WO1997012604A1 - Process for producing solid vitamin preparations - Google Patents
Process for producing solid vitamin preparations Download PDFInfo
- Publication number
- WO1997012604A1 WO1997012604A1 PCT/EP1996/004272 EP9604272W WO9712604A1 WO 1997012604 A1 WO1997012604 A1 WO 1997012604A1 EP 9604272 W EP9604272 W EP 9604272W WO 9712604 A1 WO9712604 A1 WO 9712604A1
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- Prior art keywords
- vitamin
- vitamins
- melt
- preparations
- weight
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Definitions
- the present invention relates to a process for the production of vitamin-containing solid preparations by extrusion of a polymer melt containing us and subsequent shaping, as well as pharmaceutical forms from these preparations.
- the preparation of active substance-containing preparations by melt extrusion is generally known.
- the object of the present invention was to find an improved process for the production of vitamin preparations.
- the vitamin-containing melt is preferably produced in the extruder at temperatures of 80 to 110 ° C.
- a water-soluble, thermoplastically processable hydroxypropyl cellulose is preferably used as the polymer matrix for the vitamin-containing preparations, which preferably has a molar degree of substitution of 3.0 to 4.4.
- “Moler degree of substitution” refers to the average Number of moles of propylene oxide that are converted per cellulose glucose unit.
- the hydroxypropyl celluloses can have melt viscosities according to DIN 53735 in the range from 0.075 to 54.8 g / 10 min.
- the molecular weight of the hydroxypropyl cellulose can be varied within a wide range, depending on whether a slower or a faster drug release is desired.
- High molecular weight hydroxypropyl cellulose with molecular weights in the range from 200,000 to 1,500,000 are particularly suitable for the production of pharmaceutical forms in which a slow release of active substance is desired, e.g. in slow release forms, since the higher molecular polymers dissolve less well and only swell in water.
- 60,000 to 200,000 preferably 60,000 to 100,000, can be used.
- hydroxypropyl cellulose used according to the invention is generally known. They are commercially available, for example under the brand name Klucel® (from Aqualon).
- the proportion of hydroxypropyl cellulose in the total amount of the dosage form can be 5 to 95% by weight, preferably 15 to 40% by weight.
- Vitamins in the sense of the invention are also provitamins or vitamin derivatives.
- Suitable vitamins are accordingly:
- Thiamine (Bi), riboflavin (B 2 ), the B 6 vitamins pyridoxal, pyridoxamine and pyridoxine, cobalamins (B ⁇ ) such as cyanocobalamin, bio-tin, folic acid, nicotinic acid, nicotinamide, pantothenic acid,
- Ascorbic acid and its physioligially tolerated salts such as ascorbyl palmitate
- Vitamin F essential fatty acids
- Vitamin F essential fatty acids
- linolenic acid linoleic acid or arachidonic acid
- Combination preparations can also be produced.
- the dosage forms can the vitamins in amounts from 0.1 to
- Type of vitamins the other depends on the use.
- the pharmaceutical forms according to the invention can also contain customary pharmaceutical auxiliaries, provided that they are thermally stable under the processing conditions and are compatible with the vitamins used, e.g. Fillers, lubricants, plasticizers, stabilizers, dyes or pigments, disintegrants, preservatives of the flavorings.
- Suitable fillers are, for example, organic compounds such as lactose, sorbitol or mannitol or inorganic substances such as silica or silicates.
- Well water-soluble fillers such as xylitol, isomalt, lactose, sorbitol or mannitol are suitable, for example, for the preparation of preparations with accelerated release of active ingredients.
- the proportion of fillers in the preparation depends on the dosage of the active ingredient. In the case of active ingredients with a low dosage, a higher tablet weight can be achieved according to the invention by means of higher filler proportions without the thermoplastic processability being impaired. At very low to dose materials, the amount of filler can be up to approximately 90% by weight.
- Flow regulators such as the mono-, di- and triglycerides of the long-chain fatty acids such as C 2 , C 1, C 6 and C 6 fatty acid or waxes such as carnauba wax can be used in the usual amounts as further pharmaceutical auxiliaries.
- plasticizers e.g. in addition to low molecular weight polyalkylene oxides such as polyethylene glycol, polypropylene glycol and polyethylene propylene glycol, also polyhydric alcohols such as propylene glycol, glycerin, pentaerythritol and sorbitol as well as sodium diethylsulfosuccinate, mono-, di- and triacetate of glycerol and polyethylene glycol stearic acid ester, these substances are not called, these substances are not called esters Show incompatibility with the vitamins used.
