NO781688L - PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICAL ACTIVE AGENTS - Google Patents
PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICAL ACTIVE AGENTSInfo
- Publication number
- NO781688L NO781688L NO78781688A NO781688A NO781688L NO 781688 L NO781688 L NO 781688L NO 78781688 A NO78781688 A NO 78781688A NO 781688 A NO781688 A NO 781688A NO 781688 L NO781688 L NO 781688L
- Authority
- NO
- Norway
- Prior art keywords
- tinidazole
- solution
- nitroimidazole
- drug
- aqueous solution
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 17
- 239000013543 active substance Substances 0.000 title description 2
- 230000000144 pharmacologic effect Effects 0.000 title 1
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 claims description 30
- HJLSLZFTEKNLFI-UHFFFAOYSA-N Tinidazole Chemical compound CCS(=O)(=O)CCN1C(C)=NC=C1[N+]([O-])=O HJLSLZFTEKNLFI-UHFFFAOYSA-N 0.000 claims description 28
- 229960005053 tinidazole Drugs 0.000 claims description 28
- 239000000243 solution Substances 0.000 claims description 22
- YZEUHQHUFTYLPH-UHFFFAOYSA-N 2-nitroimidazole Chemical compound [O-][N+](=O)C1=NC=CN1 YZEUHQHUFTYLPH-UHFFFAOYSA-N 0.000 claims description 14
- 229960005219 gentisic acid Drugs 0.000 claims description 13
- 229940079593 drug Drugs 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 10
- PUZSUVGRVHEUQO-UHFFFAOYSA-N gentisyl alcohol Chemical compound OCC1=CC(O)=CC=C1O PUZSUVGRVHEUQO-UHFFFAOYSA-N 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- -1 dihydroxybenzyl alcohol Chemical compound 0.000 claims description 4
- 229960000282 metronidazole Drugs 0.000 claims description 4
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 claims description 4
- JOVXEDBYAWFQQX-UHFFFAOYSA-N 2-(2-methyl-5-nitroimidazol-1-yl)ethyl carbamate Chemical compound CC1=NC=C([N+]([O-])=O)N1CCOC(N)=O JOVXEDBYAWFQQX-UHFFFAOYSA-N 0.000 claims description 3
- IPWKIXLWTCNBKN-UHFFFAOYSA-N Madelen Chemical compound CC1=NC=C([N+]([O-])=O)N1CC(O)CCl IPWKIXLWTCNBKN-UHFFFAOYSA-N 0.000 claims description 3
- 150000003863 ammonium salts Chemical class 0.000 claims description 3
- 229950005881 bamnidazole Drugs 0.000 claims description 3
- 229960004918 nimorazole Drugs 0.000 claims description 3
- MDJFHRLTPRPZLY-UHFFFAOYSA-N nimorazole Chemical compound [O-][N+](=O)C1=CN=CN1CCN1CCOCC1 MDJFHRLTPRPZLY-UHFFFAOYSA-N 0.000 claims description 3
- 229960002313 ornidazole Drugs 0.000 claims description 3
- 238000004108 freeze drying Methods 0.000 claims description 2
- 230000001954 sterilising effect Effects 0.000 claims description 2
- 238000004659 sterilization and disinfection Methods 0.000 claims description 2
- 229940102223 injectable solution Drugs 0.000 claims 1
- 239000007972 injectable composition Substances 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- 238000001990 intravenous administration Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 8
- CQRYARSYNCAZFO-UHFFFAOYSA-N o-hydroxybenzyl alcohol Natural products OCC1=CC=CC=C1O CQRYARSYNCAZFO-UHFFFAOYSA-N 0.000 description 6
- 238000009472 formulation Methods 0.000 description 5
- BVJSUAQZOZWCKN-UHFFFAOYSA-N p-hydroxybenzyl alcohol Chemical compound OCC1=CC=C(O)C=C1 BVJSUAQZOZWCKN-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
- GLDQAMYCGOIJDV-UHFFFAOYSA-N Pyrocatechuic acid Natural products OC(=O)C1=CC=CC(O)=C1O GLDQAMYCGOIJDV-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 208000022506 anaerobic bacteria infectious disease Diseases 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 239000004599 antimicrobial Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- 150000004958 5-nitroimidazoles Chemical class 0.000 description 1
- 208000004881 Amebiasis Diseases 0.000 description 1
- 206010001980 Amoebiasis Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000010362 Protozoan Infections Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- ABBQHOQBGMUPJH-UHFFFAOYSA-M Sodium salicylate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O ABBQHOQBGMUPJH-UHFFFAOYSA-M 0.000 description 1
- 208000005448 Trichomonas Infections Diseases 0.000 description 1
- 206010044620 Trichomoniasis Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical class OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229960004249 sodium acetate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 229960004025 sodium salicylate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940074404 sodium succinate Drugs 0.000 description 1
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Fremgangsmåte ved fremstilling av farmakologisk aktive midler. Procedure for the production of pharmacologically active agents.
