroxypropyl cellulose
0.20 0.20 0.20
7. Natural orange flavour
0.55 0.55 0.55
8. Methyl
0.18 0.18 0.18 parahydroxybenzoate
9. Propyl
0.02 0.02 0.02 parahydroxybenzoate
10. Purified water
ad. 100 ad. 100 ad. 100
Form Light yellow Yellow Very yellow suspension suspension suspension
Time after which the furazidine
deposit occurred during After 30 minutes, no formation of deposit was observed centrifugation (3500 rpm) which would not redispersed
The acceptance criterion for this part of experimental tests was to maintain the physical and chemical stability of the active substance as well as additionally the resistance to centrifugation which would result in the formation of a dense deposit of the active substance which did not redispersed.
Claims
1. A furazidine liquid dosage form characterised in that it contains furazidine in the amount from 0.10 g/100 g to 5.04 g/100 g, a sweetening agent selected from a group of disaccharides , a suspension stabilising agent, preservatives, suspension stabilising and viscosity controlling agents, a suspension stabilising and surface-active agent, a bitter taste masking agent and purified water as a solvent.
2. The form according to claim 1, characterised in that the sweetening agent is sucrose.
3. The form according to claim 1 or 2, characterised in that the suspension stabilising agent is selected from a group comprising polyhydric alcohols or mixtures thereof, preferably, these are glycerol, propylene glycol, sorbitol.
4. The form according to any claim from 1 to 3, characterised in that the preservatives are selected from a group of parahydroxybenzoic acid esters and mixtures thereof, preferably, methyl parahydroxybenzoate, most preferably these are methyl parahydroxybenzoate, propyl parahydroxybenzoate, or acids and salts thereof, most conveniently sorbic acid and potassium sorbate, benzoic acid and sodium benzoate.
5. The form according to any claim from 1 to 4, characterised in that the suspension stabilising and viscosity controlling
agents are selected from a group comprising natural polysaccharides, including xanthan gums, and/or from a group of cellulose derivatives, preferably these are hydroxypropyl celluloses, hypromellose .
6. The form according to any claim from 1 to 5, characterised in that the suspension stabilising and surface-active agent is selected from a group comprising ethers of higher fatty alcohols with polyoxyethylated glycols, including macrogolglycerol ricinoleate, or from a group of polyoxyethylene sorbitan and higher fatty acids esters, or from a group of sorbitan and higher fatty acids esters, preferably these are polysorbates.
7. The form according to any claim from 1 to 6, characterised in that the bitter taste masking agent is a natural orange flavour .
8. The form according to any claim from 1 to 7, characterised in that it contains furazidine, sucrose, glycerol, methyl parahydroxybenzoate, propyl parahydroxybenzoate, macrogolglycerol ricinoleate, hydroxypropylcellulose, xanthan gum, natural orange flavour, and purified water.
9. A method for the preparation of furazidine liquid dosage form, characterised in that it involves: a) preparing a solution containing suspension stabilising and viscosity controlling agents are selected from a group of natural polysaccharides and/or from a group of cellulose derivatives ;
b) preparing a solution containing the sweetening agent and preservatives selected from a group of parahydroxybenzoic acid esters and mixtures thereof, or acids and salts thereof, dissolved in heated purified water, preferably subsequently cooling the prepared solution; c) preparing a solution by mixing a wetting agent from a group of polyhydric alcohols or mixtures thereof, suspension stabilising and surface-active agents, bitter taste masking agents, preferably a natural orange flavour, and furazidine with purified water, and, subsequently, preparing a suspension by combining the solution from step a) , the filtered solution from step b) and the solution from step c) , wherein more preferably the suspension is formed by mixing the solution from step a) and a solution of mixed substances from steps b) and c) , most preferably the suspension is formed by mixing the substances from steps a) , b) , and c) .
10. The method according to claim 9, characterised by that the suspension stabilising and viscosity controlling agent is xanthan gum, hydroxypropyl celluloses or hypromellose .
11. The method according to claim 9 or 10, characterised by that the sweetening agent is sucrose, and the preservative are parahydroxybenzoic acid esters, preferably methyl parahydroxybenzoate and propyl parahydroxybenzoate, or acids and salts thereof, most preferably sorbic acid and potassium sorbate, benzoic acid and sodium benzoate.
