NO331876B1 - Formulering som omfatter antibiotikum-/antibiotika-preparat med retardert virkestoffrigivning, anvendelse av denne samt en fremgangsmate - Google Patents
Formulering som omfatter antibiotikum-/antibiotika-preparat med retardert virkestoffrigivning, anvendelse av denne samt en fremgangsmate Download PDFInfo
- Publication number
- NO331876B1 NO331876B1 NO20021390A NO20021390A NO331876B1 NO 331876 B1 NO331876 B1 NO 331876B1 NO 20021390 A NO20021390 A NO 20021390A NO 20021390 A NO20021390 A NO 20021390A NO 331876 B1 NO331876 B1 NO 331876B1
- Authority
- NO
- Norway
- Prior art keywords
- antibiotic
- antibiotics
- formulation
- alkyl
- absorbable
- Prior art date
Links
- 230000003115 biocidal effect Effects 0.000 title claims abstract description 93
- 239000000203 mixture Substances 0.000 title claims abstract description 51
- 238000009472 formulation Methods 0.000 title claims description 23
- 238000000034 method Methods 0.000 title claims description 9
- 238000002360 preparation method Methods 0.000 title abstract description 19
- -1 cycloalkyl sulfonates Chemical class 0.000 claims abstract description 85
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 67
- 229940088710 antibiotic agent Drugs 0.000 claims abstract description 46
- 239000007943 implant Substances 0.000 claims abstract description 20
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 11
- 239000000194 fatty acid Substances 0.000 claims abstract description 11
- 229930195729 fatty acid Natural products 0.000 claims abstract description 11
- PMZDQRJGMBOQBF-UHFFFAOYSA-N quinolin-4-ol Chemical compound C1=CC=C2C(O)=CC=NC2=C1 PMZDQRJGMBOQBF-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000004665 fatty acids Chemical class 0.000 claims abstract description 8
- 150000008055 alkyl aryl sulfonates Chemical class 0.000 claims abstract description 7
- 150000008051 alkyl sulfates Chemical class 0.000 claims abstract description 7
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 claims abstract description 7
- 150000008052 alkyl sulfonates Chemical class 0.000 claims abstract description 7
- 125000005228 aryl sulfonate group Chemical group 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims description 41
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- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 6
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- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 3
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 3
- 239000000920 calcium hydroxide Substances 0.000 claims description 3
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 3
- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 claims description 3
- 239000001527 calcium lactate Substances 0.000 claims description 3
- 229960002401 calcium lactate Drugs 0.000 claims description 3
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- 239000001506 calcium phosphate Substances 0.000 claims description 3
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- ZOMBKNNSYQHRCA-UHFFFAOYSA-J calcium sulfate hemihydrate Chemical compound O.[Ca+2].[Ca+2].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O ZOMBKNNSYQHRCA-UHFFFAOYSA-J 0.000 claims description 3
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- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 3
- 239000001095 magnesium carbonate Substances 0.000 claims description 3
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 3
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 3
- 239000000347 magnesium hydroxide Substances 0.000 claims description 3
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 3
- 239000000395 magnesium oxide Substances 0.000 claims description 3
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 3
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 3
- VSIIXMUUUJUKCM-UHFFFAOYSA-D pentacalcium;fluoride;triphosphate Chemical compound [F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O VSIIXMUUUJUKCM-UHFFFAOYSA-D 0.000 claims description 3
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- 239000003120 macrolide antibiotic agent Substances 0.000 claims description 2
- 238000002844 melting Methods 0.000 claims description 2
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- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 claims description 2
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- A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
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- 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
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
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Abstract
Den foreliggende oppfinnelsen vedrører et antibiotikum-Zantibiotika-preparat for resorberbare og ikke-resorberbare implantater for human- og veterinærmedisin, for behandling av lokale mikrobielle infeksjoner i hard- og i mykvev. Antibiotikum-Zantibiotika- preparatet ifølge oppfinnelsen er en blanding bestående av minst en amfifil komponent av en representant for alkylsulfatene, alkylarylsulfatene, cykloalkyisulfatene, alkylcykloalkylsulfatene, alkylsulfamatene, cykloalkylsulfamatene, alkylcykloalkylsulfamatene, arylsulfamatene, alkylarylsulfamatene, alkylsulfonatene, fettsyre-2-sulfonatene, arylsulfonatene, alkylarylsulfonatene, cykloalkylsulfonatene, alkylcykloalkylsulfonatene, alkyldisulfatene, cykloalkyldisulfatene, alkyldisulfonatene, cykloalkyldisulfonatene, aryldisulfonatene, alkylaryldisulfonatene, aryltrisulfonatene og alkylaryltrisulfonatene såvel som minst en antibiotisk komponent fra gruppen av aminoglykosid- antibiotika, linkosamid-antibiotika. 4-kinolon-antibiotika eller tetracyklin-antibiotika og eventuelt minst en vannfri, organisk hjelpekomponent og eventuelt minst en uorganisk hjelpekomponent og eventuelt minst en biologisk aktiv hjelpekomponent. Antibiotikum-Zantibioitika-preparater ifølge oppfinnelsen utviser en retarderende virkestoffrigivnig.
Description
Oppfinnelsen vedrører et antibiotikum-/antbiotika-formulering, flere anvendelser samt fremgangsmåte.
Behandlingen av lokale mikrobielle infeksjoner av det myke- og harde vev innen human- og veterinærmedisin krever høye lokale antibiotikakonsentrasjoner i det infiserte vevsområdet. Det har i lengre tid vært kjent at en systemisk anvendelse av antibiotika er forbundet med en rekke problemer. Ved den systemiske anvendelsen er det ofte nødvendig å anvende meget høye antibiotikadoser for at det i det infiserte vev oppnås antimikrobielle virksomme antibiotikakonsentrasjoner. Herved kan det spesielt ved aminoglykosid-antibiotika og ved antibiotika av tetracyklin-typen på grunn av deres nefro- og ototoksisitet skje tungtveiende beskadigelse av organismen. Derfor var det nærliggende å anvende antibiotika i lokal administrerbare frigivningssystemer, hhv. overføre dem i egnede depotformer.
Depotsystemer til forsinket frigivning av antibiotika for behandlingen av lokale infeksjoner er gjenstand for et flertall av publikasjoner og patenter. Disse kan man generelt inndele etter to grunnleggende retarderingsmekanismer. Det ene virkningsprinsippet består i den fysikalske fikseringen av antibiotikaen ved adsorpsjon på en matrise henholdsvis ved innleiring i en ikke-resorberbar eller resorberbar matrise. Det andre kjemiske forsinkelsesprinsipp består i anvendelsen i tungt oppløselig antibiotika-salter som etter tilsvarende administrering i den humane eller animalske organisme oppløser seg langsomt under virkestoffrigivning.
