NO169575B - PROCEDURE FOR PREPARING A GALENIC FORM OF SULPIRIDE - Google Patents
PROCEDURE FOR PREPARING A GALENIC FORM OF SULPIRIDE Download PDFInfo
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- NO169575B NO169575B NO841367A NO841367A NO169575B NO 169575 B NO169575 B NO 169575B NO 841367 A NO841367 A NO 841367A NO 841367 A NO841367 A NO 841367A NO 169575 B NO169575 B NO 169575B
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- weight
- sulpiride
- methyl methacrylate
- microgranules
- alcoholic solution
- Prior art date
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- 229960004940 sulpiride Drugs 0.000 title claims description 30
- 238000000034 method Methods 0.000 title claims description 7
- BGRJTUBHPOOWDU-UHFFFAOYSA-N sulpiride Chemical compound CCN1CCCC1CNC(=O)C1=CC(S(N)(=O)=O)=CC=C1OC BGRJTUBHPOOWDU-UHFFFAOYSA-N 0.000 title 1
- BGRJTUBHPOOWDU-NSHDSACASA-N (S)-(-)-sulpiride Chemical compound CCN1CCC[C@H]1CNC(=O)C1=CC(S(N)(=O)=O)=CC=C1OC BGRJTUBHPOOWDU-NSHDSACASA-N 0.000 claims description 29
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- 230000001476 alcoholic effect Effects 0.000 claims description 8
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 8
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 8
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 8
- 238000000338 in vitro Methods 0.000 claims description 7
- 230000007935 neutral effect Effects 0.000 claims description 7
- 229920002472 Starch Polymers 0.000 claims description 6
- 229930006000 Sucrose Natural products 0.000 claims description 6
- 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 6
- 239000008107 starch Substances 0.000 claims description 6
- 235000019698 starch Nutrition 0.000 claims description 6
- 239000005720 sucrose Substances 0.000 claims description 6
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims description 5
- 229920001577 copolymer Polymers 0.000 claims description 5
- QPNHNCISNUAHNE-UHFFFAOYSA-N methyl 2-methylprop-2-enoate;trimethylazanium;chloride Chemical compound [Cl-].C[NH+](C)C.COC(=O)C(C)=C QPNHNCISNUAHNE-UHFFFAOYSA-N 0.000 claims description 5
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims description 5
- 125000005395 methacrylic acid group Chemical group 0.000 claims description 4
- 229920000642 polymer Polymers 0.000 claims description 4
- 239000000454 talc Substances 0.000 claims description 4
- 229910052623 talc Inorganic materials 0.000 claims description 4
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000002775 capsule Substances 0.000 description 11
- 239000004480 active ingredient Substances 0.000 description 9
- 238000010521 absorption reaction Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 238000000576 coating method Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229920003134 Eudragit® polymer Polymers 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000004531 microgranule Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- SZYUUAPBNBZSRP-UHFFFAOYSA-N N-(1-ethylpyrrolidin-2-yl)-2-methoxy-3-methyl-5-sulfamoylbenzamide Chemical compound CC1=C(C(C(=O)NC2N(CCC2)CC)=CC(=C1)S(N)(=O)=O)OC SZYUUAPBNBZSRP-UHFFFAOYSA-N 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 230000000701 neuroleptic effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- 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
- A61K9/5073—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 having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—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 having two or more different coatings optionally including drug-containing subcoatings with drug-free core
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Description
Denne oppfinnelse angår en fremgangsmåte for fremstilling av en galenisk form av sulpirid som kan anvendes oralt. This invention relates to a method for producing a galenic form of sulpiride that can be used orally.
