IL92190A - Liquid oral formulation of diclofenac in suspended form - Google Patents
Liquid oral formulation of diclofenac in suspended formInfo
- Publication number
- IL92190A IL92190A IL9219089A IL9219089A IL92190A IL 92190 A IL92190 A IL 92190A IL 9219089 A IL9219089 A IL 9219089A IL 9219089 A IL9219089 A IL 9219089A IL 92190 A IL92190 A IL 92190A
- Authority
- IL
- Israel
- Prior art keywords
- preparation according
- acid
- diclofenac
- preparation
- cellulose
- Prior art date
Links
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 239000000203 mixture Substances 0.000 title claims abstract description 30
- 229960001259 diclofenac Drugs 0.000 title claims abstract description 29
- 238000009472 formulation Methods 0.000 title abstract description 4
- 239000007788 liquid Substances 0.000 title description 3
- 238000002360 preparation method Methods 0.000 claims abstract description 34
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 54
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 15
- 235000010199 sorbic acid Nutrition 0.000 claims description 15
- 239000004334 sorbic acid Substances 0.000 claims description 15
- 229940075582 sorbic acid Drugs 0.000 claims description 15
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 14
- -1 ammonium halides Chemical class 0.000 claims description 14
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 14
- 239000004480 active ingredient Substances 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 12
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 claims description 10
- 239000003381 stabilizer Substances 0.000 claims description 10
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 8
- 239000003205 fragrance Substances 0.000 claims description 8
- 239000006188 syrup Substances 0.000 claims description 8
- 235000020357 syrup Nutrition 0.000 claims description 8
- 239000000725 suspension Substances 0.000 claims description 7
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 6
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 6
- 239000003963 antioxidant agent Substances 0.000 claims description 6
- 235000006708 antioxidants Nutrition 0.000 claims description 6
- 235000010980 cellulose Nutrition 0.000 claims description 6
- 239000001913 cellulose Substances 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 235000003599 food sweetener Nutrition 0.000 claims description 6
- 239000003755 preservative agent Substances 0.000 claims description 6
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 6
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 6
- 239000003765 sweetening agent Substances 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 235000010323 ascorbic acid Nutrition 0.000 claims description 5
- 239000011668 ascorbic acid Substances 0.000 claims description 5
- 229960005070 ascorbic acid Drugs 0.000 claims description 5
- 229920006184 cellulose methylcellulose Polymers 0.000 claims description 5
- 239000000975 dye Substances 0.000 claims description 5
- 239000008183 oral pharmaceutical preparation Substances 0.000 claims description 5
- 239000000080 wetting agent Substances 0.000 claims description 5
- 229920001817 Agar Polymers 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 4
- 229940023476 agar Drugs 0.000 claims description 4
- 235000010419 agar Nutrition 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 235000015165 citric acid Nutrition 0.000 claims description 4
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 claims description 4
- 229920002907 Guar gum Polymers 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- 229910052782 aluminium Inorganic materials 0.000 claims description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 3
- 229920003086 cellulose ether Polymers 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 235000010417 guar gum Nutrition 0.000 claims description 3
- 239000000665 guar gum Substances 0.000 claims description 3
- 229960002154 guar gum Drugs 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 3
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 3
- 239000000375 suspending agent Substances 0.000 claims description 3
- 230000008961 swelling Effects 0.000 claims description 3
- 229920002554 vinyl polymer Polymers 0.000 claims description 3
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000010443 alginic acid Nutrition 0.000 claims description 2
- 229920000615 alginic acid Polymers 0.000 claims description 2
- 230000000202 analgesic effect Effects 0.000 claims description 2
- 239000008122 artificial sweetener Substances 0.000 claims description 2
- 235000021311 artificial sweeteners Nutrition 0.000 claims description 2
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 2
