DK161365B - Flydende farmaceutisk praeparat til oral indgivelse med kontrolleret frigivelse og god stabilitet, samt fremgangsmaade til fremstilling heraf - Google Patents
Flydende farmaceutisk praeparat til oral indgivelse med kontrolleret frigivelse og god stabilitet, samt fremgangsmaade til fremstilling heraf Download PDFInfo
- Publication number
- DK161365B DK161365B DK272383A DK272383A DK161365B DK 161365 B DK161365 B DK 161365B DK 272383 A DK272383 A DK 272383A DK 272383 A DK272383 A DK 272383A DK 161365 B DK161365 B DK 161365B
- Authority
- DK
- Denmark
- Prior art keywords
- release
- drug
- sorbitol
- pharmaceutical composition
- water
- Prior art date
Links
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- UYXAWHWODHRRMR-UHFFFAOYSA-N hexobarbital Chemical compound O=C1N(C)C(=O)NC(=O)C1(C)C1=CCCCC1 UYXAWHWODHRRMR-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229960002474 hydralazine Drugs 0.000 description 1
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 229950000886 isetionate Drugs 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 229960005287 lincomycin Drugs 0.000 description 1
- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 description 1
- 229940041290 mannose Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229960004815 meprobamate Drugs 0.000 description 1
- 229960001797 methadone Drugs 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- LRMHVVPPGGOAJQ-UHFFFAOYSA-N methyl nitrate Chemical compound CO[N+]([O-])=O LRMHVVPPGGOAJQ-UHFFFAOYSA-N 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 1
- 229960002237 metoprolol Drugs 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- PLPRGLOFPNJOTN-UHFFFAOYSA-N narcotine Natural products COc1ccc2C(OC(=O)c2c1OC)C3Cc4c(CN3C)cc5OCOc5c4OC PLPRGLOFPNJOTN-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229960001454 nitrazepam Drugs 0.000 description 1
- KJONHKAYOJNZEC-UHFFFAOYSA-N nitrazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1 KJONHKAYOJNZEC-UHFFFAOYSA-N 0.000 description 1
- 229960000564 nitrofurantoin Drugs 0.000 description 1
- NXFQHRVNIOXGAQ-YCRREMRBSA-N nitrofurantoin Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)NC(=O)C1 NXFQHRVNIOXGAQ-YCRREMRBSA-N 0.000 description 1
- 229960004708 noscapine Drugs 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000003538 oral antidiabetic agent Substances 0.000 description 1
- 229960004535 oxazepam Drugs 0.000 description 1
- ADIMAYPTOBDMTL-UHFFFAOYSA-N oxazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1 ADIMAYPTOBDMTL-UHFFFAOYSA-N 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 239000011236 particulate material Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 description 1
- 229960005301 pentazocine Drugs 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 229960000762 perphenazine Drugs 0.000 description 1
- 229960000482 pethidine Drugs 0.000 description 1
- 229960005222 phenazone Drugs 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 229960002695 phenobarbital Drugs 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 229960002036 phenytoin Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229960002508 pindolol Drugs 0.000 description 1
- PHUTUTUABXHXLW-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=NC=C[C]12 PHUTUTUABXHXLW-UHFFFAOYSA-N 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 150000004804 polysaccharides Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 229960002816 potassium chloride Drugs 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229960003910 promethazine Drugs 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 description 1
- 229960001225 rifampicin Drugs 0.000 description 1
- JZWFDVDETGFGFC-UHFFFAOYSA-N salacetamide Chemical group CC(=O)NC(=O)C1=CC=CC=C1O JZWFDVDETGFGFC-UHFFFAOYSA-N 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
- 229960004306 sulfadiazine Drugs 0.000 description 1
- VLYWMPOKSSWJAL-UHFFFAOYSA-N sulfamethoxypyridazine Chemical compound N1=NC(OC)=CC=C1NS(=O)(=O)C1=CC=C(N)C=C1 VLYWMPOKSSWJAL-UHFFFAOYSA-N 0.000 description 1
- 229960004936 sulfamethoxypyridazine Drugs 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229960000195 terbutaline Drugs 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 229960002872 tocainide Drugs 0.000 description 1
- 229960002277 tolazamide Drugs 0.000 description 1
- OUDSBRTVNLOZBN-UHFFFAOYSA-N tolazamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CCCCCC1 OUDSBRTVNLOZBN-UHFFFAOYSA-N 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 229940086542 triethylamine Drugs 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5015—Organic compounds, e.g. fats, sugars
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
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- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
i
DK 161365 B
Den foreliggende opfindelse angår et flydende farmaceutisk præparat til oral indgivelse med kontrolleret frigivelse og god stabilitet af det aktive stof samt fremgangsmåde til fremstilling heraf.
5 Det er formålet med opfindelsen at tilvejebringe et præparat, hvori frigivelse af det aktive stof fra kapslerne er kontrolleret.
Blandt de forskellige former for oral indgivelse af farmaceutisk aktive stoffer er anvendelse af en opløsning eller suspension af det 10 aktive princip i en vandig opløsning, en form, der ofte bruges ved pædiatrisk anvendelse. Af praktiske grunde betegnes et sådant præparat i det følgende en mikstur. De farmaceutisk aktive stoffer til brug i miksturen foreligger indkapslet, enten for at maskere dårlig smag eller for at kontrollere frigørelsen deraf i legemet.