Den fysikalske fikseringen av antibiotika under anvendelse av ikke-resorberbare
plastikker er omfattet av en rekke av patenter av hvilke det her kun eksempelvis anføres noen. Således foreslår Klemm (K. Klemm: Surgical synthetic-resin material and method of treating osteomyelitis. 13.05.1995, US 3,882,858) behandlingen av osteomyelitt med plastikkpartikler av polymetakrylat, polyakrylat såvel som deres kopolymerer som er
ladet med gentamisin eller andre antibiotika. Klemm beskriver anvendelsen av septopal (K. Klemm: Septopal - a new way of local antibiotic therapy. I T. J. G. Van Rens, F. H. Kayser (Eds.), Local antibiotic Treatment in Osteomyelitis and Soft-Tissue Infections, Excerpta Medica, Amsterdam (1981) 24-31; K. Klemm: Antibiotic beat chains. Clin. Orthop. Relat. Res. 295 (1993) 63-76). Her dreier det seg om kommersielt tilgjengelig gentamysin-frigivende kjeder av polymetakrylat. Heuser og Dingeldein beskriver en komposisjon på basis av polymetylmetakrylat som er tilsatt aminosyrer som ytterligere komponenter D. Heuser, E. Dingeldein: Synthetic resin-base, antibiotic compositions containing amino acids. 04.04.1980, US 4,191,740; D. Heuser, E. Dingeldein: Synthetic
resin-base, antibiotic compositions containing amino acids. 11.11.1980, US 4,233,287). Videre ble antibiotika, spesielt aminoglykosid-antibiotika også integrert i knokkel-sement (A. Gross, R. Schaefer, S. Reiss: Bone cement compositions containing gentamycin. 22.11.1977, US 4,059,684; A. Welch: Antibiotics in acrylic bone cement. In vitro studies, J. Biomed. Mater. Res. 12 (1978) 679; R.A. Elson, A. E. Jephott, D. B. McGechie, D. Vereitas: Antibiotic-loaded acrylic cement. J. Bone Joint Surg-. 59B
(1977) 200-205.
Den fysikalske fikseringen av antibiotika ved hjelp av resorberbare plastikk spesielt polyestrer av a-hydroksykarboksylsyrer var også gjenstand for en rekke publikasjoner av hvilke det her også kun eksempelvis refereres noen. Sampath et. al. foreslår et gentamisin-frigivende system bestående av poly-L-laktid og gentamisin som ble fremstilt ved presning av poly-L-laktid/gentamisin-mikrokapsler (S. S. Sampath, K. Garvin, D. H. Robinson: Preparation and characterization of biodegradable poly(-L-lactic acid) gentamicin delivery systems. Int. J. Pharmaceutics 78 (1992) 165-174). Dette systemet viser avhengig av den anvendte mengden av gentamisin en ikke ubetraktelig forsinkelse av virkestoffrigivningen. Ved et lignende system ble poly-D,L-laktid benyttet for fremstilling av virkestoffholdige mikrosfærer (R. Bodmeier, J. W. McGinity: The preparation and evaluation of drug-containing poly(D,L-lactide) microspheres formed by solvent evaporation method. Pharm. Res. 4 (1987) 465-471). Av Fries og Schlapp beskrives også mikropartikler av polylaktid som er belagt med kollagen/gentamisin-sulfat (W. Friess, M. Schlapp: Advanced implants for local delivery of gentamicin. Sixth World Biometerials Congress Transactions (2000) 1488). Disse belagte mikrosfærer viser kun en ganske liten tendens til å forsinke gentamisin-frigivningen. Av Schmidt et al. ble det foreslått gentamisinholdige resorberbare formlegemer (C. Schmidt, R. Wenz, B. Nies, F. Moll: Antibiotic in vivo/in vitro release, histocompatibility and biodegradation of gentamicin implants based on lactic acid polymers and copolymers. J. Control. Release 37 (1995) 83-94). Disse legemer ble fremstilt ved presning av blandingen av gentamisin-sulfat/poly-D,L-laktid, gentamicin-sulfat/poly-D,L-laktid og gentamisin-sulfat/poly-D,L-laktid-co-glykolid. Disse depotpreparater frigir ca. 90% av antibiotikaet i løpet av 24 timer.
Ved siden av den fysikalske fikseringen av antibiotika under anvendelse av plastikk ble det også beskrevet tallrike uorganiske systemer med retarderende virkning. I den følgende blir det eksempelvis kun kort referert noen av de med kalsiumsulfat fremstilte systemene. Således beskriver Randolph et al. et retarderende system som bygger på innleiringen av virkestoffer i en kalsiumsulfat-matrise (D. A. Randolph, J. L. Negri, T. R. Devine, S. Gitelis: Calcium sulfate controlled release matrix. 15.09.1998, US 5,807,567). Fremstillingen av disse kalsiumsulfat-pellets foregår herved utgående fra en blanding av a-kalsiumsulfat-hemihydrat, (}-kalsiumsulfat-hemihydrat, et additiv og vann. Herdingen foregår ved dannelse av kalsiumsulfat-dihydrat. Turner et al. beskriver tabletter av kalsiumsulfat som inneholder tobramysin og som skal finne anvendelse for behandling av medullar-defekter (T. M. Turner, R. M. Urban, S. Gitelis, A. M. Lawrence-Smith, D. J. Hall: Delivery of tobramycin using calcium sulfate tablets to graft a large medullary defect: Local and systemic effects. Sixth World Biomaterials Congress Transactions (2000) 767). Lignende frigivningssytemer av kalsiumsulfat, men med amikasin-sulfat blir også beskrevet (D. W. Petersen, W. O. Haggard, L. H. Morris, K. C. Richelsoph, J. E. Parr: Elution of amikacin from calcium sulfate pellets: An in vitro study. Sixth World Biomaterials Congress Transactions (2000) 767).