- 239000008119 colloidal silica Substances 0.000 claims description 2
- 229940109275 cyclamate Drugs 0.000 claims description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 2
- 150000002016 disaccharides Chemical class 0.000 claims description 2
- 235000011389 fruit/vegetable juice Nutrition 0.000 claims description 2
- 229940074391 gallic acid Drugs 0.000 claims description 2
- 235000004515 gallic acid Nutrition 0.000 claims description 2
- 229920001519 homopolymer Polymers 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 150000002772 monosaccharides Chemical class 0.000 claims description 2
- 150000002989 phenols Chemical class 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000008363 phosphate buffer Substances 0.000 claims description 2
- 238000006116 polymerization reaction Methods 0.000 claims description 2
- 229920005862 polyol Polymers 0.000 claims description 2
- 150000003077 polyols Chemical class 0.000 claims description 2
- 235000019204 saccharin Nutrition 0.000 claims description 2
- 229940081974 saccharin Drugs 0.000 claims description 2
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 150000004760 silicates Chemical class 0.000 claims description 2
- 230000000996 additive effect Effects 0.000 claims 2
- 239000007853 buffer solution Substances 0.000 claims 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims 1
- 108010011485 Aspartame Proteins 0.000 claims 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims 1
- 239000005977 Ethylene Substances 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 claims 1
- 229940072056 alginate Drugs 0.000 claims 1
- 230000003110 anti-inflammatory effect Effects 0.000 claims 1
- 239000012736 aqueous medium Substances 0.000 claims 1
- 239000000605 aspartame Substances 0.000 claims 1
- 235000010357 aspartame Nutrition 0.000 claims 1
- 229960003438 aspartame Drugs 0.000 claims 1
- 229940105329 carboxymethylcellulose Drugs 0.000 claims 1
- 229920002678 cellulose Polymers 0.000 claims 1
- 229960004106 citric acid Drugs 0.000 claims 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 claims 1
- 239000000451 gelidium spp. gum Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000002335 preservative effect Effects 0.000 claims 1
- 230000000087 stabilizing effect Effects 0.000 claims 1
- 150000005846 sugar alcohols Chemical class 0.000 claims 1
- 230000004054 inflammatory process Effects 0.000 abstract description 2
- 239000008203 oral pharmaceutical composition Substances 0.000 abstract 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 12
- 229930003268 Vitamin C Natural products 0.000 description 12
- 235000019154 vitamin C Nutrition 0.000 description 12
- 239000011718 vitamin C Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- 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 description 9
- 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 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 239000000600 sorbitol Substances 0.000 description 9
- 235000010356 sorbitol Nutrition 0.000 description 9
- 239000011734 sodium Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 229920000151 polyglycol Polymers 0.000 description 7
- 239000010695 polyglycol Substances 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 5
- 235000019800 disodium phosphate Nutrition 0.000 description 5
- 229910000397 disodium phosphate Inorganic materials 0.000 description 5
- 239000001488 sodium phosphate Substances 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 235000005979 Citrus limon Nutrition 0.000 description 3
- 244000131522 Citrus pyriformis Species 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 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 description 3
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- 239000008272 agar Substances 0.000 description 3
- 159000000007 calcium salts Chemical class 0.000 description 3
- UZUODNWWWUQRIR-UHFFFAOYSA-L disodium;3-aminonaphthalene-1,5-disulfonate Chemical compound [Na+].[Na+].C1=CC=C(S([O-])(=O)=O)C2=CC(N)=CC(S([O-])(=O)=O)=C21 UZUODNWWWUQRIR-UHFFFAOYSA-L 0.000 description 3
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 3
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
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- OJIYIVCMRYCWSE-UHFFFAOYSA-M Domiphen bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CCOC1=CC=CC=C1 OJIYIVCMRYCWSE-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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- 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
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
The invention relates to an aqueous oral pharmaceutical formulation of diclofenac, which can be used for treating pain and inflammatory processes, and also to the preparation of such a formulation.