Sulpirid, som har formelen N-(l-ethyl-2-pyr-rolidinyl)-methyl-2-methoxy-5-sulfamoylbenzamid, er kjent som en utmerket neuroleptisk desinhibitor som har som sitt vik-tigste terapeutiske anvendelsesområde behandling av akutte og kroniske psykoser. Sulpiridets karakteristika og egenskaper er beskrevet i franske patentskrifter nr. 1.472.025, 4879 M og 5916 M. Sulpiride, which has the formula N-(1-ethyl-2-pyrrolidinyl)-methyl-2-methoxy-5-sulfamoylbenzamide, is known as an excellent neuroleptic disinhibitor whose main therapeutic application is the treatment of acute and chronic psychoses. Sulpiride's characteristics and properties are described in French patent documents No. 1,472,025, 4879 M and 5916 M.
Oralt aktive medikamenter inneholdende sulpirid gis for tiden i form av tabletter, kapsler eller vandige oppløs-ninger for oralt inntak. Disse medikamentformer krever at det tas flere daglige doser, og den prosentive absorpsjon av medi-kamentene i organismen er av og til lav. Orally active drugs containing sulpiride are currently given in the form of tablets, capsules or aqueous solutions for oral intake. These drug forms require several daily doses to be taken, and the percentage absorption of the drugs in the organism is sometimes low.
Da halveringstiden for den aktive bestanddel sulpirid i plasmaet er omtrent åtte og en halv time, synes det i ut-gangspunktet å være mulig å fremstille en galenisk form av forbindelsen som muliggjør en reduksjon av den daglige dose til to kapsler eller tabletter pr. dag, med en mengde sulpirid på 100 mg pr. kapsel eller tablett (idet den ene tas om mor-genen og den andre tas om kvelden), eventuelt til én kapsel eller én tablett pr. dag, med en 200 mg dose sulpirid. As the half-life of the active ingredient sulpiride in the plasma is approximately eight and a half hours, it seems to be initially possible to produce a galenic form of the compound which enables a reduction of the daily dose to two capsules or tablets per day. day, with an amount of sulpiride of 100 mg per capsule or tablet (with one taken at bedtime and the other taken in the evening), possibly to one capsule or one tablet per day, with a 200 mg dose of sulpiride.
Det er derfor nu blitt gjort forsøk på å modifisere den galeniske form, slik at pasientene lettere blir å stand til å oppta legemidlet, samtidig som det nødvendige antall daglige doser reduseres. Attempts have therefore now been made to modify the galenic form, so that patients are more easily able to absorb the medicine, while at the same time reducing the required number of daily doses.
Det ble således forsøkt fremstilt mikrogranuler med forlenget virkning, i henhold til de konvensjonelle frem-gangsmåter som er beskrevet spesielt i franske patentskrifter nr. 2.313.915 og 2.453.642. På i og for seg konvensjonell måte ble det benyttet nøytrale korn av diameter ca. 0,50 mm, bestående av 25% stivelse og 75% sakkarose, på hvilket sulpiridet ble påført i en sentrifugalprosess, under anvendelse av en alkoholisk oppløsning av polyvinylpyrrolidon. Siktemålet var å oppnå en på forhånd fastsatt kinetikk for frigjøringen av den aktive bestanddel sulpirid in vitro i standardiserte magesekk- og tarmmedier i henhold til de følgende spesifika-sjoner: An attempt was thus made to produce microgranules with prolonged action, according to the conventional methods described in particular in French patent documents no. 2,313,915 and 2,453,642. In a per se conventional manner, neutral grains of diameter approx. 0.50 mm, consisting of 25% starch and 75% sucrose, to which the sulpiride was applied in a centrifugal process, using an alcoholic solution of polyvinylpyrrolidone. The aim was to achieve a predetermined kinetics for the release of the active ingredient sulpiride in vitro in standardized gastric and intestinal media according to the following specifications:
Første time: frigjøring av mindre enn 40% First hour: release of less than 40%
Fjerde time: frigjøring av mindre enn 75% Fourth hour: release of less than 75%
Åttende time: frigjøring av mer enn 75%. Eighth hour: release of more than 75%.
