NL8005702A - Nylidrin solns. for topical treatment of glaucoma - contg. para-hydroxy N-1-methyl-3-phenyl-propyl nor-ephedrine or its salts, reduces intra:ocular pressure for prolonged periods - Google Patents
Nylidrin solns. for topical treatment of glaucoma - contg. para-hydroxy N-1-methyl-3-phenyl-propyl nor-ephedrine or its salts, reduces intra:ocular pressure for prolonged periods Download PDFInfo
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- NL8005702A NL8005702A NL8005702A NL8005702A NL8005702A NL 8005702 A NL8005702 A NL 8005702A NL 8005702 A NL8005702 A NL 8005702A NL 8005702 A NL8005702 A NL 8005702A NL 8005702 A NL8005702 A NL 8005702A
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- 150000003839 salts Chemical class 0.000 title claims abstract description 31
- 208000010412 Glaucoma Diseases 0.000 title claims abstract description 7
- 229960000395 phenylpropanolamine Drugs 0.000 title claims description 4
- 230000000699 topical effect Effects 0.000 title abstract description 3
- PTGXAUBQBSGPKF-UHFFFAOYSA-N 4-[1-hydroxy-2-(4-phenylbutan-2-ylamino)propyl]phenol Chemical compound C=1C=C(O)C=CC=1C(O)C(C)NC(C)CCC1=CC=CC=C1 PTGXAUBQBSGPKF-UHFFFAOYSA-N 0.000 title abstract 4
- 229960003455 buphenine Drugs 0.000 title abstract 3
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 title description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 18
- 239000002253 acid Substances 0.000 claims abstract description 11
- 239000000203 mixture Substances 0.000 claims abstract description 11
- 239000011780 sodium chloride Substances 0.000 claims abstract description 9
- 239000008363 phosphate buffer Substances 0.000 claims abstract description 8
- 239000007979 citrate buffer Substances 0.000 claims abstract description 6
- 230000004410 intraocular pressure Effects 0.000 claims abstract description 6
- 239000008351 acetate buffer Substances 0.000 claims abstract description 5
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 4
- 229910021538 borax Inorganic materials 0.000 claims abstract description 4
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000004327 boric acid Substances 0.000 claims abstract description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 4
- 235000010339 sodium tetraborate Nutrition 0.000 claims abstract description 4
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 claims abstract description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims abstract 3
- 238000002360 preparation method Methods 0.000 claims description 25
- 239000000243 solution Substances 0.000 claims description 18
- 230000001225 therapeutic effect Effects 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- -1 ephedrine compound Chemical class 0.000 claims description 7
- 238000011200 topical administration Methods 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 3
- 239000000872 buffer Substances 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000005493 quinolyl group Chemical group 0.000 claims description 3
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 3
- 239000007864 aqueous solution Substances 0.000 claims 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 2
- KWGRBVOPPLSCSI-WPRPVWTQSA-N L-Ephedrine Natural products CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 claims 1
- 239000013543 active substance Substances 0.000 claims 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 claims 1
- 229960002179 ephedrine Drugs 0.000 claims 1
- 239000000644 isotonic solution Substances 0.000 claims 1
- 239000006071 cream Substances 0.000 abstract description 2
- 239000006210 lotion Substances 0.000 abstract description 2
- 239000003889 eye drop Substances 0.000 abstract 1
- 229940012356 eye drops Drugs 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 229960000686 benzalkonium chloride Drugs 0.000 description 4
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 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
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 230000001088 anti-asthma Effects 0.000 description 2
- 239000000924 antiasthmatic agent Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 2
- 150000008054 sulfonate salts Chemical class 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000003247 decreasing effect Effects 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
- 230000004406 elevated intraocular pressure Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000002837 heart atrium Anatomy 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229940054534 ophthalmic solution Drugs 0.000 description 1
- 239000002997 ophthalmic solution Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 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
- 229940037001 sodium edetate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002195 soluble material Substances 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 230000002792 vascular 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
- C07D213/71—Sulfur atoms to which a second hetero atom is attached
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
·% &»*·- »' t ¥% & »* · -» 't ¥
VO llOUVO llOU
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Behandeling van en preparaat tegen glaucoom.Treatment of and preparation against glaucoma.
De uitvinding "betreft een "behandeling van en een preparaat tegen glaucoom.The invention "relates to" a treatment of and a composition against glaucoma.