- the amount of plasticizer is about 0.5 to 15, preferably 0.5 to 5 wt .-%.
- lubricants e.g. Glycerol monostearate and other glycerol mono- and diesters and stearates of aluminum, magnesium or calcium as well as talc and silicones are mentioned, their amount being about 0.1 to 5, preferably 0.1 to 3% by weight.
- compositions containing vitamins are particularly preferred which contain lipids as mold release agents and auxiliaries for influencing the plasticity of the melt.
- the lipids present invention mono-, di- and triglycerides come from naturally occurring fatty acids into consideration beispiels ⁇ as glycerol, glyceryl, glycerol tristearate, Glyceroltripalmitat, GTM, glycerol tribehenate, Glycerolpalmitylstearylester or glyceride as occur in natural oils, preferably hydrogenated castor oil.
- Ceramides are also suitable for this purpose.
- Preferred lipids are primarily phospholipids, with phosphoglycerides such as lecithins being particularly preferred. Hydrogenated lecithins such as soya and egg lecitin are particularly preferred.
- the lipids can be used in amounts of 0.1-10% by weight, based on the total amount of the active substance-containing preparations, 1 to 5% by weight being preferred.
- Stabilizers which may be mentioned are, for example, light stabilizers, antioxidants, radical scavengers and stabilizers against microbial attack which can be used in the customary amounts.
- flavoring and sweetening for example for use as a lozenge, natural, nature-identical or artificial flavors and sweeteners such as e.g. Cyclamate, aspartame, neoresperidin or saccharin sodium or mixtures thereof are used.
- natural, nature-identical or artificial flavors and sweeteners such as e.g. Cyclamate, aspartame, neoresperidin or saccharin sodium or mixtures thereof are used.
- the vitamins can either be melted directly as a physical mixture with the matrix polymer or can be mixed with the polymer melt already present.
- the latter procedure is particularly recommended for very temperature-sensitive vitamins.
- auxiliaries can be incorporated into the polymer melt together with the active ingredient. Mixtures of auxiliaries, the active ingredient and the polymers can also be melted directly.
- the matrix polymer is melted and mixed with active ingredients and auxiliaries at from 50 to 150 ° C., preferably from 80 to 110 ° C., in a twin-screw extruder.
- the vitamin-containing melt leaving the extruder can, as described in US Pat. No. 4,880,585, be pressed directly into tablets via opposing pairs of forming rolls.
- processes for the production of small particles are also possible, e.g. by using the hot cutting process (extrusion of the melt through thin holes; cutting the extrudate strands directly in front of the die plate by rotating knives into pellets).
- pellets are suitable e.g. for filling in hard gelatin capsules, but also as a preliminary stage for a subsequent tableting pressing process.
- the process according to the invention is particularly suitable for the production of vitamin preparations which contain vitamins, provitamins or vitamin derivatives which are sensitive to oxidation and temperature.
- Ascorbic acid can thus be processed largely without decomposition, which was surprising in view of the known temperature sensitivity of this substance.
- ⁇ -carotene can also be processed excellently without significant isomerization taking place.
- the storage stabilities of the formulations according to the invention were also good; after three months of storage at 10.degree. C., no losses of vitamins were found, for example.
- the vitamin preparations produced according to the invention can be used for pharmaceutical or veterinary purposes
- compositions containing carotenoids can also be used for coloring foods.
- the area of application is animal nutrition.
- the raw materials listed in the table were mixed to-35 present in an adequate mixer and entered h as a mixture in the ex ⁇ screw extruder via a weigh feeder with capacities ranging from 20 to 30 kg /.
- the speed of the extruder screw was in al ⁇ len cases from 100 to 150 rev / min.
- the vitamin C content of a sample according to Example 3 was analyzed a few days after production using an HPLC method (isocratic system). The actual value found was 41.46% by weight (target value: 41.66% by weight), and no by-products were observed. The actual values found for the beta-carotene were 3.8% by weight (target: 3.34% by weight), of which 90.7% were all-trans-beta-carotene.
- the vitamin-containing tablets according to Example 12 were examined using the reversed phase high pressure liquid chromatography.