Etter undersøkelse av en rekke preparater med forlenget virkning, som alle ga resultater som var uforlikelige med kravene til en godt absorbert oral form, fant man å ville basere seg på mikrogranulformen (hovedsakelig kuleformede korn av diameter mellom 0,2 og 2 mm), som i praksis burde gi mulig-het for bedre absorpsjon av den aktive bestanddel enn det konvensjonelle pulver i kapsler og tabletter, samtidig som den ville gi en kinetikk med hensyn til frigjøring in vitro som ligger langt nærmere den for formene for umiddelbar fri-gjøring, nemlig slik at man ville få frigjort praktisk talt 90% av den aktive bestanddel etter 1 time i et kunstig mage-medium med en pH-verdi på 1,3. After examining a number of long-acting preparations, all of which gave results incompatible with the requirements of a well-absorbed oral form, it was found to be based on the microgranule form (mainly spherical grains of diameter between 0.2 and 2 mm), which in practice should provide the possibility for better absorption of the active ingredient than the conventional powder in capsules and tablets, while at the same time it would provide a kinetics with regard to release in vitro that is much closer to that of the forms for immediate release, namely so that practically 90% of the active ingredient would be released after 1 hour in an artificial gastric medium with a pH value of 1.3.
Siktemålet ble oppnådd ved hjelp av en fremgangsmåte for fremstilling av en ny galenisk form av sulpirid for oral anvendelse, hvilken fremgangsmåte utmerker seg ved at sulpirid, i en mengde av 70-75 vekt% og i en 20% alkoholisk opp-løsning av polyvinylpyrrolidon, påføres på 14-20 vekt% nøy-trale mikrogranuler bestående av 25 vekt% stivelse og 75 vekt% sakkarose, at de resulterende mikrogranuler tørkes og siktes og deretter påføres en 20% alkoholisk oppløsning av methacrylpolymerer omfattende 3-4 vektdeler av en copolymer av methacrylsyre og methylmethacrylat og 0,5-2 vektdeler av en copolymer av ethylacrylat, methylmethacrylat og trimethylammoniumethylmethacrylatklorid, og at det så foretas tørking med talkum og deretter tørking i en tørkeovn ved 37°C, før det ytre lag fullføres ved påføring av en 12-15% alkoholisk opp-løsning av en copolymer av ethylacrylat, methylmethacrylat og trimethylammoniumethylmethacrylatklorid for justering av kinetikken for in vitro frigjøring av sulpirid. The aim was achieved by means of a method for the production of a new galenic form of sulpiride for oral use, which method is distinguished by the fact that sulpiride, in an amount of 70-75% by weight and in a 20% alcoholic solution of polyvinylpyrrolidone, is applied to 14-20% by weight of neutral microgranules consisting of 25% by weight of starch and 75% by weight of sucrose, that the resulting microgranules are dried and sieved and then a 20% alcoholic solution of methacrylic polymers comprising 3-4 parts by weight of a copolymer of methacrylic acid is applied and methyl methacrylate and 0.5-2 parts by weight of a copolymer of ethyl acrylate, methyl methacrylate and trimethylammonium methyl methacrylate chloride, and that drying with talc is then carried out and then drying in a drying oven at 37°C, before the outer layer is completed by applying a 12-15 % alcoholic solution of a copolymer of ethyl acrylate, methyl methacrylate and trimethylammonium methyl methacrylate chloride for adjusting the kinetics of in vitro release of sulpiride.
Frigjøringen av den aktive bestanddel sulpirid fra den fremstilte galeniske form den første time avstedkommes i en kunstig magesaft med en pH-verdi på 1,3, mens frigjøringen den fjerde time og den åttende time avstedkommes i kunstig magesaft med pH-verdi på henholdsvis 4,5 og 7. Betingelsene for undersøkelse av frigjøringen av den aktive bestanddel er kjent og beskrevet i ovennevnte patentskrifter. The release of the active ingredient sulpiride from the manufactured galenic form in the first hour takes place in an artificial gastric juice with a pH value of 1.3, while the release in the fourth hour and the eighth hour takes place in artificial gastric juice with a pH value of 4, respectively. 5 and 7. The conditions for examining the release of the active ingredient are known and described in the above-mentioned patents.