Foreliggende oppfinnelse vedrører farmasøytiske formuleringer og spesielt formuleringer av nitroimidazol-antimi-krobiske midler med forbedrede løselighet-karakteristika. The present invention relates to pharmaceutical formulations and in particular formulations of nitroimidazole antimicrobial agents with improved solubility characteristics.
Nitroimidazol-antimikrobielle droger er en verdifull klasse av middelet som erkarakterisert vedat de har en 5-nitroimidazol-kjerne og er spesielt anvendelige ved behandling av protozo-infeksjoner som trichomoniasis og amoebiasis og også ved behandling av anaerobe bakterie-infeksjoner. Klas-sen innbefatter sådanne forbindelser som tinidazol, metronidazol og nimorazol. Et problem med denne, forbindelses-klassen er deres dårlige løselighet i vandig media som vanskeliggjør formulering av vandige injeserbart komposisjoner. Det er nå funnet en fordelaktig metode for å sblubilisere nitroimidazol-antimikrobielle droger som. gjør det mulig lett å fremstille vandige løsninger egnet for parenteral injeksjon. Sl.ike formuleringer er av spesiell verdi ved systemisk behandling av anerobe bakterie-infeksjoner. Nitroimidazole antimicrobial drugs are a valuable class of agents characterized by having a 5-nitroimidazole nucleus and are particularly useful in the treatment of protozoan infections such as trichomoniasis and amoebiasis and also in the treatment of anaerobic bacterial infections. The class includes such compounds as tinidazole, metronidazole and nimorazole. A problem with this class of compounds is their poor solubility in aqueous media, which makes formulation of aqueous injectable compositions difficult. An advantageous method of slubilizing nitroimidazole antimicrobial drugs has now been found. makes it possible to easily prepare aqueous solutions suitable for parenteral injection. Such formulations are of particular value in the systemic treatment of anaerobic bacterial infections.
Således tilveibringes ifølge oppfinnelsen en farmasøytisk komposisjon som omfatter en nitroimidazol-antimikrobiell droge i blanding med et farmasøytisk fordragelig salt av Thus, according to the invention, a pharmaceutical composition is provided which comprises a nitroimidazole antimicrobial drug in mixture with a pharmaceutically acceptable salt of
en mono- eller di-hydroksybenzosyre eller med en mono- eller di-hydroksybenzyl-alkohol. a mono- or di-hydroxybenzoic acid or with a mono- or di-hydroxybenzyl alcohol.
Den farmasøytiske komposisjonen ifølge oppfinnelsen kan foreligge i form av en steril vandig løsning eller i form av en fast blanding fremstilt ved å blande komponentene eller ved lyofilisering av en steril vandig løsning av komponentene. The pharmaceutical composition according to the invention can be in the form of a sterile aqueous solution or in the form of a solid mixture prepared by mixing the components or by lyophilizing a sterile aqueous solution of the components.
Også andre bestanddeler kan være tilstede, f.eks. en syre eller base kan tilsettes for å nøytralisere oppløsningen Other components may also be present, e.g. an acid or base may be added to neutralize the solution
(om nødvendig) og for å gi en pH i det fysiologisk fordragelige området seg er egnet for en injeserbar formulering. Salter (f.eks. natriumacetat, natriumlactat, natriumsuccinat eller natriumklorid) og andre løsnings-bestanddeler (f.eks. dekstrose eller mannitol) kan også tilsettes for å gjør løsningen isotonisk. (if necessary) and to provide a pH in the physiologically tolerable range suitable for an injectable formulation. Salts (eg sodium acetate, sodium lactate, sodium succinate or sodium chloride) and other solution ingredients (eg dextrose or mannitol) can also be added to make the solution isotonic.