15
Hidtil er lægemidler blevet belagt med polymerer eller med polymerer i kombination med blødgøringsmidler til kontrollering af lægemiddel -frigivelsen (mikroindkapsling). Anvendt på granulater af et lægemiddel nedsætter det opløsningshastigheden.
20
Den fremherskende måde til styring af frigivelsen af lægemidler fra mi krokapsl er er regulering af mængden af den påførte polymer til opnåelse af den forventede plasmaprofil af lægemidlet. Dette kan opnås ved tilsætning af vandopløselige stoffer i belægningen under 25 belægningsprocessen.
I DK patentansøgning nr. 3721/81 er der beskrevet suspensioner af mi krokapsl er af bacampicillin-HCl. Indkapslingsmaterialet er fortrinsvis en blanding af ethyl cel lul ose og hydroxypropylcellulose, og 30 i produktet indgår der tillige suspensionsmidler af en sådan art, at den færdige suspensions pH er mindst 6,9. Som eksempler på sådanne ingredienser nævner skriftet suspensionsstabilisatorer, sukkerstoffer, kunstige sødemidler, aromaingredienser, konserveringsmidler og - til maskering af mi krokapsl ernes synlighed - parti kelformige 35 materialer, såsom titandioxid. Skriftet indeholder tre eksempler (eksempel 3, 5 og 7) på brugsfærdige miksturer og disse indeholder under 40% suspensionsmiddelbestanddele, herunder mannitol, og som største komponent "komprimeret" sukker. Formålet med det komprimerede sukker ifølge denne kendte teknik er kun at fungere som
DK 161365 B
2 sødemiddel, d.v.s. at fungere som maskeringsmiddel for ubehaglig smag af fra mi krokapsl erne udsivet lægemiddel i suspensionsvæsken.
Det har imidlertid nu vist sig, at det med suspensionsmidler af 5 nærmere angiven art er muligt ikke blot at maskere ubehagelig afsmag af fra mikrokapsler udsivet lægemiddel, men også at styre lægemidlets udsivningshastighed fra mi krokapsl erne i suspensionsvæsken.
Dette opnås ved, at det flydende farmaceutiske præparat (miksturen) 10 ifølge opfindelsen er ejendommeligt ved, at det indeholder det aktive stof i indkapslet form i kombination med 60-99 vægt%, regnet på det brugsfærdige præparat, af et frigivelseskontrollerende stof udvalgt blandt kulhydraterne polysaccharider, oligosaccharider, disaccharider og monosaccharider og de med kulhydrater beslægtede 15 forbindelser mannitol, sorbitol, glycerol, glycol, et glykosid af et monosaccharid, og polyethylenglycol med en molekylvægt af størrelsesordenen 400, samt blandinger af sådanne frigivelseskontrollerende stoffer.
20 Det er kendt, at en del af disse stoffer kan indgå i faste eller flydende lægemiddelpræparater til oral indgivelse som sødemidler, men det er udtryk for en overraskende ny erkendelse, at de tillige kan virke som frigivningsregulerende og stabiliserende stoffer. Sødemiddel virkningen er i den sammenhæng en tilfældighed, hvilket 25 også fremgår af, at en del af de omhandlede stoffer hverken er søde eller kan virke som sødemidler.
Ifølge opfindelsen er det frigivelseskontrollerende stof fortrinsvis saccharose, glucose, fructose eller sorbitol.
30
Opfindelsen angår endvidere en fremgangsmåde til fremstilling af det flydende farmaceutiske præparat ifølge opfindelsen som angivet i krav 4.
35 Man kan således enten først blande det indkapslede faste stof og sædvanlige hjælpestoffer med den ønskede mængde - mindst 60% af det færdige præparats vægt - af det eller de frigivelseskontrollerende stoffer og derefter tilsætte vand. Eller man kan blande det indkapslede aktive stof med en vandig opløsning af sædvanlige
DK 161365 B
3 hjælpestoffer og tillige indeholdende mindst 60% (beregnet som nævnt) af det eller de frigivelseskontrollerende stoffer. I begge tilfælde opnås der en mikstur, hvor lægemidlets ubehagelige smag ikke blot er maskeret, men lægemidlets opløsningsproces er 5 forsinket, og det aktive stof derfor kun frigives langsomt til væsken i suspensionen.
Lægemiddel frigøre!sen fra mi krokapsl erne i blandingen, her betegnet udsivning, er meget lav, men efter indtagelse frigives lægemidlet 10 fra mi krokapsl erne og bliver tilgængelig for absorption. Lægemidlets stabilitet i miksturen er derimod høj.
Som eksempler på kulhydrater som frigivelseskontrollerende stof kan nævnes poly- eller oligosaccharider, såsom dextran, disaccharider, 15 såsom saccharose, maltose og lactose og monosaccharider, såsom glucose, fructose, galactose, mannose og xylitol. Som eksempel på en polyethylenglycol med en molekylvægt af størrelsesordenen 400 kan f.eks. nævnes "Carbowax"® og "Carbopol"®.
20 Som frigivelseskontrollerende stof kan der bruges en blanding af to eller flere af de nævnte stoffer.
Mængden heraf er fortrinsvis 60-75 vægt% af hele præparatet, d.v.s. den brugsklare suspension til oral indgivelse (miksturen).