Mikrogranulene som ble oppnådd ved fremgangsmåten ifølge oppfinnelsen ble benyttet for fremstilling av kapsler og tabletter inneholdende en dose på 100 mg. Absorpsjonen av sulpiridet ble undersøkt ved å bestemme radioimmunologisk sirkulasjonsmengden av sulpirid i plasmaet. For dette formål ble det benyttet mikrogranuler som var blitt fremstilt i henhold til det nedenstående eksempel. Disse inneholdt 730 mg aktiv bestanddel pr. gram mikrogranuler og er nedenfor beteg-net form III. De oppnådde resultater ble sammenlignet med resultater oppnådd for kjente galeniske former, nedenfor beteg-net former I, II og IV. The microgranules obtained by the method according to the invention were used for the production of capsules and tablets containing a dose of 100 mg. The absorption of sulpiride was investigated by radioimmunologically determining the circulating amount of sulpiride in the plasma. For this purpose, microgranules were used which had been produced according to the example below. These contained 730 mg of active ingredient per grams of microgranules and is referred to below as form III. The results obtained were compared with results obtained for known galenic forms, hereinafter referred to as forms I, II and IV.
De kjente galeniske former som det ble foretatt sam-menligning med, var: The known Galenic forms with which a comparison was made were:
Form I: Mikrogranuler bestående av Form I: Microgranules consisting of
- 47,5 vekt% nøytrale korn bestående av 25 vekt% stivelse og 75 vekt% sakkarose, - 51,5 vekt% av et lag bestående 85 vekt% sulpirid og 25 vekt% polyvinylpyrrolidon, og - 1 vekt% av et overtrekk bestående av en blanding av schellak og ethylcellulose. - 47.5% by weight of neutral grains consisting of 25% by weight of starch and 75% by weight of sucrose, - 51.5% by weight of a layer consisting of 85% by weight of sulpiride and 25% by weight of polyvinylpyrrolidone, and - 1% by weight of a coating consisting of a mixture of shellac and ethyl cellulose.
Form II: Mikrogranuler bestående av Form II: Microgranules consisting of
- 47,5 vekt% nøytrale korn bestående av 25 vekt% stivelse og 75 vekt% sakkarose, - 51,5 vekt% av et lag bestående av 85 vekt% sulpirid og 25 vekt% polyvinylpyrrolidon, og - 1 vekt% av et overtrekk bestående av en blanding av methacrylpolymerer som beskrevet i fransk patentskrift nr. 2.453.642. - 47.5% by weight of neutral grains consisting of 25% by weight of starch and 75% by weight of sucrose, - 51.5% by weight of a layer consisting of 85% by weight of sulpiride and 25% by weight of polyvinylpyrrolidone, and - 1% by weight of a coating consisting of of a mixture of methacrylic polymers as described in French patent document No. 2,453,642.
Form IV: Et pulver bestående av en blanding av 100 mg sulpirid med eksipienter bestående av laktose, methyl-cellulose, talkum og magnesiumstearat for en gelatinbelagt pille på 230 mg. Denne form tilsvarer de gelatinbelagte piller som føres i handelen. Form IV: A powder consisting of a mixture of 100 mg of sulpiride with excipients consisting of lactose, methyl cellulose, talc and magnesium stearate for a gelatin-coated pill of 230 mg. This form corresponds to the gelatin-coated pills sold in the market.
De anvendte former I og II oppviste følgende kinetikk med hensyn til frigjøring in vitro i kunstige medier: The forms I and II used showed the following kinetics with regard to release in vitro in artificial media:
Resultatene er oppført i tabell A nedenfor og viser at med de to benyttede mikrogranulpreparater (form I og form II) er tapet i mengden av sirkulerende aktiv bestanddel for stort sammenlignet med den normale kapselform (form IV) til at det er mulig å tilveiebringe et effektivt medikament med forlenget virkning. The results are listed in table A below and show that with the two microgranule preparations used (form I and form II) the loss in the amount of circulating active ingredient is too great compared to the normal capsule form (form IV) for it to be possible to provide an effective drug with prolonged action.
