NO794044L - PROCEDURE FOR PREPARING INCLUSION COMPLEXES OF ALLYCIN WITH CYCLODEXTRINES - Google Patents
PROCEDURE FOR PREPARING INCLUSION COMPLEXES OF ALLYCIN WITH CYCLODEXTRINESInfo
- Publication number
- NO794044L NO794044L NO794044A NO794044A NO794044L NO 794044 L NO794044 L NO 794044L NO 794044 A NO794044 A NO 794044A NO 794044 A NO794044 A NO 794044A NO 794044 L NO794044 L NO 794044L
- Authority
- NO
- Norway
- Prior art keywords
- cyclodextrin
- allycin
- inclusion complex
- mixture
- inclusion
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 11
- 229920000858 Cyclodextrin Polymers 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 17
- 239000000243 solution Substances 0.000 claims description 13
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- JDLKFOPOAOFWQN-VIFPVBQESA-N Allicin Natural products C=CCS[S@](=O)CC=C JDLKFOPOAOFWQN-VIFPVBQESA-N 0.000 claims description 9
- JDLKFOPOAOFWQN-UHFFFAOYSA-N allicin Chemical compound C=CCSS(=O)CC=C JDLKFOPOAOFWQN-UHFFFAOYSA-N 0.000 claims description 9
- 235000010081 allicin Nutrition 0.000 claims description 9
- 229940097362 cyclodextrins Drugs 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000008298 dragée Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 230000000845 anti-microbial effect Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000001408 fungistatic effect Effects 0.000 claims description 3
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 claims description 3
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 2
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 230000007717 exclusion Effects 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 claims 1
- 229940043377 alpha-cyclodextrin Drugs 0.000 claims 1
- 239000011541 reaction mixture Substances 0.000 claims 1
- 239000007921 spray Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- PFRGXCVKLLPLIP-UHFFFAOYSA-N diallyl disulfide Chemical compound C=CCSSCC=C PFRGXCVKLLPLIP-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 240000002234 Allium sativum Species 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 235000004611 garlic Nutrition 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- FCSSPCOFDUKHPV-UHFFFAOYSA-N 2-Propenyl propyl disulfide Chemical compound CCCSSCC=C FCSSPCOFDUKHPV-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RMKCQUWJDRTEHE-UHFFFAOYSA-N Diallyltetrasulfane Chemical compound C=CCSSSSCC=C RMKCQUWJDRTEHE-UHFFFAOYSA-N 0.000 description 2
- 239000001116 FEMA 4028 Substances 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical group OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 2
- 229960004853 betadex Drugs 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- UBAXRAHSPKWNCX-UHFFFAOYSA-N diallyl trisulfide Chemical compound C=CCSSSCC=C UBAXRAHSPKWNCX-UHFFFAOYSA-N 0.000 description 2
- WQOXQRCZOLPYPM-UHFFFAOYSA-N dimethyl disulfide Chemical compound CSSC WQOXQRCZOLPYPM-UHFFFAOYSA-N 0.000 description 2
- ALVPFGSHPUPROW-UHFFFAOYSA-N dipropyl disulfide Chemical compound CCCSSCCC ALVPFGSHPUPROW-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 238000012009 microbiological test Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- WHGYBXFWUBPSRW-FEYSZYNQSA-N β-dextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)C(O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FEYSZYNQSA-N 0.000 description 2
- 239000001754 3-prop-2-enyldisulfanyldisulfanylprop-1-ene Substances 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- XUHLIQGRKRUKPH-UHFFFAOYSA-N S-allyl-L-cysteine sulfoxide Natural products OC(=O)C(N)CS(=O)CC=C XUHLIQGRKRUKPH-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- -1 allyl ester Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000013080 microcrystalline material Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000004810 partition chromatography Methods 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000005077 polysulfide Substances 0.000 description 1
- 229920001021 polysulfide Polymers 0.000 description 1
- 150000008117 polysulfides Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003214 pyranose derivatives Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
- C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Nanotechnology (AREA)
- Biophysics (AREA)
- Emergency Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Medical Informatics (AREA)
- Oncology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Communicable Diseases (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biochemistry (AREA)
- Materials Engineering (AREA)
- Polymers & Plastics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
Fremgangsmåte ved fremstilling av inklusjonskomplekser av allycin med cyclodextriner Procedure for the production of inclusion complexes of allycin with cyclodextrins
Foreliggende oppfinnelse angår inklusjonskomplekser av allycin med cyclodextriner, fremstilling av disse og farma-søytiske komposisjoner inneholdende dem. The present invention relates to inclusion complexes of allicin with cyclodextrins, their production and pharmaceutical compositions containing them.