25 I stedet for at sætte det frigivelseskontrollerende stof til det indkapslede lægemiddel, kan man indkapsle det frigive!seskontrolle-rende stof sammen med lægemidlet inden i indkapslingsskallen.
30 Som farmaceutisk aktivt stof kan et hvilket som helst lægemiddel anvendes, f.eks. et af følgende:
Kemoterapeutika: 35 Bacampicillin, ampici11 in, flue!oxacillin, tetracyclin, dicloxacil-lin, chloramphenicol, gentamicin, erythromycin, lincomycin, rifampi-cin, sulfadiazin, sulfamethoxypyridazin, griseofulvin, nitrofuranto in.
DK 161365 B
4
Adrenerae oa betareceptorstimulanter:
Ephedrin, terbutalin, teophyllin, enprophyllin.
5 Ekspektoranter og hostedepressanter:
Ethylmorfin, dextromethorphan, noscapin, bromhexin.
H.iertealucosider oo antiarvtmiske midler: 10
Digitoxin, digoxin, disopyramid, procainid, tocainid, alprenolol, atenolol, metoprolol, pindolol, propranolol.
Blodtrvksdepressanter: 15
Betanidin, chlonidin, guanethidin, methyldopa, reserpintrimethaphan, hydralazin, bendroflumethiazid, furosemid, chlorthiazid.
Antihistaminer: 20
Brompheniramin, chlorcyclizin, chlorpheniramin, diphenhydramin, prometazin.
Perorale antidiabetiske midler: 25
Carbutamid, chlorpropamid, tolazamid, tolbutamid.
Sedativer hvonotika antideoressanter: 30 Hexobarbital, pentobarbital, phenobarbital, meprobamat, chlordiazep-oxid, diazepam, flunitrazepam nitrazepam, oxazepam, chlormetiazol, chlorpromazin, flufenazin, perfenazin, prochlorperazin, haloperidol, lithium, alaproklat, zimeldin, amitriptilin, imipramin, nortripty-lin.
35
Antiepileotika:
Phenytoin, etotoin, ethosuximid, carbamazepin.
DK 161365B s
Analoetika anæstetika:
Codein, morphin, pentazocin, pethidin, dextropropoxyphen, methadon, acetylsalicylsyre, di fluni sal, phenazon, phenylbutazon, acetamino-5 fen, indometacin, naproxen, piroxicam, lidocain, etidocain.
Andre:
Cimetidin, chinidin, dicoumarin, warfarin, kaliumchlorid, chloro-10 chin.
Ifølge opfindelsen er det aktive stof fortrinsvis bacampicillin (bacampicillinhydrochlorid) eller teophyllin.
15 Det aktive stof er til stede i neutral form eller i saltform.
Følgende salte af ovennævnte lægemidler kan anvendes:
Acetat, benzensul fonat, benzoat, bicarbonat, bitartrat, bromid, calciumedetat, kamsyl at, carbonat, chlorid, citrat, dihydrochlorid, 20 edetat, edisylat, estolat, esylat, fumarat, gluceptat, gluconat, glutamat, glycolylarsanilat, hexylresorcinat, hydrabamin, hydrobro-mid, hydrochlorid, hydroxynaphthoat, iodid, isetionat, lactat, lactobionat, mal at, maleat, mandel at, mesylat, methyl bromid, methyl-nitrat, methyl sul fat, mucat, napsul at, nitrat, pamoat (embonat), 25 pantotenat, phosphat/diphosphat, polygalacturonat, salicyl at, stearat, subacetat, succinat, sulfat, tannat, tartrat, teoklat, trietiodid.
Der kan også anvendes kationiske salte. Velegnede kationiske salte 30 indbefatter alkalimetalsalte, f.eks. natrium- og kaliumsalte samt ammoniumsalte og salte med aminer, der er kendt inden for fagområdet som værende farmaceutisk acceptable, f.eks. glycin, ethylendiamin, cholin, di ethanolamin, tri ethanolamin, octadecylamin, di ethylamin, tri ethylamin, l-amino-2-propanol-2-amino-2-(hydroxymethyl)-propan-35 1,3-diol og 1-(3,4-dihydroxyphenyl(-2-isopropylaminoethanol.
Indkapslingen af lægemidlet kan udføres i form af mikrokaplser.
Som belægningsmateriale kan der især bruges polymerer såsom:
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6
Syntetiske polymerer af polyvinyl typen, f.eks. polyvinylchlorid, polyvinyl acetat, polyvinylal kohol.
Polyethylentypen, f.eks. polyethylen, polystyren.
5 i
Polymerer af acrylsyre- eller acrylsyreestertypen, f.eks. methylme- j thacrylat eller copolymerer af acrylmonomerer.
Biopolymerer eller modificerede biopolymererer af cellulose, f.eks.
10 ethyl cellulose, celluloseacetatphthalat.
Polymeren kan være vanduopløselig, syreopløselig eller alkalisk opløselig og blandet med blødgører eller andre fyldstoffer og vandopløselige modificerede biopolymer, f.eks. hydroxypropylcellu-15 lose.
Også fedtstoffer og olier, vokser, højere fedtsyrer, højere alkoholer eller polyvalente alkoholer kan anvendes som sådanne eller i kombination.
