NO321076B1 - Pharmaceutical preparation for oral administration containing cyclosporin - Google Patents
Pharmaceutical preparation for oral administration containing cyclosporin Download PDFInfo
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- NO321076B1 NO321076B1 NO19954152A NO954152A NO321076B1 NO 321076 B1 NO321076 B1 NO 321076B1 NO 19954152 A NO19954152 A NO 19954152A NO 954152 A NO954152 A NO 954152A NO 321076 B1 NO321076 B1 NO 321076B1
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- pharmaceutical preparation
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- cyclosporine
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- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 title claims abstract description 22
- 108010036949 Cyclosporine Proteins 0.000 title claims abstract description 22
- 229930182912 cyclosporin Natural products 0.000 title claims abstract description 22
- 229960001265 ciclosporin Drugs 0.000 title claims abstract description 20
- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 18
- 229930105110 Cyclosporin A Natural products 0.000 title claims description 3
- 239000000203 mixture Substances 0.000 claims abstract description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229920005862 polyol Polymers 0.000 claims abstract description 5
- 235000015112 vegetable and seed oil Nutrition 0.000 claims abstract description 5
- 239000008158 vegetable oil Substances 0.000 claims abstract description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000004721 Polyphenylene oxide Substances 0.000 claims abstract description 4
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 4
- 229920001515 polyalkylene glycol Polymers 0.000 claims abstract description 4
- 229920000570 polyether Polymers 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000002360 preparation method Methods 0.000 claims description 26
- 239000004480 active ingredient Substances 0.000 claims description 12
- -1 alkylene ester Chemical class 0.000 claims description 9
- 125000005456 glyceride group Chemical group 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- 239000000654 additive Substances 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- 229920002535 Polyethylene Glycol 1500 Polymers 0.000 claims description 5
- 239000008172 hydrogenated vegetable oil Substances 0.000 claims description 5
- VUYXVWGKCKTUMF-UHFFFAOYSA-N tetratriacontaethylene glycol monomethyl ether Chemical compound COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO VUYXVWGKCKTUMF-UHFFFAOYSA-N 0.000 claims description 5
- 239000004359 castor oil Substances 0.000 claims description 3
- 235000019438 castor oil Nutrition 0.000 claims description 3
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 3
- 229930195729 fatty acid Natural products 0.000 claims description 3
- 239000000194 fatty acid Substances 0.000 claims description 3
- 239000007903 gelatin capsule Substances 0.000 claims description 3
- 235000011187 glycerol Nutrition 0.000 claims description 3
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 3
- 239000000314 lubricant Substances 0.000 claims description 3
- 239000003981 vehicle Substances 0.000 claims description 3
- 235000019482 Palm oil Nutrition 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 claims description 2
- 150000004665 fatty acids Chemical class 0.000 claims description 2
- 239000002540 palm oil Substances 0.000 claims description 2
- 239000003755 preservative agent Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 239000002562 thickening agent Substances 0.000 claims description 2
- 239000000796 flavoring agent Substances 0.000 claims 1
- 239000003346 palm kernel oil Substances 0.000 claims 1
- 235000019865 palm kernel oil Nutrition 0.000 claims 1
- 239000003381 stabilizer Substances 0.000 claims 1
- 239000013543 active substance Substances 0.000 abstract description 10
- 150000003077 polyols Chemical class 0.000 abstract description 2
- 150000002009 diols Chemical class 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 229920000728 polyester Polymers 0.000 abstract 1
- 108010036941 Cyclosporins Proteins 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- 208000027866 inflammatory disease Diseases 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 229960003444 immunosuppressant agent Drugs 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 208000010362 Protozoan Infections Diseases 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 229940125687 antiparasitic agent Drugs 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000002875 fluorescence polarization Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000012153 long-term therapy Methods 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000003589 nefrotoxic effect Effects 0.000 description 1
- 231100000381 nephrotoxic Toxicity 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000011253 protective coating Substances 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 210000003752 saphenous vein Anatomy 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
Abstract
Description
J. J.
Oppfinnelsen vedrører nye farmasøytiske preparater for oral administrasjon inne-holdende cyklosporin som virkestoff. The invention relates to new pharmaceutical preparations for oral administration containing cyclosporine as active ingredient.