ïïylidrine, p-hydroxy-ïï-(l-methyl-3-fenylpropyl )-norefedrine, "beschreven in de Amerikaanse octrooischriften 2.661.372 en 2.661.373, 5 is een β-adrenergisch stimulerend middel. Hét is gehruikt als een perifeer vaatverwi jdend middel en als een anti-astmaticum. (Amerikaans octrooischrift 4.086.363)· ïïylidrine en andere structureel verwante verbindingen zijn "bij konijnen "beproefd voor een "behandeling van glaucoom door intraveneuze 10 injectie (E. Genee , Dtsch.Opfhalmol. GES. Heidelberg, Ber. Zusammen-kunft, (1972), 71, 354-7; C.A. 82, 25826c (1975)).Ilylidrine, p-hydroxy-ii- (1-methyl-3-phenylpropyl) norephredrine, "disclosed in U.S. Pat. Nos. 2,661,372 and 2,661,373.5 is a β-adrenergic stimulant. It has been used as a peripheral vascular anti-asthmatic and as an anti-asthmatic. (US Pat. Heidelberg, Ber Zusammen-kunft, (1972), 71, 354-7; CA 82, 25826c (1975)).
Hoewel nylidrine daarbij enig effect had in een verlaging van de oculaire druk, was dit effect bijzonder kortdurend, n.1. niet meer dan slechts 6 minuten. Voorts bleek de bloeddruk van het proefdier 15 tegelijkertijd sterk te worden, verlaagd. Een dergelijke gelijktijdige verlaging van de bloeddruk kan soms ongewenst zijn.Although nylidrine had some effect in reducing ocular pressure, this effect was particularly short-lived, n.1. no more than just 6 minutes. Furthermore, the blood pressure of the experimental animal was found to become strong at the same time, lowered. Such a simultaneous decrease in blood pressure can sometimes be undesirable.
Verder onderzoek,-weergegeven door Lorenzetti in Annuals of Ophthalmology 3., ÏÏo. 3.282 (van maart 1971), gaven aan, dat instillatie van nylidrine in de ogen van konijnen met een door methylcellulose ge-20 induceerde verhoogde intraoculaire druk geen duidelijke reductie van deze verhoogde druk qpleverde.Further research, reported by Lorenzetti in Annuals of Ophthalmology 3., io. 3,282 (March 1971) indicated that instillation of nylidrine in the eyes of rabbits with an elevated intraocular pressure induced by methyl cellulose did not produce a marked reduction in this elevated pressure.
Er werd nu verrassenderwijs gevonden, dat een tcpicale toediening van nylidrine, bij .voorkeur in de vorm van een farmaceutisch geschikt, niet giftig zuuradditiezout daarvan, resulteert in een dui-25 delijke vermindering, d.w.z. in de orde van ca. 5-7 mm, van de intraoculaire druk bij een glaucocm-oog en wel gedurende tenminste 5 uren.It has now surprisingly been found that a topical administration of nylidrine, preferably in the form of a pharmaceutically suitable, non-toxic acid addition salt thereof, results in a marked reduction, ie on the order of about 5-7 mm, of intraocular pressure in a glaucoma eye for at least 5 hours.
De uitvinding betreft derhalve een therapeutisch preparaat voor het verlagen van de intraoculaire druk van een menselijk oog in de vorm van een gebufferd zoutpreparaat met de gewenste iso-30 tone eigenschappen en daarin een effectieve hoeveelheid p-hydroxy-ïï-(l-methyl-3-fenylpropyl)-norefedrine of een farmaceutisch geschikt zuuradditiezout daarvan.The invention therefore relates to a therapeutic composition for lowering the intraocular pressure of a human eye in the form of a buffered salt preparation with the desired isotonic properties and containing an effective amount of p-hydroxy-1 (1-methyl-3). phenylpropyl) norephedrine or a pharmaceutically suitable acid addition salt thereof.
De uitvinding betreft tevens een werkwijze voor het bereiden van een dergelijk therapeutisch preparaat door een gebufferd zout-35 preparaat met de gewenste isotoniciteit te bereiden, dat tevens een 8005702 % -2- «k _ a effectieve hoeveelheid aan p-hydroxy-ïï-(lniiethyl-3-f enylpr opyl)-nor-efedrine of een farmaceutisch geschikt zuuradditiezout daarvan "bevat. De uitvinding betreft in het bijzonder de behandeling van glaucoom door een topicale toediening aan het oog van een preparaat met daarin een zout van nylidrine of een nieuw zout van nylidrine dat speciaal bruikbaar is voor een dergelijke behandeling.The invention also relates to a method of preparing such a therapeutic composition by preparing a buffered salt formulation of the desired isotonicity, which also contains an 8005702% -2-% effective amount of p-hydroxy-i- ( The invention relates in particular to the treatment of glaucoma by topical administration to the eye of a composition containing a salt of nylidrine or a new nylphrine, or a pharmaceutically suitable acid addition salt thereof. nylidrine salt which is especially useful for such treatment.
