WO1998017285A1 - Pharmaceutical preparations comprised of salts of hyaluronic acid with local anaesthetics - Google Patents
Pharmaceutical preparations comprised of salts of hyaluronic acid with local anaesthetics Download PDFInfo
- Publication number
- WO1998017285A1 WO1998017285A1 PCT/IB1997/001288 IB9701288W WO9817285A1 WO 1998017285 A1 WO1998017285 A1 WO 1998017285A1 IB 9701288 W IB9701288 W IB 9701288W WO 9817285 A1 WO9817285 A1 WO 9817285A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hyaluronic acid
- solution
- medicament
- topical administration
- bupivacaine
- Prior art date
Links
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical class CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 title claims abstract description 112
- 229920002674 hyaluronan Polymers 0.000 title claims abstract description 111
- 229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 109
- 150000003839 salts Chemical class 0.000 title claims abstract description 54
- 239000000825 pharmaceutical preparation Substances 0.000 title abstract description 5
- 229960005015 local anesthetics Drugs 0.000 title description 7
- CNBGNNVCVSKAQZ-UHFFFAOYSA-N benzydamine Chemical compound C12=CC=CC=C2C(OCCCN(C)C)=NN1CC1=CC=CC=C1 CNBGNNVCVSKAQZ-UHFFFAOYSA-N 0.000 claims abstract description 160
- 229960000333 benzydamine Drugs 0.000 claims abstract description 82
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 claims abstract description 76
- 229960003150 bupivacaine Drugs 0.000 claims abstract description 64
- 230000003444 anaesthetic effect Effects 0.000 claims abstract description 37
- 125000003277 amino group Chemical group 0.000 claims abstract description 5
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 178
- 230000007935 neutral effect Effects 0.000 claims description 40
- 229910052708 sodium Inorganic materials 0.000 claims description 38
- 239000011734 sodium Substances 0.000 claims description 38
- 239000003814 drug Substances 0.000 claims description 24
- 229910052791 calcium Inorganic materials 0.000 claims description 21
- 239000011575 calcium Substances 0.000 claims description 21
- 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 claims description 20
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 11
- 229940124326 anaesthetic agent Drugs 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
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- 238000002627 tracheal intubation Methods 0.000 claims description 2
- 208000000143 urethritis Diseases 0.000 claims description 2
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- 238000011200 topical administration Methods 0.000 claims 13
- 229910052751 metal Inorganic materials 0.000 claims 1
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 57
- 239000002244 precipitate Substances 0.000 description 56
- 239000000047 product Substances 0.000 description 51
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 44
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 39
- 239000007864 aqueous solution Substances 0.000 description 35
- 239000011521 glass Substances 0.000 description 35
- 229960004194 lidocaine Drugs 0.000 description 29
- WCDDVEOXEIYWFB-VXORFPGASA-N (2s,3s,4r,5r,6r)-3-[(2s,3r,5s,6r)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylic acid Chemical class CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O)[C@H](O)[C@H]1O WCDDVEOXEIYWFB-VXORFPGASA-N 0.000 description 22
- 239000007787 solid Substances 0.000 description 21
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- 238000002360 preparation method Methods 0.000 description 11
- 206010002091 Anaesthesia Diseases 0.000 description 10
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- 230000037005 anaesthesia Effects 0.000 description 10
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- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 241000283973 Oryctolagus cuniculus Species 0.000 description 9
- 229940014041 hyaluronate Drugs 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 8
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- 150000001875 compounds Chemical class 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- KIUKXJAPPMFGSW-YXBJCWEESA-N (2s,4s,5r,6s)-6-[(2s,3r,5s,6r)-3-acetamido-2-[(3s,4r,5r,6r)-6-[(3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H](C(O[C@@H]3[C@@H]([C@@H](O)C(O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)C(C(O)=O)O1 KIUKXJAPPMFGSW-YXBJCWEESA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 230000000622 irritating effect Effects 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