Cyklosporiner er en klasse peptider som spesielt anvendes som immunsuppressiver. Dessuten er det kjent at cyklosporiner oppviser en inflammasjonshemmende og anti-parasitær virkning. Anvendelse av cyklosporiner er derfor ikke begrenset bare til immunsuppressiver, men vedrører alle inflammasjonssykdommer inklusive forskjellige autoimmunsykdommer samt ytterligere inflammatoriske tilstander, spesielt inflammatoriske sykdommer hvor autoimmunprosesser spiller en rolle. Til de tidligere nevnte inflammatoriske sykdommer regnes spesielt også artrittiske sykdommer, så som rev-matoid artritt samt revmatiske sykdommer. Som antiparasittmiddel kan cyklosporiner anvendes f.eks. for behandling av protozo-infeksjoner, så som f.eks. malaria. Cyclosporins are a class of peptides that are particularly used as immunosuppressants. In addition, it is known that cyclosporins exhibit an anti-inflammatory and anti-parasitic effect. The use of cyclosporins is therefore not limited to immunosuppressants, but concerns all inflammatory diseases including various autoimmune diseases as well as further inflammatory conditions, especially inflammatory diseases where autoimmune processes play a role. Among the previously mentioned inflammatory diseases, arthritic diseases, such as rheumatoid arthritis and rheumatic diseases, are also considered in particular. As an antiparasitic agent, cyclosporins can be used, e.g. for the treatment of protozoan infections, such as e.g. malaria.
Cyklosporiner er sterkt hydrofobe substanser med den følge at det er vanskelig å bear-beide dem videre på en enkel måte til farmasøytiske preparater som videre sikrer tilstrekkelig biotilgjengelighet. Sistnevnte aspekt er spesielt viktig med hensyn til dette, fordi cyklosporinene innehar nefrotoksiske bivirkninger av vesentlig betydning. Hittil foreslåtte cyklospoirnholdige farmasøytiske preparater baserer seg på anvendelse av en alkohol og/eller oljer eller lignende vehikler sammen med et overflateaktivt middel. Sådanne preparater er f.eks. kjent fra DE-OS 29 07 460. Anvendelse av sådanne flytende preparater er dog forbundet med en rekke ulemper og vanskeligheter. Anvendelse av oljer eller dermed sammenlignbare bærerstoffer på oljebasis fører spesielt ved lengre anvendelsestid i rammen av en langtidsterapi til smaksforringelser. Da det for oppløsning av virkestoffet er nødvendig med en høy alkoholandel, medfører dette nødvendigvis at det dessuten tilføres pasienten alkohol permanent, og ved fordampning av alkoholen innenfor rammen av lengre bruk faller virkestoffet ut. Også forsøk på å fremstille slike preparater i form av bløtgelatinkapsler, førte på grunn av de dermed forbundne høyere omkostninger ikke til en tilfredsstillende løsning. Cyclosporins are strongly hydrophobic substances with the consequence that it is difficult to process them further in a simple way into pharmaceutical preparations which further ensure sufficient bioavailability. The latter aspect is particularly important in this respect, because the ciclosporins have significant nephrotoxic side effects. Hitherto proposed cyclosporine-containing pharmaceutical preparations are based on the use of an alcohol and/or oils or similar vehicles together with a surface-active agent. Such preparations are e.g. known from DE-OS 29 07 460. The use of such liquid preparations is, however, associated with a number of disadvantages and difficulties. The use of oils or thus comparable oil-based carriers leads to taste deterioration, especially in the case of a longer period of use in the context of a long-term therapy. As a high proportion of alcohol is necessary for the dissolution of the active substance, this necessarily means that alcohol is also permanently supplied to the patient, and when the alcohol evaporates within the framework of prolonged use, the active substance falls out. Attempts to produce such preparations in the form of soft gelatin capsules also did not lead to a satisfactory solution due to the associated higher costs.