12. The method according to any claim from 9 to 11, characterised by that the wetting agent is selected from a group of polyhydric alcohols, glycerol, propylene glycol, sorbitol, suspension stabilising and surface-active agents from a group of ethers of higher fatty alcohols with polyoxyethylated glycols, preferably macrogolglycerol ricinoleate, or from a group of polyoxyethylene sorbitan and higher fatty acids esters, or from a group of sorbitan and higher fatty acids esters, preferably polysorbates.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP18819858.4A EP3641729A4 (en) | 2017-06-21 | 2018-06-19 | Furazidin composition in the form of suspension and method for preparation thereof |
| UAA202000320A UA126867C2 (en) | 2017-06-21 | 2018-06-19 | Furazidin composition in the form of suspension and method for preparation thereof |
| RU2020101969A RU2770041C2 (en) | 2017-06-21 | 2018-06-19 | Furazidin composition in the form of a suspension and a method for its preparation |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PLP.421967 | 2017-06-21 | ||
| PL421967A PL236891B1 (en) | 2017-06-21 | 2017-06-21 | Fluid form of furagin administering and method for obtaining it |
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| Publication Number | Publication Date |
|---|---|
| WO2018236236A1 true WO2018236236A1 (en) | 2018-12-27 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/PL2018/050026 WO2018236236A1 (en) | 2017-06-21 | 2018-06-19 | Furazidin composition in the form of suspension and method for preparation thereof |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP3641729A4 (en) |
| PL (1) | PL236891B1 (en) |
| RU (1) | RU2770041C2 (en) |
| UA (1) | UA126867C2 (en) |
| WO (1) | WO2018236236A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2103997C1 (en) * | 1995-04-19 | 1998-02-10 | Акционерное общество закрытого типа "Гекта" | Medicinal agent for treatment of animal disease of bacterial etiology, method of treatment of animal gastroenteric disease of bacterial etiology and methods of treatment of gynecological disease of bacterial etiology in animals |
| PL419047A1 (en) * | 2016-10-10 | 2017-11-20 | Centrum Badawczo-Rozwojowe Novasome Spółka Z Ograniczoną Odpowiedzialnością | Composition that contains furazidin and method for producing it |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU1782587A1 (en) * | 1989-03-10 | 1992-12-23 | Lvovskij G Med Inst | Composition for treating parodontitis |
| US6521270B1 (en) * | 2001-06-11 | 2003-02-18 | The Procter & Gamble Company | Compositions comprising nitrofurantoin and uva ursi |
| RU2583945C1 (en) * | 2015-05-13 | 2016-05-10 | Федеральное государственное бюджетное учреждение науки Институт органического синтеза им. И.Я. Постовского Уральского отделения Российской академии наук (ИОС УрО РАН) | Agent for local treatment of lichen acuminatus of oral mucosa and method of treating lichen acuminatus of oral mucosa |
| WO2018069804A2 (en) * | 2016-10-10 | 2018-04-19 | Przedsiebiorstwo Produkcji Farmaceutycznej Hasco-Lek S.A. | New furazidin compositions and methods of their manufacture |
-
2017
- 2017-06-21 PL PL421967A patent/PL236891B1/en unknown
-
2018
- 2018-06-19 RU RU2020101969A patent/RU2770041C2/en active
- 2018-06-19 UA UAA202000320A patent/UA126867C2/en unknown
- 2018-06-19 EP EP18819858.4A patent/EP3641729A4/en active Pending
- 2018-06-19 WO PCT/PL2018/050026 patent/WO2018236236A1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2103997C1 (en) * | 1995-04-19 | 1998-02-10 | Акционерное общество закрытого типа "Гекта" | Medicinal agent for treatment of animal disease of bacterial etiology, method of treatment of animal gastroenteric disease of bacterial etiology and methods of treatment of gynecological disease of bacterial etiology in animals |
| PL419047A1 (en) * | 2016-10-10 | 2017-11-20 | Centrum Badawczo-Rozwojowe Novasome Spółka Z Ograniczoną Odpowiedzialnością | Composition that contains furazidin and method for producing it |
Non-Patent Citations (2)
| Title |
|---|
| STRICKLEY, ROBERT G. ET AL.: "Pediatric drugs - a review of commercially available oral formulations", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 97, no. 5, 1 May 2008 (2008-05-01), pages 1731 - 1774, XP055121290 * |
| TSAGAREISHVILI, G. V. ET AL.: "Stabilization of the suspensions of 5-nitrofuran derivatives", IZVESTIYA AKADEMII NAUK GRUZINSKOI SSR, vol. 1, no. 2, 1975, Seriya Khimicheskaya, pages 185 - 191, XP009518474, ISSN: 0132-6074 * |
Also Published As
| Publication number | Publication date |
|---|---|
| EP3641729A1 (en) | 2020-04-29 |
| RU2020101969A (en) | 2021-07-21 |
| RU2020101969A3 (en) | 2021-09-20 |
| RU2770041C2 (en) | 2022-04-14 |
| UA126867C2 (en) | 2023-02-15 |
| PL421967A1 (en) | 2019-01-02 |
| EP3641729A4 (en) | 2021-03-24 |
| PL236891B1 (en) | 2021-02-22 |
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