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- 229910052700 potassium Inorganic materials 0.000 description 3
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 3
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- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 2
- 230000004397 blinking Effects 0.000 description 2
- SIEYLFHKZGLBNX-UHFFFAOYSA-N bupivacaine hydrochloride (anhydrous) Chemical compound [Cl-].CCCC[NH+]1CCCCC1C(=O)NC1=C(C)C=CC=C1C SIEYLFHKZGLBNX-UHFFFAOYSA-N 0.000 description 2
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- UXAWFWFJXIANHZ-UHFFFAOYSA-N 1-[2-[2-[di(propan-2-yl)amino]ethoxy]phenyl]butan-1-one Chemical compound CCCC(=O)C1=CC=CC=C1OCCN(C(C)C)C(C)C UXAWFWFJXIANHZ-UHFFFAOYSA-N 0.000 description 1
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- 230000003547 miosis Effects 0.000 description 1
- GDDYCOSWVJRUHM-UHFFFAOYSA-N n-(2,4-dichlorophenyl)-3-piperidin-1-ylbutanamide Chemical compound C1CCCCN1C(C)CC(=O)NC1=CC=C(Cl)C=C1Cl GDDYCOSWVJRUHM-UHFFFAOYSA-N 0.000 description 1
- UJCARUGFZOJPMI-UHFFFAOYSA-N n-(2-methoxy-4,6-dimethylphenyl)-3-(2-methylpiperidin-1-yl)propanamide Chemical compound COC1=CC(C)=CC(C)=C1NC(=O)CCN1C(C)CCCC1 UJCARUGFZOJPMI-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229960000986 oxetacaine Drugs 0.000 description 1
- 229960003502 oxybuprocaine Drugs 0.000 description 1
- CMHHMUWAYWTMGS-UHFFFAOYSA-N oxybuprocaine Chemical compound CCCCOC1=CC(C(=O)OCCN(CC)CC)=CC=C1N CMHHMUWAYWTMGS-UHFFFAOYSA-N 0.000 description 1
- 239000004177 patent blue V Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229950007049 phenacaine Drugs 0.000 description 1
- QXDAEKSDNVPFJG-UHFFFAOYSA-N phenacaine Chemical compound C1=CC(OCC)=CC=C1N\C(C)=N\C1=CC=C(OCC)C=C1 QXDAEKSDNVPFJG-UHFFFAOYSA-N 0.000 description 1
- 229960001045 piperocaine Drugs 0.000 description 1
- BMIJYAZXNZEMLI-UHFFFAOYSA-N piridocaine Chemical compound NC1=CC=CC=C1C(=O)OCCC1NCCCC1 BMIJYAZXNZEMLI-UHFFFAOYSA-N 0.000 description 1
- 229950001038 piridocaine Drugs 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229960001896 pramocaine Drugs 0.000 description 1
- DQKXQSGTHWVTAD-UHFFFAOYSA-N pramocaine Chemical compound C1=CC(OCCCC)=CC=C1OCCCN1CCOCC1 DQKXQSGTHWVTAD-UHFFFAOYSA-N 0.000 description 1
- 229960001807 prilocaine Drugs 0.000 description 1
- MVFGUOIZUNYYSO-UHFFFAOYSA-N prilocaine Chemical compound CCCNC(C)C(=O)NC1=CC=CC=C1C MVFGUOIZUNYYSO-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229950008865 propanocaine Drugs 0.000 description 1
- 229960003981 proparacaine Drugs 0.000 description 1
- STHAHFPLLHRRRO-UHFFFAOYSA-N propipocaine Chemical compound C1=CC(OCCC)=CC=C1C(=O)CCN1CCCCC1 STHAHFPLLHRRRO-UHFFFAOYSA-N 0.000 description 1
- 229950011219 propipocaine Drugs 0.000 description 1
- 229950003255 propoxycaine Drugs 0.000 description 1
- OYCGKECKIVYHTN-UHFFFAOYSA-N pyrrocaine Chemical compound CC1=CC=CC(C)=C1NC(=O)CN1CCCC1 OYCGKECKIVYHTN-UHFFFAOYSA-N 0.000 description 1
- 229950000332 pyrrocaine Drugs 0.000 description 1
- 229960005038 quinisocaine Drugs 0.000 description 1
- 229940051201 quinoline yellow Drugs 0.000 description 1
- 229960001549 ropivacaine Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 208000003265 stomatitis Diseases 0.000 description 1
- JCQBWMAWTUBARI-UHFFFAOYSA-N tert-butyl 3-ethenylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(C=C)C1 JCQBWMAWTUBARI-UHFFFAOYSA-N 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 229960002372 tetracaine Drugs 0.000 description 1
- GKCBAIGFKIBETG-UHFFFAOYSA-N tetracaine Chemical compound CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 GKCBAIGFKIBETG-UHFFFAOYSA-N 0.000 description 1
- UDKICLZCJWQTLS-UHFFFAOYSA-N tolycaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C(=O)OC UDKICLZCJWQTLS-UHFFFAOYSA-N 0.000 description 1
- 229950006609 tolycaine Drugs 0.000 description 1
- 206010044008 tonsillitis Diseases 0.000 description 1
- 230000036346 tooth eruption Effects 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- GOZBHBFUQHMKQB-UHFFFAOYSA-N trimecaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=C(C)C=C1C GOZBHBFUQHMKQB-UHFFFAOYSA-N 0.000 description 1