Description
REF 1336/89 92190/2 ΆΟΆ I!TO^ pr KDi^' bv o^o'rnn d ¾ .) o^vu n LIQUID ORAL FORMULATION OF DICLOFENAC IN SUSPENDED FORM 4-17295/+ Liquid oral formulation The invention relates to an aqueous oral pharmaceutical preparation of diclofenac, and to its use and preparation.
Diclofenac, chemical name o-(2,6-dichloroanilino)phenylacetic acid, is known as a potent analgesic and antirheumatic and is described, for example, in US Patent No. 3,558,690.
Much effort has been directed toward developing for this active ingredient an aqueous, individually dosable oral form of administration which has a neutral or pleasant taste and, in addition, has a satisfactory shelf life so as to make available to doctors and patients an appropriate alternative to other oral preparations.
It is known that diclofenac has a bitter taste and causes a scratching sensation in the throat. In addition, it has proven disadvantageous that, when customary aqueous oral solutions are used, water-insoluble hydrates are formed which result in precipitations. It is furthermore known that diclofenac cyclizes, in particular in acid solution, to form l-(2,6-dichloro-phenyl)indolin-2-one. Thus, corresponding aqueous pharmaceutical formulations of diclofenac do not have an adequate shelf life and, as a consequence, would not meet the criteria for registration as a medicament.
The present invention had the object of developing an aqueous oral pharmaceutical preparation of diclofenac which does not have the disadvantages mentioned.
This object is achieved by the preparation according to the invention. This has the features that a pH range is selected in which the active ingredient has the lowest water solubility and that diclofenac is in suspended form.
Surprisingly, when aqueous formulations of this type are used, absolutely no prohibitive formation of indolinone, in particular, is observed. In addition, preparations of this type have a pleasant taste and do not cause a scratching sensation in the throat.
The preferred active ingredient concentration of the preparation according to the invention is about 0.5 to about 10% by weight, in particular about 1 to about 5% by weight, primarily about 1% by weight.
The pH range according to the invention is, in particular, between about 2 and about 3.5, preferably between about 2.5 and about 3.5, and is established by means of pharmaceutically acceptable acids or buffer systems which are known per se. Suitable pharmaceutically acceptable acids are preferably carboxylic acids, such as acetic acid, malonic acid, fumaric acid, maleic acid, succinic acid, lactic acid, tartaric acid or primarily citric acid. Examples of buffer systems of this type are sodium citrate HCl or citric acid/phosphate buffer.
Appropriate forms of administration of the suspension according to the invention are drops, mixtures, juices or syrups, which may also be used in dose-unit forms.
The composition according to the invention may contain further pharmaceutically acceptable adjuncts and additives, for example preservatives, antioxidants, fragrances, dyes, sweeterners, suspension stabilizers and/or wetting agents.
Suitable preservatives, which protect against infestation by microorganisms, are benzoic acid or salts thereof, such as sodium, potassium or calcium salts, 4-hydroxybenzoic acid esters, such as methyl, ethyl or propyl 4-hydroxybenzoate (PHB esters), phenols, such as tert-butyl-4-methoxy- or 2,6-ditert-butyl-4-methylphenol, phenyl (lower alkanols), benzyl alcohol, 4-chloro- or 2,4-dichlorobenzyl alcohol, 2-phenylethanol or 3-phenylpropanol, chlorohexidine diacetate or digluconate, thiabendazole, furthermore nitrofural, quarternary ammonium halides, such as alkonium bromide, benzalkonium chloride, cetrimonium bromide, phenododecinium bromide or cetylpyridinium chloride, or primarily sorbic acid, for example in a proportion of about 0.01 to about 0.1% by weight.
Suitable antioxidants, which are intended to inhibit oxidative processes, are, for example, sulfites, such as alkali metal sulfites, alkali metal bisulfites or alkali metal pyrosulfites, for example the corresponding sodium or potassium salts, thiodipropionic acid, thioglycol, thiolactic acid, glutathione, but preferably cystein, ascorbic acid and esters thereof, for example ascorbic acid myristate, palmitate or stearate, or esters of gallic acid, such as propyl, octyl or dodecyl esters, for example in a proportion of about 0.01 to about 0.1% by weight. Synergists, such as citric acid, citraconic acid, phosphoric acid or tartaric acid, may be admixed.