Hvitløk (Allium sativum L.) olje omfatter forskjellige svovelholdige komponenter. I tillegg til hovedkomponen-ten diallyldisulfid, inneholder hvitolje diallyltrisulfid, diallyltetrasulfid, dipropyldisulfid, propylallyldisulfid, di-methyldisulfid og allyin. Garlic (Allium sativum L.) oil comprises various sulfur-containing components. In addition to the main component diallyl disulfide, white oil contains diallyl trisulfide, diallyl tetrasulfide, dipropyl disulfide, propylallyl disulfide, dimethyl disulfide and allyin.
Allyin er kjemisk (+)-S-allyl-L-cisteinsulfoxyd [Heiv. Chim. Acta, 21'189 (1948)], og kan omdannes enzymatisk til allycin, dvs. allylthiosulfinsyreallylester [J.A. Chem. Soc, 66, 1950)]. Den sistnevnte forbindelse er en farveløs, ustabil væske med en meget utiltrekkende duft, dens vannløse-lighet er 2,5 %. Allycin er et kraftig antibakterielt middel, og kan lett fremstilles ved flere metoder kjent innen faget Allyin is chemically (+)-S-allyl-L-cysteine sulfoxide [Heiv. Chim. Acta, 21'189 (1948)], and can be enzymatically converted to allicin, i.e. allylthiosulfinic acid allyl ester [J.A. Chem. Soc, 66, 1950)]. The latter compound is a colourless, unstable liquid with a very unattractive smell, its water solubility is 2.5%. Allycin is a powerful antibacterial agent, and can be easily produced by several methods known in the art
[se for eksempel J.Am. Chem. Soc. 66_, 1950 (1944)] .[see, for example, J. Am. Chem. Soc. 66_, 1950 (1944)] .
I vandige og ikke-vandige løsninger såvel som i form av dets faste preparater, spaltes allycin i løpet av ca. 2 da-ger ved romtemperatur og i en inaktiv forbindelse. In aqueous and non-aqueous solutions as well as in the form of its solid preparations, allycin breaks down within approx. 2 days at room temperature and in an inactive compound.
Ifølge foreliggende oppfinnelse tilveiebringes et inklusjonskompleks av allycin med et cyclodextrin. Dette kompleks erholdes i en stabil, krystallinsk form, og kan anvendes som aktiv bestanddel i farmasøytiske komposisjoner med antimikrobiell og/eller fungistatisk aktivitet. According to the present invention, an inclusion complex of allycin with a cyclodextrin is provided. This complex is obtained in a stable, crystalline form, and can be used as an active ingredient in pharmaceutical compositions with antimicrobial and/or fungistatic activity.
Cyclodextriner er cycliske molekyler bestående avCyclodextrins are cyclic molecules consisting of
6, 7 eller 8 glucopyranoséenheter som danner a-1,4-glucoseen-heter. Strukturelt er dissekarakterisert vedet spesialarran-gement av hydroxylgruppene. Alle de sekundære hydroxylgrupper er anbragt på kanten av ringen, mens alle de primære hydroxylgrupper er anbragt på den andre kant av ringen. Derfor er' den ytre overflate av ringen hovedsakelig hydrofob som sikrer at cyclodextrinene er vannløselige. På den annen side har den indre overflate av ringene en hydrofob karakter da det i denne del av molekylet bare finnes hydrogenatomer og glycosidiske oxygenbroer. Hvis molekyler som er mindre polare enn vann og hvis form og størrelse muliggjør penetrering av disse i den hule innside av cyclodextrinene, tilsettes til en vandig løs-ning av cyclodextriner, dannes et cyclodextrininklusjonskom-pleks selv i en vandig løsning. Ringen bestående av 6 gluco- 6, 7 or 8 glucopyranose units forming α-1,4-glucose units. Structurally, these are characterized by the special arrangement of the hydroxyl groups. All the secondary hydroxyl groups are placed on the edge of the ring, while all the primary hydroxyl groups are placed on the other edge of the ring. Therefore, the outer surface of the ring is mainly hydrophobic which ensures that the cyclodextrins are water soluble. On the other hand, the inner surface of the rings has a hydrophobic character as in this part of the molecule there are only hydrogen atoms and glycosidic oxygen bridges. If molecules that are less polar than water and whose shape and size enable their penetration into the hollow interior of the cyclodextrins are added to an aqueous solution of cyclodextrins, a cyclodextrin inclusion complex is formed even in an aqueous solution. The ring consisting of 6 gluco-
pyranoseenheter kalles a-cyclode' trin, ringen bestående av 7 enheter kalles 3_cyclodextrin og ringen med 8 glucopyranose-enheter kalles ycyclodextrin. pyranose units are called a-cyclode' trin, the ring consisting of 7 units is called 3_cyclodextrin and the ring with 8 glucopyranose units is called ycyclodextrin.