Ganske overraskende viste resultatene med hensyn til sulpirid-innholdet i plasmaet for mikrogranulene med den ovenfor angitte kinetikk at form III, dvs. den galeniske form fremstilt i henhold til oppfinnelsen, anbragt i en kapsel i en dose på 100 mg, gjør det mulig å oppnå en dobbelt så høy absorpsjon som den som oppnås med de konvensjonelle sulpirid-kapsler (form IV), samtidig som det oppnås en virkningstid som er noe lengre, og forskjellen i absorpsjon fra pasient til pasient reduseres vesentlig. Den ovenfor angitte forbedring av absorpsjonen av sulpirid, både med hensyn til mengde og med hensyn til regelmessighet, gjør det mulig å redusere både den totale dose og antallet daglige inntak. Quite surprisingly, the results with regard to the sulpiride content in the plasma for the microgranules with the above-mentioned kinetics showed that form III, i.e. the galenic form prepared according to the invention, placed in a capsule in a dose of 100 mg, makes it possible to obtain an absorption twice as high as that achieved with the conventional sulpiride capsules (form IV), while achieving a slightly longer duration of action, and the difference in absorption from patient to patient is significantly reduced. The above-mentioned improvement in the absorption of sulpiride, both in terms of quantity and in terms of regularity, makes it possible to reduce both the total dose and the number of daily intakes.
Resultatene er angitt i tabell A og likeledes vist på fig. 1. Resultatene viser utviklingen i sirkulasjonsmengden i plasmaet, uttrykt i ng/ml sulpirid, i tidsrommet fra 0 til 32 timer, for former III og IV. The results are given in table A and likewise shown in fig. 1. The results show the development in the circulating amount in the plasma, expressed in ng/ml sulpiride, in the period from 0 to 32 hours, for forms III and IV.
Supplerende undersøkelser, hvor de ytre overtrekk på mikrogranulene ble variert, gjorde det mulig å fastslå at den foretrukne form som ga forbedret absorpsjon av sulpiridet, i det vesentlige måtte svare til de følgende betingelser med hensyn til frigjøring in vitro: Supplementary investigations, in which the external coatings on the microgranules were varied, made it possible to establish that the preferred form which gave improved absorption of the sulpiride had essentially to correspond to the following conditions with regard to release in vitro:
Dessuten ble det observert en total frigjøring av mer enn 90% i et kunstig tarmkanalmedium med pH 6,9. Moreover, a total release of more than 90% was observed in an artificial intestinal medium of pH 6.9.
Nedenfor gis som et utførelseseksempel produksjonsre-septen for 2500 kapsler med en dose på 100 mg av form III, dvs. den galeniske form fremstilt i henhold til oppfinnelsen, foruten fremstillingsprosessen. Below is given as an exemplary embodiment the production recipe for 2500 capsules with a dose of 100 mg of form III, i.e. the galenic form produced according to the invention, in addition to the manufacturing process.
Eksempel Example
Det ble benyttet 50 g nøyrale korn, bestående av 25% stivelse og 75% sakkarose, av størrelse svarende i det vesentlige til en diameter på 0,50 mm, på hvilke det i en sen-trifuge ble påført 250 g sulpirid i en 20%-ig oppløsning av polyvinylpyrrolidon i ethanol. 50 g of neural granules were used, consisting of 25% starch and 75% sucrose, of a size corresponding essentially to a diameter of 0.50 mm, to which 250 g of sulpiride in a 20% -ig solution of polyvinylpyrrolidone in ethanol.