- 229950002569 trimecaine Drugs 0.000 description 1
- 229950005920 vadocaine Drugs 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
-
- 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
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
- A61P23/02—Local anaesthetics
-
- 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
Definitions
- the present invention relates to the use of new pharmaceutical preparations in the field of local anaesthetics and, more precisely, preparations consisting of a stoichiometrically neutral salt of a hyaluronic acid with a basic anaesthetic with local action containing aliphatic and/or aromatic amino groups with an aliquot of the carboxy groups of hyaluronic acid possibly salified with an alkaline or alkaline earth metal.
- the invention also concerns some new compositions of the aforesaid type which, thanks to their specific pharmaceutical properties as described hereafter, are suitable for use as infiltrations and injections as well as for surface use
- European patent No 0197718 Bl granted on December 15, 1993 describes the advantageous use of hyaluronic acid and molecular fractions thereof as vehicles for medicinal substances for topical use and demonstrates that associations of hyaluronic acid with known drugs in various fields of medicine give better effects than the same drugs administered on their own. That patent emphasises above all a greater degree of bioavailability than that obtained with the pharmaceutical formulations used in the past, and this advantage is illustrated especially in the ophthalmic field, where marked compatibility with the corneal epithelium was observed, with subsequent excellent tolerability with no sensitization effects, with the formation of homogeneous and stable films which are perfectly transparent, have excellent adhesive properties and guarantee prolonged bioavailability of the drug.
- the above patent discusses the importance of said perfected bioavailability in the veterinary field with regard to the administration of chemotherapeutics.
- the patent also lists miotic, anti- inflammatory, wound healing and antimicrobial effects for ophthalmic use in the fields of both veterinary and human medicine.
- hyaluronic acid indicates a purified hyaluronic acid such as those already on the market or described in the literature or in patents such as those obtained by extraction from animal or fermentation sources, or of biotechnological origin, or molecular fractions of hyaluronic acids, likewise purified, such as those described in European patent No. 0138572 (describing commercial products known as Hyalastine and Hyalectin) or hyaluronic acids with higher molecular weights such as the fraction known as Hyaloftil, described in EP 0535200 Al, or other products available on the market.
- hyaluronic acid Besides the hyaluronic acid described above, its partial esters obtained according to the procedure described in EP 0216453 Bl can also be used.
- the local anaesthetics for use in the preparation of salts with hyaluronic acid according to the present invention are essentially those reported in the literature and/or found on the market or used for clinical purposes, and which contain aliphatic and/or aromatic amino groups (with between 12 and 30 carbon atoms) which can be salified with an acid. While the salts of hyaluronic acid with lidocaine, dibucaine and benzocaine are known, as they are described in the aforesaid European patent No.
- the salts of hyaluronic acid with the following aminic-type local anaesthetics to be used according to the invention are new and constitute a particular object of the invention: tetracaine, amylocaine, bucricaine, bupivacaine, butacaine sulfate, butanilicaine, butoxycaine, car- ticaine, chloroprocaine, clibucaine, chlormecaine, cyclomethycaine, dimethisoquin hydrochloride, diperodon, diclocaine, ethyl p-piperidine acetylamine benzoate, ethidocaine, hexylcaine, phenacaine, fomocaine, hydroxyprocaine, hydroxytetracaine, ketocaine, oxethazaine, oxybuprocaine, paretoxy- caine, piperocaine, piridocaine, pyrrocaine, pramoxine, pri
- the salts of hyaluronic acid with a strong anaesthetic effect according to the present invention are above all stoichiometrically neutral salts with the abovesaid aminic bases, that is, the total salts of the polysaccharide with aminic bases.