Hvis et salt eller en hydroksybenzosyre benyttes, foretrekkes en di-hydroksybenzosyre, spesielt gentisinsyre (2,5-di-hydroksybenzosyre). Videre egnet er 2,3-, 3,4- og 3,5-dihydroksybenzensyrer og salisylsyre. Det foretrukne salt er ammdniumsaltet, men natriumsaltet er også egnet såvel som salter med organiske baser som L-arginin, meglumin (N-metyl glukamin), etanolamin og cholin. Alternativt kan hydroksybenzosyre anvendes som fri syre og kan nøytrali-seres ved tilsetning av en ekvivalent mengde av den ønskede base for å gi en vandig løsning av salter for tilsetning av nitroimidazol-drogen. If a salt or a hydroxybenzoic acid is used, a dihydroxybenzoic acid, especially gentisic acid (2,5-dihydroxybenzoic acid), is preferred. Also suitable are 2,3-, 3,4- and 3,5-dihydroxybenzene acids and salicylic acid. The preferred salt is the ammonium salt, but the sodium salt is also suitable as well as salts with organic bases such as L-arginine, meglumine (N-methyl glucamine), ethanolamine and choline. Alternatively, hydroxybenzoic acid can be used as the free acid and can be neutralized by adding an equivalent amount of the desired base to give an aqueous solution of salts for addition of the nitroimidazole drug.
En foretrukket hydroksybenzyl-alkohol er gentisyl-alkohol, eller mono- eller dihydorksybenzyl-alkoholer, f.eks. salisyl-alkohol kan også anvendes. Anvendelsen av en hydroksybenzyl-alkohol har den fordel at en base ikke er nødvendig for å A preferred hydroxybenzyl alcohol is gentisyl alcohol, or mono- or dihydroxybenzyl alcohols, e.g. salicylic alcohol can also be used. The use of a hydroxybenzyl alcohol has the advantage that a base is not necessary to
nøytralisere formuleringen.neutralize the formulation.
Mengden av hydroksybenzosyre eller hydroksybenzyl-alkohol som kreves avhenger av den enkelte og den endelige konsentrasjon som er nødvendig for den anvendte nitroimidazol samt typen av den spesielle hydroksybenzysyre eller hydroksybenzyl-alkohol som anvendes. The amount of hydroxybenzoic acid or hydroxybenzyl alcohol required depends on the individual and final concentration required for the nitroimidazole used as well as the type of particular hydroxybenzoic acid or hydroxybenzyl alcohol used.
Det er nå funnet at å fremstille en vandig løsning av tinidazol i en konsentrasjon anvendelig for intravenøs administre-ring, dvs. :.i en konsentrasjon på opptil 50 mg pr. ml, krever en mengde gentisinsyre fra 2 til 4 vekt-deler basert på tinidazol fortrinnsvis ca. 2,8 vekt-deler. For å fremstille en høyere konsentrasjon av tinidazol, mer egnet for intra muskulær injeksjon, dvs. en konsentrasjon opptil 200 mq pr. ml, krever et lavere forhold av gentisinsyre til tinidazol, dvs. en gentisinsyremengde fra 1 til 2 vekt-deler basert på tinidazolet, fortrinnsvis ca. 1,4 vekt-deler. It has now been found that preparing an aqueous solution of tinidazole in a concentration suitable for intravenous administration, i.e. in a concentration of up to 50 mg per ml, requires an amount of gentisic acid from 2 to 4 parts by weight based on tinidazole, preferably approx. 2.8 parts by weight. To produce a higher concentration of tinidazole, more suitable for intramuscular injection, i.e. a concentration up to 200 mq per ml, requires a lower ratio of gentisic acid to tinidazole, i.e. an amount of gentisic acid from 1 to 2 parts by weight based on the tinidazole, preferably approx. 1.4 parts by weight.
Uten solubiliseringsmiddel er tinidazol bare løselig i vann opptil 5 mg pr. ml. Without a solubilizer, tinidazole is only soluble in water up to 5 mg per ml.