Ifølge oppfinnelsen fremstilles inklusjonskomplekser av allycin med cyclod extriner ved at en løsning av allycin i et. vannblandbart løsningsmiddel bringes i kontakt med en vandig løsning av a-, (3- eller ycyclodextrin eller en blanding av hvilke som helst av disse under utelukkelse av luft, og isole-ring av det dannede kompleks fra løsningen, om ønsket etter eliminering av løsningsmidlet fra blandingen hensiktsmessig ved lyofilisering eller krystallisering ved lav temperatur. According to the invention, inclusion complexes of allycin with cyclodextrins are produced by a solution of allycin in a water-miscible solvent is contacted with an aqueous solution of α-, (3-) or γ-cyclodextrin or a mixture of any of these under the exclusion of air, and isolating the complex formed from the solution, if desired after elimination of the solvent from the mixture conveniently by lyophilization or crystallization at low temperature.
Ifølge en foretrukket utførelsesform av prosessen blandes løsningene ved forhøyet temperatur, fortrinnsvis ved 40 - 70° C. Det dannede inklusjonskompleks er mindre løselig i modervæsken enn forbindelsene det fremstilles fra, og utfel-les derfor i visse tilfeller fra modervæsken spontant. Utfel-lingen kan aktiveres ved avkjøling av modervæsken, fortrinnsvis til en temperatur på 0 - 5° C. Alternativt kan inklusjonskomplekset separeres ved lyofilisering av modervæsken. According to a preferred embodiment of the process, the solutions are mixed at an elevated temperature, preferably at 40 - 70° C. The inclusion complex formed is less soluble in the mother liquor than the compounds from which it is produced, and is therefore precipitated from the mother liquor spontaneously in certain cases. The precipitation can be activated by cooling the mother liquor, preferably to a temperature of 0 - 5° C. Alternatively, the inclusion complex can be separated by lyophilization of the mother liquor.
Selv om a-, (3- og ycyclodextrin og eventuelt blan-dinger derav er like egnet for formålet, foretrekkes (3-cyclodextrin. Although α-, β-, β- and β-cyclodextrin and possibly mixtures thereof are equally suitable for the purpose, β-cyclodextrin is preferred.
Allycin løses i vannblandbare løsningsmidler. For dette formål anvendes fortrinnsvis lavere alkanoler og ketoner, men også andre vann-blandbare løsningsmidler såvel som blan-dinger av to eller flere av disse kan anvendes. Allycin løses fortrinnsvis i ethanol. Allycin dissolves in water-miscible solvents. For this purpose, lower alkanols and ketones are preferably used, but other water-miscible solvents as well as mixtures of two or more of these can also be used. Allycin is preferably dissolved in ethanol.
De fysiologisk aktive inklusjonskomplekser fremstilt som ovenfor beskrevet, kan overføres til konvensjonelle farma-søytiske komposisjoner på i og foe seg kjent måte, med formu-lering med en farmasøytisk akseptabel bærer eller exipient. Disse komposisjoner omfatter således inklusjonskompleksene ifølge oppfinnelsen i forbindelse med konvensjonelle exipien-ter, fortynningsmidler.og/eller andre additiver, og kan administreres som tabletter, kapsler, dragéer, suspensjoner, emulsjoner, løsninger, pulvere og/eller forstøvningsmidler. The physiologically active inclusion complexes produced as described above can be transferred to conventional pharmaceutical compositions in a known manner, with formulation with a pharmaceutically acceptable carrier or excipient. These compositions thus comprise the inclusion complexes according to the invention in connection with conventional excipients, diluents and/or other additives, and can be administered as tablets, capsules, dragees, suspensions, emulsions, solutions, powders and/or nebulizers.