- the degree of salification may vary within an ample range, for example between 10% and 90%, preferably between 20% and 80%, and especially between 50% and 75%, with the remaining carboxy groups of the polysaccharide are salified with one of the abovesaid ions of an alkaline or alkaline earth metal.
- a preferred object of the invention is represented by the total and partial salts, as described above, of benzydamine with a hyaluronic acid. It has been observed that salts of this kind not only present a far more pronounced and longer-lasting anaesthetic effect than benzydamine or the hydrochloride thereof but also enhance the anti-inflammatory effect and, surprisingly reduce the irritating action, thus widening the gap between active and irritant concentrations or doses.
- benzydamine presents some disadvantages, such as the brevity of its topical action, as the drug quickly passes from the application site into the system, and the onset of an irritant action, which occurs at doses not far removed from those required for the desired effects. It has further been found according to the invention that the activity of the hyaluronic acid salts with anaesthetics can vary depending upon the molecular weight of the hyaluronic acid. For one of the preferred anaesthetics, benzydamine, it was found that the product has the most improved characteristics when salified with a low molecular weight fraction of hyaluronic acid.
- bupivacaine For another preferred anaesthetic, bupivacaine, it was found that the product has the most improved characteristics when salified with a high molecular weight fraction of hyaluronic acid. It has also been found that of the alkaline and alkaline earth metals, sodium salts are the preferred monovalent salts, and calcium salts are the preferred bivalent salts.
- the new benzydamine salts of the present invention besides their advantageous application in ophthalmology, like the other anaesthetic bases mentioned previously, have proved to be new drugs with a very wide field of application, for example in inflammatory processes in the mouth or airways such as stomatitis of various origin, tonsillitis or tracheitis, in mucositis caused by radio- or chemotherapy, by surgical or diagnostic intubation, such as bronchoscopy, in dental and gingival disorders in general, including teething trouble in babies, in rhinitis, in inflammatory processes affecting the auditory canal, in conjunctivitis of various origin, in proctological conditions, in traumatic and degenerative-inflammatory processes in the joints, in vulvovaginitis and urethritis of various kinds, including those caused by radio- and chemotherapy, surgical operations, diagnostic manoeuvres, childbirth and, in general, any inflammatory disorder of any kind.
- Corneal anaesthesia was assessed by the method of Camougis and Tankman (Camougis et al. (1971), "Methods in Pharmacology", Vol. 1, A. Schwartz Ed., Appleton-Century-Crofts, New York, p. 1) by measuring the blinking reflex in rabbit. Fifty ml of solution was instilled in the conjunctival sac. The blinking reflex, tested with a bristle, was measured before instillation and then every 5-10 minutes until one hour after treatment. At each test time the degree of anaesthesia was expressed by means of a score of up to 10 given by the number of stimulations before the eye-blink reflex was obtained. The overall anaesthetic effect for each compound was then quantified by the area under curve (AUC) of the degree of anaesthesia over time.
- AUC area under curve
- the hyaluronate salts of lidocaine, bupivacaine and benzydamine present greater local activity than their respective hydrochloride salts.
- the effect of increasing the action of the anaesthetics varies according to the alkaline or alkaline/earth ion; the presence of calcium, unlike sodium, selectively favours lidocaine rather than bupivacaine or benzydamine.
- Table 1 Anaesthetic effect in rabbit eye by hyaluronate of lidocaine, bupivacaine, benzydamine (FID 60.20XX) and their respective hydrochloride salts.
- hyaluronate salts For the hyaluronate salts, the % of active principle and that of alkaline or alkaline earth ion are shown; ⁇ the doses refer in all cases to the active principle as a hydrochloride salt; $ AUC measurements of the anaesthetic effect are calculated by taking the reference active principle value as 100. This ion selectivity has proved to also depend upon the molecular weight of the hyaluronic acid used.