I praksis kan en løsning av nitroimidazol-drogen fremstilles ved å sette den til en vandig løsning av saltet av hydroksybenzosyre eller til én løsning av hydroksybenzyl-alkoholen. Blandingen røres inntil nitroimidazolet er oppløst, pH justeres om nødvendig og løsningen sterilfiltreres så ved å bruke en bakterie-tett membran og fylles i steriel beholdere med et passende volum for den tilsiktede anvendelsen av drogen. Således vil for humant bruk som en intravenøs injeserbar formulering beholdere som inneholder 10 ml av en løsning av tinidazol i en konsentrasjon på 50 mg pr. ml være egnet, mens for intramuskulær bruk kunne beholdere som inneholder 4 ml av en løsning av tiniadzol på 200 mg pr. ml anvendes. In practice, a solution of the nitroimidazole drug can be prepared by adding it to an aqueous solution of the salt of hydroxybenzoic acid or to a solution of the hydroxybenzyl alcohol. The mixture is stirred until the nitroimidazole is dissolved, the pH is adjusted if necessary and the solution is then sterile filtered using a bacteria-tight membrane and filled into sterile containers of an appropriate volume for the intended use of the drug. Thus, for human use as an intravenous injectable formulation, containers containing 10 ml of a solution of tinidazole at a concentration of 50 mg per ml would be suitable, while for intramuscular use containers containing 4 ml of a solution of tiniazole at 200 mg per ml are used.
Alternativt kan oppløsningen etter sterilisering lyofiliseres ved fryst-tørking på konvensjonell måte, f.eks. ved ned-kjøling til -40°C og underkaste den frosne løsningen høy-vakuum i 24 timer for å gi et fast produkt. Det kan være ønskelig å lagre produktet i denne formen idet løsningen lett tilbakeføres umiddelbart før bruk ved å bare tilsette det nødvendige volum vann. Alternatively, the solution after sterilization can be lyophilized by freeze-drying in a conventional manner, e.g. by cooling to -40°C and subjecting the frozen solution to high vacuum for 24 hours to give a solid product. It may be desirable to store the product in this form, as the solution is easily returned immediately before use by simply adding the required volume of water.
Liknende formuleringer kan fremstilles ved å bruk andre nitroimidazoldroger, f.eks. vandig injeserbare formuleringer kan fremstilles ved å bruke metronidazol, nimorazol, ornidazol og bamnidazol med gentisinsyre. Similar formulations can be prepared using other nitroimidazole drugs, e.g. aqueous injectable formulations can be prepared using metronidazole, nimorazole, ornidazole and bamnidazole with gentisic acid.
De følgende er eksempler på farmasøytiske komposisjoner ifølge oppfinnelsen. The following are examples of pharmaceutical compositions according to the invention.
EKSEMPEL 1EXAMPLE 1
En intravenøs injeserbar formulering av tinidazol ble fremstilt med følgende sammensetning: An intravenous injectable formulation of tinidazole was prepared with the following composition:
Gentisinsyren ble rørt med halvparten av vann og den for-tynnede ammoniakkløsningen ble tilsatt langsomt inntil alt det faste stoffet var oppløst og den endelig pH i løsningen var 0,25 + 0,2. Langsomt tilsetning er nødvendig for å unngå misfarging av gentisinsyren. Tinidazolet ble så tilsatt og rørt til en klor-løsning oppstod som ble fortynnet med vann for å gi det endelig volumet på 1 liter. Løsningen ble sterilisert ifølge metoden fra British Farmacopoea (1973) ved filtrering gjennom et bakterie-tett filter under asep-tiske betingelser og fylt i sterile glassbeholdere. The gentisic acid was stirred with half of the water and the dilute ammonia solution was added slowly until all the solid had dissolved and the final pH of the solution was 0.25 + 0.2. Slow addition is necessary to avoid discoloration of the gentisic acid. The tinidazole was then added and stirred until a chlorine solution formed which was diluted with water to give the final volume of 1 liter. The solution was sterilized according to the method from the British Pharmacopoeia (1973) by filtering through a bacteria-tight filter under aseptic conditions and filled into sterile glass containers.
EKSEMPEL 2EXAMPLE 2
En intravenøs injeserbar formulering av tinidazol ble fremstilt som beskrevet i eksempel 1 men med følgende sammensetning: An intravenous injectable formulation of tinidazole was prepared as described in Example 1 but with the following composition:
EKSEMPEL 3 - 5 EXAMPLE 3 - 5
Intravenøs injeserbare formuleringer av tinidazol ble frem-.stilt som beskrevet i eksempel 2 bortsatt fra følgende syrer ble brukt i stedet for para-hydroksybenzosyre: Intravenous injectable formulations of tinidazole were prepared as described in Example 2 except that the following acids were used instead of para-hydroxybenzoic acid:
EKSEMPEL 6 EXAMPLE 6
En intravenøs, injeserbar formulering av tinidazol ble fremstilt med følgende sammensetning: An intravenous, injectable formulation of tinidazole was prepared with the following composition:
Natrium-salisylatet ble oppløset i halvparten av vannet og tinidazolet ble tilsatt og rørt hvilket ga en klar løs-ning. Vann ble tilsatt til et sluttvolum på 100 ml og løsningen ble sterilt filtrert i beholdere som beskrevet i eksempel 1. The sodium salicylate was dissolved in half the water and the tinidazole was added and stirred which gave a clear solution. Water was added to a final volume of 100 ml and the solution was sterile filtered into containers as described in example 1.