To improve the flavour, suitable fragrances are, for example, etherial oils, in particular those derived from fruits, such as oranges* and oils from Seville oranges, mandarines or lemons, and furthermore caramel.
Examples of suitable dyes are Indigo Tin I(blue), Amaranth (red), Yellow orange S (orange), Tartrazine XX (yellow) or chlorophyll (green).
Examples of suitable sweeteners, which are present in high concentration, in for example, syrups, are sugar such as monosaccharides or disaccharides, for example D-glucose, D-fructose, D-xylose, maltose or sucrose, polyols, such as glycerol, dulcitol, mannitol, sorbitol or xylitol, or artificial sweeteners, such as saccharine or the corresponding sodium, potassium or calcium salt, cyclamate or the corresponding sodium or calcium salt, aspartam or acesulfam or the potassium salt thereof, furthermore Dulcin or ammonium glycyrrhizinate.
The suspension stabilizers are intended to ensure that the individual doses removed have a constant active ingredient content. Examples of appropriate stabilizers are inorganic suspension stabilizers, for example colloidal silicates having a high aluminium and magnesium content, such as bentonite, Veegum or Gel White, colloidal silica, for example Aerosil® (Degussa), Cabosil® (Cabot), organic stabilizers, for example swelling agents, such as alginates, for sodium alginate, calcium alginate or propylene glycol alginate, gum arabic, tragasanth, karaya gum, sterculia gum, carrageen, guar gum or agar, synthetic or semisynthetic swelling agents, for example 1,2-epoxide polymers, in particular ethylene oxide homopolymers having a degree of polymerization of about 2,000-100,000, which are known, for example, under the trade name Polyox® (Union Carbide), preferably swellable cellulose ethers, for example methyl- or ethyl cellulose, hydroxy ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl- or ethylhydroxyethyl cellulose, carboxymethyl cellulose or an alkali metal salt thereof, or microcrystalline cellulose, or water-soluble polyvinyl compounds, such as polyvinyl acetate, polyvinyl alcohol or polyvinylpyrrolidone.
Wetting agents may advantageously be added to the stabilizers. Examples of suitable wetting agents are sulfosuccinates, such as dihexyl sulfosuccinate, dioctyl sulfosuccinate or diamyl sulfosuccinate, sulfonates or sulfates, for example Na alkylnaphthalene- sulfonates, fatty alcohol sulfonates or fatty alcohol polyglycol ether sulfates, fatty acid polyglycol esters, for example polyethylene glycol stearates, polyglycol esters of C8-C18 fatty acids, fatty alcohol polyglycol ethers, for example lauryl, cetyl, stearyl or oleyl alcohol polyglycol ether or cetylstearyl alcohol polyglycol ether, poly(fatty acid) ester polyglycol ethers, for example polyethylene glycol sorbitan monolaurate, monopalmitate, monostearate or monooleate, glycerol fatty acid ester polyglycol ether or pentaerythritol fatty acid polyglycol ether, sucrose esters, for example sucrose monostearate or distearate or sucrose monopalmitate, ethoxylated vegetable oils, for example ethoxylated castor oil or hydrogenated and ethoxylated castor oil, or block polymers, such as polyoxyethylene-polyoxypropylene polymers.
The aqueous oral pharmaceutical preparations of diclofenac according to the invention are prepared, for example, as follows depending on the nature of the form of administration.
Thus, for example, the adjuncts and additives are incorporated into the water with or without warming, for example in a temperature range of from about 20° to about 100°C. The active ingredient is then suspended in this base. However, the sequence of mixing the components of the preparation according to the invention is not important.
To prepare syrups, for example, the suspension agent and the appropriate suspension stabilizer are added to the water. A sweetener and, if desired, preservatives, antioxidants, fragrances and/or dyes are incorporated with or without warming, for example in a temperature range of from about 50° to about 100°C. The active ingredient is then suspended in the medium.