Abstract
A process for preparing vitamin-containing pharmaceutical products by extruding then moulding a vitamin-containing molten polymer is characterised in that a hydroxypropyl cellulose is used as matrix polymer.
Description
Verfahren zur Herstellung von vitaminhaltigen festen ZubereitungenProcess for the preparation of vitamin-containing solid preparations
Beschreibungdescription
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von vitaminhaltigen festen Zubereitungen durch Extrusion einer wir stoffhaltigen Polymerschmelze und anschließender Formgebung sowie Arzneiformen aus diesen Zubereitungen.The present invention relates to a process for the production of vitamin-containing solid preparations by extrusion of a polymer melt containing us and subsequent shaping, as well as pharmaceutical forms from these preparations.
Die Herstellung von wirkstoffhaltigen Zubereitungen durch Schmelzextrusion ist allgemein bekannt.The preparation of active substance-containing preparations by melt extrusion is generally known.
In der US-A 4,801,460 wird die Herstellung von festen Arznei - formen durch Schmelzextrusion von Mischungen aus Wirkstoff und thermoplastischen N-Vinylpyrrolidon-Polymeren beschrieben. Als Wirkstoffe sind beispielsweise auch Vitamine genannt.US Pat. No. 4,801,460 describes the production of solid medicament forms by melt extrusion of mixtures of active ingredient and thermoplastic N-vinylpyrrolidone polymers. Vitamins are also mentioned as active ingredients.
Viele Vitamine sind chemisch labile Substanzen, die schon durch Luftsauerstoff, Hitze und Wasserzutritt zersetzt werden (vgl. V. Bühler, "Vademecum for Vitamin Formulations" , Wissenschaftliche Verlagsgesellschaft Stuttgart (1988), z.B. Seite 9) und insofern für einen thermischen Verarbeitungsprozeß wie die Schmelz- extrusion nicht unbedingt geeignet. In der US-A 4,880,585 ist zwar die Verarbeitung von Vitamine beschrieben, jedoch bestand hinsichtlich der Stabilität der Zubereitungen noch Raum für Ver¬ besserungen.Many vitamins are chemically labile substances that are already decomposed by atmospheric oxygen, heat and water (see V. Bühler, "Vademecum for Vitamin Formulations", Wissenschaftliche Verlagsgesellschaft Stuttgart (1988), eg page 9) and in this respect for a thermal processing process like that Melt extrusion is not necessarily suitable. The processing of vitamins is described in US Pat. No. 4,880,585, but there was still room for improvement with regard to the stability of the preparations.
Aufgabe der vorliegenden Erfindung war es, ein verbessertes Ver¬ fahren zur Herstellung von Vitamin-Zubereitungen zu finden.The object of the present invention was to find an improved process for the production of vitamin preparations.
Demgemäß wurde ein Verfahren zur Herstellung von vitaminhaltigen festen Zubereitungen durch Extrusion einer vitaminhaltigen Polymerschmelze und anschließender Formgebung gefunden, welches dadurch gekennzeichnet ist, daß als Matrixpolymer eine wasserlös¬ liche thermoplastische Hydroxypropylcellulose verwendet wird.Accordingly, a process for the production of vitamin-containing solid preparations by extrusion of a vitamin-containing polymer melt and subsequent shaping has been found, which is characterized in that a water-soluble thermoplastic hydroxypropyl cellulose is used as the matrix polymer.
Die Herstellung der vitaminhaltigen Schmelze im Extruder erfolgt bevorzugt bei Temperaturen von 80 bis 110°C.The vitamin-containing melt is preferably produced in the extruder at temperatures of 80 to 110 ° C.
Als polymere Matrix für die vitaminhaltigen Zubereitungen wird erfindungsgemäß bevorzugt eine wasserlösliche, thermoplastisch verarbeitbare Hydroxypropylcellulose verwendet, die vorzugsweise einen molaren Substitutionsgrad von 3,0 bis 4,4 aufweist. "Mola¬ rer Substitutionsgrad" bezieht sich auf die durchschnittliche
Anzahl von Molen Propylenoxid, die pro Glucoseeinheit der Cellu- lose umgesetzt sind.According to the invention, a water-soluble, thermoplastically processable hydroxypropyl cellulose is preferably used as the polymer matrix for the vitamin-containing preparations, which preferably has a molar degree of substitution of 3.0 to 4.4. "Moler degree of substitution" refers to the average Number of moles of propylene oxide that are converted per cellulose glucose unit.