EKSEMPEL 7 - 11 EXAMPLE 7 - 11
Intravenøs injeserbare formulering av tinidazol ble fremstilt som beskrevet i eksempel 1 unntatt at i stedet for ammoniakk-løsning 1 ble ekvivalente mengder av de følgende baser tilsatt i hvert tilfelle for å nøytralisere gentisinsyren: Intravenous injectable formulation of tinidazole was prepared as described in Example 1 except that instead of ammonia solution 1, equivalent amounts of the following bases were added in each case to neutralize the gentisic acid:
EKSEMPEL 12 EXAMPLE 12
En intravenøs injeserbar formulering av tinidazol ble fremstilt med følgende sammensetning: An intravenous injectable formulation of tinidazole was prepared with the following composition:
Gentisyl-alkoholen ble oppløst i halvparten av vann og tinidazolet ble tilsatt og rørt hvilket ga en klar opp-løsning. Volumet av oppløsningen ble fylt opp til 100 The Gentisyl alcohol was dissolved in half of the water and the tinidazole was added and stirred to give a clear solution. The volume of the solution was made up to 100
ml og løsningen ble steril filtrert inn i glassbeholdere som beskrevet i eksempel 1. ml and the solution was sterile filtered into glass containers as described in example 1.
EKSEMPEL 13EXAMPLE 13
Et intravenøs injeserbar formulering av tinidazol ble fremstilt som beskrevet i eksempel 12 bortsett fra et metahyd-roksybenzyl-alkohol ble brukt i stedet for gentisyl-alkohol. An intravenous injectable formulation of tinidazole was prepared as described in Example 12 except a metahydroxybenzyl alcohol was used instead of gentisyl alcohol.
EKSEMPEL 14EXAMPLE 14
En steril vandig oppløsning av tinidazol og gentisinsyreA sterile aqueous solution of tinidazole and gentisic acid
(4 ml) fremstilt som beskrevet i eksempel 1 ble fryse-tørket over vakuum ved -40°C i 24 timer hvilket ga et gulaktig fast stoff. (4 mL) prepared as described in Example 1 was freeze-dried under vacuum at -40°C for 24 hours to give a yellowish solid.
EKSEMPEL 15EXAMPLE 15
Produktet fra eksempel 14 ble tilbakeført ved tilsetning av vann for injeksjon E.P. til beholderen. Det faste stoffet gikk øyeblikkelig i oppløsning hvilket ga en klar løsning. Volumet av tilsatt vann ble variert hvilket ga løsninger av tinidazol med følgende konsentrasjoner: The product from example 14 was recovered by adding water for injection E.P. to the container. The solid dissolved immediately giving a clear solution. The volume of added water was varied, giving solutions of tinidazole with the following concentrations:
EKSEMPEL 16 EXAMPLE 16
En intramuskulær injeserbar formulering av tinidazol ble fremstilt som beskrevet i eksempel 1 men med følgende sammensetning: An intramuscular injectable formulation of tinidazole was prepared as described in Example 1 but with the following composition:
EKSEMPEL 17 EXAMPLE 17
Én intravenøs injeserbar formulering av metronidazol med følgende sammensetning ble fremstilt ved å bruke frem-gangsmåten fra eksempel 1: One intravenous injectable formulation of metronidazole of the following composition was prepared using the procedure of Example 1:
EKSEMPEL.18 EXAMPLE.18
En intravenøs injeserbar formulering av himorazol med den følgende sammensetning.ble fremstilt ved å bruke fremgangs-måten fra eksempel 1: An intravenous injectable formulation of himorazole of the following composition was prepared using the procedure of Example 1:
EKSEMPEL 19 EXAMPLE 19
En intravenøs injserbar formulering av bamnidazol medAn intravenous injectable formulation of bamnidazole with