Oppfinnelsen illustreres ytterligere i de etterføl-gende eksempler. The invention is further illustrated in the following examples.
Eksempel 1Example 1
10 g 3-cyclodextrin (vanninnhold: 11,4 %) ble løst10 g of 3-cyclodextrin (water content: 11.4%) was dissolved
i 180 ml vann ved 50° C under kontinuerlig omrøring mens nitro-gengass ble boblet gjennom løsningen. 1,45 g allycin ble løst i 5 ml 96 % ethanol, og den erholdte løsning ble langsomt til-satt til den vandige løsning av [3-cyclodextrin. Blandingen ble avkjølt til romtemperatur i løpet av 4 timer med en kon-stant hastighet og holdt ved 0° C i 16 timer. Det utfelte ■ faste materiale ble filtrert fra og lufttørket, under dannelse av 11,02 g av et hvitt mikrokrystallinsk materiale som hadde en svak hvitløkduft. Ifølge gasskromatografi inneholder produktet 10,12 % allycin. Utbytte beregnet for cyclodexrrin: 99,1 % in 180 ml of water at 50° C. with continuous stirring while nitrogen gas was bubbled through the solution. 1.45 g of allicin was dissolved in 5 ml of 96% ethanol, and the resulting solution was slowly added to the aqueous solution of [3-cyclodextrin. The mixture was cooled to room temperature over 4 hours at a constant rate and held at 0°C for 16 hours. The precipitated solid was filtered off and air-dried to yield 11.02 g of a white microcrystalline material having a faint garlic odor. According to gas chromatography, the product contains 10.12% allicin. Yield calculated for cyclodextrin: 99.1%
Utbytte beregnet for allycin: 76,5 %Yield calculated for allycin: 76.5%
Allycin er blitt fremstilt syntetisk etter den metode som er beskrevet i J.Am. Chem. Soc. 6_6 , 1950 (1944). Allycin has been produced synthetically according to the method described in J. Am. Chem. Soc. 6_6 , 1950 (1944).
Produktet har følgende fysikalske karakteristika: Kornstørrelse: 8-11 mikrometer The product has the following physical characteristics: Grain size: 8-11 micrometres
Løselighet i vann: 0,82 g/100 ml ved 25° CSolubility in water: 0.82 g/100 ml at 25° C
Løselighet i ethanol: 0,080 g/100 ml ved 25° C Inklusjonskomplekset er ubegrenset løselig i dimethylformamid og dimethylsulfoxyd. Solubility in ethanol: 0.080 g/100 ml at 25° C. The inclusion complex is infinitely soluble in dimethylformamide and dimethylsulfoxide.
Tynnskiktskromatografi utført på en kieselgel G-plate (Merck) med kloroform gir følgende resultater: Rf = 0,33 (allycin) og Rf = 0,89 (diallyldisulfid). Thin layer chromatography performed on a silica gel G plate (Merck) with chloroform gives the following results: Rf = 0.33 (allycin) and Rf = 0.89 (diallyl disulfide).
Fordelingskromatografi ble utført .med en 5:5:1 blanding av carbontetraklorid, methanol og vann og gir følgen-de resultater: Rf = 0,21 (allycin) og Rf = 0,87 (diallyldisulfid). Kromatogrammer ble fremkalt i joddamp eller med en 1:1 blanding av en 2 %-ig FeCl3og 1 %-ig I<3 [Fe (CN) g]-reaktant. Partition chromatography was carried out with a 5:5:1 mixture of carbon tetrachloride, methanol and water and gives the following results: Rf = 0.21 (allycin) and Rf = 0.87 (diallyl disulphide). Chromatograms were developed in iodine vapor or with a 1:1 mixture of a 2% FeCl3 and 1% I<3 [Fe (CN) g] reactant.
Den aktive bestanddels konsentrasjon av produktet bestemmes fortrinnsvis ved gasskromatografi på en kolonne. The active ingredient concentration of the product is preferably determined by gas chromatography on a column.
Som løsningsmiddel anvendes diethylether, og temperaturen he-ves fra en begynnelsesverdi på 80° C i en hastighet på 10°C/ min. Injektortemperatur: 250° C, detektortemperatur: 300° C (flammionisering). Bærergass: nitrogen, strømningshastighet: 21 ml/min. Diethyl ether is used as solvent, and the temperature is raised from an initial value of 80°C at a rate of 10°C/min. Injector temperature: 250° C, detector temperature: 300° C (flame ionization). Carrier gas: nitrogen, flow rate: 21 ml/min.