- the ion selectivity only exists in low-molecular-weight hyaluronic acid, specifically molecular weight range of 50-350 kDa (derivatives FID 6020XX), and not in high-molecular-weight hyaluronic acid, molecular weight range of 500-730 Kda and 750-1200 (derivatives FID 61.20XX and FID 62.20XX, respectively).
- Table 2 Anaesthetic effect in rabbit eye by hyaluronate salts of bupivacaine, according to the molecular weight of the hyaluronic acid of the alkaline or alkaline earth counterion.
- the degree of activity depends on the molecular weight of the hyaluronic acid used.
- Table 3 Anaesthetic effect on rabbit eye by hyaluronate salts of bupivacaine according to the molecular weight of the hyaluronic acid.
- Table 4 Anaesthetic effect on rabbit eye by hyaluronate salts of lidocaine and its alkaline salts.
- the degree of salification influences the biological activity of the derivatives, as can be seen in Table 5, where partial salts with bupivacaine and sodium of hyaluronic acid having a molecular weight range between 500 and 730 Kda are reported in comparison to the hydrochloride and the total salt; and in Table 6, where partial salts with benzydamine and sodium of hyaluronic acid having a molecular weight range between 50 and 350 Kda are reported in comparison to the hydrochloride.
- Table 5 Anaesthetic effect on rabbit eye by hyaluronate salts of bupivacaine according to the degree of salification.
- Table 6 Anaesthetic effect on rabbit eye by hyaluronate salts of benzydamine according to the degree of salification.
- 0.1 ml of each of the test solutions was injection into the hind paw of rat.
- the paw volume was measured with a plethismometer before injection and then 30-60- 120-240-480 minutes after.
- the oedema and consequent irritant effect were measured on the basis of the increase in the volume of the paw.
- the irritant effect is expressed by the sum of the increase in volume at the various measuring times.
- the hyaluronate salt proved to be less irritating than the hydrochloride salt, as indicated by its lesser oedema-forming effect (Table 7).
- Table 7 Irritant effect of benzydamine Hcl and FID 60.2108 in rat paw.
- the hyaluronic acid sodium salt (molecular weight 50 - 350 Kda) is solubilized in water to a concentration of 16 mg/ml.
- a column is filled with acid resin Bio-Rad AG50W-X8, pretreated with Hcl IN, using a glass column fitted with a jacket inside which there is a flow of fluid at 4°C; 5 ml of resin in acid form are loaded in the column and washed with water to a neutral Ph.
- the solution of hyaluronic acid sodium salt is passed through the resin, and the resulting solution is collected in a container with a thermostat set at 4°C.
- the flow in the column is regulated by a peristaltic pump fitted to the outlet of the column.
- the resin is washed with water to minimize any loss of product, and the products of these washes are added to the hyaluronic acid solution, thus obtaining a final solution with a concentration of 11.8 mg/ml, expressed as hyaluronic acid.
- the hyaluronic acid sodium salt (molecular weight 500 - 730 Kda) is solubilized in water to a concentration of 5.0 mg/ml.
- a column is filled with acid resin Bio-Rad AG50W-X8, pretreated with HCl IN, using a glass column fitted with a jacket, inside which fluid flows at a temperature of 4°C; 5 ml of resin in acid form are loaded in the column and washed with water until a neutral pH is reached. At this point the hyaluronic acid sodium salt solution is passed through the resin, collecting the resulting solution in a container set at temperature of 4°C.
- the fluid in the column is regulated by a peristaltic pump fitted onto the outlet of the column.
- Hyaluronic acid sodium salt (molecular weight 750 - 1200 kDa) is solubilized in water to a concentration of 3.0 mg/ml.
- a column is filled with acid resin.
- the hyaluronic acid sodium salt is passed through the resin, collecting the resulting solution in a container with a thermostat set at 4°C.
- the flow through the column is regulated by a peristaltic pump fitted onto the outlet of the column.
- the benzydamine to use as starting product can be prepared as of follows: 3.0 g of benzydamine hydrochloride are solubilized in water at a concentration of 50 mg/ml. An equimolar quantity of NaOH IN is added, plus 5% excess, so as to give the aqueous solution a pH of between 10 and 11.
- the benzydamine to be used as starting product can be prepared as described in Example 4.