Hoewel het normale fysiologische pH-traject bij het menselijk oog is gelegen tussen 7 »3 en 7»^, kunnen oogoplossingen voor een oogbehande-ling afhankelijk van de stabiliteit van de diverse bestanddelen een pH ^ bezitten tussen 3 en 9» liefst tussen 5s5 en 8,0. De onderhavige oplossing kan het best worden gehouden in een stabiele vorm door de pH tussen 6,0 en 7»5 te houden.Although the normal physiological pH range in the human eye is between 7 »3 and 7» ^, eye solutions for eye treatment, depending on the stability of the various components, can have a pH between 3 and 9, preferably between 5-5 and 8.0. The present solution is best kept in a stable form by keeping the pH between 6.0 and 7.5.
Elk farmacologisch geschikt buffersysteem kan aan de oogoplossing worden toegevoegd om deze oplossing op de gewenste pH te houden. Buffer-middelen, die bruikbaar zijn voor de onderhavige oogoplossing zijn na-triumboraat, boorzuur, dinatriummonowaterstoffosfaat, natriumdiwater-stoffosfaat, een citraatbuffer uit natriumcitraat en citroenzuur of een acetaatbuffer uit azijnzuur en natriumacetaat alsmede combinaties van fosfaat en citraatbuffers.Any pharmacologically suitable buffer system can be added to the eye solution to maintain this solution at the desired pH. Buffer agents useful for the present ophthalmic solution are sodium borate, boric acid, disodium monohydrogen phosphate, sodium dihydrogen phosphate, a citrate buffer from sodium citrate and citric acid or an acetate buffer from acetic acid and sodium acetate as well as combinations of phosphate and citrate buffers.
20 Het zoutgehalte van de oplossing is bij voorkeur isotonisch, d.w.z. equivalent met 0,9 % natriumchloride, maar het traject tussen 0,8 en 1,0 % is nog redelijk isotonisch van activiteit. Elk farmacologisch geschikt zout kan worden gebruikt voor het isotonisch maken van de uiteindelijke oplossing. Omdat de isotonische behoeften van sommige 2i- patiënten kan wisselen, kan de gewenste isotoniciteit voor een bepaalde patiënt worden verkregen door de hoeveelheid zout·;in de oplossing te verhogen of te verlagen. Ook kan in plaats van een zout een niet iono-geen, farmacologisch geschikt, in water oplosbaar materiaal· worden toegepast om de gewenste isotone eigenschappen te verkrijgen. Non-2q ionogene materialen, die hiervoor kunnen worden gebruikt^zijn b.v. poly-ethyleenglycol en polypropyleenglycol. Meer verrassend nog werd gevonden, dat indien het nylidrinezuuradditiezout een sulfonaat is met de formule 1 van het formuleblad, waarin R een alkylgroep met 1-8 kool-stofatomen, fenyl, alkylfenyl (b.v. tolyl, ethylfenyl, propylfenyl e.d.), ^ fenylalkyl (b.v. benzyl, fenethyl of dergelijke), danwel heterocyclyl (b.v. pyridyl, chinolyl, furyl of dergelijke) is de duur van de activiteit 8005702 • _5 -3- tenminste 2k uren bedraagt.The salinity of the solution is preferably isotonic, i.e. equivalent to 0.9% sodium chloride, but the range between 0.8 and 1.0% is still fairly isotonic in activity. Any pharmacologically suitable salt can be used to make the final solution isotonic. Because the isotonic needs of some 2i patients may vary, the desired isotonicity for a particular patient can be obtained by increasing or decreasing the amount of salt in the solution. Alternatively, a nonionic, pharmacologically suitable, water-soluble material may be used in place of a salt to obtain the desired isotonic properties. Non-2q ionic materials which can be used for this purpose are e.g. polyethylene glycol and polypropylene glycol. More surprisingly, it has been found that if the nylidric acid addition salt is a sulfonate of the formula I, wherein R is an alkyl group of 1-8 carbon atoms, phenyl, alkylphenyl (eg tolyl, ethylphenyl, propylphenyl, etc.), phenylalkyl (eg benzyl, phenethyl or the like) or heterocyclyl (eg pyridyl, quinolyl, furyl or the like), the duration of the activity is 8005702-5 -3- at least 2 hours.