Die Hydroxypropylcellulosen können Schmelzviskositäten nach DIN 53735 im Bereich von 0,075 bis 54,8 g/10 min aufweisen.The hydroxypropyl celluloses can have melt viscosities according to DIN 53735 in the range from 0.075 to 54.8 g / 10 min.
Das Molekulargewicht der Hydroxypropylcellulose kann in breiten Bereichen variiert werden, je nachdem, ob eine langsamere oder eine schnellere Wirkstoff-Freisetzung gewünscht ist. Hochmoleku- lare Hydroxypropylcellulose mit Molekulargewichten im Bereich von 200.000 bis 1.500.000 eignen sich insbesondere zur Herstellung von Arzneiformen, bei denen eine langsame Wirkstoff-Freisetzung erwünscht ist, z.B. bei Retard-Formen, da sich die höher- molekularen Polymere weniger gut und nur unter Quellung in Wasser lösen.The molecular weight of the hydroxypropyl cellulose can be varied within a wide range, depending on whether a slower or a faster drug release is desired. High molecular weight hydroxypropyl cellulose with molecular weights in the range from 200,000 to 1,500,000 are particularly suitable for the production of pharmaceutical forms in which a slow release of active substance is desired, e.g. in slow release forms, since the higher molecular polymers dissolve less well and only swell in water.
Will man jedoch Arzneiformen mit einer schnelleren Wirkstoff- Freisetzung herstellen, so empfiehlt sich die Verwendung nieder¬ molekularer Polymere, die gut wasserlöslich sind, wobei in diesem Falle Hydroxypropylcellulosen mit einem Molekulargewicht vonHowever, if one wants to manufacture pharmaceutical forms with a faster release of active substance, the use of low molecular weight polymers which are readily water-soluble is recommended, in which case hydroxypropyl celluloses with a molecular weight of
60.000 bis 200.000, bevorzugt 60.000 bis 100.000 eingesetzt wer¬ den können.60,000 to 200,000, preferably 60,000 to 100,000, can be used.
Die Herstellung der erfindungsgemäß verwendeten Hydroxypropylcel- lulosen ist allgemein bekannt. Sie sind kommerziell erhältlich, beispielsweise unter dem Markennamen Klucel® (Fa. Aqualon) .The production of the hydroxypropyl cellulose used according to the invention is generally known. They are commercially available, for example under the brand name Klucel® (from Aqualon).
Der Anteil der Hydroxypropylcellulose an der Gesamtmenge der Arzneiform kann 5 bis 95 Gew.- , bevorzugt 15 bis 40 Gew.-% be- tragen.The proportion of hydroxypropyl cellulose in the total amount of the dosage form can be 5 to 95% by weight, preferably 15 to 40% by weight.
Als Vitamine kommen erfindungsgemäß prinzipiell alle Vitamine in Betracht, da aufgrund der niedrigen Verarbeitungstemperaturen auch empfindliche Substanzen eingesetzt werden können. Vitamine im Sinne der Erfindung sind auch Provitamine oder Vitaminderi¬ vate.According to the invention, all vitamins can in principle be considered as vitamins, since sensitive substances can also be used due to the low processing temperatures. Vitamins in the sense of the invention are also provitamins or vitamin derivatives.