20 I en udførelsesform for miksturen er bacampicillinhydrochlorid (BAPC) indkapslet i en uopløselig, mikroporøs polymer, såsom ethyl-cellulose, og saccharose anvendes som undertrykker til fremstilling af et tørt pulver til blanding, som derpå opløses i vand til dannel-25 se af en blanding.
Ifølge en anden udførelsesform for miksturen er BAPC indkapslet i en polymer, der er opløselig i syre, såsom "Eudragit"® E 100, og saccharose anvendes som frigivelseskontrollerende stof til frem-30 stilling af et tørt pulver, som derpå opløses i vand til dannelse af mi ksturen.
I en anden udførelsesform for miksturen er teophyllin indkapslet i en skal af ethyl cel lulose, og sorbitol anvendes som frigivelses-35 kontrollerende stof til fremstilling af et tørt pulver, som derpå opløses i vand.
I en yderligere udførelsesform er acetylsalicylsyre indkapslet i en skal af celluloseacetatphthalat, og saccharose til stede som
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7 frigivelseskontrollerende stof.
Der er foretaget forsøg over betydningen af koncentrationen af det frigivelseskontrollerende stof i miksturen.
5 10 ml af den kulhydratopløsning som angivet i nedenståene tabel 1.
Tabel 1 10 Kulhydrat_Koncentration. væat%_
Saccharose 40 60 65 (mættet)
Levulose 40 60 75 (mættet)
Sorbitol 40 60 70 (mættet) 15 blev indført i en 20 ml stor glasflaske og der blev afvejet mikro-kaplser, som anført i nedenstående tabel 2 til hver flaske.
Tabel 2 20
Mikroindkapslet a) b) c) Bølge- Absorptionslægemiddel Over- Ind- Kone., længde, koefficient 3 -1 -1 _træk hold. % mq/ml nm_dm mg cm 25 Bacampicillin EC 69,9 50 255 0,000667
Pc-V kalium EC 75,5 50 267 0,00313
Paracetamol EC 91,2 10 272 0,0139
Teophyllin EC 72,0 15 270 0,0556 30 a) EC = ethyl cellul ose b) Mi krokapslernes lægemiddel indhold c) Koncentration af lægemiddel i den dannede mi krokapsel suspension til den i tabellen angivne koncentration, hvorpå flaskerne blev 35 rystet for at sikre, at mi krokapsl erne blev suspenderet.
Suspensionen blev filtreret og filtraterne analyseret spektrofotome-trisk ved de i tabel 2 angivne bølgelængder. Frigivelseshastigheden blev beregnet som mængde lægemiddel i opløsning efter lagring som
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8 suspension i sammenligning med den tilførte mængde lægemiddel som mikrokapsl er.
Resultaterne fremgår af nedenstående tabel 3.
5
Tabel 3 Saccharose 10 Mikroindkapslet Hastighed Koncentration, vægt% lægemiddel_40 60 65
Bacampicillin %/time 38 6,0 3,7 PC-kalium %/time 17 1,7 0,48 15 Paracetamol %/time 5,1 0,21 0,17
Teophyllin %/dag 3,1 0,28 0,18
Sorbitol 20 Mikroindkapslet Hastighed Koncentration, vægt% lægemiddel_40_60 70
Bacampicillin %/time 38 6,0 2,5
Pc-V-kalium %/time 20 2,7 0,40 25 Paracetamol %/time 4,9 0,24 0,24
Teophyllin %/dag 3,1 0,28 0,18
Levulose 30 Mikroindkapslet Hastighed Koncentration, vægt% lægemiddel_40_60 75
Bacampicillin %/time 41 13 1,2
Pc-V-kalium %/time 20 2,5 0,13 35 Paracetamol %/time 5,4 0,24 0,23
Teophyllin %/dag 1,3 0,097 0,033
Som det fremgår af tabel 3, varierer frigivelseshastigheden inden for samme kulhydratkoncentation mere mellem samme type mi krokapsl er,
DK 161365 B
9 end mellem de forskellige kulhydrater. Forskellem mellem mikrokaps-lerne er af størrelsesordnen med en faktor på 100 på 40%'s niveauet.
Denne forskel skyldes lægemidlets opløselighed i den anvendte kulhydratopløsning og tillige mi krokapsl ernes opløselighed i den 5 anvendte opløsningsvæske (vand).
Den største forskel i frigivelseshastigheden mellem forskellige typer kulhydratopløsninger med samme type mi krokapsl er, kan findes for teophyllin, hvor relationen mellem den hurtigste og den langsom-10 ste frigivelseshastighed er en faktor 3.
Forskellen i frigivelseshastighed mellem 40%'s og 60%'s kulhydratkoncentration er signifikant. Den største forskel er en faktor 20 for paracetamol i sorbitol. Den mindste forskel er en faktor 3 for 15 bacampicillin i levulose. For de fleste af eksemplerne i tabel 3 er forskellen en faktor på ca. 10. En sådan frigivelseshastighed vil med hensyn til smagsmaskering og stabilitet gælde for en farmaceutisk mikstur baseret på et mikroindkapslet lægemiddel. Den mængde af lægemidlet, som er lækket ud af mi krokapsl erne til opløsningen vil 20 bevirke ubehagelig smag eller stabilitetsproblemer. I tilfælde hvor man bruger mikrokapsler til at opnå kontrolleret frigivelse af et lægemiddel er det vigtigt, at lægemidlet bliver inden i mikro-kapslerne.