RT-verdier: 3,13 (diallyldisulfid)RT values: 3.13 (diallyl disulfide)
5,83 (allycin)5.83 (allycin)
8,51 og 8,69 (ukjente forbindelser med en høyere molekylvekt, sannsynligvis tri- og polysulfider). 8.51 and 8.69 (unknown compounds with a higher molecular weight, probably tri- and polysulfides).
Inklusjonskomplekset av allycin har en RT-verdi på 5,80 under de ovenfor angitte betingelser. The inclusion complex of allycin has an RT value of 5.80 under the above conditions.
Ved røntgendiffraksjonsanalyse av et pulver av 3-cyclodextrin og av et inklusjonskompleks av 3-cyclodextrin og allycin, erholdes etter krystallisering utført under samme betingelser, følgende karakteristiske refleksjonstopper: In X-ray diffraction analysis of a powder of 3-cyclodextrin and of an inclusion complex of 3-cyclodextrin and allicin, after crystallization carried out under the same conditions, the following characteristic reflection peaks are obtained:
Eksempel 2 Example 2
Prosedyren beskrevet i eksempel 1 ble gjentatt, men det krystallinske inklusjonskompleks ble fraskilt fra løsnin-gen ved frysetørking. Det lyofiliserte produkt er et finopp-delt kornaktig materiale, og har bare en svak, knapt luktbar hvitløkduft da det bare er en meget liten mengde av allycin som adsorberes på overflaten av komplekset ved anvendelse av denne teknikk. The procedure described in Example 1 was repeated, but the crystalline inclusion complex was separated from the solution by freeze-drying. The lyophilized product is a finely divided granular material, and has only a faint, barely perceptible garlic odor as only a very small amount of allicin is adsorbed on the surface of the complex using this technique.
Ifølge litteraturdata [Oyo Yakuri 10, 449 (1975)] bevirker. (3-cyclodextrin når den administreres til rotter i en daglig dose på 1,6 g/kg i 6 måneder, ingen toksiske bivirk-ninger . According to literature data [Oyo Yakuri 10, 449 (1975)] effects. (3-cyclodextrin when administered to rats in a daily dose of 1.6 g/kg for 6 months, no toxic side effects.
LDj-q for allycin i rotter: 0,6 g/kg [Heiv. Chim. Acta 31, .189 (1948) ] . LDj-q for allycin in rats: 0.6 g/kg [Heiv. Chim. Acta 31, .189 (1948) ] .
Mikrobiologiske testerMicrobiological tests
Mikrobiologiske tester ble utført med løsninger av allycin og inklusjonskomplekser av allycin med 3_cyclodextrin, i en blanding av ethanol, methanol og "Tween 80". Inklusjonskomplekser av allycin med (B-cyclodextrin ble også testet på den måte at de ble oppløst i dimethylsulfoxyd og den erholdte løsning ble fortynnet med methanol til den ønskede konsentrasjon. De samme.resultater ble erholdt som med den første løs-ningsmiddelblanding. Den observasjon at noe høyere konsentra-sjoner er nødvendig for å oppnå de samme resultater når allycin administreres i form av dets inklusjonskompleks enn i det tilfelle allycin administreres alene, skyldes det faktum at en del av den aktive bestanddel er til stede som et kompleks selv i løsningene. Stabilitetsforsøk viste at inklusjonskomplekser av allycin har en øket stabilitet som muliggjør at disse er effektive i lengre tid. Microbiological tests were carried out with solutions of allycin and inclusion complexes of allycin with 3_cyclodextrin, in a mixture of ethanol, methanol and "Tween 80". Inclusion complexes of allycin with (B-cyclodextrin) were also tested in such a way that they were dissolved in dimethylsulfoxide and the resulting solution was diluted with methanol to the desired concentration. The same results were obtained as with the first solvent mixture. The observation that somewhat higher concentrations are required to achieve the same results when allicin is administered in the form of its inclusion complex than when allicin is administered alone, due to the fact that part of the active ingredient is present as a complex even in the solutions. showed that inclusion complexes of allycin have an increased stability which enables them to be effective for a longer time.