Inntil nå har tungt oppløselige salter av aminoglykosid-antibiotika, tetracyklin-antibiotika og linkosamid-antibiotika fått relativt liten oppmerksomhet ved fremstillingen av depotpreparater. Dannelsen av tungt oppløselige salter henholdsvis kelater av antibiotika av tetracyklintypen har i flere tiår vært generell kjent teknikk. Således beskriver Folch Vazquez fremstillingen av tetracyklindodecylsulfat ved omsetning av tetracyklinhydroklorid med natriumdodecylsulfat i vann (C. Folch Vazquez: Tetracycline lauryl sulfate. 08.02.1966, ES 3 309 402; C. Folch Vazquez: Tetracycline derivatives. 09.01.1967, NL 6609490). Alternativt kan fremstillingen også utgå fra tetracyklin og dodecylsvovelsyre (C. Folch Vazquez: Tetracykline lauryl sulfate. 0802.1966, ES 322 771). Videre ble også anvendelsen av tetracyklin-sulfamat for antibiotisk terapi foreslått (A. Juranco, J. M. Puigmarti: Antibiotic tetracycline sulfamate and its derivatives. 27.10.1970, US 3,536,759; Anonym: Antibiotic tetracycline alkylsulfamates. 16.10.1969, ES 354 173; C. Ciuro, A. Jurado: Stability of tetracycline derivative. Afinidad28 (292) 1971,1333-5). Ved aminoglykosid-antibiotika er også en rekke av tungt oppløselige salter prinsipielt kjente. Således ble det for gentamisin beskrevet fremstillingen av tungt oppløselige salter basert på høyere fettsyrer, akrylalkylkarboksylsyre, alkylsulfater og alkylsulfonater (G. M. Luedemann, M. J. Weinstein: Gentamycin and method of production. 16.07.1962, US 3,091,572). Eksempler herpå er gentamisin-salter av laurinsyre, stearinsyre, palmitinsyre, oljesyre, fenylsmørsyre, naftalen-1-karboksylsyre, laurylsvovelsyre og dodecylbenzensulfonsyre. Disse salter viste seg mange ganger å være ufordelaktige fordi de utgjør voksaktige, hydrofobe substanser som forhindrer en galenisk anvendelse. På tross av dette ble fettsyresalter av gentamisin og av etamysin av den frie basen henholdsvis av deres salter i vann ved 50-80°C syntetisert (H. Voege, P. Stadier, H. J. Zeiler, S. Samaan, K. G. Metzger: Sparingly-soluble salts of aminoglycosides and formations containing them with inhibited substance-release. 28-12.1982 DE 3 248 328). Disse antibiotika-fettsyresaltene skal være egnet som injeksjonspreparater. Fremstillingen av gentamisindodecylsulfat og dets anvendelse i salver, kremer ble også beskrevet. (C. Folch Vazquez: Gentamicin derivates. 29.10.1974, BE 821 600). Også ved linkosamid-antibiotikaene er tungt oppløselige salter kjent som for eksempel glindamysin-plamitatet (M. Cimbollek, B. Nies, R. Wenz, J. Kreyter: Antibiotic-impregnated heart valve sewing rings for treatment and prophylaxis of bacterial endocarditis. Antimicrob. Agents. Chemother. 40(6) (1996) 1432-1437). En nyere utvikling utgjør tungt oppløselig aminoglykosid-flavonoid-fosfater (H. Wahlig, E. Dingeldein, R. Kirchlechner, D. Orth, W. Rogalski; Flavonoid phosphate salts of aminoglycoside antibiotics. 13.10.1986, US 4,617,293). Der beskrives saltene av fosforsyrehalvestrer av derivater av hydroksyflavan, hydroksflaven, hydroksyflavanon, hydroksyflavon og hydroksyflavylium. Spesielt foretrukket er derivatene av flavanon og flavon. Disse tungt oppløselige saltene skal finne anvendelse som depotpreparater. Således blir som eksempel disse salter innført i ullaktig kollagen (H. Wahlig, E. Dingeldein, D. Braun: Medicinally useful, shaped mass of collagen resorbable in the body. 22.09.1981, US 4,291,013). Videre ble også kunstige hjerteklaffer impregnert med disse tungt oppløselige gentamisinsalter, gentamisin-krobefat (M. Cimbollek, B. Nies, R. Wenz, J. Kreuter: Antibiotic-impregnated heart valve sewing rings for treatment and prphylaxis of bacterial endocarditis. Antimicrob. Agents Chemother. 40(6) (1996) 1432-1437). Det interessante ved dette patentet, er spesielt at en blanding av lett oppløselig gentamisin-sulfat og tungt oppløselig gentamisin-krobefat anvendes. Formålet var her på den ene siden etter innføring av hjerteklaffringene i organismen henholdsivs i en modellvæske og oppnå en høy innledende gentamisin-konsentrasjon gjennom det lett oppløselig gentamisin-sulfat og på den andre siden gjennom det relativt tungt oppløselige gentamisin-krobefat blir en frigivning av gentamisin over et lengre tidsrom mulig. Dette betyr at den tidsavhengige frigivning av gentamisinet styres av forholdet mellom lett oppløselig gentamisin-sulfat og tungt oppløselig gentamisin-krobefat. For en målrettet innstilling av frigivningskrakteristikken er det derfor nødvendig å innføre begge gentamisinsaltene i definerte mengdeforhold i den galeniske formuleringen. Denne medtode for depotdannelse ved kombinasjon av et lett oppløselig antibiotikasalt med tungt oppløselig antibiotikasalt forutsetter tilgjengeligheten av en ren tung oppløselig saltform av et antibiotikum.
Sammenfattende kan det fastslås at de kjente antibiotikadepotsystemene med fysikalisk forårsaket forsinkelse av antibiotikafrigivningen i sterk grad avhenger av sammensetningen og strukturen til den anvendte matrisen. Videre er fremstillings-prosessen for disse antibiotika-depotsystemene av ikke ubetydelig innflytelse på frigivningskarakteristikken. Ulempen ved systemene med tungt oppløselig antibiotika-salter består i at det for hvert anvendt antibiotikum må syntetiseres en spesiell saltform for fremstillingen av depotpreparatene.
Probelemet som ligger til grunn for den foreliggende oppfinnelsen er å utvikle et antibiotikum-/antibiotika-preparat med retarderende virkestoffrigivning som resorberbare eller også ikke-resorberbare implantater innen området human- og veterinærmedisin, for behandling av lokale mikrobielle infeksjoner i knokkel- og i mykvev, som overvinner ulempene ved de kjente retarderende antibiotika-formuleringene. Det tilstrebes et antibiotikum-/antibiotika-preparat som muliggjør en kontrolert antibiotika-frigivning over et tidsrom opp til ca. tre uker. Mekanismen for forsinket virkestoffrigivning skal i det vesentlige være uavhengig av bærematerialene og ikke bero på adsorpsjonseffekten på overflaten av bærematerialene. Det tilstrebes et antibiotikum-/antibiotika-preparat som under opprettholdelse av virkestoffretarderingen kan forarbeides med resorberbare såvel som ikke-resorberbare hjelpestoffer med forskjellig struktur til implantater. Videre skal typen av antibiotikum-/antibiotika-preparatet ikke kun være anvendelig for et spesielt antibiotikum, men bør i større utstrekning være egnet for en rekke antibiotika med lignende struktur.
Dette problem blir ifølge oppfinnelsen løst gjennom et antibiotika-preparat ifølge krav 1, anvendelse ifølge kravene 7-13 og en fremgangsmåte ifølge krav 14.