DE-OS 40 03 844 foreslår et preparatsystem som i tillegg til virkestoffet inneholder en fettsyresakkaridmonoester og et fortynningsmiddel eller bærerstoff, med hvilket det skal være mulig å tilveiebringe faste, halvfaste og flytende preparater med et innhold av cyklosporin i tilstrekkelig høy konsentrasjon, slik at en bekvem oral administrasjon er mulig og det oppnås forbedret virkning f.eks. med hensyn til biotilgjengelighet. Dessuten inneholder disse administrasjonsformer i tillegg til virkestoffet minst to ytterligere komponenter. DE-OS 40 03 844 proposes a preparation system which, in addition to the active substance, contains a fatty acid saccharide monoester and a diluent or carrier substance, with which it should be possible to provide solid, semi-solid and liquid preparations with a content of cyclosporine in a sufficiently high concentration, so that a convenient oral administration is possible and an improved effect is achieved, e.g. with regard to bioavailability. In addition to the active substance, these forms of administration also contain at least two further components.
Søkeren har nå overraskende funnet et preparatsystem for oral administrasjon, hvormed det er mulig å tilveiebringe en cyklospoirnholdig farmasøytisk preparat for orale administrasjon, hvilken preparat inneholder bare én bærerkomponent i tillegg til virkestoffet. Denne komponent er en alkylenpolyeter eller -ester eller en vilkårlig blanding derav, hvor bærersystemet må oppvise en HLB-verdi på minst 10. De oppfinnelsesmessige preparater gir en virkestoffbiotilgjengelighet som kan sammenlignes med de beste kjente cyklospoirnho Idige tilbedninger. The applicant has now surprisingly found a preparation system for oral administration, with which it is possible to provide a cyclosporine-containing pharmaceutical preparation for oral administration, which preparation contains only one carrier component in addition to the active ingredient. This component is an alkylene polyether or ester or an arbitrary mixture thereof, where the carrier system must exhibit an HLB value of at least 10. The inventive preparations provide an active substance bioavailability that can be compared with the best known cyclosporine preparations.
De oppfinnelsesmessige farmasøytiske preparater kan ved sammenlignbar god biotilgjengelighet fremstilles billigere, tilsetninger som påvirker smaken og ufordelaktig alkoholinnhold kan unngås, og de fører til en bedre pasientfordragelighet i den forstand at den inntatte preparatform ved lik virkestoffkonsentrasjon er redusert i totalvekt sammenlignet med kjente preparater. With comparably good bioavailability, the pharmaceutical preparations according to the invention can be produced more cheaply, additives that affect the taste and disadvantageous alcohol content can be avoided, and they lead to better patient tolerability in the sense that the ingested preparation form with the same active ingredient concentration is reduced in total weight compared to known preparations.
Oppfinnelsen vedrører således farmasøytisk preparat for oral administrasjon, kjennetegnet ved at det består av: The invention thus relates to a pharmaceutical preparation for oral administration, characterized in that it consists of:
a) et cyklosporin som aktiv ingrediens, og a) a ciclosporin as active ingredient, and
b) en alkylenpolyeter eller alkylenester, enten alene eller i en hvilken som helst blanding b) an alkylene polyether or alkylene ester, either alone or in any mixture
som en vehikel, hvori HLB til komponent (b) som anvendes er minst 10. as a vehicle, in which the HLB of component (b) used is at least 10.
Oppfinnelsen vedrører også farmasøytisk preparat for oral administrasjon, kjennetegnet ved at det inneholder The invention also relates to a pharmaceutical preparation for oral administration, characterized in that it contains
(a) et cyklosporin som aktiv ingrediens, og (a) a cyclosporine as active ingredient, and
(bl) et mettet polyglykolisert glycerid oppnådd ved polyglykolyse av naturlige hydrogenene vegetabilske oljer med PEG, særlig PEG 1500, og som har en HLB-verdi på minst 10, eller en hvilken som helst blanding, hvorved HLB til komponenten (b) som (bl) a saturated polyglycolized glyceride obtained by polyglycolysis of naturally hydrogenated vegetable oils with PEG, in particular PEG 1500, and which has an HLB value of at least 10, or any mixture, whereby the HLB of component (b) as
anvendes er minst 10, med den betingelsen at preparatet ikke inneholder fettsyresakkarosemonoester. used is at least 10, with the condition that the preparation does not contain fatty acid sucrose monoester.
