NO174086B - PROCEDURE FOR PREPARING A PHARMACEUTICAL PREPARATION WITH DELAYED ACTIVE SUBSTANCE - RELEASE - Google Patents
PROCEDURE FOR PREPARING A PHARMACEUTICAL PREPARATION WITH DELAYED ACTIVE SUBSTANCE - RELEASE Download PDFInfo
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- NO174086B NO174086B NO86862907A NO862907A NO174086B NO 174086 B NO174086 B NO 174086B NO 86862907 A NO86862907 A NO 86862907A NO 862907 A NO862907 A NO 862907A NO 174086 B NO174086 B NO 174086B
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- Prior art keywords
- release
- active ingredient
- film
- emulsion
- active substance
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- 230000003111 delayed effect Effects 0.000 title claims abstract description 8
- 239000013543 active substance Substances 0.000 title claims description 19
- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 13
- 238000000034 method Methods 0.000 title claims description 8
- 239000002245 particle Substances 0.000 claims abstract description 24
- 230000009477 glass transition Effects 0.000 claims abstract description 13
- 239000012876 carrier material Substances 0.000 claims abstract description 11
- 239000004480 active ingredient Substances 0.000 claims description 24
- 229920000642 polymer Polymers 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 15
- 239000011521 glass Substances 0.000 claims description 14
- 229920000058 polyacrylate Polymers 0.000 claims description 13
- 239000000839 emulsion Substances 0.000 claims description 12
- 239000004908 Emulsion polymer Substances 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 239000002775 capsule Substances 0.000 claims description 7
- 238000001704 evaporation Methods 0.000 claims description 5
- 230000008020 evaporation Effects 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 229920001577 copolymer Polymers 0.000 claims description 4
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 3
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 3
- 230000007423 decrease Effects 0.000 claims description 3
- 125000004494 ethyl ester group Chemical group 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 abstract 2
- 239000008177 pharmaceutical agent Substances 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 239000003826 tablet Substances 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000004816 latex Substances 0.000 description 7
- 229920000126 latex Polymers 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 230000001105 regulatory effect Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 229960002896 clonidine Drugs 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- HBLPYIOKPJVFQW-UHFFFAOYSA-N 6-ethyl-4,5,7,8-tetrahydro-[1,3]oxazolo[4,5-d]azepin-2-amine;hydron;dichloride Chemical compound Cl.Cl.C1CN(CC)CCC2=C1OC(N)=N2 HBLPYIOKPJVFQW-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000010408 film Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000012907 medicinal substance Substances 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920003148 Eudragit® E polymer Polymers 0.000 description 1
- 229920003159 Eudragit® RS 100 Polymers 0.000 description 1
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical group COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 1
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical compound ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 1
- 125000005396 acrylic acid ester group Chemical group 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000012790 adhesive layer Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- NEDGUIRITORSKL-UHFFFAOYSA-N butyl 2-methylprop-2-enoate;2-(dimethylamino)ethyl 2-methylprop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound COC(=O)C(C)=C.CCCCOC(=O)C(C)=C.CN(C)CCOC(=O)C(C)=C NEDGUIRITORSKL-UHFFFAOYSA-N 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000007720 emulsion polymerization reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000008202 granule composition Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000010422 painting Methods 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
-
- 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
-
- 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
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Macromonomer-Based Addition Polymer (AREA)
- Polyesters Or Polycarbonates (AREA)
- Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Saccharide Compounds (AREA)
Abstract
Description
Denne oppfinnelse angår fremstilling av et farmasøytisk preparat i form av et bæremateriale med et legemiddel-virkestoff med varierbar, kontrollert og forsinket virkestoff-fri-<g>jøring. This invention relates to the production of a pharmaceutical preparation in the form of a carrier material with a pharmaceutical active ingredient with variable, controlled and delayed active ingredient release.