Geeignete Vitamine sind demgemäß:Suitable vitamins are accordingly:
- Vitamin A-Gruppe- Vitamin A group
Retinol (Ai) , Dehydroretinol (A2) , Retinoide wie beispielsweise Vitamin-A-säure, Carotinoide wie z.B. ß-Carotin,
- Vitamin B-GruppeRetinol (Ai), dehydroretinol (A 2 ), retinoids such as vitamin A acid, carotenoids such as ß-carotene, - Vitamin B group
Thiamin (Bi) , Riboflavin (B2) , die B6-Vitamine Pyridoxal, Pyri- doxamin und Pyridoxin, Cobalamine (Bι ) wie Cyanocobalamin, Bio- tin, Folsäure, Nicotinsäure, Nicotinamid, Pantothensäure,Thiamine (Bi), riboflavin (B 2 ), the B 6 vitamins pyridoxal, pyridoxamine and pyridoxine, cobalamins (Bι) such as cyanocobalamin, bio-tin, folic acid, nicotinic acid, nicotinamide, pantothenic acid,
- Vitamin C-Gruppe- Vitamin C group
Ascorbinsäure und deren physioligial verträglichen Salze wie beispielsweise AscorbylpalmitatAscorbic acid and its physioligially tolerated salts such as ascorbyl palmitate
- Vitamin D-Gruppe- Vitamin D group
Ergocalciferol (D2) , Colecalciferol (D3) , Provitamin D3 (7-Dehy- drocholesterin) , Provitamin D2 (Ergosterin)Ergocalciferol (D 2 ), colecalciferol (D 3 ), provitamin D 3 (7-dehydrocholesterol), provitamin D 2 (ergosterol)
- Vitamin E-Gruppe α-Tocopherol, Tocopherolacetat, γ-Tocopherol, Tocopherolsucci- nat- Vitamin E group α-tocopherol, tocopherol acetate, γ-tocopherol, tocopherol succinate
- Vitamin F (essentielle Fettsäuren) wie beispielsweise Linolensäure, Linolsäure oder Arachidon- säure,Vitamin F (essential fatty acids) such as linolenic acid, linoleic acid or arachidonic acid,
- Vitamin K-Gruppe- Vitamin K group
Phyllochinon (Ki) , Menachinon 7 (K2) .Phylloquinone (Ki), menaquinone 7 (K 2 ).
Es können auch Kombinationspräparate hergestellt werden.Combination preparations can also be produced.
Die Arzneiformen können die Vitamine in Mengen von 0,1 bisThe dosage forms can the vitamins in amounts from 0.1 to
95 Gew.-% enthalten, wobei sich die Dosierung zum einen nach derContain 95 wt .-%, the dosage depending on the one hand
Art der Vitamine, zum anderen nach der Verwendung richtet.Type of vitamins, the other depends on the use.
Weiterhin können die erfindungsgemäßen Arzneiformen noch übliche pharmazeutische Hilfsstoffe enthalten, sofern sie unter den Ver¬ arbeitungsbedingungen thermisch stabil und mit den eingesetzten Vitaminen kompatibel sind, z.B. Füllstoffe, Schmiermittel, Weich- macher, Stabilisatoren, Farbstoffe oder Pigmente, Sprengmittel, Konservierungsmittel der Geschmackstoffe. Geeignete Füllstoffe sind beispielsweise organische Verbindungen wie Lactose, Sorbit oder Mannit oder anorganische Stoffe wie Kieselsäure oder Sili- cate. Gut wasserlösliche Füllstoffe wie Xylit, Isomalt, Lactose, Sorbit oder Mannit eignen sich beispielsweise zur Herstellung von Zubereitungen mit beschleunigter Wirkstoff-Freisetzung.Furthermore, the pharmaceutical forms according to the invention can also contain customary pharmaceutical auxiliaries, provided that they are thermally stable under the processing conditions and are compatible with the vitamins used, e.g. Fillers, lubricants, plasticizers, stabilizers, dyes or pigments, disintegrants, preservatives of the flavorings. Suitable fillers are, for example, organic compounds such as lactose, sorbitol or mannitol or inorganic substances such as silica or silicates. Well water-soluble fillers such as xylitol, isomalt, lactose, sorbitol or mannitol are suitable, for example, for the preparation of preparations with accelerated release of active ingredients.
Der Anteil an Füllstoffen in der Zubereitung richtet sich nach der Wirkstoff-Dosierung. Bei Wirkstoffen mit niedriger Dosierung kann erfindungsgemäß durch höhere Füllstoffanteile ein höheres Tablettengewicht erzielt werden, ohne daß die thermoplastische Verarbeitbarkeit beeinträchtigt wird. Bei sehr niedrig zu dosie-
renden Werkstoffen kann die Füllstoffmenge bis zu circa 90 Gew.-% betragen.The proportion of fillers in the preparation depends on the dosage of the active ingredient. In the case of active ingredients with a low dosage, a higher tablet weight can be achieved according to the invention by means of higher filler proportions without the thermoplastic processability being impaired. At very low to dose materials, the amount of filler can be up to approximately 90% by weight.