Oppfinnelsen angår også farmasøytisk preparat for oral administrasjon, kjennetegnet ved at det inneholder The invention also relates to a pharmaceutical preparation for oral administration, characterized in that it contains
(a) et cyklosporin som aktiv ingrediens, og (a) a cyclosporine as active ingredient, and
(bl) et mettet polyglykolisert glycerid oppnådd ved polyglykolyse av naturlige hydrogenene vegetabilske oljer med PEG, særlig PEG 1500, og som har en HLB-verdi på minst 10, og (c) en alkylenpolyol, en alkylenglykol, en polyalkylenglykol, en alkyldieter eller delvis eter av et C2-C15 monooksyalkandiol eller polyoksyalkandiol og/eller en vegetabilsk olje eller dens hydratiserte eller hydrolyserte produkt, enten alene eller i en hvilken som helst blanding. (bl) a saturated polyglycolized glyceride obtained by polyglycolysis of natural hydrogenated vegetable oils with PEG, in particular PEG 1500, and which has an HLB value of at least 10, and (c) an alkylene polyol, an alkylene glycol, a polyalkylene glycol, an alkyl dieter or partially ether of a C2-C15 monooxyalkanediol or polyoxyalkanediol and/or a vegetable oil or its hydrated or hydrolysed product, either alone or in any mixture.
Videre kan de oppfinnelsesmessige preparater inneholde ytterligere kjente, vanlige og farmasøytisk akseptable tilsetningsstoffer (d) som er kjent på området fremstilling av orale preparatformer. Furthermore, the inventive preparations may contain further known, common and pharmaceutically acceptable additives (d) which are known in the field of the production of oral preparation forms.
De oppfinnelsesmessige preparater inneholder i vektandeler pr. vektdel virkestoff 1-50 vektdeler av (b) hhv. 0,5-20 vektdeler (c), fortrinnsvis pr. 1 del virkestoff 5-10 vektdeler (b) hhv. 1-10 vektdeler (c) og spesielt pr. 1 vektdel virkestoff 5 vektdeler (b) hhv. 1 vektdel (c). The preparations according to the invention contain in proportions by weight per part by weight active substance 1-50 parts by weight of (b) or 0.5-20 parts by weight (c), preferably per 1 part active substance 5-10 parts by weight (b) or 1-10 parts by weight (c) and especially per 1 part by weight active substance 5 parts by weight (b) or 1 part by weight (c).
Vedrørende komponent (b) dreier det seg med fordel om C3- til Cs-alkylentriol-, spesielt glyserin, -eter eller -ester. Til disse regnes f.eks. også omestringsprodukter av alkylentri-olestere med andre mono-, di- eller polyoler samt de substanser som er beskrevet i DE-OS 40 03 844 under avsnittet "komponent C<5>". Spesielt fordelaktige er mettede polyglykoliserte glycerider som oppviser en HLB-verdi på minst 10. Fortrinnsvis anvendes de under varebetegnelsen gelucirer (betegnelsen gelucirer er en varebetegnelse fra fabrik-ken Gattefossé) kjente mettede polyglykoliserte glyserider og spesielt Gelucir®35/10, 44/14, 42/12, 50/13, 53/10 samt vilkårlige blandinger derav, hvorved HLB-verdien av den anvendte bærerkomponent er minst 10. Regarding component (b), it is advantageously a C3 to C5 alkylene triol, especially glycerine, ether or ester. These include e.g. also transesterification products of alkylene triol esters with other mono-, di- or polyols as well as the substances described in DE-OS 40 03 844 under the section "component C<5>". Particularly advantageous are saturated polyglycolized glycerides that exhibit an HLB value of at least 10. Preferably, known saturated polyglycolized glycerides are used under the trade name gelucir (the term gelucir is a trade name from the factory Gattefossé) and especially Gelucir®35/10, 44/14, 42/12, 50/13, 53/10 as well as arbitrary mixtures thereof, whereby the HLB value of the carrier component used is at least 10.