Det er kjent å fremstille farmasøytiske preparater i form av kapsler, tabletter og filmer, som garanterer en jevn virke-stof f -frigjøring og sålédes opprettholder en konstant konsen-trasjon av virkestoffet i kroppen. I kapsler og tabletter reguleres vanligvis frigjøringen av virkestoffet ved hjelp av egnede overtrekk, som f.eks. i filmtabletter. Depotformer kan også fremstilles av granulatblandinger med forskjellige bæremidler, som frigjør legemiddel-virkestoffet med varierende hastighet. En delbar tablett med forsinket virkestoff-frigjøring er kjent fra DE-OS 33 14 003. For denne tablett som er fremstilt av et emulsjonspolymerisert polyakrylat, reguleres frigjøringshastigheten ved hjelp av kornstørrelsen og også kornstørrelsesfordelingen. It is known to produce pharmaceutical preparations in the form of capsules, tablets and films, which guarantee a uniform release of the active substance and thus maintain a constant concentration of the active substance in the body. In capsules and tablets, the release of the active ingredient is usually regulated by means of suitable covers, such as e.g. in film-coated tablets. Sustained-release forms can also be produced from granule mixtures with different carriers, which release the medicinal active ingredient at varying rates. A divisible tablet with delayed active substance release is known from DE-OS 33 14 003. For this tablet, which is produced from an emulsion polymerised polyacrylate, the release rate is regulated by means of the grain size and also the grain size distribution.
I systemer for transdermal administrering kan frigjøringen av virkestoffet reguleres ved hjelp av spesielle membraner (US-PS 3 731 683) eller også ved hjelp av hjelpestoffer så som aminer, fett eller høyere alkoholer. In systems for transdermal administration, the release of the active substance can be regulated by means of special membranes (US-PS 3 731 683) or also by means of auxiliary substances such as amines, fats or higher alcohols.
De kjente farmasøytiske preparater med forsinket virke-stof f-frigjøring viser seg i praksis ikke alltid å være fullt ut tilfredstillende. På den ene side vil tabletter som er overtrukket med en film, få endret sine frigjøringsegenskaper efter deling, og på den annen side er grenser for den kontrollmulighet som er kjent fra DE-OS 33 14 003 med hensyn til virkestoff-frigjøring ved regulering av kornstørrelsen, eftersom kornstørrelsen ikke kan velges fritt. På grunn av tekniske problemer, som f.eks. inhomogenitet, minste antall av granulatpartikler inneholdende virkestoff etc, er korn-størrelsen begrenset både oppad og nedad, slik at det ikke i et hvert tilfelle kan oppnås en optimal frigjøringshastighet for virkestoffet. The known pharmaceutical preparations with delayed active substance f-release do not always prove to be fully satisfactory in practice. On the one hand, tablets that are coated with a film will have their release properties changed after splitting, and on the other hand, there are limits to the control possibility known from DE-OS 33 14 003 with regard to active ingredient release by regulating the grain size , since the grain size cannot be chosen freely. Due to technical problems, such as inhomogeneity, minimum number of granule particles containing the active ingredient, etc., the grain size is limited both upwards and downwards, so that an optimal release rate for the active ingredient cannot be achieved in every case.
Det er nu overraskende funnet at i et farmasøytisk preparat med et emulsjonspolymerisert bæremateriale kan frigjøringshastigheten innstilles ved enkel variasjon av partikkelstørrelsen av de emulsjonspolymeriserte polymerkuler og også ved variasjon av polymerens glasstemperatur. It has now surprisingly been found that in a pharmaceutical preparation with an emulsion polymerised carrier material, the release rate can be set by simple variation of the particle size of the emulsion polymerised polymer spheres and also by variation of the polymer's glass transition temperature.
Ifølge oppfinnelsen tilveiebringes en fremgangsmåte for fremstilling av et farmasøytisk preparat med varierbar, kontrollert og forsinket virkestoff-frigjøring, inneholdende et bæremateriale på basis av en emulsjonspolymer. Fremgangs-måten karakteriseres ved at en emulsjonspolymer valgt blant emulsjonspolymeriserte kopolymerer av metyl- og/eller etylestere av akryl- og metakrylsyre, med en glasstemperatur mellom -2 0 og +40°C og en partikkelstørrelse fra 50 til 500 nm suspenderes sammen med legemiddel-virkestoffet i et egnet oppløsningsmiddel, a) den virkestoffholdige polymeroppløsning støpes til en film, og efter avdampning av oppløsningsmidlet forsynes eventuelt den virkestoffholdige film med et damp-ugjennomtrengelig dekksjikt og konfeksjoneres, eller According to the invention, a method is provided