The aqueous oral pharmaceutical preparation according to the invention can be used, for example, for treating pain and inflammatory processes.
The invention also relates, in particular, to the preparations and preparation processes described in the Examples.
The Examples below serve merely to illustrate the above-described invention; however, they are not intended to represent a limitation.
Example 1: Syrup containing 1% by weight of diclofenac.
Composition: Diclofenac (free acid) 1.00 g Hydroxyethyl cellulose (Natrosol 250 G) 0.50 g Cellulose and sodium carboxymethyl cellulose (Avicel RC 591) 1.20 g Sorbitol solution 25.00 g Sorbic acid 0.05 g Vitamin C 0.10 g Citric acid 0.20 g Saccharine sodium 0.06 g Demineralized water 71.89 g 100.00 g pH: 2.9 Preparation: Avicel is suspended in the water using a high-speed mixer, Natrosol is admixed, and the mixture is left to swell for about 1 hour. Sorbitol solution and sorbic acid are added, and the mixture is heated to about 85° with stirring. After the mixture has been cooled to room temperature, Vitamin C, citric acid and saccharine are dissolved consecutively therein with stirring. The active ingredient is suspended in the mixture with the aid of the mixer, and the mixture is subsequently deaerated.
Example 2: Syrup containing 1% of diclofenac: Diclofenac (free acid) 1.0 g Sucrose 40.0 g Agar powder 0.3 g Sorbic acid 0.1 g Vitamin C 0.1 g Citric acid 1 AQ 0.2 g Disodium phosphate 2 AQ 0.08 g Lemon aroma 0.1 g Demineralized water 58.12 g 100.00 g pH; 3.2 Preparation: The water is warmed to about 90°C and sorbic acid is dissolved therein. Agar powder is subsequently scattered into the mixture and dispersed using a high-speed mixer. The mixture is then left to swell at 90°C for about 30 minutes. The sucrose is added and dissolved with stirring. After the mixture has cooled to about 40°C, citric acid, disodium phosphate and Vitamin C are added consecutively and dissolved. After the fragrance has been added, the active ingredient is ground with a small amount of the base and then distributed in the remainder of the base.
Example 3: Mixture containing 1% of diclofenac.
Diclofenac (free acid) Hydoxyethylcellulose (Natrosol 250 G) Cellulose and sodium carboxymethylcellulose (Avicel RC 591) Sorbic acid Vitamin C Citric acid 1 AQ Saccharine sodium Disodium phosphate 2 AQ Lemon aroma Demineralized water 100.00 g pH: 3.2 Preparation: Avicel is dispersed in 50 g of water using a high-speed mixer, Natrosol is admixed, and the mixture is left to swell for about 1 hour. The remainder of the water (47.16 g) is heated to about 60°C and sorbic acid is dissolved therein. After the latter mixture has cooled to 40°C, saccharin, citric acid, disodium phosphate and Vitamin C are added consecutively and dissolved. This solution is mixed with the Avicel dispersion. After the fragrance has been added, the active ingredient is ground with a small amount of the base and then distributed in the remainder of the base.
Example 4: Drops containing 1% of diclofenac: Diclofenac (free acid) 1.0 g Meyprogat 150 (guar gum) 0.5 g Sorbitol solution 50.0 g Sorbic acid 0.1 g Vitamin C 0.1 g Citric acid 1 AQ 0.2 g Disodium phosphate 1 AQ 0.08 g Lemon aroma 0.1 g Demineralized water 47.92 g 100.00 g pH: 3.1 Preparation: The water is warmed to about 90°C and sorbic acid is dissolved therein. Meyprogat is scattered into the mixture and dispersed using a high-speed mixer. The mixture is then left to swell at 90°C for about 30 minutes. Sorbitol solution is then added. After the mixture has cooled to about 40°C, citric acid, disodium phosphate and Vitamin C are added consecutively and dissolved with stirring. After the fragrance has been added, the active ingredient is ground with a small amount of the base and then distributed in the remainder of the base.