Elk. oogpreparaat, geschikt voor topicale toediening, kan worden gebruikt. Deze omvatten cremes, lotions en oplossingen. Voor een gemakkelijke toediening, liefst via een oogdruppelaar, wordt aan oplossingen 5 de voorkeur gegeven.Each. eye preparation suitable for topical administration can be used. These include creams, lotions and solutions. For easy administration, preferably via an eye dropper, solutions 5 are preferred.
De oplossingen geschikt voor topicale toediening aan het oog kunnen 0,01 - 0,2 gew.$ van een passend nylidrinezout bevatten. .Zij kunnen aan het oog worden toegediend met tussenpozen van een- tot viermaal per dag. Uiteindelijk zal de arts beslissen welke dosering en met welke 10 frequentie het geschiktst is voor een bepaalde patiënt.The solutions suitable for topical administration to the eye may contain 0.01 to 0.2% by weight of an appropriate nylidrine salt. They can be administered to the eye at intervals of one to four times a day. Ultimately, the doctor will decide which dose and frequency is most appropriate for a particular patient.
De voorbeelden I-IX geven passende oplossingen voor topieaal gebruik weer. De cijfers zijn gevichtsprocenten.Examples I-IX show suitable solutions for topical use. The figures are percents.
Voorbeeld I: ÏTylidrinehydr ochloride 0,1 15 natriumchloride 0,85 dinatriumedetaat 0,02 fosfaatbuffer (tot pH 6,0) 0,1 benzalkoniumchloride 0,005 water q,.s. 100 20 Voorbeeld II: nyli drinehydrochloride 0,1 n atriumchloride 0,85 dinatriumedetaat 0,02 hydroxyethylcellulose 0,3 25 polyvinylalcohol 0,1 fosfaatbuffer (tot pH 6,0) 0,1 benzalkoniumchloride 0,005 water q,.s. 100Example I: Tylidrine hydrochloride 0.1 15 sodium chloride 0.85 disodium edetate 0.02 phosphate buffer (to pH 6.0) 0.1 benzalkonium chloride 0.005 water q. 100 20 Example II: Nyl amine hydrochloride 0.1 n atrium chloride 0.85 disodium edetate 0.02 hydroxyethyl cellulose 0.3 25 polyvinyl alcohol 0.1 phosphate buffer (to pH 6.0) 0.1 benzalkonium chloride 0.005 water q. 100
Voorbeeld III: 30 nylidrine-ethaansulfonaat 0,1 natriumchloride 0,85 din atr iumedet aat 0,02 fosfaatbuffer (tot pH 6,0) 0,1 thimeros al 0,00¼ 35 water q.s. 100 8005702Example III: 30 nylidrine ethanesulfonate 0.1 sodium chloride 0.85 dinatium edate 0.02 phosphate buffer (to pH 6.0) 0.1 thimeros al 0.00¼ 35 water q.s. 100 8005702
% -V% -V
-fc--fc-
Voorbeeld IV:Example IV:
Gelijk voorbeeld II, met dit verschil, dat thimerosal (0,00U) werd gebruikt in plaats van benzalkoniumchloride (0,005).Similar to Example II, except that thimerosal (0.00U) was used in place of benzalkonium chloride (0.005).
Voorbeelden V-VIII: 5 Gelijk aan de voorbeelden I-IV, met dit verschil, dat in plaats van de fosfaatbuffer een citraatbuffer tot pH 6,0 werd gebruikt.Examples V-VIII: 5 Same as Examples I-IV, except that instead of the phosphate buffer, a citrate buffer up to pH 6.0 was used.
Voorbeeld IX: nylidrine-ethaansulfonaat 0,05 natriumchloride 0,85 10 natriumedetaat 0,02 acetaatbuffer (tot pH 6,0) 0,1 benzalkoniumchloride 0,005 water q.s. 100Example IX: Nylidrine ethanesulfonate 0.05 sodium chloride 0.85 sodium edetate 0.02 acetate buffer (to pH 6.0) 0.1 benzalkonium chloride 0.005 water q.s. 100
Voorbeelden X en XII illustreren de bereiding van de nieuwe sul-’ 15 fonaatzouten.Examples X and XII illustrate the preparation of the new sulfonate salts.