for the production of a pharmaceutical preparation with variable, controlled and delayed active substance release, containing a carrier material based on an emulsion polymer. The method is characterized by the fact that an emulsion polymer selected from among emulsion polymerized copolymers of methyl and/or ethyl esters of acrylic and methacrylic acid, with a glass transition temperature between -20 and +40°C and a particle size from 50 to 500 nm is suspended together with medicinal the active ingredient in a suitable solvent, a) the polymer solution containing the active ingredient is molded into a film, and after evaporation of the solvent, the active ingredient-containing film is optionally provided with a vapor-impermeable cover layer and assembled, or
b) oppløsningsmidlet avdampes, den faste, virkestoffholdige emulsjonspolymer males til en kornstørrelse b) the solvent is evaporated, the solid, active ingredient-containing emulsion polymer is ground to a grain size
på 10 - 500 ura ved en temperatur under glasstemperaturen, bearbeides med vanlige tabletteringshjelpestoffer og presses til tabletter eller fylles i kapsler, of 10 - 500 ura at a temperature below the glass transition temperature, processed with usual tableting aids and pressed into tablets or filled into capsules,
hvor en reduksjon av partikkelstørrelsen bevirker en forhøyelse av frigjøringshastigheten, og en økning av glasstemperaturen bevirker en nedsettelse av frigjøringshastigheten, where a reduction of the particle size causes an increase in the release rate, and an increase in the glass temperature causes a decrease in the release rate,
idet fremstilling av preparater av et emulsjonspoly-akrylat med en partikkelstørrelse på ca. 140 nm og med en glasstemperatur på ca. 30'C er unntatt. in that the production of preparations of an emulsion polyacrylate with a particle size of approx. 140 nm and with a glass temperature of approx. 30'C is exempt.
Ved kombinert variasjon av kornstørrelsen, partikkel-størrelsen og glasstemperaturen har man for pulverformige farmasøytiske preparater, f.eks. tabletter eller kapsler, mulighet til å innstille virkestoff-frigjøringen for farma-søytiske preparater innenfor et vidt område. For farma-søytiske preparater i form av transdermale filmer kan frigjøringshastigheten innstilles ved å variere skikttykkelsen i området mellom 40 og 200 /Lim, fortrinnsvis 60 til 140 /um, partikkelstørrelsen og glasstemperaturen*. By combined variation of the grain size, the particle size and the glass temperature, one has for powdered pharmaceutical preparations, e.g. tablets or capsules, possibility to adjust the release of the active ingredient for pharmaceutical preparations within a wide range. For pharmaceutical preparations in the form of transdermal films, the release rate can be adjusted by varying the layer thickness in the range between 40 and 200 µm, preferably 60 to 140 µm, the particle size and the glazing temperature*.
Partikkelstørrelsen er partikkeldiameteren for det poly-mere materiale efter dets fremstilling og er ifølge oppfinnelsen 50-500 nm. Partikkelstørrelsen (diameteren) kan innstilles avhengig av polymerisasjonsbetingelsene. En reduksjon av partikkelstørrelsen bevirker en forhøyelse av frigjøringshastigheten. The particle size is the particle diameter of the polymeric material after its manufacture and is, according to the invention, 50-500 nm. The particle size (diameter) can be adjusted depending on the polymerization conditions. A reduction of the particle size causes an increase in the release rate.
Glasstemperaturen kan innstilles ved endring av monomer-sammensetningen og ligger ifølge oppfinnelsen -20 og +40°C, særlig mellom -10 og + 30^C^ En økning av glasstemperaturen er forbundet med en nedsettelse av frigjøringshastigheten. The glass temperature can be set by changing the monomer composition and, according to the invention, lies between -20 and +40°C, in particular between -10 and + 30°C. An increase in the glass temperature is associated with a reduction in the release rate.
Kornstørrelsen ligger i et område mellom 10 og 500 /im. The grain size lies in a range between 10 and 500 µm.
For innstilling av kornstørrelsen oppløses den emulsjonspolymeriserte polymer med en definert partikkelstørrelse sammen med virkestoffet i et egnet oppløsningsmiddel, støpes derefter til en film, og oppløsningsmidlet avdampes. Filmen blir derefter, eventuelt under sin glasstemperatur, malt til den ønskede kornstørrelse og eventuelt siktet. To set the grain size, the emulsion polymerized polymer with a defined particle size is dissolved together with the active ingredient in a suitable solvent, then cast into a film, and the solvent is evaporated. The film is then, optionally below its glass transition temperature, ground to the desired grain size and optionally sieved.