- Example 6 80 ml of an aqueous solution of hyaluronic acid, prepared as described in Example 1, at a concentration of 11.8 mg/ml, is placed in a 100 ml flask. The solution is shaken in a thermostat bath set at 4°C. 0.39 g of benzydamine base is diluted with 10 ml of tert-butanol and the solution is slowly added drop by drop into the hyaluronic acid solution. A white precipitate is formed which disappears within a few hours. The container used to weigh the benzydamine is washed with two 5 ml aliquots of tert-butanol which are then added to the hyaluronic acid solution.
- the benzydamine used as starting product can be prepared as described in Example 4.
- Example 7 80 ml of an aqueous solution of hyaluronic acid, prepared as described in Example 1, at a concentration of 11.8 mg/ml, is placed in a 100 ml flask. The solution is shaken in a thermostat bath set at 4°C. 0.39 g of benzydamine base is diluted with 10 ml of tert-butanol and the solution is slowly added drop by drop to the hyaluronic acid solution: a white precipitate is formed which disappears within a few hours. The container used to weigh the benzydamine is washed with two 5 ml aliquots of tert-butanol which are then added to the hyaluronic acid solution.
- the benzydamine used as starting product can be prepared as described in Example 4.
- the benzydamine used as starting product can be prepared as described in Example 4.
- the benzydamine used as starting product can be prepared as described in Example 4.
- Example 10 400 ml of an aqueous solution of hyaluronic acid, prepared as in Example 3, at a concentration of 2.36 mg/ml, is placed in a 500 ml flask. The solution is shaken in a thermostat bath set at 4°C. 0.39 g of benzydamine base is diluted with 10 ml of tert-butanol and the solution is slowly added drop by drop to the hyaluronic acid solution. A white precipitate is formed which disappears within a few hours. The container used to weigh the benzydamine is washed with two 10 ml aliquots of tert-butanol which are then added to the hyaluronic acid solution. Some hours later, when there is no more suspended precipitate in the solution, 1.25 ml of NaOH is added and the mixture is shaken for another 30 minutes.
- the benzydamine used as starting product can be prepared as described in Example 4.
- the benzydamine used as starting product can be prepared as described in Example 4.
- the bupivacaine used as starting product can be prepared as described in Example 12.
- the bupivacaine used as starting product can be prepared as described in Example 12.
- the bupivacaine used as starting product can be prepared as described in Example 12.
- the bupivacaine used as starting product can be prepared as described in Example 12.
- the bupivacaine used as starting product can be prepared as described in Example 12.
- the bupivacaine used as starting product can be prepared as described in Example 12.
- the bupivacaine used as starting product can be prepared as described in Example 12.
- the bupivacaine used as starting product can be prepared as described in Example 12.
- the bupivacaine used as starting product can be prepared as described in Example 12.
- the bupivacaine used as starting product can be prepared as described in Example 12.
- the solution is filtered through a Gooch G4 filter, subdivided into yellow glass bottles and freeze-dried.
- the neutral salt partially salified (50%) with bupivacaine and partially salified (50%) with calcium is thus obtained.
- the bupivacaine used as starting product can be prepared as described in Example 12
- the solution is filtered through a Gooch G4 filter, subdivided into yellow glass bottles and freeze-dried.
- the stoichiometrically neutral salt of hyaluronic acid with lidocaine is thus obtained.
- the lidocaine used as starting product can be prepared as follows; 3.0 g of lidocaine hydrochloride is solubilized in water to a concentration of 25 mg/ml. An equimolar quantity of NaOH is slowly added, plus an excess of 5%, so as to give the aqueous solution a pH of between 10 and 11. In these conditions, lidocaine base is released and this separates from the water in the form of a precipitate.
- the solution is filtered through a Gooch G4 filter, subdivided into yellow glass bottles and freeze-dried.
- the neutral salt partially salified (75%) with lidocaine and partially salified (50%) with sodium is thus obtained.
- the lidocaine used as starting product can be prepared as described in Example 24.
- the solution is filtered through a Gooch G4 filter, subdivided into yellow glass bottles and freeze-dried.
- the neutral salt partially salified (50%) with lidocaine and partially salified (50%) with sodium is thus obtained.
- the lidocaine used as starting product can be prepared as described in Example 24.
- the lidocaine used as starting product can be prepared as described in Example 24.