25 Konklusionen af denne undersøgelse er, at kulhydratopløsning med en koncentration på 60% er bedre egnet til fremstilling af en mikstur end en kulhydratopløsning med en koncentration på ca. 40% for så vidt angår utilsigtet udsivning af lægemidlet fra mi krokapsl erne.
30 Der er i øvrigt blevet udført en række i de følgende eksempler beskrevne forsøg for at vise, at mi krokapsl erne ikke vil frigive nogen signifikant mængde af lægemidlet ud til det frigivelseskontrollerende stof og derved forårsage dårlig smag i kontakt med vand, forårsage nedbrydning eller tab af dets evne til at virke som 35 kontrolleret frigivelsespæparat.
Mikrokapsler blev sat til en opløsning indeholdende det frigivelseskontrollerende stof. Mængden af lægemiddel, som var blevet frigivet fra mi krokapsl erne, analyseredes. Dette betegnes udsivning. Prøverne
DK 161365 B
10 blev i nogle tilfælde opbevaret i op til 80 dage ved stuetemperatur. Resultaterne er anført i % udsivning, d.v.s. den mængde af lægemidlet, som er i opløsning divideret med den oprindelige mængde af det mi kroindkapslede lægemiddel.
5
For at demonstrere virkningen af det frigivelseskontrollerende stof blev der også udført frigivelsesundersøgelser i vand. Mi krokapsl er blev anbragt i et bægerglas og der tilsattes vand. Omrøringshastigheden var 30 opm og den frigivne mængde blev beregnet som beskrevet 10 ovenfor.
Eksempel 1 25,8 g farmaceutisk blanding indeholdende: 15 bacampicillin-hydrochlorid, "Eudragit"® E 100 mikrokapsler (54% lægemiddel) 0,80 g fructose 18,75 g vand 6,25 g 20 Det frigi velseskontrollerende stof, fructosen, opløstes i vand før mi krokapsl erne blev tilsat. Blandingen indeholdt 73% frigivelseskon-trollerende stoffer.
Tid (timer) Udsivning (%) 25 2 <0,2
Tid (timer) Frigivelse i vand 1%) 0,008 50 0,05 90 30 35
Eksempel 2 DK 161365 B π a) 31,3 g farmaceutisk blanding indeholdende: teophyllin, ethyl cel 1ulose-mi krokapsl er 5 (72% lægemiddel) 0,05 g fructose 23,44 g vand 7,82 g b) 28,8 g farmaceutisk blanding indeholdende: 10 teophyllin, ethyl cel lul ose-mi krokapsl er (72% lægemiddel) 0,05 g sorbitol 20,94 g vand 7,82 g 15 De to blandinger fremstilledes i overensstemmelse med eksempel 1. Blandingerne indeholdt a) 75% b) 72% frigivelseskontrollerende stof.
Tid (dage) Udsivning (%) a) b) 20 1 <0,2 0,7 3 <0,2 5 <0,2 7 <0,2 10 <0,2 25
Tid (dage) Frigivelse i vand (%) 0,21 50 0,33 90 30 35
Eksempel 3
DK 161365 B
12 31,3 g farmaceutisk blanding indeholdende: teophyllin, ethyl cel1ulose-mi krokapsl er 5 (72% lægemiddel) 0,05 g /saccharose 9,38 g "^sorbitol 9,38 g b (saccharose 9,38 g 10 (glycerol 9,38 g ^glucose 9,38 g Ί fructose 9,38 g vand 12,5 g 15
De tre blandinger fremstilledes i overensstemmelse med eksempel 1. Blandingerne indeholdt 60% fri gi velseskontrollerende stoffer.
Tid (daael Udsivning (%) 20 a) b) c) 1 0,20 <0,2 0,26 2 0,31 0,35 0,28 5 0,65 0,82 0,49 9 1,15 1,77 0,90 25
Tid (dage) Frigivelse i vand (%) 0,21 50 0,33 90 30 Eksempel 4 75,1 g farmaceutisk blanding indeholdende: acetyl sal i cylsyre, cel1uloseacetatphthalat-mikrokapsler (69% lægemiddel) 0,100 g 35 saccharose 48,75 g phosphatpuffer (pH 7,0) 26,25 g
Saccharose opløstes i phosphatpufferen. Derpå tilsattes mi krokapslerne. Blandingen indeholdt 65% frigivelseskontrollerende stof.
DK 161365 B
13
Tid (dage) Udsivning (%) 1 3,5
Frigivelse i phosphatpuffer 5 Tid idaae) pH 7,0 (%)_ 0,008 50 0,017 90
Eksempel 5 10
Fire forskellige mikrokapsler belagt med ethyl cellul ose suspenderedes i sorbitol opløst i vand i overensstemmelse med følgende sammensætning.
15 mikrokapsler 50 mg sorbitol 45,1 g vand 19,3 g
Blandingen indeholdt 70% frigivelseskontrollerende stof.
20
Udsivning i sorbitol- Frigivelse undertrykker i vand
Mikrokapsler_(%) (dage)_1%) (timer! 25 KC1 (86)x 16 21 56 3 paracetaminofen (91)x 19 21 35 1 flucloxacillin (89)x 20 1 90 0,5 phenoxymethyl- (83)x 10 1 80 1 30 penicillin-kalium_ x indhold af aktivt lægemiddel i mikrokapslen.