Als weitere pharmazeutische Hilfsstoffe können Fließregulierungs- mittel wie beispielsweise die Mono-, Di- und Triglyceride der langkettigen Fettsäuren wie Cι2-, Cι -, Cι6- und Ciβ-Fettsäure oder Wachse wie Carnaubawachs in den üblichen Mengen verwendet werden.Flow regulators such as the mono-, di- and triglycerides of the long-chain fatty acids such as C 2 , C 1, C 6 and C 6 fatty acid or waxes such as carnauba wax can be used in the usual amounts as further pharmaceutical auxiliaries.
Als Weichmacher seien z.B. neben niedermolekularen Polyalkylen- oxiden wie Polyethylenglykol, Polypropylenglykol und Polyethylen- propylenglykol auch mehrwertig Alkohole wie Propylenglykol, Gly- cerin, Pentaerythrit und Sorbit sowie Natriumdiethylsulfosucci- nat, Mono-, Di- und Triacetat des Glycerin und Polyethylenglykol- stearinsäureester genannt, sofern diese Stoffe keine Inkompatibi- lität mit den jeweils eingesetzten Vitaminen zeigen. Dabei liegt die Menge an Weichmacher bei ca. 0,5 bis 15, vorzugsweise 0,5 bis 5 Gew.-%.As plasticizers e.g. in addition to low molecular weight polyalkylene oxides such as polyethylene glycol, polypropylene glycol and polyethylene propylene glycol, also polyhydric alcohols such as propylene glycol, glycerin, pentaerythritol and sorbitol as well as sodium diethylsulfosuccinate, mono-, di- and triacetate of glycerol and polyethylene glycol stearic acid ester, these substances are not called, these substances are not called esters Show incompatibility with the vitamins used. The amount of plasticizer is about 0.5 to 15, preferably 0.5 to 5 wt .-%.
Als Schmiermittel seien z.B. Glycerinmonostearat und andere Glycerin-Mono- und Diester sowie Stearate von Aluminium, Mag¬ nesium oder Calcium sowie Talkum und Silikone genannt, wobei ihre Menge bei ca. 0,1 bis 5, vorzugsweise 0,1 bis 3 Gew.-% liegt.As lubricants e.g. Glycerol monostearate and other glycerol mono- and diesters and stearates of aluminum, magnesium or calcium as well as talc and silicones are mentioned, their amount being about 0.1 to 5, preferably 0.1 to 3% by weight.
Besonders bevorzugt sind vitaminhaltige Arzneiformen, die als Formentrennmittel und Hilfsmittel zur Beeinflussung der Plasti¬ zität der Schmelze Lipide enthalten.Pharmaceutical forms containing vitamins are particularly preferred which contain lipids as mold release agents and auxiliaries for influencing the plasticity of the melt.
Als Lipide kommen erfindungsgemäß Mono-, Di- und Triglyceride von natürlich vorkommenden Fettsäuren in Betracht, beispiels¬ weise Glycerolmonostearat, Glyceroldistearat, Glyceroltristearat, Glyceroltripalmitat, Glyceroltrimyristat, Glyceroltribehenat, Glycerolpalmitylstearylester oder Glyceridgemische wie sie in natürlichen Ölen vorkommen, vorzugsweise hydriertes Rizinusöl.The lipids present invention mono-, di- and triglycerides come from naturally occurring fatty acids into consideration beispiels¬ as glycerol, glyceryl, glycerol tristearate, Glyceroltripalmitat, GTM, glycerol tribehenate, Glycerolpalmitylstearylester or glyceride as occur in natural oils, preferably hydrogenated castor oil.
Weiterhin eignen sich auch Ceramide für diesen Zweck.Ceramides are also suitable for this purpose.
Bevorzugte Lipide sind vor allem Phospholipide, wobei Phosphogly- ceride wie Lecithine besonders bevorzugt sind. Ganz besonders be- vorzugt sind hydrierte Lecithine wie Soja- und Eilecitin.Preferred lipids are primarily phospholipids, with phosphoglycerides such as lecithins being particularly preferred. Hydrogenated lecithins such as soya and egg lecitin are particularly preferred.
Die Lipide können in Mengen von 0,1 - 10 Gew. -%, bezogen auf die Gesamtmenge der wirkstoffhaltigen Zubereitungen, verwendet wer¬ den, bevorzugt sind 1 bis 5 Gew. -%.