Etter tørking og siktig ble det påført ytterlag bestående av methacrylpolymerer markedsført under varemerket Eudragit<®> i alkoholoppløsning i mengdeforholdet 4 vektdeler Eudragil<®> type L (en copolymer av methacrylsyre og methylmethacrylat) pr. vektdel Eudragil® type RL (en copolymer av ethylacrylat, methylmethacrylat og trimethylammoniumethylmethacrylatklorid). After drying and sifting, an outer layer consisting of methacrylic polymers marketed under the trademark Eudragit<®> was applied in an alcohol solution in the proportion of 4 parts by weight of Eudragil<®> type L (a copolymer of methacrylic acid and methyl methacrylate) per part by weight Eudragil® type RL (a copolymer of ethyl acrylate, methyl methacrylate and trimethylammonium methyl methacrylate chloride).
Det ble så foretatt tørking med talkum i små mengder, inntil det var blitt oppnådd mikrogranuler som frigjorde hovedsakelig 100% i løpet av 1 time i henhold til de ovenfor angitte analysebetingelser. Drying with talc in small amounts was then carried out, until microgranules had been obtained which released essentially 100% within 1 hour according to the above stated analysis conditions.
Det ble så foretatt tørking i en tørkeovn ved 37°C i ca. 2 døgn, hvoretter ytterlaget ble fullført ved påføring av 40 g av en 13,5% oppløsning av Eudragit<®> type RL i ethanol. Den målte titer var ca. 730 mg aktiv bestanddel pr. gram mikrogranuler . Drying was then carried out in a drying oven at 37°C for approx. 2 days, after which the outer layer was completed by applying 40 g of a 13.5% solution of Eudragit<®> type RL in ethanol. The measured titer was approx. 730 mg of active ingredient per grams of microgranules.
De på denne måte fremstilte mikrogranuler tilfreds-stilte de ovenfor angitte fordringer med hensyn til frigjøring in vitro, som er representative for den nye galeniske form av sulpirid som fremstilles i henhold til oppfinnelsen. The microgranules produced in this way satisfied the above stated requirements with regard to release in vitro, which are representative of the new galenic form of sulpiride produced according to the invention.
Deres akselererte og naturlige stabilitet var utmerket, og de viste ingen tegn til potensiell toksisitet. Their accelerated and natural stability was excellent and they showed no signs of potential toxicity.
Mikrogranulene kunne anvendes i form av kapsler, tabletter eller suspensjoner, i nøytrale medier. The microgranules could be used in the form of capsules, tablets or suspensions, in neutral media.
Claims (2)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8320635A FR2556964A1 (en) | 1983-12-23 | 1983-12-23 | NEW GALENIC FORMS OF SULPIRIDE USED ORALALLY |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO841367L NO841367L (en) | 1985-06-24 |
| NO169575B true NO169575B (en) | 1992-04-06 |
| NO169575C NO169575C (en) | 1992-07-15 |
Family
ID=9295477
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO841367A NO169575C (en) | 1983-12-23 | 1984-04-06 | PROCEDURE FOR PREPARING A GALENIC FORM OF SULPIRIDE |
Country Status (38)