Den fakultative komponent (c) omfatter f.eks. dietere eller partialetere av lavmolekylære (C2-i2)mono- eller polyoksyalkandioler som er beskrevet i DE-OS 39 30 928 i avsnittet vedrørende komponent 1.1. Den fakultative komponent (c) omfatter videre C3_5-alkylen-polyoler, C2-4-alkylenglykoler, poly-(C2-4-alkylen)-glykoler og planteoljer samt deres hydrerings- og/eller hydrolyseprodukter, så som ricinusolje, olivenolje, palmeolje, ko-kosolje, maisolje, sesamolje. Komponent (c) kan foreligge som enkeltsubstans eller i vilkårlige blandinger. Foretrukne eksempler for komponent (c) er glyserin, propylenglykol og polyalkylenglykoler med en molekylvekt inntil spesielt 600, transcutol og ricinusolje og dens hydrerte og hydrolyserte produkter. The facultative component (c) includes e.g. diethers or partial ethers of low molecular weight (C2-i2) mono- or polyoxyalkanediols which are described in DE-OS 39 30 928 in the section regarding component 1.1. The optional component (c) further comprises C3-5-alkylene polyols, C2-4-alkylene glycols, poly-(C2-4-alkylene)-glycols and vegetable oils as well as their hydration and/or hydrolysis products, such as castor oil, olive oil, palm oil, cow-cow oil, corn oil, sesame oil. Component (c) can be present as a single substance or in arbitrary mixtures. Preferred examples for component (c) are glycerin, propylene glycol and polyalkylene glycols with a molecular weight up to especially 600, transcutol and castor oil and its hydrogenated and hydrolysed products.
Vedrørende de ytterligere anvendelige tilsetningsstoffer dreier det seg om farmasøytisk akseptable tilsetningsstoffer som er vanlige på området orale administrasjonsformer. Eksempler på disse er stoffer som styrer frigivelsen, fortykningsmidler, konserveringsmidler, bindemidler, glidemidler og lignende. Andelen av disse tilsetningsstoffer kan utgjøre inntil 50% av den totale sammensetning, men utgjør fortrinnsvis ikke mer enn 25%, spesielt ikke mer enn 10%, av den totale sammensetning. Regarding the additional usable additives, these are pharmaceutically acceptable additives which are common in the field of oral administration forms. Examples of these are substances that control the release, thickeners, preservatives, binders, lubricants and the like. The proportion of these additives can make up to 50% of the total composition, but preferably make up no more than 25%, especially no more than 10%, of the total composition.
Egnet for anvendelse i de oppfinnelsesmessige preparater er alle kjente naturlige og syntetiske cyklosporiner inklusive deres analoger og derivater. Eksempler på sådanne cyklosporiner befinner seg i DE-OS 40 03 844 og DE-OS 40 05 190. Fortrinnsvis anvendes cyklosporin A. Suitable for use in the inventive preparations are all known natural and synthetic cyclosporins including their analogues and derivatives. Examples of such cyclosporins can be found in DE-OS 40 03 844 and DE-OS 40 05 190. Cyclosporin A is preferably used.
Blant de orale administrasjonsformer regnes f.eks. væsker, granulater og faste former så som tabletter og kapsler som kan fremstilles ifølge for fagmannen kjente og vanlige fremgangsmåter. Among the oral forms of administration are e.g. liquids, granules and solid forms such as tablets and capsules which can be prepared according to methods known and common to the person skilled in the art.
De oppfinnelsesmessige orale administrasjonsformer foreligger normalt som enhetsdo-seform og inneholder ca 20-200 mg, fortrinnsvis 50 eller 100 mg virkestoff, pr. enhets-dose. The oral administration forms according to the invention are normally available as unit dosage form and contain approximately 20-200 mg, preferably 50 or 100 mg of active ingredient, per unit dose.
Følgende eksempler tjener som ytterligere illustrasjon av oppfinnelsen. The following examples serve as further illustration of the invention.