Eksempel 6 35 0,2 g teophylli n-mi krokapsl er ifølge eksempel 2 suspenderes i forskellige sukkeropløsninger.
14
DK 161365 B
Fri gi vel seskontrol1 erende stof. væqt%_Udsivning (%)_Tid (dagel xylitol 55 13 80 5 glucose 50 17 40 sorbitol 70 3 80 fructose 75 3 80 fructose-xylitol 19-41 10 80 fructose-xylitol 38-28 6 80 10 fructose-xvlitol 56-14_4_80_
Det er således muligt at begrænse udsivningen i blandingen til kun nogle få procent efter næsten tre måneders lagring ved stuetemperatur, når mængden af det frigivelseskontrollerende kulhydrat er 60 15 vægt% eller mere.
Eksempel 7 65,4 g farmaceutisk blanding indeholder: 20 teophyllin, voksbelagte mi krokapsl er (52% lægemiddel) 1 g sorbitol 45,1 g vand 19,3 g 25 Blandingen fremstilledes i overensstemmelse med eksempel 1. Blandingen indeholdt 69% frigørelseskontrollerende stof.
Tid (dage) Udsivning (%) 22 0,7 30
Tid (dagel Frigivelse i vand (%1 0,5 19 35
DK 161365 B
15
Eksempel 8 26,31 g farmaceutisk blanding indeholder prochlorperazin, voksbelagte mi krokapsl er 5 (3,4% lægemiddel) 10 mg sorbitol 18 g vand 8,3 g
Blandingen fremstilledes i overensstemmelse med eksempel 1. Blan-10 di ngen indeholdt 70% frigivelseskontrollerende stof.
Tid (dage) Udsivning (%) 12 2,7 15 Tid (dage) Frigivelse i vand (%) 0,25 28
Eksempel 9 20 27,15 g farmaceutisk blanding indeholder: teophyllin, ethyl cellulosebel agte mi krokapsl er (72%) 0,15 g polyethylenglycol ("Carbowax"® 400) 20,25 g vand 6,75 g 25
Polyethylenglycol blandedes med vand og mi krokapsl erne tilsattes. Blandingen indeholdt 75% frigivelseskontrollerende stof.
Tid (dage) Udsivning (%) 30 15 2,4
Frigivelse i vand, se eksempel 2.
35
Eksempel 10
DK 161365 B
16 13,877 g farmaceut!sk blanding indeholdende: erytromycin, cel 1uloseacetatbelagte 5 mikrokapsler (57% lægemiddel) 0,877 mg fructose 9,75 g vand 3,25 g
Mi krokapsl erne sattes til en opløsning af fructose i vand. Den 10 færdige blanding indeholdt 71% frigivelseskontrollerende stof.
Tid (dage) Udsivning 1%) 10 <1 15 Tid (dage) Frigivelse i vand (%) 0,25 46
Stabi1 i tetsundersøgelser 20 Der fremstilledes mi krokapsel suspensioner med undertrykkeropløsninger ifølge opfindelsen. Suspensionerne opbevaredes og lægemiddel indholdet måltes ved HPLC-analyse som en selektiv og nøjagtig metode.
a) Bacampicillin-HCl, ethyl cel lulose-25 belagte mikrokapsler (72% lægemiddel) 0,36 g
Saccharose 8,32 g
Vand 4,48 g 30 b) Bacampicillin-HCl, ethyl cellul osebel agte mikrokapsler (72% lægemiddel) 0,36 g
Fructose 9,6 g
Vand 3,2 g 35 17
DK 161365 B
c) Acetylsalicylsyre, cel!uloseacetat-phthalatbelagte mi krokapsl er (69% lægemiddel) 0,72 g
Saccharose 8,32 g 5 Citratpuffer pH 3 4,48 g d) Erytromycin, celluloseacetat-phthalatbelagte mi krokapsl er (87% lægemiddel) 0,44 g 10 Saccharose 8,32 g
Phosphatpuffer pH 7,0 4,48 g
Opbevaringsbetingelse Intakt lægemiddelx
Blanding_Tid (dage) Temp. CCl_{%)_ 15 a 7 25 83 b 7 25 89 c 30 50 70 d_30_50_82_ 20 x oprindelig var mængden af intakt lægemiddel 100%.
Resultaterne viser, at blandinger ifølge opfindelsen har en forbedret virkning på lægemidlers stabilitet.
25 30 35
Claims (5)
1. Flydende farmaceutisk præparat til oral indgivelse med kontrolleret frigivelse og god stabilitet af det aktive stof, kende- 5 tegnet ved, at det indeholder det aktive stof i indkapslet form i kombination med 60-99 vægt%, regnet på det brugsfærdige præparat, af et frigive!seskontrollerende stof udvalgt blandt kulhydraterne polysaccharider, oligosaccharider, disaccharider og monosaccharider og de med kulhydrater beslægtede forbindelser 10 mannitol, sorbitol, glycerol, glycol, et glycosid af et monosaccha-rid og polyethyl englycol med en molekylvægt af størrelsesordenen 400, samt blandinger af sådanne forbindelser.
2. Farmaceutisk præparat ifølge krav 1, kendetegnet 15 ved, at det frigivelseskontrollerende stof er saccharose, glucose, fructose eller sorbitol.