Foreliggende oppfinnelse omfatter formulering som omfatter antibiotikum/antibiotika, kjennetegnet ved en blanding av minst én amfifil komponent fra et medlem av alkylsulfatene, arylsulfatene, alkylarylsulfatene, cykloalkylsulfatene, alkylcykloalkylsulfatene, alkylsulfamatene, cykloalkylsulfamatene, alkylcykloalkylsulfamatene, arylsulfamatene, alkylarylsulfamatene, alkylsulfonatene, fettsyre-2-sulfonatene, arylsulfonatene, alkylarylsulfonatene, cykloalkylsulfonatene, alkylcykloalkylsulfonatene, alkyldisulfatene, cykloalkyldisulfatene, alkyldisulfonatene, cykloalkyldisulfonatene, aryldisulfonatene, alkylaryldisulfonatene, aryltrisulfonatene og alkylaryltrisulfonatene, såvel som minst en antibiotisk komponent fra gruppen av aminoglykosid-antibiotika, likosamid-antibiotika, 4-quinolon-antibiotoka og tetracyklin-antibiotika og
a)
minst en uorganisk hjelpekomponent fra gruppen bestående av
hydroksyapatitt, fluorapatitt, kalsiumpolyfosfat,
trikalsiumfosfat, tetrakalsiumfosfat, kalsiumsulfat, kalsiumsulfat-hemihydrat, kalsiumsulfat-dihydrat, kalsiumlaktat, natriumbikarbonat, kalsiumkarbonat, magnesiumkarbonat, kalsiumhydroksid, magnesiumhydroksid, magnesiumoksid, - inneholder de ovenfor nevnte stoffen i form av grovdisperse og/eller høydisperse pulver, absorberbart glass, ikke-absorberbart glass, absorberbar glasskeramikk, ikke-absorberbar glasskeramikk, absorberbar keramikk og ikke-absorberbar keramikk.
b)
minst en vannfri, organisk hjelpekomponent som har hydrolytisk spaltbar
karboksylsyreesterbindinger og/eller hydrolytisk spaltbare karboksamidbindinger og/eller hydrolytisk spaltbare karboksylsyreanhydrid-bindinger og/eller hydrolytisk spaltbare fosforsyreesterbindinger og/eller hydrolytisk spaltbare fosforsyreamidbindinger og/eller enzymatisk spaltbare karboksylsyre-esterbindinger og/eller enzymatisk spaltbare karboksylsyreamidbindinger og/eller enzymatisk spaltbare karboksylsyreanhydridbindinger og/eller enzymatisk spaltbare fosforsyreesterbindinger og/eller enzymatisk spaltbare fosforsyreamidbindinger.
Foreliggende oppfinnelse omfatter også anvendelse av en formulering omfattende et antibiotikum/antibiotika ifølge ett hvilket som helst av kravene 1 til 6 for produksjon av et implantat.
Videre omfatter oppfinnelsen fremgangsmåte for fremstilling av implantater inneholdende en formulering som omfatter antibiotikum/antibiotika ifølge ett hvilket som helst av kravene 1 til 6,kjennetegnet ved at implantatene i form av formlegemer, granulater, pulvere, slanger, folier, ikke-vevede materialer og filamenter belegges med formuleringen omfattende et antibiotikum/antibiotika ifølge ett hvilket som helst av kravene 1 til 6 ved pressing og/eller neddypning og/eller påspraying og/eller kalandrering og/eller ekstrudering og/eller sintring og/eller smeltning.
Til grunn for oppfinnelsen ligger det overraskende funnet at en blanding av minst en amfifil komponent av en representant for alkylsulfatene, arylsulfatene, alkylarylsulfåtene, cykloalkylsulfatene, alkylcykloalkylsulfatene, alkylsulfamatene, cykloalkylsulfamatene, alkylcykloalkylsulfamatene, arylsulfamatene, alkylarylsulfamatene, alkylsulfonatene, fettsyre-2-sulfonatene, arylsulfonatene, alkylarylsulfonatene, cykloalkylsulfonatene, alkylcykloalkylsulfonatene, alkyldisulfatene, cykloalkyldisulfatene, alkyldisulfonatene, cykloalkyldisulfonatene, aryldisulfonatene, alkylaryldisulfonatene, aryltrisulfonatene og alkylaryltrisulfotanene såvel som minst en antibotisk komponent fra gruppen av aminoglykosid-antibiotika, linkosamid-antibiotika og tetracyklin-antibiotika utviser en retarderende virkestoffrigivning i vandig miljø over et tidsrom på flere dager opp til flere uker.
De etterfølgende utførelsesformer har i praksis vist seg å være spesielt fordelaktige.
For det første er det fordelaktig at antibiotika-preparatet har minst en vannfri, organisk hjelpekomponent som har hydrolytisk spaltbare karboksylsyreesterbindinger og/eller hydrolytisk spaltbare karboksylsyreamidbindinger og/eller hydrolytisk spaltbare karboksylsyreanhydridbindinger og/eller hydrolytisk spaltbare fosforsyreesterbindinger og/eller hydrolytisk spaltbare fosforsyreamidbindinger og/eller enzymatisk spaltbare karboksylsyreesterbindinger og/eller enzymatisk spaltbare karboksylsyreamidbindinger og/eller enzymatisk spaltbare karboksylsyreanhydridbindinger og/eller enzymatisk spaltbare fosforsyreesterbindinger og/eller enzymatisk spaltbare fosforsyreamidbindinger.
Videre er det fordelaktig når antibiotika-preparatet inneholder minst en uorganisk hjelpekomponent fra gruppen kalsiumhydrogenfosfat, kalciumhydrogenfosfat-dihydrat, hydroksylapatitt, fluorapatitt, kalsiumpolyfosfat, trikalsiumfosfat, tetrakalsiumfosfat, kalsiumsulfat, kalsiumsulfat-hemihydrat, kalsiumsulfat-dihydrat, kalsiumlaktat, natriumhydrogenkarbonat, kalsiumkarbonat, magnesiumkarbonat, kalsiumhydroksid, magnesiumhydroksid, magnesiumoksid, inneholder de før nevnte stoffer i form av grovdisperse og/eller høydisperse pulver, resporberbare glasser, ikke-resorberbare glasser, resorberbar glasskeramikk, ikke-resorberbar glasskeramikk, resorberbar keramikk og ikke-resorberbar keramikk.
Derutover er det fordelaktig at antibiotika-preparatet inneholder minst en biologisk aktiv hjelpestoffkomponent fra gruppen av penicilin-antibiotika, cefalosporin-antibiotika, 4-kinolon-antibiotika og makrolid-antibiotika eller eventuelt en eller flere representanter for sulfonamid-kemoterapeutika, analgetika og antifiogistika.
Det er fordelaktig at den amfifile komponenten fra gruppen av alkylsulfater, arylsulfater, alkylarylsulfater, cykloalkylsulfater og alkylcykloalkylsulfater foreligger som halvester i form av natriumsaltet og/eller kaliumsaltet og/eller ammoniumsaltet og/eller trialkylammoniumsaltet og/eller dialkylammoniumsaltet og/eller monoalkylammoniumsaltet og/eller triarylammoniumslatet og/eller diarylammoniumsaltet og/eller arylammoniumsaltet og/eller alkyldiarylarnmoniumsaltet og/eller dialkylarylammoniumsaltet og/eller tricykloalkylammoniumsaltet og/eller dicykloalkylammoniumsaltet og/eller monocykloalkylammoniumsaltet og/eller alkyldicykloalkylammoniumsaltet og/eller dialkylcykloalkylammoniumsaltet og/eller på syreformen og/eller på anhydridformen.