den følgende sammensetning ble fremstilt ved å bruke frem-gangsmåten fra eksempel 1: the following composition was prepared using the procedure of Example 1:
EKSEMPEL 20 EXAMPLE 20
En intravenøs injeserbar formulering av ornidazol med den følgende sammensetning ble fremstilt ved å bruke fremgangs-måten fra eksempel 1: An intravenous injectable formulation of ornidazole of the following composition was prepared using the procedure of Example 1:
Claims (9)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB2037977 | 1977-05-14 |
Publications (1)
Publication Number | Publication Date |
---|---|
NO781688L true NO781688L (en) | 1978-11-15 |
Family
ID=10144988
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO78781688A NO781688L (en) | 1977-05-14 | 1978-05-12 | PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICAL ACTIVE AGENTS |
Country Status (16)
Country | Link |
---|---|
JP (1) | JPS542315A (en) |
AU (1) | AU504551B1 (en) |
BE (1) | BE867040A (en) |
DE (1) | DE2820992A1 (en) |
DK (1) | DK212678A (en) |
ES (1) | ES469749A1 (en) |
FI (1) | FI781507A (en) |
FR (1) | FR2390162A1 (en) |
IL (1) | IL54687A0 (en) |
IT (1) | IT1115599B (en) |
LU (1) | LU79655A1 (en) |
NL (1) | NL7805158A (en) |
NO (1) | NO781688L (en) |
PT (1) | PT68034B (en) |
SE (1) | SE7805471L (en) |
ZA (1) | ZA782736B (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3070778D1 (en) * | 1979-08-11 | 1985-07-25 | Bayer Ag | Antimycotic agents with enhanced release of the active ingredients |
FR2624736B1 (en) * | 1987-12-16 | 1991-03-22 | Dietlin Francois | NEW WATER-DISPERSIBLE PHARMACEUTICAL COMPOSITIONS BASED ON ORNIDAZOLE |
CN104127379A (en) * | 2014-08-14 | 2014-11-05 | 珠海亿邦制药股份有限公司 | Ornidazole injection and preparation method thereof |
CN110538144A (en) * | 2019-06-13 | 2019-12-06 | 南京瓦尔生物医药有限公司 | Ornidazole injection and S-ornidazole injection |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4032645A (en) * | 1975-06-19 | 1977-06-28 | G. D. Searle & Co. | Injectable metronidazole composition |
-
1978
- 1978-05-10 IL IL54687A patent/IL54687A0/en unknown
- 1978-05-11 ES ES469749A patent/ES469749A1/en not_active Expired
- 1978-05-12 PT PT68034A patent/PT68034B/en unknown
- 1978-05-12 BE BE187664A patent/BE867040A/en unknown
- 1978-05-12 NL NL7805158A patent/NL7805158A/en not_active Application Discontinuation
- 1978-05-12 DK DK212678A patent/DK212678A/en not_active Application Discontinuation
- 1978-05-12 FR FR7814291A patent/FR2390162A1/en not_active Withdrawn
- 1978-05-12 DE DE19782820992 patent/DE2820992A1/en active Pending
- 1978-05-12 AU AU36078/78A patent/AU504551B1/en not_active Expired
- 1978-05-12 LU LU79655A patent/LU79655A1/en unknown
- 1978-05-12 SE SE7805471A patent/SE7805471L/en unknown
- 1978-05-12 IT IT23351/78A patent/IT1115599B/en active
- 1978-05-12 ZA ZA00782736A patent/ZA782736B/en unknown
- 1978-05-12 NO NO78781688A patent/NO781688L/en unknown
- 1978-05-12 FI FI781507A patent/FI781507A/en not_active Application Discontinuation
- 1978-05-13 JP JP5706378A patent/JPS542315A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
PT68034A (en) | 1978-06-01 |
JPS542315A (en) | 1979-01-09 |
IT7823351A0 (en) | 1978-05-12 |
NL7805158A (en) | 1978-11-16 |
ZA782736B (en) | 1979-05-30 |
FR2390162A1 (en) | 1978-12-08 |
IT1115599B (en) | 1986-02-03 |
IL54687A0 (en) | 1978-07-31 |
LU79655A1 (en) | 1979-12-06 |
PT68034B (en) | 1979-10-24 |
DK212678A (en) | 1978-11-15 |
DE2820992A1 (en) | 1978-12-07 |
BE867040A (en) | 1978-11-13 |
AU504551B1 (en) | 1979-10-18 |
ES469749A1 (en) | 1978-12-16 |
FI781507A (en) | 1978-11-15 |
SE7805471L (en) | 1978-11-15 |
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