3. Farmaceutisk pæparat ifølge krav 1, kendetegnet ved, at det aktive stof er bacampicillin eller teofyllin. 20
4. Fremgangsmåde til fremstilling af et flydende farmaceutisk præparat som angivet i krav 1, kendetegnet ved, at man a) blander et indkapslet aktivt stof med sædvanlige hjælpestoffer 25 og derudover en mængde på 60-99%, regnet på det færdige præpa rats vægt, af et frigivelseskontrollerende stof udvalgt blandt kulhydraterne polysaccharider, oligosaccharider, disaccharider og monosaccharider og de med kulhydrater beslægtede forbindelser mannitol, sorbitol, glycerol, glycol, et glycosid af et 30 monosaccharid og en polyethylenglycol med en molekylvægt af størrelsesordenen 400, samt blandinger deraf, hvorpå man tilsætter vand til dannelse af det brugsfærdige præparat, eller b) blander et indkapslet aktivt stof med en vandig opløsning af 35 sædvanlige hjælpestoffer og tillige indeholdende 60-99%, regnet på det færdige præparats vægt, af et frigivelseskontrollerende stof udvalgt blandt kulhydraterne polysaccharider, oligosaccharider, disaccharider og de med kulhydrater beslægtede forbindelser mannitol, sorbitol, glycerol, glycol, et glycosid af et
5 DK 161365 B 19 monosaccharid og polyethylenglycol med en molekylvægt af størrelsesordenen 400, samt blandinger deraf. 10 15 20 25 30 35
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE8203953 | 1982-06-24 | ||
| SE8203953A SE8203953D0 (sv) | 1982-06-24 | 1982-06-24 | Pharmaceutical mixture |
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| Publication Number | Publication Date |
|---|---|
| DK272383D0 DK272383D0 (da) | 1983-06-14 |
| DK272383A DK272383A (da) | 1983-12-25 |
| DK161365B true DK161365B (da) | 1991-07-01 |
| DK161365C DK161365C (da) | 1991-12-09 |
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| Application Number | Title | Priority Date | Filing Date |
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| DK272383A DK161365C (da) | 1982-06-24 | 1983-06-14 | Flydende farmaceutisk praeparat til oral indgivelse med kontrolleret frigivelse og god stabilitet, samt fremgangsmaade til fremstilling heraf |
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| EP (1) | EP0101418B1 (da) |
| JP (1) | JPS5916822A (da) |
| KR (1) | KR910000028B1 (da) |
| AR (1) | AR231075A1 (da) |
| AT (1) | ATE59286T1 (da) |
| AU (1) | AU561954B2 (da) |
| BG (1) | BG51341A3 (da) |
| CA (1) | CA1214726A (da) |
| CS (1) | CS257769B2 (da) |
| CY (1) | CY1468A (da) |
| DD (1) | DD209971A5 (da) |
| DE (1) | DE3382086D1 (da) |
| DK (1) | DK161365C (da) |
| ES (1) | ES8403720A1 (da) |
| FI (1) | FI85213C (da) |
| GB (1) | GB2122490B (da) |
| GR (1) | GR78604B (da) |
| HK (1) | HK98786A (da) |
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| MY (1) | MY8700292A (da) |
| NO (1) | NO168745C (da) |
| NZ (1) | NZ204639A (da) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPH0729927B2 (ja) * | 1983-04-09 | 1995-04-05 | 日研化学株式会社 | テオフィリン徐放性製剤 |
| SE8405611D0 (sv) * | 1984-11-09 | 1984-11-09 | Astra Laekemedel Ab | Process for stabilization of bacampicillin hydrochloride |
| IT1183575B (it) * | 1985-05-08 | 1987-10-22 | Eurand Spa | Formulazione deodorando ad effetto modulante sulla trfaspirazione |
| NL8503539A (nl) * | 1986-01-02 | 1987-07-16 | Warner Lambert Co | Sucrose-vrije preparaten. |
| US4780320A (en) * | 1986-04-29 | 1988-10-25 | Pharmetrix Corp. | Controlled release drug delivery system for the periodontal pocket |
| SE8605515D0 (sv) * | 1986-12-22 | 1986-12-22 | Astra Laekemedel Ab | A liquid dosage form for oral administration of a pharmaceutically active substance |
| US4874613A (en) * | 1987-03-06 | 1989-10-17 | Baker Cummins Pharmaceuticals, Inc. | Taste concealing pharmaceutical dosage unit |
| US5427935A (en) * | 1987-07-24 | 1995-06-27 | The Regents Of The University Of Michigan | Hybrid membrane bead and process for encapsulating materials in semi-permeable hybrid membranes |
| SE463542B (sv) * | 1987-08-31 | 1990-12-10 | Lejus Medical Ab | Granulaer instanticerbar produkt samt foerfarande foer dess framstaellning |
| JPH03504968A (ja) * | 1988-04-19 | 1991-10-31 | サウスウェスト・リサーチ・インスティチュート | 塩感受性シェル物質を有するカプセルからの活性成分の制御放出 |
| US5064650A (en) * | 1988-04-19 | 1991-11-12 | Southwest Research Institute | Controlled-release salt sensitive capsule for oral use and adhesive system |