Som bæremateriale anvendes emulsjonspolymeriserte kopolymerer' av metyl- og/eller etylestere av akryl- og metakrylsyre. Emulsjonspolymerenes molekylvekt bør ligge mellom 10<*> og 10<7>. Utvinning av bærematerialet som faststoff kan f.eks. skje ved frysetørring, hvorved polymerpartiklene beholder sin form og størrelse. Emulsion-polymerized copolymers of methyl and/or ethyl esters of acrylic and methacrylic acid are used as carrier material. The molecular weight of the emulsion polymers should be between 10<*> and 10<7>. Extraction of the carrier material as a solid can e.g. happen by freeze-drying, whereby the polymer particles retain their shape and size.
Fremstillingen av de nye farmasøytiske preparater kan skje ved at en emulsjonspolymer med den ønskede partikkel-størrelse og glasstemperatur oppløses eller suspenderes sammen med virkestoffet i et mest mulig lettflyktig oppløsnings-middel. Som oppløsningsmiddel for den virkestoff- og emulsjonspolymer- inneholdende suspensjon kan anvendes slike, som har et lavt fordampningspunkt, f.eks. lavtkokende alkoholer å som metanol, etanol, aceton, metyletylketon, halogenerte hydrokarboner så som metylenklorid, eddiksyremetyl- og -etylestere, aceteddiksyremetyl- og -etylestere, eller etere, som f.eks. tetrahydrofuran eller dioksan, eller dimetylsulfoksyd, lavtkokende frigener, og også blandinger av disse oppløsnings- The production of the new pharmaceutical preparations can take place by dissolving or suspending an emulsion polymer with the desired particle size and glass transition temperature together with the active ingredient in a solvent that is as volatile as possible. Solvents for the active substance and emulsion polymer-containing suspension can be used which have a low evaporation point, e.g. low-boiling alcohols such as methanol, ethanol, acetone, methyl ethyl ketone, halogenated hydrocarbons such as methylene chloride, acetic acid methyl and -ethyl esters, acetoacetic acid methyl and -ethyl esters, or ethers, such as e.g. tetrahydrofuran or dioxane, or dimethylsulfoxide, low-boiling freegens, and also mixtures of these solvent
midler. funds.
Frigjøringshastigheten av virkestoffet kan varieres ytterligere ved tilsetning av hjelpestoffer, f.eks. diffu-sjonspåvirkende stoffer. Disse såkalte hjelpestoffer omfatter f.eks. polyvinylpyrrolidon, cellulose-estere, aminer, fett eller høyere alkoholer. Når det ønskes kan disse stoffer settes til virkestoffoppløsningen. The release rate of the active ingredient can be further varied by adding excipients, e.g. substances affecting diffusion. These so-called excipients include e.g. polyvinylpyrrolidone, cellulose esters, amines, fats or higher alcohols. When desired, these substances can be added to the active substance solution.
Denne oppløsning kan viderebearbeides som følger: This solution can be further processed as follows:
For fremstilling av et virkestoffholdig farmasøytisk preparat i form av en film for transdermal terapeutisk administrering, støpes den oppnådde oppløsning til en film med definert skikttykkelse, som er avpasset slik at filmen efter avdampning av oppløsningsmidlet har en skikttykkelse mellom 40 og 200 nm, fortrinnsvis 60 til 140 /xm. Derefter kan filmen forsynes med et dampugjennomtrengelig dekkskikt og eventuelt et klebeskikt og konfeksjoneres. For the production of a pharmaceutical preparation containing an active ingredient in the form of a film for transdermal therapeutic administration, the obtained solution is molded into a film with a defined layer thickness, which is tailored so that the film after evaporation of the solvent has a layer thickness between 40 and 200 nm, preferably 60 to 140/xm. The film can then be supplied with a vapor-permeable cover layer and possibly an adhesive layer and assembled.
For fremstilling av et virkestoffholdig farmasøytisk preparat i pulverform avdrives oppløsningsmidlet i den ovenfor beskrevne oppløsning, for fuktighets- eller oksydasjonsøm-fintlige legemidler eventuelt under beskyttelsesgass, og det oppnådde residuum males under sin glasstemperatur til den ønskede kornstørrelse mellom 10 og 500 /nm. Når det ønskes, kan malingen også skje i nærvær av inerte hjelpestoffer eller bæremidler, som f.eks. laktose, magnesiumstearat, finfordelt kiseljord eller lignende findelte glidemidler. Masseforholdet av virkestoffholdig emulsjonspolymer til findelt fyllstoff kan varieres innenfor videre grenser og ligger ved ca. 10:1 til 1:4. Den videre bearbeidelse til tabletter eller kapsler skjer ved kjente metoder med vanlige hjelpestoffer, som f.eks. bindemidler, inerte fyllstoffer, glidemidler, smøremidler og sprengmidler. For the production of a pharmaceutical preparation containing an active ingredient in powder form, the solvent in the above-described solution is removed, for moisture- or oxidation-sensitive medicinal products possibly under protective gas, and the obtained residue is ground below its glass temperature to the desired grain size between 10 and 500 /nm. When desired, the painting can also take place in the presence of inert auxiliaries or carriers, such as e.g. lactose, magnesium stearate, finely divided silica or similar finely divided lubricants. The mass ratio of active substance-containing emulsion polymer to finely divided filler can be varied within further limits and is at approx. 10:1 to 1:4. The further processing into tablets or capsules takes place by known methods with common excipients, such as e.g. binders, inert fillers, lubricants, lubricants and explosives.