Videre er det fordelaktig at den amfifile komponenten fra gruppen av alkylsulfonater, fettsyre-2-sulfonater, alkylsulfamater, cykloalkylsufamater, arylsulfamater, alkylarylsulfamater, arylsulfonater, alkylarylsulfonater, cykloalkylsulfonater, alkylcykloalkylsulfonater, alkyldisulfater, cykloalkyldisulfater, alkyldisulfonater, cykloalkyldisulfonater, aryldisulfonater, alkylaryldislulfonater, aryltrisulfonater og alkylaryltrisulfonater i form av natriumsaltet og/eller kaliumsaltet og/eller ammoniumsaltet og/eller trialkylammoniumsaltet og/eller dialkylamoniumsaltet og/eller monoalkylammoniumsaltet og/eller triarylammoniumsaltet og/eller diarylammoniumsaltet og/eller arylammoniumsaltet og/eller alkyldiarylarnmoniumsaltet og/eller dialkylarylammoniumsaltet og/eller tricykloalkylammoniumsaltet og/eller dicykloalkylammoniumsaltet og/eller monocykloalkylammoniumsaltet og/eller alkyldicykloalkylammoniumsaltet og/eller dialkylcykloalkylammoniumsaltet og/eller på sulfonsyreformen og/eller sulfonsyreanhydridformen.
Ifølge oppfinnelsen er det også fordelaktig at den antibiotiske komponenten minst inneholder en aminogruppe.
Videre er det fordelaktig at det som amfifil komponent foretrekkes minst en forbindelse fra gruppen av alkylsulfater, cykloalkylsulfater, cykloalkylalkyl-sulfater, arylsulfater, alkylarylsulfater, alkylsulfamater, cykloalkylsulfamater, alkylcykloalkylsulfamater, arylsulfamater, alkylarylsulfamater, alkylsulfonater, fettsyre-2-sulfonater, cykloalkylsulfonater, cykloalkylsulfonater, arylsulfonater, og alkylarylsulfonater med respektivt 6 til 30 karbonatomer.
Det er de ut fra monocykliske, dicykliske, tricykliske, tetracykliske, pentacykliske, heksacykliske, heptacykliske og oktacykliske aromatiske ringsystemer oppbyggede arylsulfater, alkylarylsulfater, arylsulfamater, alkylarylsulfamater, aryldisulfonater, alkylaryldisulfonater, aryltrisulfonater og alkylaryltrisulfonater som er foretrukket som amfifil komponent.
Som amfifil komponent foretrekkes cykloalkylsulfater, alkylcykloalkylsulfater, cykloalkylsulfonater, alkylcykloalkylsulfonater, cykloalkyl-sulfonater og alkylcykloalkylsulfonater oppbygget av monocykliske, dicykliske, tricykliske, tetracykliske, pentacykliske, heksacykliske, heptacykliske og oktacykliske mettede ringsystemer.
Som amfifil komponent foretrekkes spesielt natriumdodecylsulfat, natriurnheksadecylsulfat, natriumoktadecylsulfat, natriumdokosanylsulfat, natriumdodecylsulfonat, natriumtetradecylsulfonat, natriumheksadecylsulfonat, natriumoktadecylsulfonat, natriumdodecylbenzylsulfonat og natriumkolesterolsulfat.
Videre foretrekkes som antibiotisk komponent fra gruppen av aminoglykosid-antibiotika spesielt allomysin, amisetin, amikasin, apramysin mekanamysin, betamisin, butirosin, destomysin, dibekasin, dihydrostreptomysin, flambamysin, fortimysin A, fortimysin B, framysetin, gentamisin, hikizimysin, homomysin, hybrimysin, hygromysin B, kanamysin, kasuhamysin, lividomysin, minosaminoysin, neomysin, netilmisin, paramomysin, parvulomysin, pyromysin A, ribsotamysin, rimosidin, ristosamin, ristomysin, sagamysin, sisomisin, sorbistin, spektinomysin, streptomysin, tobramysin, tunicamysin, vancomysin, verdamysin.
Som antibiotisk komponent foretrekkes fra gruppen av likosamid-antibiotika klindamysin og linkomysin.
Videre foretrekkes som antibiotisk komponent kiprofloksasin og moksifioksasin fra gruppen av 4-kinolon-antibiotika.
Den antibiotiske komponenten fra gruppen av tetracyklin-antibiotika fortrinnsvis tetracyklin, klortetracyklin, oksytetracyklin, demetylklor-tetracyklin, metacyklin, doksycyklin, rolitetracyklin og minocyklin.
Det er også ifølge oppfinnelsen at den antibiotiske komponenten foreligger på protonert saltform, hvor klorid-ioner, bromid-ioner, hydrogensulfat-ioner, sulfat-ioner, dihydrogenfosfat-ioner, hydrogenfosfat-ioner, fosfat-ioner, acetat-ioner, succinat-ioner og laktat-ioner anvendes som motion.
Det er videre foretrukket at 0,01 til 10 molmengdeandel av de amfifile komponentene blandes med en molmengdeandel av de antibiotiske komponentene.
Det er vesentlig ifølge oppfinnelsen at andelen av den forsinket frigitte antibiotiske komponenten fra totalmengden av antibiotiske komponenter kan bestemmes ut fra forholdet av stoffmengden av de amfifile komponenter til stoffmengden av de antibiotiske komponentene.
Det er også fordelaktig at det som vannfri, organisk hjelpekomponent anvendes minst en forbindelse fra gruppen av oligoester og polyester av L-melkesyre og/eller D-melkesyre og/eller 2-hydroksyetansyre og/eller 2-hydroksyetoksyetansyre og/eller 3-hydroksybutansyre og/eller 4-hydroksybutansyre og/eller 4-hydroksyheksansyre og/eller 6-hydroksyheksansyre og eventuelt kooligoester og/eller kopolyester og eventuelt teroligoester og/eller terpolyester av disse hydroksykarboksylsyrer.
Det kan anvendes oligoamin og/eller polyamid som inneholder aminosyre som bestanddel som vannfrie, organiske hjelpekomponenter.