| Country | Link |
|---|---|
| EP (1) | EP0147244A1 (en) |
| JP (1) | JPS60139616A (en) |
| KR (1) | KR910004570B1 (en) |
| AR (1) | AR231398A1 (en) |
| AU (1) | AU569516B2 (en) |
| BE (1) | BE899331A (en) |
| BG (1) | BG49707A3 (en) |
| CH (1) | CH659386A5 (en) |
| CZ (1) | CZ262984A3 (en) |
| DD (1) | DD220782A5 (en) |
| DE (1) | DE3412868A1 (en) |
| DK (1) | DK165729C (en) |
| ES (1) | ES8502332A1 (en) |
| FI (1) | FI82603C (en) |
| FR (1) | FR2556964A1 (en) |
| GB (1) | GB2151920B (en) |
| GR (1) | GR79584B (en) |
| HU (1) | HU190924B (en) |
| IE (1) | IE57164B1 (en) |
| IL (1) | IL71470A (en) |
| IN (1) | IN160415B (en) |
| IS (1) | IS1364B6 (en) |
| IT (1) | IT1177655B (en) |
| LU (1) | LU85290A1 (en) |
| MA (1) | MA20088A1 (en) |
| MX (1) | MX7715E (en) |
| NO (1) | NO169575C (en) |
| NZ (1) | NZ207753A (en) |
| OA (1) | OA07700A (en) |
| PH (1) | PH21938A (en) |
| PL (1) | PL144356B1 (en) |
| PT (1) | PT78382B (en) |
| RO (1) | RO89437A (en) |
| SU (1) | SU1478993A3 (en) |
| YU (1) | YU44762B (en) |
| ZA (1) | ZA842573B (en) |
| ZM (1) | ZM2084A1 (en) |
| ZW (1) | ZW6084A1 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8414220D0 (en) * | 1984-06-04 | 1984-07-11 | Sterwin Ag | Medicaments in unit dose form |
| DE3678643D1 (en) * | 1985-08-16 | 1991-05-16 | Procter & Gamble | PARTICLES WITH CONSTANT RELEASE OF ACTIVE SUBSTANCES. |
| US4853229A (en) * | 1987-10-26 | 1989-08-01 | Alza Corporation | Method for adminstering tiny pills |
| JPH0791184B2 (en) * | 1988-03-31 | 1995-10-04 | 田辺製薬株式会社 | Controlled release formulation and process for producing the same |
| GB8903328D0 (en) * | 1989-02-14 | 1989-04-05 | Ethical Pharma Ltd | Nifedipine-containing pharmaceutical compositions and process for the preparation thereof |
| FR2762213B1 (en) * | 1997-04-18 | 1999-05-14 | Synthelabo | PHARMACEUTICAL COMPOSITION WITH GASTRIC RETENTION |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3342826A (en) * | 1964-01-13 | 1967-09-19 | Ile De France | Heterocyclic aminoalkyl benzamides |
| FR2313915A1 (en) * | 1976-01-26 | 1977-01-07 | Corneille Gilbert | Sustained release vincamine microcapsules - with inert core, vincamine (deriv.) intermediate layer and microporous outer coating |
| US4285665A (en) * | 1978-05-08 | 1981-08-25 | Johnson, Matthey & Co., Limited | Engines |
| FR2453639A1 (en) * | 1979-04-09 | 1980-11-07 | Sanofi Sa | NAFTIDROFURYL-BASED IMMEDIATE-DELAYED RELEASE DRUG COMPOSITION |
| FR2453642A1 (en) * | 1979-04-12 | 1980-11-07 | Sanofi Sa | Controlled release of ergo-toxin methane sulphonate - from micro-granules coated with anionic and cationic methacrylic! polymers and a plasticiser |
| FR2454804B1 (en) * | 1979-04-26 | 1986-11-21 | Sanofi Sa | DIHYDROERGOTOXIN-BASED MEDICINAL PRODUCT AND PROCESS FOR PREPARING THE SAME |
| FR2470599A1 (en) * | 1979-12-07 | 1981-06-12 | Panoz Donald | IMPROVEMENTS IN PROCESSES FOR THE PREPARATION OF GALENIC SHAPES WITH DELAYED ACTION AND PROGRAMMED RELEASE AND GALENIC FORMS OF MEDICAMENTS THUS OBTAINED |
| SE8003805L (en) * | 1980-05-21 | 1981-11-22 | Haessle Ab | A PHARMACEUTICAL PREPARATION WITH IMPROVED EMISSION PROPERTY |