En foretrukket utførelsesform er en delbar tablett, eftersom preparatet fremstilt ifølge oppfinnelsen beholder sine fordelaktige egenskaper også i hvert bruddstykke. Ved fremstilling av filmer for transdermal administrering kan ved forholdsgitt filmtykkelse og innarbeidet legemiddelmengde frigjøringshastigheten innstilles ved å variere partikkel- A preferred embodiment is a divisible tablet, since the preparation produced according to the invention retains its advantageous properties also in each broken piece. When producing films for transdermal administration, the release rate can be adjusted by varying the particle
størrelsen og glasstemperaturen. the size and glass temperature.
Det er kjent at ved et forhøyet innhold i bærematerialet vil frigjøringshastigheten økes vesentlig, slik at en forsinket frigjøring av virkestoffet ikke mer kan garanteres. Dette kunne oppveies av en økning av kornstørrelsen, men herved oppstod imidlertid den fare at det minste antall av de virkestoffholdige granulatpartikler i en tablett synker under det kritiske tall på 4 00 (idet en homogen fordeling av legemiddel-virkestoffet fra tablett til tablett ikke lenger er sikret). Ifølge oppfinnelsen kan problemet løses ved en høyere glasstemperatur hos det emulsjonspolymeriserte bæremateriale og en større partikkelstørrelse, idet kornstørrelsen da ialt vesentlig kan holdes konstant. Dette betyr at man i tabletter, kapsler eiler filmer kan innføre et vesentlig høyere innhold av legemiddel i bærematerialet. It is known that with an increased content in the carrier material, the release rate will be increased significantly, so that a delayed release of the active ingredient can no longer be guaranteed. This could be offset by an increase in the grain size, but this, however, created the danger that the smallest number of the granule particles containing the active substance in a tablet would fall below the critical number of 400 (as a homogeneous distribution of the medicinal active substance from tablet to tablet is no longer secured). According to the invention, the problem can be solved by a higher glass transition temperature of the emulsion polymerized carrier material and a larger particle size, since the grain size can then be essentially kept constant. This means that in tablets, capsules or films, a significantly higher content of medicine can be introduced into the carrier material.
Ifølge oppfinnelsen kan også gunstigere forhold mellom legemiddelstoff og bæremateriale innstilles, og derved kan depotprinsippet utvides til legemiddelstoffer som skal doseres i større mengder, eftersom frigjøringshastigheten også ved høyere innhold kan innstilles ved hjelp av de beskrevne para-metre, partikkelstørrelse, kornstørrelse og glasstemperatur, innenfor et bredt område. According to the invention, a more favorable ratio between medicinal substance and carrier material can also be set, and thereby the depot principle can be extended to medicinal substances that are to be dosed in larger quantities, since the release rate can also be set at higher contents using the described parameters, particle size, grain size and glass temperature, within a wide area.
Vanligvis inneholder preparatene fremstilt ifølge oppfinnelsen mellom 0,1 og 30 vekt%, fortrinnsvis 1 til 10 vekt% virkestoff. Generally, the preparations produced according to the invention contain between 0.1 and 30% by weight, preferably 1 to 10% by weight, of active substance.
EKSEMPLER EXAMPLES
A) Filmer A) Movies
Eksempel 1: Example 1:
De i tabell 1 angitte emulsjonspolymeriserte polyakrylater forarbeides til transdermale filmer og undersøkes med hensyn til sine frigivelseshastigheter. The emulsion polymerized polyacrylates listed in Table 1 are processed into transdermal films and examined with regard to their release rates.