Som byggesten til oligoamidene og poly amidene kan det anvendes aminosyrene: gly sin og/eller L-alanin og/eller D-alanin og/eller L-valin og/eller D-valin og/eller L-treonin og/eller D-treonin og/eller L-asparinsyre og/eller D-asparaginsyre og/eller L-asparagin og/eller D-asparagin og/eller L-glutaminsyre og/eller D-glutaminsyre og/eller L-glutamin og/eller D-glutamin og/eller L-ornitin og/eller D-ornitin og/eller L-lysin og/eller D-lysin og/eller 3-aminopropansyre og/eller R-2-aminobutansyre og S-2-aminobutansyre og/eller 3-aminobutansyre og/eller 4-aminobutansyre og/eller R-2-aminopentansyre og/eller S-2-aminobutansyre og/eller 3-aminopentansyre og/eller 4-aminopentansyre og/eller 5-aminopentansyre og/eller R-2-aminoheksansyre og/eller S-2-aminoheksansyre og/eller 3-aminoheksansyre og/eller 4-aminoheksansyre og/eller 5-aminoheksansyre og/eller 6-aminoheksansyre og/eller R-2-aminoheptansyre og/eller S-2-aminoheptansyre og/eller 3-aminoheptansyre og/eller 4-aminoheptansyre og/eller 5-aminoheptansyre og/eller 6-aminoheptansyre og/eller 7-aminoheptansyre og/eller R-2-aminooktansyre og/eller S-aminooktansyre og/eller 3-aminooktansyre og/eller 4-aminooktansyre og/eller 5-aminooktansyre og6-aminooktansyre og/eller 7-aminooktansyre og/eller 8-aminooktansyre og/eller R-2-aminononansyre og/eller S-2-aminononansyre og/eller 3-aminononansyre og/eller 4-aminononansyre og/eller 5-aninononansyre og/eller 6-aminononansyre og/eller 7-aminononansyre og/eller 8-aminononansyre og/eller 9-aminononansyre og/eller R-2-aminodekansyre og/eller S-2- aminodekansyre og/eller 3-aminodekansyre og/eller 4-aminodekansyre og/eller 5-aminodekansyre og/eller 6-aminodekansyre og/eller 7-aminodekansyre og/eller 8-aminodekansyre og/eller 9-aminodekansyre og/eller 10-aminodekansyre og/eller 11-aminoundekansyre og/eller L-fenylalanin og/eller D-fenylalanin og/eller L-tyrosin og/eller D-tyrosin og/eller L-histidin og/eller Dhistidin og/eller L-tryptofan og/eller D-tryptofan.
Det kan anvendes som vannfrie organiske hjelpekomponenter, fortrinnsvis alifatiske alkoholer, med et antall karbonatomer på 12 til 30.
Videre kan det anvendes som vannfrie, organiske hjelpekomponenter fortrinnsvis fettsyrer med antall karbonatomer på 12 til 30.
Det foretrekkes også glyserintrifettsyreestere, glyserindifettsyreestere og glyserinmonofettsyreestere som vannfrie organiske hjelpekomponenter, hvor fettsyreesterne respektivt inneholder 14 til 22 karbonatomer.
Det foretrekkes n-alkaner og iso-alkaner med 6 til 30 karbonataomer som vannfrie, organiske hjelpekomponenter.
Det foretrekkes polyetylenglykol og/eller polypropylenglykol med molmasse i området fra 200 til 35.000 som vannfrie, organiske hjelpekomponenter.
Det foretrekkes polyetylenoksid og/eller polypropylenoksid med molmasser i området fra 35.000 til 1.000.000 som vannfrie, organiske hjelpekomponenter.
Som vannfrie, organiske hjelpekomponenter foretrekkes minst en forbindelse fra gruppen gelatin, kollagen, cellulose, karboksymetylcellulose, metylcellulose, etylcellulose hydroksyetylcellulsoe, propylcellulose, hydroksypropyl-cellulose, butylcellulose, stivelse, karboksymetylstivelse, metylstivelse, etylstivelse, hydroksyetylstivelse, propylstivelse, hydroksypropylstivelse, butylstivelse, kitin karboksymetylkitin, kitosan, karboksymetylkitosan, glykogen, karboksymetylglykogen, alginsyre, alginsyremetyleter, hyaluronsyre, karboksymetylhyaluronsyre, celluloseacetat, cellulosepropionat, cellulosebutyrat, celluloseftalat, cellulosesulfat, cellulosefosfat, stivelseacetat, stivelsepropionat, stivelsebutyrat, stivelseftalat, stivelsesulfat, stivelsefosfat, oksidert cellulose, oksidert stivelse, pullulan, araban, xanan og guargummi.
Det foretrekkes som vannfrie organiske hjelpekomponenter karnaubavoks, bivoks, benzoharpiks, kollofonium og kopalharpiks.
Det foretrekkes som vannfri organisk hjelpekomponent minst en forbindelse fra gruppen polyetylen, polypropylen, polybutadien, polyisopren, polyklorbutandien, polymetylmetakrylat, poly-2-hydroksyetylmetakrylat, polymetakrylat, polystyrol, polyvinylacetat, polyvinylalkohol, polyvinylklorid, polyvinylidenklorid, polyvinylfluorid, polyvinylpyrrolidon, polytetrafluoretylen, polykarbonat, polysulfon, polysiloksan og blandinger av disse polymerer.
Det foretrekkes som vannfrie, organiske hjelpekomponenter minst en forbindelse fra gruppen akrylsyreester, akrylsyreamid, metakrylsyreester, metakrylsyreamid, itakonsyreester, maleinimid og deres blandinger.
Det er fordelaktig at de vannfrie, organiske hjelpekomponentene foreligger på fast og/eller flytende aggregattilstand.
Det er også slik at arylsulfatene, arylsulfonatene, arylsulfamatene og alkylarylsulfonatene eventuelt er bestanddeler til en ikke-tverrbundet og/eller tverrbundet polymer, hvor det foretrekkes polymerer fra gruppen polystyren, polymetakrylat, polyakrylat, polyamid, polykarbonat og/eller deres kopolymerer og/eller deres terpolymerer.
Det er fordelaktig i følge oppfinnelsen når antibiotika-preparatet foreligger som formlegemer, granulater, folier, pulver, slanger, ullaktig materiale eller tråd fremstilt ved presning og/eller ekstrudering og/eller maling og/eller kalandrering og/eller støpning og/eller spinning og/eller sintring.
Derutover er det fordelaktig at de saltdannende komponentene og de antibiotiske komponentene er suspenderbare i den vannfrie, organiske hjelpekomponenten og danner en injiserbar suspensjon.
Endelig er det spesielt fordelaktig at antibiotika-preparater ifølge oppfinnelsen kan anvendes som implantat i form av formlegemer, granulater, pulver, slanger, folier, ikke vevede materialer og filamenter, spesielt når disse er plastisk deformerbare og modellerbare. Dette gjelder også for mulige belegg på resorberbare porøse glass, på ikke-resorberbare glasser, resorberbar porøs glasskeramikk, ikke-resorberbar porøs glasskeramikk, resorberbar porøs keramikk og ikke-resorberbar porøs keramikk inklusiv resorbar plastikkimplantater, ikke-resorberbare plastikkimplantater og metallimplantater.
Gjennom forholdet av stoffmengden av den amfifile komponenten til stoffmengden av den antibiotiske komponenten kan andelen av forsinket frigivning av antibiotisk komponent av totalmengden av antibiotisk komponent bestemmes.
Gjenstanden for den foreliggende oppfinnelsen skal forklares nærmere ved hjelp av de etterfølgende eksemplene 1-6.
Fremstilling av antibiotikum-/antibiotika-preparatet
Eksempel 1:
Det fremstilles en blanding av 51 mg gentamisinsulfat (700 U/mg, Fluka), 51 mg natriumdodecylsulfat (Aldrich), 280 mg poly-L-laktid (molmasse -10.000 gmoi"<1>) og 1118 mg kalsiumhydrogenfosfat (Fluka). Respektivt 200 mg av denne blandingen presses med en presse ved trykk på 5 tonn i løpet av to minutter til skiveformede formlegemer med en diameter på 13 mm.