| JPS5753326A (en) * | 1980-09-17 | 1982-03-30 | Dainippon Printing Co Ltd | Manufacture of biaxially stretching blow molded vessel of saturated polyester |
| FR2492661A1 (en) * | 1980-10-28 | 1982-04-30 | Laruelle Claude | NOVEL GALENIC FORM OF ADMINISTRATION OF METOCLOPRAMIDE, ITS PREPARATION METHOD AND MEDICINAL PRODUCT COMPRISING THIS NOVEL FORM |
| FR2494112B1 (en) * | 1980-11-19 | 1986-01-10 | Laruelle Claude | |
| FR2534139B1 (en) * | 1982-10-07 | 1986-08-29 | Laruelle Claude | NOVEL GALENIC FORM OF SULPIRIDE, METHOD FOR PREPARING SAME, AND MEDICINAL PRODUCT COMPRISING THIS NEW FORM |
-
1983
- 1983-12-23 FR FR8320635A patent/FR2556964A1/en not_active Withdrawn
-
1984
- 1984-03-30 IS IS2900A patent/IS1364B6/en unknown
- 1984-04-02 IE IE817/84A patent/IE57164B1/en not_active IP Right Cessation
- 1984-04-04 MA MA20309A patent/MA20088A1/en unknown
- 1984-04-04 EP EP84400661A patent/EP0147244A1/en not_active Withdrawn
- 1984-04-05 BE BE1/10992A patent/BE899331A/en not_active IP Right Cessation
- 1984-04-05 DE DE19843412868 patent/DE3412868A1/en not_active Withdrawn
- 1984-04-05 CZ CS842629A patent/CZ262984A3/en unknown
- 1984-04-05 NZ NZ207753A patent/NZ207753A/en unknown
- 1984-04-05 ZA ZA842573A patent/ZA842573B/en unknown
- 1984-04-06 JP JP59069883A patent/JPS60139616A/en active Granted
- 1984-04-06 LU LU85290A patent/LU85290A1/en unknown
- 1984-04-06 FI FI841376A patent/FI82603C/en not_active IP Right Cessation
- 1984-04-06 PH PH30510A patent/PH21938A/en unknown
- 1984-04-06 NO NO841367A patent/NO169575C/en unknown
- 1984-04-06 YU YU640/84A patent/YU44762B/en unknown
- 1984-04-06 OA OA58273A patent/OA07700A/en unknown
- 1984-04-06 HU HU841362A patent/HU190924B/en not_active IP Right Cessation
- 1984-04-06 DD DD84261741A patent/DD220782A5/en not_active IP Right Cessation
- 1984-04-06 AR AR296218A patent/AR231398A1/en active
- 1984-04-06 IN IN242/MAS/84A patent/IN160415B/en unknown
- 1984-04-06 GR GR74337A patent/GR79584B/el unknown
- 1984-04-06 PL PL1984247098A patent/PL144356B1/en unknown
- 1984-04-06 GB GB08408978A patent/GB2151920B/en not_active Expired
- 1984-04-06 PT PT78382A patent/PT78382B/en not_active IP Right Cessation
- 1984-04-06 BG BG064985A patent/BG49707A3/en unknown
- 1984-04-06 IT IT48001/84A patent/IT1177655B/en active
- 1984-04-06 CH CH1755/84A patent/CH659386A5/en not_active IP Right Cessation
- 1984-04-06 SU SU843728542A patent/SU1478993A3/en active
- 1984-04-06 DK DK180784A patent/DK165729C/en not_active IP Right Cessation
- 1984-04-07 RO RO84114201A patent/RO89437A/en unknown
- 1984-04-07 KR KR1019840001840A patent/KR910004570B1/en not_active IP Right Cessation
- 1984-04-08 IL IL71470A patent/IL71470A/en unknown
- 1984-04-10 ZW ZW60/84A patent/ZW6084A1/en unknown
- 1984-04-16 MX MX84101994U patent/MX7715E/en unknown
- 1984-04-24 ZM ZM20/84A patent/ZM2084A1/en unknown
- 1984-05-03 ES ES532125A patent/ES8502332A1/en not_active Expired
- 1984-05-31 AU AU28904/84A patent/AU569516B2/en not_active Ceased
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