Example 5: Syrup containing 1% by weight of diclofenac.
Diclofenac (free acid) Hydroxyethyl cellulose (Natrosol 250 G) Cellulose and sodium carboxymethylcellulose (Avicel RC 591) Sorbitol solution Sorbic acid Vitamin C Citric acid Saccharine sodium Demineralized water 100.00 g pH: 2.3 Preparation: Avicel is suspended in the water using a high-speed mixer, Natrosol is admixed and the mixture is left to swell for about 1 hour. Sorbitol solution and sorbic acid are added, and the mixture is heated to about 85° with stirring. After the mixture has cooled to room temperature, Vitamin C, citric acid and saccharine are dissolved consecutively therein with stirring. The active ingredient is then suspended therein using the mixer, and the mixture is subsequently deaerated.
Example 6: Syrup containing 1% by weight of diclofenac.
Diclofenac (free acid) 1.00 g Hydroxyethylcellulose (Natrosol 250 G) 0.50 g Cellulose and sodium carboxymethylcellulose (Avicel RC 591) 1.20 g Sorbitol solution 25.00 g Vitamin C 0.60 g Citric acid 1.00 g Methylparaben 0.12 g Propylparaben 0.05 g Saccharine sodium 0.06 g Demineralized water 70.49 g 100.00 g pH: 3.0 Preparation: Avicel is suspended in the water using a high-speed mixer, Natrosol is admixed, and the mixture is left to swell for about 1 hour. Sorbitol solution and sorbic acid are added, and the mixture is heated to about 85° with stirring. After the mixture has cooled to room temperature, Vitamin C, citric acid and saccharine are dissolved consecutively therein with stirring. The active ingredient is suspended therein using the mixer, and the mixture is subsequently deaerated.
Claims (22)
1. An aqueous oral pharmaceutical preparation comprising about 0.4% to about 10% by weight diclofenac is suspended form, said preparation having a pH selected from the range of between about 2 to about 3.5 wherein said pH is established by a pharmaceutically acceptable acid or buffer system and which contains a pharmaceutically acceptable adjunct or additive selected from the group consisting of preservatives, antioxidants, fragrances, dyes,' sweeteners, suspension agents, and wetting agents.
2. A preparation according to claim 1, wherein the active ingredient concentration is about 0.5 to about 2% by weight .
3. A preparation according to claim 1, wherein the pH is set using citric acid.
4. A preparation according to claim 1, wherein the pH is set using citric acid/phosphate buffer.
5. A preparation according to claim 1, which contains, as preservative, benzoic acid or salts thereof, 4-hydroxy-benzoid acid esters, phenols, phenyl (lower alkanols) , quarternary ammonium halides or sorbic acid.
6. A preparation according to claim 1, which contains sorbic acid.
7. A preparation according to claim 1, which contains, as antioxidants, cystein, ascorbic acid or esters thereof, or an ester of gallic acid.
8. A preparation according to claim 1, which contains ascorbic acid. 11 92190/3
9. A preparation according to claim 1, which contains, as a sweetener, a monosaccharide, disaccharide, polyol or artificial sweetener.
10. A preparation according to claim 1, which contains, as sweetener, saccharin, cyclamate, aspartame, a sugar alcohol or a mono- or di-saccharide .
11. A preparation according to claim 1, which contains, as suspension stabilizer, colloidal silicates having a high aluminum and magnesium content, colloidal silica, swelling agnes, swellable cellulose ethers, carboxy-methylcellulose or an alkali metal salts thereof, micro-crystalline cellulose or water-soluble polyvinyl compounds .
12. A preparation according to claim 1, which contains hydroxyethylcellulose and/or cellulose and sodium carboxymethylcellulose or agar or guar gum.