Eksempel 2:
Det fremstilles en blanding av 51 mg gentamisinsulfat (700 U/mg, Fluka) 51 mg natriumdodecylsulfat (Aldrich), 280 mg poly-L-laktid (molmasse~10.000 gmol"<1>) og 1118 mg kalsiumhydrogenfosfat-dihydrat (Fluka). Respektivt 200 mg av denne blanding presses med en presse ved et trykk på 5 tonn i løpet av to minutter til skiveformede formlegemer med en diameter på 13 mm.
Eksempel 3:
Det fremstilles en blanding av 51 mg gentamisinsulfat (700 U/mg, Fluka) 51 mg natriumdodecylsulfat (Aldrich), 280 mg poly-L-laktid (molmasse~10.000 gmol"<1>) og 1118 mg kalsiumsulfat-dihydrat (Fluka). Respektivt 200 mg av denne blandingen presses med en presse ved et trykk på 5 tonn i løpet av to minutter til skiveformede formlegemer med en diameter på 13 mm.
Eksempel 4:
Det fremstilles en blanding av 51 mg gentamisinsulfat (700 U/mg, Fluka), 51 natriumdodecylsulfat (Aldrich), 280 mg karnaubavoks (Alrich) og 1118 mg kalsiumhydrogenfosfat (Fluka). Respektivt 200 mg av denne blandingen presses med en presse ved et trykk på 5 tonn i løpet av to minutter til skiveformede formlegemer med en diameter på 13 mm.
Eksempel 5:
Det fremstilles en blanding av 51 mg gentamisinsulfat (700 U/mg, Fluka) 51 mg natriumdodecylsulfonat (Fluka), 280 mg poly-L-laktid (molmasse~10.000 gmol"<1>) og 1118 mg kalsiumhydrogenfosfat (Fluka). Respektivt 200 mg av denne blandingen presses med en presse ved et trykk på 5 tonn i løpet av to minutter til skiveformede formlegemer med en diameter på 13 mm.
Eksempel 6:
Det fremstilles en blanding av 51 mg gentamisinsulfat (700 U/mg, Fluka) 51 mg natriumdodecylbenzylsulfonat (Fluka), 280 mg poly-L-laktid (molmasse~10.000 gmol"<1>) og 1118 mg kalsiumhydrogenfosfat (Fluka). Respektivt 200 mg av denne blandingen presses med en presse ved et trykk på 5 tonn i løpet av to minutter til skiveformede formlegemer med en diameter på 13 mm.
Antibiotika-frigivningsforsøk
Formlegemene fremstilt i eksemplene 1-6 ble anbrakt i fysiologisk kokesaltoppløsning og lagret i denne ved 37°C over et tidsrom på fire uker for å bestemme den retarderte antibiotoka-frigivningen. Prøvetakning foregikk etter 1, 3, 6, 9,12, 14 og 21 dagers lagringstid. Antibiotoka-verdibestemmelsen ble gjennomført med en agardiffusjonstest under anvendelse av Bacillus subtilis ATCC 6633 som testkim (resultater se Tabell 1).
Tabell 1: Kumulert gentamisin-frigivning fra prøvelegemer fra eksemplene 1-6
avhengig av lagringstiden i fysiologisk kokesaltoppløsning ved 37°C.
Eksempel Kumulert gentamisin- frigiving [ Ma%]
Lagringstid [d]
1 3 6 9 12 14 21 52
J 32 54 67 72 77 83 94 100
2 45 54 63 71 77 82 88 100 3 48 57 64 78 _84 91 100 100 4 43 _51 58 71 81 93 100 100 5 50 69 85 95 99 100 100 100617718218619019419711001100
Claims (14)
1.
Formulering som omfatter antibiotikum/antibiotika ,karakterisert veden blanding av minst en amfifil komponent fra et medlem av alkylsulfatene, arylsulfatene, alkylarylsulfatene, cykloalkylsulfatene, alkylcykloalkylsulfatene, alkylsulfamatene, cykloalkylsulfamatene, alkylcykloalkylsulfamatene, arylsulfamatene, alkylarylsulfamatene, alkylsulfonatene, fettsyre-2-sulfonatene, arylsulfonatene, alkylarylsulfonatene, cykloalkylsulfonatene, alkylcykloalkylsulfonatene, alkyldisulfatene, cykloalkyldisulfatene, alkyldisulfonatene, cykloalkyldisulfonatene, aryldisulfonatene, alkylaryldisulfonatene, aryltrisulfonatene og alkylaryltrisulfonatene, såvel som minst en antibiotisk komponent fra gruppen av aminoglykosid-antibiotika, likosamid-antibiotika, 4-quinolon-antibiotoka og tetracyklin-antibiotika og a)
minst en uorganisk hjelpekomponent fra gruppen bestående av
hydroksyapatitt, fluorapatitt, kalsiumpolyfosfat,
trikalsiumfosfat, tetrakalsiumfosfat, kalsiumsulfat, kalsiumsulfat-hemihydrat, kalsiumsulfat-dihydrat, kalsiumlaktat, natriumbikarbonat, kalsiumkarbonat, magnesiumkarbonat, kalsiumhydroksid, magnesiumhydroksid, magnesiumoksid, - inneholder de ovenfor nevnte stoffen i form av grovdisperse og/eller høydisperse pulver, absorberbart glass, ikke-absorberbart glass, absorberbar glasskeramikk, ikke-absorberbar glasskeramikk, absorberbar keramikk og ikke-absorberbar keramikk. b)
minst en vannfri, organisk hjelpekomponent som har hydrolytisk spaltbar karboksylsyreesterbindinger og/eller hydrolytisk spaltbare karboksamidbindinger og/eller hydrolytisk spaltbare karboksylsyreanhydrid-bindinger og/eller hydrolytisk spaltbare fosforsyreesterbindinger og/eller hydrolytisk spaltbare fosforsyreamidbindinger og/eller enzymatisk spaltbare karboksylsyre-esterbindinger og/eller enzymatisk spaltbare karboksylsyreamidbindinger og/eller enzymatisk spaltbare karboksylsyreanhydridbindinger og/eller enzymatisk spaltbare fosforsyreesterbindinger og/eller enzymatisk spaltbare fosforsyreamidbindinger.
2.
Formulering omfattende et antibiotikum/antibiotika ifølge krav 1,karakterisert vedat det inneholder minst en biologisk aktiv hjelpekomponent fra gruppen bestående av penicillin-antibiotika, cefalosporin-antibiotika, 4-quinolon-antibiotika og makrolid-antibiotika og eventuelt en eller flere representanter for sulfonamid-kjemoterapeutika, analgetika og antiflogistika.
3.
Formulering omfattende antibiotikum/antibiotika ifølge ett hvilket som helst av kravene log2,karakterisert vedat den antibiotiske komponenten inneholder minst én aminogruppe.
4.