Fremstilling: Sammensetningene fra eksemplene 1-9 fremstilles ved at komponent (b) smeltes under oppvarming, fortrinnsvis ved minst 60°C, og deri oppløses virkestoff (a). Eventuelt tilsettes til smeiten den fakultative komponent (c). Preparation: The compositions from examples 1-9 are prepared by melting component (b) under heating, preferably at at least 60°C, and dissolving active ingredient (a) therein. Optionally, the facultative component (c) is added to the mixture.
De erholdte preparater fylles deretter f.eks. i flytende form i hardgelatinkapsler av ønsket størrelse i den ønskede konsentrasjon. Sammensetningene kan også på kjent måte bearbeides videre til tabletter. Da fremstilles smeltene som beskrevet ovenfor. De flytende smeltene helles ut, og etter at de har stivnet, granuleres de med en siktemaskin. Dp s&IpHrs frfimstiltF! crrnrmlntp.r hlnnHfis merl Hf» vnnliøP! Viifilnfistnffer så sr»m aliHf»- no smøremidler, sprengmidler, fyllstoffer, smakskorrigerende stoffer osv. De ferdige blandinger presses til tabletter med det ønskede innhold av cyklosporin. Tablettene kan like-ledes overtrekkes med en beskyttelsesomhylning. The preparations obtained are then filled, e.g. in liquid form in hard gelatin capsules of the desired size in the desired concentration. The compositions can also be further processed into tablets in a known manner. The melts are then prepared as described above. The liquid melts are poured out and, after they have solidified, they are granulated with a screening machine. Dp s&IpHrs frfimstiltF! crrnrmlntp.r hlnnHfis merl Hf» vnnliøP! Viifilnfistnffer so sr»m aliHf»- no lubricants, explosives, fillers, taste-correcting substances, etc. The finished mixtures are pressed into tablets with the desired content of cyclosporine. The tablets can also be coated with a protective coating.
Biotilgjengelighet: Bioavailability:
Undersøkelser vedrørende biotilgjengelighet (BT) av de oppfinnelsesmessige sammensetninger i hund Investigations regarding the bioavailability (BT) of the inventive compositions in dogs
For BT-undersøkelsene ble det anvendt en gruppe på seks beagle-hunder. Applikasjonen av prøvepreparatene skjedde oralt ved hjelp av en svelgsonde i bevisste dyr. Fra dyrene tas til definerte tider blod fra vena saphena, og det samles i tilsvarende plastrør med EDTA-tilsetning. Blodprøvene lagres inntil bestemmelsen ved -18°C. Bestemmelsen av cyklosporin skjer i fullblod ved hjelp av fluorescens-polarisasjons-immunoassay (FPIA). A group of six beagle dogs was used for the BT examinations. The test preparations were administered orally using a pharyngeal tube in conscious animals. From the animals, blood is taken from the saphenous vein at defined times, and it is collected in corresponding plastic tubes with EDTA addition. The blood samples are stored until the determination at -18°C. The determination of ciclosporin takes place in whole blood using the fluorescence polarization immunoassay (FPIA).
Flatene under kurvene (AUC), hvor blodmedikamentkonsentrasjonen oppføres som funksjon av tiden, ble beregnet ifølge trapesregelen. De gjennomsnittlige AUC-verdier The areas under the curves (AUC), where the blood drug concentration is plotted as a function of time, were calculated according to the trapezoidal rule. The average AUC values
for de oppfinnelsesmessige sammensetninger er fremstilt i følgende tabell sammenlignet med de i handelen forekommende preparater cyklosporin-drikkeløsning og cyklosporin-kapsler (Sandimmun®) som ble erholdt på samme måte med samme dosering med like-danne hunder. for the compositions according to the invention are shown in the following table compared to the commercially available preparations ciclosporin drinking solution and ciclosporin capsules (Sandimmun®) which were obtained in the same way with the same dosage with similar dogs.