13. A preparation according to claim 1 in the form of drops, mixture, juice or syrup.
14. A preparation according to claim 1 in dose-unit form.
15. Use of a pharmaceutical preparation according to claim 1 in the manufacture of analgetic and anti inflammatory medicament, administered to a warm-blooded organism in need of such, substantially as described in the specification.
16. The preparation of claim 1 wherein said diclofenac is present in an amount of about 0.5 to about 10% by weight.
17. The preparation of claim 1 wherein said diclofenac is present in an amount of about 0.45 to about 5% by weight. 12 92190/3
18. The preparation of claim 1 further comprising a suspension stabilizer selected from a colloidal silicate having a high aluminum and magnesium content, an . alginate, an ethylene homopolymer having a degree of polymerization of about 2,000-1,000,000, a swellable cellulose ether, microcrystalline cellulose, and a water-soluble polyvinyl compound.
19. The preparation of claim 18 wherein said stabilizer is present in an amount of about 0.4 to about 1.9% by weight .
20. The preparation of claim 1 further comprising a hydroxyethylcellulose , cellulose, sodium carboxymethyl cellulose, citric acid, sorbic acid, ascorbic acid, and soribtol .
21. A method for stabilizing diclofenac in an aqueous medium in a concentration range of about 0.4% to about 10% by weight diclofenac, comprising suspending said diclofenac in water and adjusting the pH to a pH selected from the range of between about 2 to about 3.5 wherein said pH is established by a pharmaceutically acceptable acid or buffer system and which contains a pharmaceutically acceptable adjunct or additive selected from the group consisting of preservatives, antioxidants, fragrances, dyes, sweeteners, suspension agents and wetting agents.
22. A pharmaceutical preparation according to claim 1 for use as a medicament . LUZZATTO ft LUZZATTO
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH416788 | 1988-11-10 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL92190A0 IL92190A0 (en) | 1990-07-26 |
| IL92190A true IL92190A (en) | 1996-07-23 |
Family
ID=4271057
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL9219089A IL92190A (en) | 1988-11-10 | 1989-11-02 | Liquid oral formulation of diclofenac in suspended form |
Country Status (16)
| Country | Link |
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| EP (1) | EP0373103B1 (en) |
| JP (1) | JP2894744B2 (en) |
| KR (1) | KR0152983B1 (en) |
| AT (1) | ATE87476T1 (en) |
| AU (1) | AU624190B2 (en) |
| CA (1) | CA2002472C (en) |
| DE (1) | DE58903964D1 (en) |
| DK (1) | DK175752B1 (en) |
| ES (1) | ES2054089T3 (en) |
| GR (1) | GR3007995T3 (en) |
| IE (1) | IE63482B1 (en) |
| IL (1) | IL92190A (en) |
| NZ (1) | NZ231320A (en) |
| PT (1) | PT92228B (en) |
| SA (1) | SA90100152B1 (en) |
| ZA (1) | ZA898554B (en) |
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| US5011688A (en) * | 1989-02-02 | 1991-04-30 | Calam Henry D | Liquid composition for the relief of premenstrual and menstrual discomforts |
| IT1256616B (en) * | 1992-12-02 | 1995-12-12 | Zambon Spa | SYRUP CONTAINING N-ACETYL-CISTEIN |
| AUPN969796A0 (en) * | 1996-05-07 | 1996-05-30 | F.H. Faulding & Co. Limited | Taste masked liquid suspensions |
| GB9930058D0 (en) * | 1999-12-20 | 2000-02-09 | Novartis Ag | Organic compounds |