| FR2653337B1 (fr) * | 1989-10-23 | 1992-02-07 | Dow Corning Sa | Element a liberation prolongee et procede pour le fabriquer. |
| CA2068402C (en) * | 1991-06-14 | 1998-09-22 | Michael R. Hoy | Taste mask coatings for preparation of chewable pharmaceutical tablets |
| US5364634A (en) * | 1991-11-08 | 1994-11-15 | Southwest Research Institute | Controlled-release PH sensitive capsule and adhesive system and method |
| DE4200821A1 (de) * | 1992-01-15 | 1993-07-22 | Bayer Ag | Geschmacksmaskierte pharmazeutische mittel |
| JP3265680B2 (ja) * | 1992-03-12 | 2002-03-11 | 大正製薬株式会社 | 経口製剤用組成物 |
| DE4312656C2 (de) * | 1993-04-19 | 1996-01-25 | Beiersdorf Ag | Kühlend wirkende kosmetische oder dermatologische Zusammensetzungen |
| DE4423078B4 (de) * | 1994-07-01 | 2005-01-13 | Awd.Pharma Gmbh & Co. Kg | Verfahren zur Herstellung einer Carbamazepin-Arzneiform mit verzögerter Wirkstofffreisetzung |
| US5972373A (en) * | 1995-05-02 | 1999-10-26 | Taisho Pharmaceutical Co., Ltd. | Taste masking pharmaceutical composition for oral administration |
| DE19706978A1 (de) * | 1997-02-21 | 1998-08-27 | Ulrich Dr Posanski | Kombinationspräparat für oral applizierbare Antibiotika |
| US7943585B2 (en) | 2003-12-22 | 2011-05-17 | Sandoz, Inc. | Extended release antibiotic composition |
| RU2403049C1 (ru) * | 2009-06-04 | 2010-11-10 | Государственное образовательное учреждение высшего профессионального образования Московская медицинская академия им. И.М. Сеченова Федерального агентства по здравоохранению и социальному развитию (ГОУВПО ММА им. И.М. Сеченова Росздрава) | Способ получения таблеток эритромицина |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE636568A (da) * | 1961-01-31 | |||
| US3689654A (en) * | 1970-09-14 | 1972-09-05 | Morton Norwich Products Inc | Pharmaceutical compositions |
| FI750489A7 (da) * | 1974-02-22 | 1975-08-23 | Wellcome Found | |
| SE8003805L (sv) * | 1980-05-21 | 1981-11-22 | Haessle Ab | En farmaceutisk beredning med forbettrade utlosningsegenskap |
| US4321253A (en) * | 1980-08-22 | 1982-03-23 | Beatty Morgan L | Suspension of microencapsulated bacampicillin acid addition salt for oral, especially pediatric, administration |
| SE8103843L (sv) * | 1981-06-18 | 1982-12-19 | Astra Laekemedel Ab | Farmaceutisk mixtur |
| JPS57209223A (en) * | 1981-06-19 | 1982-12-22 | Tanabe Seiyaku Co Ltd | Microcapsule for intracranial anti hypotension and its production |
-
1982
- 1982-06-24 SE SE8203953A patent/SE8203953D0/xx unknown
-
1983
- 1983-05-30 CA CA000429157A patent/CA1214726A/en not_active Expired
- 1983-05-30 ZA ZA833931A patent/ZA833931B/xx unknown
- 1983-05-31 EP EP83850147A patent/EP0101418B1/en not_active Expired - Lifetime
- 1983-05-31 AT AT83850147T patent/ATE59286T1/de not_active IP Right Cessation
- 1983-05-31 DE DE8383850147T patent/DE3382086D1/de not_active Expired - Lifetime
- 1983-06-14 DK DK272383A patent/DK161365C/da not_active IP Right Cessation
- 1983-06-16 FI FI832197A patent/FI85213C/fi not_active IP Right Cessation
- 1983-06-20 NZ NZ204639A patent/NZ204639A/en unknown
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- 1983-06-20 AU AU15943/83A patent/AU561954B2/en not_active Expired
- 1983-06-21 AR AR293393A patent/AR231075A1/es active
- 1983-06-22 IE IE1462/83A patent/IE55204B1/en not_active IP Right Cessation
- 1983-06-23 SU SU833607650A patent/SU1722207A3/ru active
- 1983-06-23 DD DD83252303A patent/DD209971A5/de unknown
- 1983-06-23 GR GR71768A patent/GR78604B/el unknown
- 1983-06-23 JP JP58111990A patent/JPS5916822A/ja active Granted
- 1983-06-23 HU HU832225A patent/HU189300B/hu not_active IP Right Cessation
- 1983-06-23 PT PT76919A patent/PT76919B/pt unknown
- 1983-06-23 GB GB08317071A patent/GB2122490B/en not_active Expired
- 1983-06-23 CS CS834636A patent/CS257769B2/cs unknown
- 1983-06-23 NO NO832293A patent/NO168745C/no not_active IP Right Cessation
- 1983-06-23 ES ES523536A patent/ES8403720A1/es not_active Expired
- 1983-06-24 KR KR1019830002854A patent/KR910000028B1/ko not_active Expired
- 1983-06-24 IS IS2824A patent/IS1325B6/is unknown
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1986
- 1986-12-18 HK HK987/86A patent/HK98786A/xx not_active IP Right Cessation
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1987
- 1987-12-30 MY MY292/87A patent/MY8700292A/xx unknown
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1989
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