Antibakteriell aktivitet er illustrert i tabell I - IV hvor følgende forkortelser anvendes: Antibacterial activity is illustrated in Tables I - IV where the following abbreviations are used:
CCM: Czechoslovak Collection of MicroorganismsCCM: Czechoslovak Collection of Microorganisms
DSM: Deutsche Sammlung flir MikroorganismenDSM: Deutsche Sammlung flir Mikroorganismen
ATCC: American Type Culture CollectionATCC: American Type Culture Collection
Tester ble vurdert under anvendelse av følgende skala: Tests were rated using the following scale:
0 = ingen vekst (total inhibering)0 = no growth (total inhibition)
+ = meget svak vekst+ = very weak growth
+ = svak vekst+ = weak growth
++ = middels vekst++ = medium growth
+++ = sterk vekst (ingen inhibering) +++ = strong growth (no inhibition)
Antifungal aktivitet er illustrert ved de data som er angitt i Tabell V - X, hvor følgende ytterligere forkortelser anvendes: CBS = Cantralbureau voor Schimmelcultures, Båar, Antifungal activity is illustrated by the data indicated in Tables V - X, where the following additional abbreviations are used: CBS = Cantralbureau voor Schimmelcultures, Båar,
NetherlandNetherlands
OKI = Orszågos Kozegészségiigyi Intézet, Budapest OKI = Orszågos Kozegészségiigyi Intézet, Budapest
Eksempel 3 Example 3
Tablett inneholdende 150 mg allycin-cyclodextrin-kompleks Tablet containing 150 mg of allycin-cyclodextrin complex
Tablettene fremstilles på kjent måte. Blandingen inneholdende de ovenfor angitte bestanddeler granuleres tre etterfølgende ganger før omdannelse til tabletter. The tablets are produced in a known manner. The mixture containing the above-mentioned ingredients is granulated three consecutive times before being transformed into tablets.
Eksempel 4Example 4
Enteroløselige dragéerEnteric-soluble dragees
Tabletter fremstilt ifølge eksempel 3 ble overført til belagte.enteroløselige dragéer. Belegget kan om ønsket også inneholde forskjellige pigmenter med farver som indike-rer konsentrasjonen av den aktive bestanddel. Tablets prepared according to Example 3 were transferred to coated enteric dragees. If desired, the coating can also contain different pigments with colors that indicate the concentration of the active ingredient.
Eksempel 5Example 5
En homogen pulverblanding ble fremstilt på kjent måte . A homogeneous powder mixture was prepared in a known manner.
Blandingen ble fylt i strøbokser. The mixture was filled into litter boxes.
Claims (10)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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HU78CI1871A HU177081B (en) | 1978-12-12 | 1978-12-12 | Process for preparing the occlusion complex of allicin with cyclodextrin |
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Publication Number | Publication Date |
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NO794044L true NO794044L (en) | 1980-06-13 |
Family
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NO794044A NO794044L (en) | 1978-12-12 | 1979-12-11 | PROCEDURE FOR PREPARING INCLUSION COMPLEXES OF ALLYCIN WITH CYCLODEXTRINES |
Country Status (11)
Country | Link |
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JP (1) | JPS55115866A (en) |
AT (1) | AT363492B (en) |
CH (1) | CH642347A5 (en) |
DE (1) | DE2948869A1 (en) |
DK (1) | DK526779A (en) |
FR (1) | FR2444060A1 (en) |
GB (1) | GB2061987B (en) |
HU (1) | HU177081B (en) |
NO (1) | NO794044L (en) |
SU (1) | SU938732A3 (en) |
YU (1) | YU299079A (en) |
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HU184066B (en) | 1979-12-28 | 1984-06-28 | Chinoin Gyogyszer Es Vegyeszet | Plant growth regulating substance and process for preparing such compound |
JPS5920230A (en) * | 1982-07-19 | 1984-02-01 | チバ−ガイギ−・アクチエンゲゼルシヤフト | Drug containing piruprophen |
FR2550193A1 (en) * | 1983-08-05 | 1985-02-08 | Sal Fine Chemicals Internation | Inclusion complexes of methyl and allyl trisulphide with cyclodextrins, process for preparing them and pharmaceutical compositions containing them |