Som ovenstående forsøk vedrørende biotilgjengelighet viser, er det med de oppfinnelsesmessige farmasøytiske preparater mulig å tilveiebringe virkestoffet oralt i en sådan form at dets biotilgjengelighet tilsvarer minst de hittil kjente preparater As the above tests regarding bioavailability show, with the inventive pharmaceutical preparations it is possible to provide the active substance orally in such a form that its bioavailability corresponds at least to the hitherto known preparations
Claims (12)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4312728 | 1993-04-20 | ||
| DE4412201A DE4412201A1 (en) | 1993-04-20 | 1994-04-08 | New pharmaceutical preparations for oral administration containing cyclosporin |
| PCT/EP1994/001228 WO1994023733A1 (en) | 1993-04-20 | 1994-04-20 | New cyclosporine-containing pharmaceutical compositions for oral administration |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO954152L NO954152L (en) | 1995-10-18 |
| NO954152D0 NO954152D0 (en) | 1995-10-18 |
| NO321076B1 true NO321076B1 (en) | 2006-03-13 |
Family
ID=25925049
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| NO19954152A NO321076B1 (en) | 1993-04-20 | 1995-10-18 | Pharmaceutical preparation for oral administration containing cyclosporin |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0697881B2 (en) |
| JP (2) | JP3862273B2 (en) |
| AT (1) | ATE218878T1 (en) |
| CA (1) | CA2161143A1 (en) |
| CZ (1) | CZ291237B6 (en) |
| DK (1) | DK0697881T3 (en) |
| ES (1) | ES2178653T3 (en) |
| FI (1) | FI116120B (en) |
| HU (1) | HUT72738A (en) |
| NO (1) | NO321076B1 (en) |
| PT (1) | PT697881E (en) |
| SK (1) | SK283442B6 (en) |
| WO (1) | WO1994023733A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5766629A (en) * | 1995-08-25 | 1998-06-16 | Sangstat Medical Corporation | Oral cyclosporin formulations |
| US5834017A (en) * | 1995-08-25 | 1998-11-10 | Sangstat Medical Corporation | Oral cyclopsporin formulations |
| US5962019A (en) * | 1995-08-25 | 1999-10-05 | Sangstat Medical Corporation | Oral cyclosporin formulations |
| US5827822A (en) * | 1996-03-25 | 1998-10-27 | Sangstat Medical Corporation | Cyclosporin a formulations as nanoparticles |
| DE19545043A1 (en) * | 1995-12-02 | 1997-06-05 | Scherer Gmbh R P | Pharmaceutical preparations for oral use and process for their preparation |
| KR20040004416A (en) * | 1997-01-30 | 2004-01-13 | 노파르티스 아게 | Oil-Free Pharmaceutical Compositions Containing Cyclosporin A |
| ES2236891T3 (en) * | 1997-03-12 | 2005-07-16 | Abbott Laboratories | HYDROFILE BINARY SYSTEMS FOR THE ADMINISTRATION OF CYCLOSPORINE. |
| US6187747B1 (en) | 1997-09-08 | 2001-02-13 | Panacea Biotech Limited | Pharmaceutical composition comprising cyclosporin |
| US6008191A (en) * | 1997-09-08 | 1999-12-28 | Panacea Biotec Limited | Pharmaceutical compositions containing cyclosporin |
| US6346511B1 (en) | 1997-09-08 | 2002-02-12 | Panacea Biotec Limited | Pharmaceutical composition comprising cyclosporin |
| JP4761093B2 (en) | 1997-12-10 | 2011-08-31 | シクロスポリン セラポイティクス リミテッド | Pharmaceutical composition comprising omega-3 fatty acid oil |
| US6207179B1 (en) | 2000-05-18 | 2001-03-27 | Phoenix Scientific, Inc. | Parasiticidal formulation for animals and a method of making this formulation |