Latekspartiklene utvinnes ved å fjerne vannet fra den aktuelle dispersjon (Firma Rohm GmbH, Darmstadt). 21,3 g av det tørrede polyakrylat oppløses sammen med 1,6 g clonidin i 142 g aceton og utstøpes som filmer på en jevn flate. Skikttykkelsen var efter avdampning av oppløsningsmidlet 80/zm. Frigivelseshastigheten ble bestemt overfor et vandig medium med pH ved 37°C, idet frigivelsesanalysen ble foretatt ved hjelp av HPLC. The latex particles are recovered by removing the water from the relevant dispersion (Firma Rohm GmbH, Darmstadt). 21.3 g of the dried polyacrylate are dissolved together with 1.6 g of clonidine in 142 g of acetone and cast as films on a smooth surface. The layer thickness after evaporation of the solvent was 80/zm. The release rate was determined against an aqueous medium with pH at 37°C, the release analysis being carried out by means of HPLC.
De diffusjonskoeffisienter som ble funnet med de tre forskjellige latekstyper, er angitt i tabell II. The diffusion coefficients found with the three different latex types are given in Table II.
På figur I er frigjøringsgraden for tre fysikalsk forskjellige latekser angitt. Som det fremgår av kurveforløpene, kan frigjøringsforholdene påvirkes både av partikkelstørrelsen og av glasstemperaturen for lateksen. Figure I shows the degree of release for three physically different latexes. As can be seen from the curves, the release conditions can be influenced both by the particle size and by the glass transition temperature of the latex.
Eksempel 2: Example 2:
De i tabell III angitte emulsjonspolymeriserte kopolymerer av vinylklorid og akrylsyre-ester forarbeides til transdermale filmer og undersøkes med hensyn til sin frigivelses-grad. The emulsion polymerized copolymers of vinyl chloride and acrylic acid ester listed in Table III are processed into transdermal films and examined with regard to their degree of release.
De to materialer som ble oppnådd ved emulsjonspolymerisa-sjon, adskiller seg med hensyn til glasstemperatur og dermed mykhet hos polymeren, mens lateksstørrelsen er lik for begge produkter. Polymeren oppnås ved tørring av den vandige dispersjon, oppløses derefter sammen med legemiddelstoffet clonidin i metylenklorid og støpes ut på kjent måte til filmer på ca. 100 jLm skikt-tykkelse. Frigivelsen av legemiddelstoffet fra CPA-filmen<*> med en størrelse på 3 cm<2> bestemmes på en USP-tester, og innholdsbestemmelsen foretas med HPLC. The two materials obtained by emulsion polymerization differ with respect to the glass transition temperature and thus the softness of the polymer, while the latex size is the same for both products. The polymer is obtained by drying the aqueous dispersion, is then dissolved together with the medicinal substance clonidine in methylene chloride and cast in a known manner into films of approx. 100 jLm layer thickness. The release of the drug substance from the CPA film<*> with a size of 3 cm<2> is determined on a USP tester, and the content determination is carried out by HPLC.
* CPA = kontrollert percutan administrering. * CPA = controlled percutaneous administration.
I tabell IV er angitt de mengder klonidin (i prosent) som er frigjort på forskjellige tidspunkter. Frigjøringshastigheten avtar med stigende glasstemperatur, dvs. jo hardere lateksen er desto langsommere skjer frigjøringen. Table IV shows the amounts of clonidine (in percent) released at different times. The release rate decreases with increasing glass temperature, i.e. the harder the latex, the slower the release.
Filmtykkelse: 100 jum, legemiddel innhold 0,7 mg clonidin/cm<2>Film thickness: 100 jum, drug content 0.7 mg clonidine/cm<2>
B) Tabletter: B) Tablets:
Tre forskjellige polyakrylattyper sammen med et virkestoff forarbeides til tabletter, og deres frigjørings-forhold er illustrert i figur II. Polymer D ("Eudragit E 30 D") og E er emulsjonspolymeriserte polyakrylater, polymer F ("Eudragit RS 100") substanspolymerisert polyakrylat fra firmaet Rohm GmbH, Darmstad. Begge polymertyper E og F har omtrentlig den samme glasstemperatur (Tg ca. 3 0°C) , men befinner seg imidlertid fysikalsk i forskjellige former: Kuleformig lateks (E) resp. som polymerklumper (F). Glasstemperaturen for polyakrylatet D, likeledes en kuleformet lateks, er Tg = -8°C. Glasstemperaturen kan innstilles ved å variere mengdeforholdet mellom monomerene som bygger opp polymeren, mens formen reguleres av polymerisasjonsbetingelsene. Three different polyacrylate types together with an active substance are processed into tablets, and their release conditions are illustrated in figure II. Polymer D ("Eudragit E 30 D") and E are emulsion polymerized polyacrylates, polymer F ("Eudragit RS 100") substance polymerized polyacrylate from the company Rohm GmbH, Darmstad. Both polymer types E and F have approximately the same glass transition temperature (Tg approx. 30°C), but are physically in different forms: Spherical latex (E) or as polymer clumps (F). The glass transition temperature for the polyacrylate D, likewise a spherical latex, is Tg = -8°C. The glass temperature can be set by varying the quantity ratio between the monomers that build up the polymer, while the shape is regulated by the polymerization conditions.