HU196230B (en) * | 1983-12-29 | 1988-10-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing water-soluble forms of polyene antibiotics and pharmaceutics comprising such active ingredient and plant protective with antifungal effect |
US4678598A (en) * | 1985-08-06 | 1987-07-07 | Kao Corporation | Liquid shampoo composition |
DE3638290A1 (en) * | 1986-11-07 | 1988-05-19 | Herbe Wirkstoffe Gmbh | Pharmaceutical composition |
US4774329A (en) * | 1987-08-04 | 1988-09-27 | American Maize-Products Company | Controlled release agent for cetylpyridinium chloride |
EP0392608B1 (en) * | 1989-04-12 | 1995-06-28 | The Procter & Gamble Company | Solid consumer product compositions containing small particle cyclodextrin complexes |
SE8902235D0 (en) * | 1989-06-20 | 1989-06-20 | Haessle Ab | NOVEL CYCLODEXTRIN INCLUSION COMPLEXES |
CA2013485C (en) * | 1990-03-06 | 1997-04-22 | John Michael Gardlik | Solid consumer product compositions containing small particle cyclodextrin complexes |
DE4024155C2 (en) * | 1990-07-30 | 1995-12-07 | Marcela Dipl Ing Holzhey | Use of an "Allicin-Urotropin" product for the area of internal treatment (oral, injections and continuous drip infusions) of humans and animals for fungal diseases |
DE4338508A1 (en) * | 1993-11-11 | 1995-05-18 | Asta Medica Ag | Pharmaceutical preparations containing thioctic acid or dihydroliponic acid in the form of inclusion compounds with cyclodextrins or cyclodextrin derivatives and in the form of granules, chewable or effervescent tablets |
DE19500863A1 (en) * | 1995-01-13 | 1996-07-18 | Consortium Elektrochem Ind | Method of making ajoes |
GB0120887D0 (en) * | 2001-08-29 | 2001-10-17 | Sahajanand Biotech Private Ltd | Local drug delivery system in coronary stents |
GB0122793D0 (en) * | 2001-09-21 | 2001-11-14 | Stone Island Holdings Ltd | Allicin |
US20070160725A1 (en) * | 2004-03-03 | 2007-07-12 | Mousala, S., L. | Use of extracts and compounds of allium-genus plants as preservatives in the food and agri-food industries |
GB0422582D0 (en) * | 2004-10-11 | 2004-11-10 | Nasaleze Patents Ltd | Pharmaceutical compositions |
CN107789345B (en) * | 2016-09-07 | 2022-06-28 | 汤臣倍健股份有限公司 | Corrective allicin-cyclodextrin compound and preparation method thereof |
CN107802842B (en) * | 2016-09-07 | 2022-04-12 | 汤臣倍健股份有限公司 | Allicin flavouring preparation and its preparation method |
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US3061444A (en) * | 1960-10-07 | 1962-10-30 | Gen Foods Corp | Inclusion compounds incorporating edible juice constituents |
HU174699B (en) * | 1977-07-01 | 1980-03-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing cyclodextrin inclusion complexes of natural and synthetic spices, aromatic and flavoring materials |
-
1978
- 1978-12-12 HU HU78CI1871A patent/HU177081B/en unknown
-
1979
- 1979-12-05 DE DE19792948869 patent/DE2948869A1/en active Granted
- 1979-12-10 FR FR7930212A patent/FR2444060A1/en active Granted
- 1979-12-10 YU YU02990/79A patent/YU299079A/en unknown
- 1979-12-11 CH CH1097979A patent/CH642347A5/en not_active IP Right Cessation
- 1979-12-11 SU SU792854753A patent/SU938732A3/en active
- 1979-12-11 GB GB7942695A patent/GB2061987B/en not_active Expired
- 1979-12-11 NO NO794044A patent/NO794044L/en unknown
- 1979-12-11 DK DK526779A patent/DK526779A/en not_active Application Discontinuation
- 1979-12-12 AT AT0782979A patent/AT363492B/en not_active IP Right Cessation
- 1979-12-12 JP JP16140379A patent/JPS55115866A/en active Granted
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AT363492B (en) | 1981-08-10 |
CH642347A5 (en) | 1984-04-13 |
FR2444060A1 (en) | 1980-07-11 |
JPS642105B2 (en) | 1989-01-13 |
YU299079A (en) | 1983-06-30 |
DE2948869A1 (en) | 1980-07-03 |
FR2444060B1 (en) | 1984-06-29 |
DK526779A (en) | 1980-06-13 |
GB2061987A (en) | 1981-05-20 |
DE2948869C2 (en) | 1992-07-09 |
ATA782979A (en) | 1981-01-15 |
GB2061987B (en) | 1983-05-18 |
SU938732A3 (en) | 1982-06-23 |
JPS55115866A (en) | 1980-09-06 |
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