| US6559187B2 (en) | 2000-08-07 | 2003-05-06 | Ranbaxy Signature Llc | Liquid formulation of metformin |
| ITMI20020986A1 (en) * | 2002-05-10 | 2003-11-10 | Acraf | COMPOSITION BASED ON DICLOFENAC FOR THE TOPICAL TREATMENT OF AFFECTIONS OF THE OROPHARINGOUS CABLE |
| JP2004059488A (en) * | 2002-07-29 | 2004-02-26 | Asahi Food & Healthcare Ltd | Lactic acid bacteria intestinal composition and food |
| JP2006315966A (en) * | 2005-04-11 | 2006-11-24 | Sanei Gen Ffi Inc | Liquid composition for throat and larynx containing black bean extract |
| GB201006218D0 (en) | 2010-04-14 | 2010-06-02 | Ayanda As | Composition |
| CA2852912A1 (en) | 2011-10-31 | 2013-05-10 | Glaxosmithkline Intellectual Property Limited | Pazopanib formulation |
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|---|---|---|---|---|
| US3558690A (en) * | 1965-04-08 | 1971-01-26 | Gelgy Chemical Corp | Substituted derivatives of 2-anilinophenylacetic acids and a process of preparation |
| JPS5238030A (en) * | 1975-07-04 | 1977-03-24 | Gaba Ag | Mouth and tooth reparing agent |
| CH655507B (en) * | 1983-01-12 | 1986-04-30 |
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1989
- 1989-11-01 AT AT89810825T patent/ATE87476T1/en not_active IP Right Cessation
- 1989-11-01 ES ES89810825T patent/ES2054089T3/en not_active Expired - Lifetime
- 1989-11-01 EP EP89810825A patent/EP0373103B1/en not_active Expired - Lifetime
- 1989-11-01 DE DE8989810825T patent/DE58903964D1/en not_active Expired - Lifetime
- 1989-11-02 IL IL9219089A patent/IL92190A/en active IP Right Grant
- 1989-11-02 AU AU44343/89A patent/AU624190B2/en not_active Expired
- 1989-11-06 JP JP1287648A patent/JP2894744B2/en not_active Expired - Lifetime
- 1989-11-08 CA CA002002472A patent/CA2002472C/en not_active Expired - Lifetime
- 1989-11-08 PT PT92228A patent/PT92228B/en not_active IP Right Cessation
- 1989-11-08 NZ NZ231320A patent/NZ231320A/en unknown
- 1989-11-08 KR KR1019890016136A patent/KR0152983B1/en not_active Expired - Lifetime
- 1989-11-09 ZA ZA898554A patent/ZA898554B/en unknown
- 1989-11-09 DK DK198905615A patent/DK175752B1/en not_active IP Right Cessation
- 1989-11-09 IE IE361189A patent/IE63482B1/en not_active IP Right Cessation
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1990
- 1990-04-04 SA SA90100152A patent/SA90100152B1/en unknown
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1993
- 1993-05-28 GR GR920403069T patent/GR3007995T3/el unknown
Also Published As
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| ZA898554B (en) | 1990-08-29 |
| AU4434389A (en) | 1990-06-07 |
| DK561589D0 (en) | 1989-11-09 |
| KR0152983B1 (en) | 1998-11-16 |
| JPH02178224A (en) | 1990-07-11 |
| NZ231320A (en) | 1992-11-25 |
| DK561589A (en) | 1990-05-11 |
| ATE87476T1 (en) | 1993-04-15 |
| DK175752B1 (en) | 2005-02-07 |
| EP0373103A1 (en) | 1990-06-13 |
| SA90100152B1 (en) | 2001-04-14 |
| JP2894744B2 (en) | 1999-05-24 |
| IL92190A0 (en) | 1990-07-26 |
| CA2002472C (en) | 2000-05-30 |
| EP0373103B1 (en) | 1993-03-31 |
| AU624190B2 (en) | 1992-06-04 |
| PT92228B (en) | 1995-07-06 |
| IE893611L (en) | 1990-05-10 |
| KR910009253A (en) | 1991-06-28 |
| GR3007995T3 (en) | 1993-08-31 |
| DE58903964D1 (en) | 1993-05-06 |
| CA2002472A1 (en) | 1990-05-10 |
| ES2054089T3 (en) | 1994-08-01 |
| PT92228A (en) | 1990-05-31 |
| IE63482B1 (en) | 1995-05-03 |
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