Eksempel 1 Example 1
I et egnet kar utrøres 23,75 g av polymer E sammen med 4 00 ml aceton inntil det dannes en klar oppløsning, hvorefter virkestoffoppløsningen, bestående av 1,25 g B-HT 933 base i 100 ml metanol tilsettes. Fra den såldes oppnådde oppløsning avdampes oppløsningsmidlet under beskyttelsesgassatmosfære (N2), og gjenværende virkestoffholdig film avkjøles ved hjelp av tørris til ca. -4 0°C og males porsjonsvis sammen med laktose i mengdeforhold 9:1 i en mølle med roterende kniver under avkjøling. Man får et frittflytende pulver i hvilket det virkestoffholdige polyakrylat foreligger logaritisk normalt fordelt mellom 65 og 500 fim. In a suitable vessel, 23.75 g of polymer E are stirred together with 400 ml of acetone until a clear solution is formed, after which the active ingredient solution, consisting of 1.25 g of B-HT 933 base in 100 ml of methanol, is added. From the solution thus obtained, the solvent is evaporated under a protective gas atmosphere (N2), and the remaining film containing the active substance is cooled using dry ice to approx. -4 0°C and is ground in portions together with lactose in a quantity ratio of 9:1 in a mill with rotating knives while cooling. A free-flowing powder is obtained in which the active substance-containing polyacrylate is logarithmically normally distributed between 65 and 500 µm.
Den på den ovenfor beskrevne måte fremstilte blanding presses i neste arbeidstrinn til tabletter ved kjente metoder med vanlige tabletteringshjelpestoffer så som melkesukker, maisstivelse, kolloidal kieselsyre og/eller magnesiumstearat, idet tablettene oppviser et virkestoffinnhold på 5% basert på polymerbæreren. The mixture produced in the manner described above is pressed into tablets in the next work step by known methods with common tableting aids such as milk sugar, corn starch, colloidal silicic acid and/or magnesium stearate, the tablets having an active ingredient content of 5% based on the polymer carrier.
Eksempel 2 Example 2
Analogt med eksempel 1 forarbeides polymer F, oppløst i 250 ml diklormetan og 5,0 g B-HT 933 base i 40 ml metanol til en film, males og presses til tabletter. Analogous to example 1, polymer F, dissolved in 250 ml of dichloromethane and 5.0 g of B-HT 933 base in 40 ml of methanol, is processed into a film, ground and pressed into tablets.
Eksempel 3 Example 3
Analogt med eksempel 1 forarbeides 95 g av polyakrylat E, oppløst i 500 ml aceton og 5,0 g B-HT 933 base i 40 ml metanol til en film, males og presses til tabletter. Analogously to example 1, 95 g of polyacrylate E, dissolved in 500 ml of acetone and 5.0 g of B-HT 933 base in 40 ml of methanol, is processed into a film, ground and pressed into tablets.
In vitro frigjøringen fra tablettene ble undersøkt ved 37°C i en USP XVTI-tester, idet vann med pH 7 ble anvendt som reseptormedium. Analysen ble foretatt med HPLC. The in vitro release from the tablets was investigated at 37°C in a USP XVTI tester, using water with a pH of 7 as the receptor medium. The analysis was carried out with HPLC.
Som d'c fremgår av figur II avgis virkestoffet fra det substanspolymeriserte polyakrylat nesten fullstendig allerede efter 2 timer, mens for et emulsjonspolymerisert polyakrylat kan en ønsket f rigj øringsprof il, f. eks. tlh 19 %, t6h 60 % frigjøring av legemiddel, innstilles avhengig av glasstemperaturen . As can be seen from Figure II, the active substance from the substance-polymerized polyacrylate is almost completely released after 2 hours, while for an emulsion-polymerized polyacrylate, a desired release profile, e.g. tlh 19%, t6h 60% drug release, adjusted depending on the glass temperature.