| PL210795B1 (en) | 2001-10-19 | 2012-03-30 | Isotechnika Inc | The method of producing the ISATX247 enriched isomer (E), the method of producing the ISATX247 enriched mixture of the (Z) isomer, the method of stereoselective synthesis of the (E) ISATX247 isomer, the method of stereoselective synthesis of the (Z) isomer ISATX247 and the method of producing the mixture of ISATX247 isomers |
| US6979672B2 (en) | 2002-12-20 | 2005-12-27 | Polichem, S.A. | Cyclosporin-based pharmaceutical compositions |
| US7682433B2 (en) | 2007-05-11 | 2010-03-23 | Canon Kabushiki Kaisha | Ink set, ink jet recording method, ink cartridge, recording unit, and ink jet recording apparatus |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH641356A5 (en) * | 1979-02-27 | 1984-02-29 | Sandoz Ag | Pharmaceutical compositions containing cyclosporin |
| GB8903804D0 (en) † | 1989-02-20 | 1989-04-05 | Sandoz Ltd | Improvements in or relating to organic compounds |
| DE3580717D1 (en) * | 1984-08-02 | 1991-01-10 | Sandoz Ag | PHARMACEUTICAL APPLICATION OF (NVA) 2-CYCLOSPORINE. |
| ES2033086T3 (en) † | 1988-01-29 | 1993-03-01 | Sankyo Company Limited | A PROCEDURE FOR THE PREPARATION OF A PHARMACEUTICAL COMPOSITION. |
| KR0148748B1 (en) † | 1988-09-16 | 1998-08-17 | 장 크라메르, 한스 루돌프 하우스 | A multiphase cyclosporin composition |
| FR2642650B1 (en) † | 1989-02-09 | 1994-12-09 | Sandoz Sa | NEW PHARMACEUTICAL COMPOSITIONS BASED ON CYCLOSPORINS |
-
1994
- 1994-04-20 PT PT94915073T patent/PT697881E/en unknown
- 1994-04-20 WO PCT/EP1994/001228 patent/WO1994023733A1/en active IP Right Grant
- 1994-04-20 EP EP94915073A patent/EP0697881B2/en not_active Expired - Lifetime
- 1994-04-20 CA CA002161143A patent/CA2161143A1/en not_active Abandoned
- 1994-04-20 SK SK1298-95A patent/SK283442B6/en not_active IP Right Cessation
- 1994-04-20 ES ES94915073T patent/ES2178653T3/en not_active Expired - Lifetime
- 1994-04-20 CZ CZ19952729A patent/CZ291237B6/en not_active IP Right Cessation
- 1994-04-20 AT AT94915073T patent/ATE218878T1/en not_active IP Right Cessation
- 1994-04-20 DK DK94915073T patent/DK0697881T3/en active
- 1994-04-20 JP JP52278294A patent/JP3862273B2/en not_active Expired - Fee Related
- 1994-04-20 HU HU9503019A patent/HUT72738A/en unknown
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1995
- 1995-10-18 NO NO19954152A patent/NO321076B1/en not_active IP Right Cessation
- 1995-10-19 FI FI954986A patent/FI116120B/en active IP Right Grant
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2006
- 2006-05-10 JP JP2006131593A patent/JP2006206615A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| NO954152L (en) | 1995-10-18 |
| EP0697881B1 (en) | 2002-06-12 |
| EP0697881A1 (en) | 1996-02-28 |
| FI954986A (en) | 1995-10-19 |
| CZ272995A3 (en) | 1996-02-14 |
| CA2161143A1 (en) | 1994-10-27 |
| EP0697881B2 (en) | 2009-05-06 |
| CZ291237B6 (en) | 2003-01-15 |
| JP3862273B2 (en) | 2006-12-27 |
| ES2178653T3 (en) | 2003-01-01 |
| WO1994023733A1 (en) | 1994-10-27 |
| JPH08508984A (en) | 1996-09-24 |
| DK0697881T3 (en) | 2002-10-07 |
| HU9503019D0 (en) | 1995-12-28 |
| NO954152D0 (en) | 1995-10-18 |
| PT697881E (en) | 2002-10-31 |
| SK283442B6 (en) | 2003-07-01 |
| JP2006206615A (en) | 2006-08-10 |
| FI116120B (en) | 2005-09-30 |
| ATE218878T1 (en) | 2002-06-15 |
| FI954986A0 (en) | 1995-10-19 |
| HUT72738A (en) | 1996-05-28 |
| SK129895A3 (en) | 1997-02-05 |
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