Formulering omfattende antibiotikum/antibiotika ifølge ett hvilket som helst av kravene 1 til 3,karakterisert vedat den antibiotiske komponenten foreligger på en protonert saltform hvor klorid-ioner, bromid-ioner, hydrogensulfat-ioner, sulfat-ioner, dihydrogenfosfat-ioner, hydrogenfosfat-ioner, fosfat-ioner, acetat-ioner, succinat-ioner og laktat-ioner anvendes som motioner.
5.
Formulering omfattende antibiotikum/antibiotika ifølge ett hvilket som helst av kravene 1 til 4,karakterisert vedat det foreligger som formlegemer, granulater, folier, pulvere, slanger, ikke-vevede materialer og/eller filamenter fremstilt ved presning og/eller ekstrudering og/eller maling og/eller kalandrering og/eller støpning og/eller spinning og/eller sintring.
6.
Formulering omfattende et antibiotikum/antibiotika ifølge ett hvilket som helst av kravene 1 til 5,karakterisert vedat den amfifile komponenten og den antibiotiske komponenten er suspendert i den vannfrie, organiske hjelpekomponenten og danner en injekserbar suspensjon.
7.
Anvendelse av en formulering omfattende et antibiotikum/antibiotika ifølge ett hvilket som helst av kravene 1 til 6 for produksjon av et implantat.
8.
Anvendelse av en formulering omfattende et antibiotikum/antibiotika ifølge ett hvilket som helst av kravene 1 til 6 for produksjon av en injiserbar suspensjon.
9.
Anvendelse av en formulering omfattende et antibiotikum/antibiotika ifølge krav 8 for produksjon av et implantat i form av formlegemer, granulater, pulvere, slanger, folier, ikke-vevede materialer og filamenter.
10.
Anvendelse i følge krav 9, der formlegemer, granulater, pulvere, slanger, folier, ikke-vevede materialer og filamenter fremstilt fra formuleringen omfatter et antibiotikum/antibiotika som er plastisk deformerbar og i stand til å bli modellert.
11.
Anvendelse av en formulering omfattende et antibiotikum/antibiotika i følge et hvilket som helst av kravene 1 til 6 som et belegg på absorberbart porøst glass, ikke absorberbart glass, på absorberbar porøs glasskeramikk, på ikke absorberbar porøs glasskeramikk, på absorberbar porøs keramikk og på ikke absorberbar porøs keramikk.
12.
Anvendelse av en formulering omfattende et antibiotikum/antibiotika ifølge ett hvilket som helst av kravene 1 til 6 som belegg på absorberbare plastimplantater, på ikke-absorberbare plastimplantater og på metallimplantater.
13.
Anvendelse av en formulering omfattende et antibiotikum-/antibiotika ifølge ett hvilket som helst av kravene 1 til 6 for produksjon av et medikament, hvor forholdet av den forsinkede frigivning av den antibiotisk komponent basert på totalmengden av den antibiotiske komponenten bestemmes av ratioen av mengden av den amfifile komponenten til mengden av den antibiotiske komponenten.
14.
Fremgangsmåte for fremstilling av implantater inneholdende en formulering som omfatter antibiotikum/antibiotika ifølge ett hvilket som helst av kravene 1 til 6,karakterisert vedat implantatene i form av formlegemer, granulater, pulvere, slanger, folier, ikke-vevede materialer og filamenter belegges med formuleringen omfattende et antibiotikum/antibiotika ifølge ett hvilket som helst av kravene 1 til 6 ved presning og/eller neddypning og/eller påspraying og/eller kalandrering og/eller ekstrudering og/eller sintring og/eller smeltning.
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| DE10114244A DE10114244A1 (de) | 2001-03-22 | 2001-03-22 | Antibiotikum-/Antibiotika-Zubereitung mit retardierender Wirkstofffreisetzung |
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| DE10318991A1 (de) * | 2003-04-25 | 2004-11-18 | Heraeus Kulzer Gmbh & Co. Kg | Poröser Körper mit antibiotischer Beschichtung, Verfahren zur Herstellung sowie Verwendung |
| EP1694712A1 (en) * | 2003-12-04 | 2006-08-30 | University of Utah Research Foundation | Modified macromolecules and methods of making and using thereof |
| CA2575988C (en) | 2004-08-04 | 2014-02-18 | Brookwood Pharmaceuticals, Inc. | Methods for manufacturing delivery devices and devices thereof |
| DE102004060666B3 (de) | 2004-12-15 | 2006-03-30 | Heraeus Kulzer Gmbh | Antibiotikum/Antibiotika enthaltendes Knochenersatzmaterial mit retardierender Wirkstofffreisetzung |
| DE102005002703C5 (de) | 2005-01-19 | 2013-07-04 | Heraeus Kulzer Gmbh | Antibiotische Beschichtung von Implantaten sowie Verfahren zur antibiotischen Beschichtung |
| EP1940482B1 (de) * | 2005-10-27 | 2014-07-23 | Nexilis AG | Implantat enthaltend amino-bisphosphonate und verfahren zu dessen herstellung |
| KR101315925B1 (ko) * | 2005-10-27 | 2013-10-08 | 토멘 메디칼 아게 | 치과용 임플란트 및 그의 제조 방법 |
| US20070213835A1 (en) * | 2005-11-04 | 2007-09-13 | Markus Wimmer | Plastic implant impregnated with an antibiotic |
| DE102006007245A1 (de) | 2006-02-15 | 2007-08-23 | Heraeus Kulzer Gmbh | Implantatmaterial |
| DE102006037362B3 (de) * | 2006-08-09 | 2007-09-20 | Heraeus Kulzer Gmbh | Knochenersatzmaterial |
| US7923021B2 (en) * | 2007-07-24 | 2011-04-12 | University Of Memphis Research Foundation | Local delivery method and composition |
| DE102007039871A1 (de) | 2007-08-21 | 2009-02-26 | Friedrich-Baur-Gmbh | Weichgewebe-Implantat mit antibakterieller Wirkung |
| ES2718612T3 (es) | 2007-12-20 | 2019-07-03 | Evonik Corp | Procedimiento para preparar micropartículas que tienen un bajo volumen de disolvente residual |
| CN101758337B (zh) * | 2009-12-03 | 2012-02-15 | 湖南阿斯达生化科技有限公司 | 一种助焊剂用非卤素活性剂 |
| WO2013010045A1 (en) | 2011-07-12 | 2013-01-17 | Biotime Inc. | Novel methods and formulations for orthopedic cell therapy |
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2001
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2002
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- 2002-02-27 BG BG106454A patent/BG65467B1/bg unknown
- 2002-03-06 DK DK02005023T patent/DK1243257T3/da active
- 2002-03-06 TR TR2004/00244T patent/TR200400244T4/xx unknown
- 2002-03-06 EP EP02005023A patent/EP1243257B1/de not_active Expired - Lifetime
- 2002-03-06 AT AT02005023T patent/ATE258431T1/de active
- 2002-03-06 PT PT02005023T patent/PT1243257E/pt unknown
- 2002-03-06 ES ES02005023T patent/ES2213717T3/es not_active Expired - Lifetime
- 2002-03-06 DE DE50200223T patent/DE50200223D1/de not_active Expired - Lifetime
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