Claims (4)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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DE19853525767 DE3525767A1 (en) | 1985-07-19 | 1985-07-19 | PHARMACEUTICAL PREPARATION WITH CONTROLLED AND DELAYED ACTIVE SUBSTANCE RELEASE AND METHOD FOR THE PRODUCTION THEREOF |
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NO862907D0 NO862907D0 (en) | 1986-07-18 |
NO862907L NO862907L (en) | 1987-01-20 |
NO174086B true NO174086B (en) | 1993-12-06 |
NO174086C NO174086C (en) | 1994-03-16 |
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NO862907A NO174086C (en) | 1985-07-19 | 1986-07-18 | Process for the preparation of a delayed active release pharmaceutical composition |
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EP (1) | EP0209121B1 (en) |
JP (1) | JPH0816068B2 (en) |
KR (1) | KR930007246B1 (en) |
AT (1) | ATE72110T1 (en) |
AU (1) | AU589983B2 (en) |
CA (1) | CA1289076C (en) |
CS (1) | CS264133B2 (en) |
DD (2) | DD265327A5 (en) |
DE (2) | DE3525767A1 (en) |
DK (1) | DK343586A (en) |
ES (1) | ES2001858A6 (en) |
FI (1) | FI88674C (en) |
GR (1) | GR861872B (en) |
HU (1) | HU196314B (en) |
IE (1) | IE59024B1 (en) |
IL (1) | IL79439A (en) |
NO (1) | NO174086C (en) |
NZ (1) | NZ216897A (en) |
PH (1) | PH22993A (en) |
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GB9021674D0 (en) * | 1990-10-05 | 1990-11-21 | Ethical Pharma Ltd | Transdermal device |
DE19603402A1 (en) * | 1995-02-24 | 1996-08-29 | Basf Ag | Soft gelatin capsules |
DE19940238A1 (en) | 1999-08-25 | 2001-03-01 | Lohmann Therapie Syst Lts | Therapeutic system containing active ingredients for application to the skin with at least two polymer-containing layers |
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USRE28316E (en) * | 1968-09-03 | 1975-01-21 | Entrapment compositions and processes | |
JPS57116011A (en) * | 1981-01-08 | 1982-07-19 | Nitto Electric Ind Co Ltd | Pharmaceutical preparation |
DE3204551A1 (en) * | 1982-02-10 | 1983-08-18 | Boehringer Ingelheim KG, 6507 Ingelheim | METHOD FOR PRODUCING A PHARMACEUTICAL PREPARATION IN THE FORM OF A POLYACRYLATE FILM |
DE3314003A1 (en) * | 1983-04-18 | 1984-10-18 | Boehringer Ingelheim KG, 6507 Ingelheim | DIVISIBLE TABLET WITH DELAYED ACTIVE SUBSTANCE RELEASE AND METHOD FOR THE PRODUCTION THEREOF |
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1985
- 1985-07-19 DE DE19853525767 patent/DE3525767A1/en not_active Withdrawn
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1986
- 1986-07-16 EP EP86109726A patent/EP0209121B1/en not_active Expired - Lifetime
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- 1986-07-16 AT AT86109726T patent/ATE72110T1/en not_active IP Right Cessation
- 1986-07-16 DE DE8686109726T patent/DE3683700D1/en not_active Expired - Lifetime
- 1986-07-17 CS CS865452A patent/CS264133B2/en unknown
- 1986-07-17 IL IL79439A patent/IL79439A/en not_active IP Right Cessation
- 1986-07-17 FI FI862967A patent/FI88674C/en not_active IP Right Cessation
- 1986-07-17 PL PL1986260689A patent/PL260689A1/en unknown
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- 1986-07-18 HU HU862967A patent/HU196314B/en not_active IP Right Cessation
- 1986-07-18 IE IE191486A patent/IE59024B1/en not_active IP Right Cessation
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- 1986-07-18 ES ES8600406A patent/ES2001858A6/en not_active Expired
- 1986-07-18 AU AU60304/86A patent/AU589983B2/en not_active Ceased
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- 1986-07-19 KR KR1019860005857A patent/KR930007246B1/en not_active IP Right Cessation
- 1986-07-21 PH PH34040A patent/PH22993A/en unknown
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1988
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