- the lidocaine used as starting product can be prepared as described in Example 24.
- the lidocaine used as starting product can be prepared as described in Example 24.
- the lidocaine used as staring product can be prepared as described in Example 24.
- Example 31
- the solution is filtered through a Gooch G4 filter, subdivided into yellow glass bottles and freeze-dried.
- the neutral salt partial salified (50%) with lidocaine and partially salified (50%) with potassium is thus obtained.
- the lidocaine used as starting product can be prepared as described in Example 24.
- the benzydamine to be used as starting product can be prepared as described in Example 4.
- Example 33 80 ml of an aqueous solution of hyaluronic acid, prepared as in Example 1, at a concentration of 11.8 mg/ml is placed in a 100 ml flask. The solution is shaken in a thermostat bath set at 4°C. 0.19 g of benzydamine base are diluted with 10 ml of tert-butanol and the solution is slowly added drop by drop to the hyaluronic acid solution: a white precipitate is formed which disappears within a few hours. The container used to weigh the benzydamine is washed with two 5 ml aliquots of tert- butanol which are then added to the hyaluronic acid solution.
- the benzydamine to be used as starting product can be prepared as described in Example 4.
- the benzydamine to be used as starting product can be prepared as described in Example 4.
- the bupivacaine used as starting product can be prepared as described in Example 12.
- Preparation 3 Preparation of a proctological cream containing Benzydamine hyaluronate (75%) 100 ml of cream contain: - Benzydamine hyaluronate 1190 mg (equal to 448 mg of benzydamine base) Excipients
Abstract
Description
Claims
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/284,668 US6224857B1 (en) | 1996-10-17 | 1997-10-17 | Pharmaceutical preparations comprised of salts of hyaluronic acid with local anaesthetics |
CA002268967A CA2268967C (en) | 1996-10-17 | 1997-10-17 | Pharmaceutical preparations comprised of salts of hyaluronic acid with local anaesthetics |
PL97332873A PL190385B1 (en) | 1996-10-17 | 1997-10-17 | Pharmaceutic preparations containing a salt of hialuronic acid along with local anaesthetics |
DE69732049T DE69732049T2 (en) | 1996-10-17 | 1997-10-17 | PHARMACEUTICAL PREPARATIONS, CONTAINING SALTS OF HYALURONIC ACID AND LOCAL ANESTHETICS |
AT97943093T ATE285241T1 (en) | 1996-10-17 | 1997-10-17 | PHARMACEUTICAL PREPARATIONS CONTAINING SALTS OF HYALURONIC ACID AND LOCAL ANESTHETICS |
JP51916298A JP4334620B2 (en) | 1996-10-17 | 1997-10-17 | A pharmaceutical product comprising a salt of hyaluronic acid with a local anesthetic |
BR9713486-4A BR9713486A (en) | 1996-10-17 | 1997-10-17 | Pharmaceutical preparations comprised of salts of hyaluronic acid with local anesthetics. |
AU44700/97A AU712927B2 (en) | 1996-10-17 | 1997-10-17 | Pharmaceutical preparations comprised of salts of hyaluronic acid with local anaesthetics |
EP97943093A EP0956026B1 (en) | 1996-10-17 | 1997-10-17 | Pharmaceutical preparations comprised of salts of hyaluronic acid with local anaesthetics |
HK00102836A HK1023518A1 (en) | 1996-10-17 | 2000-05-12 | Pharmaceutical preparations comprised of salts of hyaluronic acid with local anaesthetics. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITPD96A000254 | 1996-10-17 | ||
IT96PD000254A IT1287967B1 (en) | 1996-10-17 | 1996-10-17 | PHARMACEUTICAL PREPARATIONS FOR LOCAL ANESTHETIC USE |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998017285A1 true WO1998017285A1 (en) | 1998-04-30 |
Family
ID=11391550