Voorbeeld X: ïïylindrine -e thaansulf onaat 3 20 g ny lidrine-hydrochloride werd opgelost m 1500 cm heet water, op kamertemperatuur afgekoeld en behandeld met 1000 cm van een 5#’s 20 natriumbicarbonaat oplossing onder roeren, Ha nog 2 uur roeren werd de oplossing gefiltreerd, waarbij men de onzuivere nylidrinevrije base in een kwantitatieve opbrengst van 17*6 g verkreeg. Deze werd gezuiverd door een herkristallisatie uit methanol.Example X: Ilylindrine -thanesulfonate 3 20 g of lidrine hydrochloride was dissolved with 1500 cm of hot water, cooled to room temperature and treated with 1000 cm of a 5 # 's sodium bicarbonate solution with stirring. Ha was stirred for an additional 2 hours. solution filtered to give the crude nylidine-free base in a quantitative yield of 17 * 6 g. This was purified by recrystallization from methanol.
OO
Aan 600 cm van een ethylacetaatoplossing van 30 g nylindrinevrije 25 base werd een oplossing van 12 g ethaansulfonzuur in l80 cm ethylacetaat onder roeren toegevoegd. Ha een nacht roeren bij kamertemperatuur werd deze oplossing gefiltreerd en het onzuivere zout in de vorm van een wit vast materiaal verkregen. De opbrengst (ÏO g) was kwantitatief.A solution of 12 g of ethanesulfonic acid in 180 cm of ethyl acetate was added with stirring to 600 ml of an ethyl acetate solution of 30 g of nylindrine-free base. After stirring overnight at room temperature, this solution was filtered and the crude salt was obtained as a white solid. The yield (100 g) was quantitative.
Dit materiaal werd herkristalliseerd uit een mengsel van isopropanol 30 en hexaan. Smpt. 12Ö-130°C.This material was recrystallized from a mixture of isopropanol 30 and hexane. Mp. 120-130 ° C.
Voorbeeld XI:Example XI:
Hylindrine-methaansulfonaatHylindrine methanesulfonate
Analoog voorbeeld X werd de nylidrinevrije base met methaansul-fonzuur omgezet. Het produkt werd herkristalliseerd uit een mengsel 35 van isopropanol en hexaan; smpt. l!+9-51°C.Analogous Example X, the nylidine-free base was reacted with methanesulfonic acid. The product was recrystallized from a mixture of isopropanol and hexane; m.p. l + 9-51 ° C.
800570? -5-800570? -5-
*" ♦ I* "♦ I
//
Analoog de procedures van de voorbeelden X en XI werden de volgende verdere RSO^H-zouten van nylidrine bereid.Analogously to the procedures of Examples X and XI, the following further RSO2 H salts of nylidrine were prepared.
B smpt. °CB mp. ° C
fenyl 195-97 5 p-tolyl 212-1¾ 3-pyridyl 186-88phenyl 195-97 5 p-tolyl 212-1¾ 3-pyridyl 186-88
Tevens werden analoog de voorbeelden X en XI de volgende‘verdere sulfonaatzouten bereid: p-tolyl, m-tolyl, benzyl, fenethyl, 2-pyridyl, U-pyridyl, thiofeen, furyl, 2-chinolyl en 3-chinolyl.Also, analogously to Examples X and XI, the following "further sulfonate salts were prepared: p-tolyl, m-tolyl, benzyl, phenethyl, 2-pyridyl, U-pyridyl, thiophene, furyl, 2-quinolyl.
80057028005702
Claims (21)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NL8005702A NL8005702A (en) | 1980-10-16 | 1980-10-16 | Nylidrin solns. for topical treatment of glaucoma - contg. para-hydroxy N-1-methyl-3-phenyl-propyl nor-ephedrine or its salts, reduces intra:ocular pressure for prolonged periods |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NL8005702 | 1980-10-16 | ||
| NL8005702A NL8005702A (en) | 1980-10-16 | 1980-10-16 | Nylidrin solns. for topical treatment of glaucoma - contg. para-hydroxy N-1-methyl-3-phenyl-propyl nor-ephedrine or its salts, reduces intra:ocular pressure for prolonged periods |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NL8005702A true NL8005702A (en) | 1982-05-17 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NL8005702A NL8005702A (en) | 1980-10-16 | 1980-10-16 | Nylidrin solns. for topical treatment of glaucoma - contg. para-hydroxy N-1-methyl-3-phenyl-propyl nor-ephedrine or its salts, reduces intra:ocular pressure for prolonged periods |
Country Status (1)
| Country | Link |
|---|---|
| NL (1) | NL8005702A (en) |
-
1980
- 1980-10-16 NL NL8005702A patent/NL8005702A/en not_active Application Discontinuation
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