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB1997/001288 WO1998017285A1 (en) | 1996-10-17 | 1997-10-17 | Pharmaceutical preparations comprised of salts of hyaluronic acid with local anaesthetics |
Country Status (14)
Country | Link |
---|---|
US (1) | US6224857B1 (en) |
EP (1) | EP0956026B1 (en) |
JP (1) | JP4334620B2 (en) |
KR (1) | KR20000049281A (en) |
AT (1) | ATE285241T1 (en) |
AU (1) | AU712927B2 (en) |
BR (1) | BR9713486A (en) |
CA (1) | CA2268967C (en) |
DE (1) | DE69732049T2 (en) |
ES (1) | ES2235254T3 (en) |
HK (1) | HK1023518A1 (en) |
IT (1) | IT1287967B1 (en) |
TR (1) | TR199900860T2 (en) |
WO (1) | WO1998017285A1 (en) |
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1996
- 1996-10-17 IT IT96PD000254A patent/IT1287967B1/en active IP Right Grant
-
1997
- 1997-10-17 WO PCT/IB1997/001288 patent/WO1998017285A1/en active IP Right Grant
- 1997-10-17 AU AU44700/97A patent/AU712927B2/en not_active Expired
- 1997-10-17 TR TR1999/00860T patent/TR199900860T2/en unknown
- 1997-10-17 BR BR9713486-4A patent/BR9713486A/en not_active Application Discontinuation
- 1997-10-17 EP EP97943093A patent/EP0956026B1/en not_active Expired - Lifetime
- 1997-10-17 ES ES97943093T patent/ES2235254T3/en not_active Expired - Lifetime
- 1997-10-17 DE DE69732049T patent/DE69732049T2/en not_active Expired - Lifetime
- 1997-10-17 KR KR1019990703392A patent/KR20000049281A/en not_active Application Discontinuation
- 1997-10-17 CA CA002268967A patent/CA2268967C/en not_active Expired - Lifetime
- 1997-10-17 AT AT97943093T patent/ATE285241T1/en active
- 1997-10-17 US US09/284,668 patent/US6224857B1/en not_active Expired - Lifetime
- 1997-10-17 JP JP51916298A patent/JP4334620B2/en not_active Expired - Fee Related
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2000
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EP0138572A2 (en) * | 1983-10-11 | 1985-04-24 | FIDIA S.p.A. | Hyaluronic acid fractions having pharmaceutical activity, methods for preparation thereof, and pharmaceutical compositions containing the same |
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
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EP3508197A1 (en) | 2009-10-21 | 2019-07-10 | Otonomy, Inc. | Modulation of gel temperature of poloxamer-containing formulations |
EP2985027B1 (en) | 2014-08-16 | 2021-03-31 | Church & Dwight Co., Inc. | Nasal composition comprising mixture of hyaluronic acids and saline solution |
EP2985019B1 (en) | 2014-08-16 | 2021-10-20 | Church & Dwight Co., Inc. | Nasal composition having anti-viral properties |
CN106187864A (en) * | 2016-07-11 | 2016-12-07 | 江苏天和制药有限公司 | A kind of method being prepared high-purity bupivacaine alkali by bupivacaine hydrochloride |
CN106187864B (en) * | 2016-07-11 | 2018-11-23 | 江苏天和制药有限公司 | A method of high-purity Bupivacaine alkali is prepared by bupivacaine HCl |
IT201800001890A1 (en) * | 2018-01-25 | 2019-07-25 | Fidia Farm Spa | PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF POSTOPERATIVE PAIN |
Also Published As
Publication number | Publication date |
---|---|
ITPD960254A1 (en) | 1998-04-17 |
AU4470097A (en) | 1998-05-15 |
JP4334620B2 (en) | 2009-09-30 |
DE69732049D1 (en) | 2005-01-27 |
JP2001503042A (en) | 2001-03-06 |
ATE285241T1 (en) | 2005-01-15 |
CA2268967C (en) | 2003-02-04 |
AU712927B2 (en) | 1999-11-18 |
DE69732049T2 (en) | 2006-03-02 |
US6224857B1 (en) | 2001-05-01 |
EP0956026A1 (en) | 1999-11-17 |
EP0956026B1 (en) | 2004-12-22 |
TR199900860T2 (en) | 1999-06-21 |
KR20000049281A (en) | 2000-07-25 |
CA2268967A1 (en) | 1998-04-30 |
BR9713486A (en) | 2000-04-11 |
IT1287967B1 (en) | 1998-09-10 |
HK1023518A1 (en) | 2000-09-15 |
ES2235254T3 (en) | 2005-07-01 |
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