Als Stabilisatoren seien beispielsweise Lichtstabilisatoren, Antioxidantien, Radikalf nger und Stabilisatoren gegen mikrobiel- len Befall genannt, die in den üblichen Mengen eingesetzt werden können.The lipids can be used in amounts of 0.1-10% by weight, based on the total amount of the active substance-containing preparations, 1 to 5% by weight being preferred. Stabilizers which may be mentioned are, for example, light stabilizers, antioxidants, radical scavengers and stabilizers against microbial attack which can be used in the customary amounts.
Zur Aromatisierung und Süßung, beispielsweise für die Anwendung als Lutschtablette, können natürliche, naturidentische oder künstliche Aromen und Süßstoffe wie z.B. Cyclamat, Aspartam, Neo- hesperidin oder Saccharin-Natrium oder deren Gemische eingesetzt werden.For flavoring and sweetening, for example for use as a lozenge, natural, nature-identical or artificial flavors and sweeteners such as e.g. Cyclamate, aspartame, neoresperidin or saccharin sodium or mixtures thereof are used.
Zur Durchführung des erfindungsgemäßen Verfahrens können die Vi¬ tamine entweder direkt als physikalische Mischung mit dem Matrix¬ polymer geschmolzen werden oder mit der bereits vorliegenden Polymerschmelze gemischt werden. Die letztere Vorgehensweise emp¬ fiehlt sich besonders für sehr temperaturempfindliche Vitamine.To carry out the process according to the invention, the vitamins can either be melted directly as a physical mixture with the matrix polymer or can be mixed with the polymer melt already present. The latter procedure is particularly recommended for very temperature-sensitive vitamins.
Es ist möglich, die Hilfsstoffe in die Schmelze aus Wirkstoffen und Polymeren zu mischen. Ferner können die Hilfsstoffe zusammen mit dem Wirkstoff in die Polymerschmelze eingearbeitet werden. Außerdem können Gemische aus Hilfsstoffen, dem Wirkstoff und den Polymeren direkt verschmolzen werden.It is possible to mix the auxiliary substances in the melt from active substances and polymers. Furthermore, the auxiliaries can be incorporated into the polymer melt together with the active ingredient. Mixtures of auxiliaries, the active ingredient and the polymers can also be melted directly.
Nach dem erfindungsgemäßen Verfahren erfolgt das Aufschmelzen des Matrixpolymeren und die Vermischung mit Wirkstoffen und Hilfsmit¬ teln bei Temperaturen von 50 bis 150°C, bevorzugt 80 bis 110°C in einem Doppelschneckenextruder.In the process according to the invention, the matrix polymer is melted and mixed with active ingredients and auxiliaries at from 50 to 150 ° C., preferably from 80 to 110 ° C., in a twin-screw extruder.
Die den Extruder verlassende vitaminhaltige Schmelze kann, wie in der US-A 4,880,585 beschrieben, direkt über gegenläufige Formwal¬ zenpaare zu Tabletten gepreßt werden. Andererseits sind auch Ver¬ fahren zur Herstellung kleiner Partikel (Pellets) möglich, z.B. durch Einsatz des Heißabschlagverfahrens (Extrusion der Schmelze durch dünne Bohrungen; Zerschneiden der Extrudat-Stränge direkt vor der Düsen-Lochplatte durch rotierende Messer zu Pellets) . Weiterhin ist es möglich, die Schmelze nach Verlassen des Extru¬ ders abkühlen zu lassen und erst nach Abkühlung und Aushärtung mit geeigneten Mühlen zu Granulaten oder Pulvern zu zermahlen. Derartige Pellets, Granulate oder Pulver eignen sich z.B. zum Ab- füllen in Hartgelatine-Steckkapseln, aber auch als Vorstufe für einen nachgeschalteten Tablettier-Preßvorgang.The vitamin-containing melt leaving the extruder can, as described in US Pat. No. 4,880,585, be pressed directly into tablets via opposing pairs of forming rolls. On the other hand, processes for the production of small particles (pellets) are also possible, e.g. by using the hot cutting process (extrusion of the melt through thin holes; cutting the extrudate strands directly in front of the die plate by rotating knives into pellets). Furthermore, it is possible to let the melt cool after leaving the extruder and to grind it into granules or powders only after cooling and curing with suitable mills. Such pellets, granules or powders are suitable e.g. for filling in hard gelatin capsules, but also as a preliminary stage for a subsequent tableting pressing process.
Das erfindungsgemäße Verfahren eignet sich besonders zur Herstel¬ lung von Vitaminpräparaten, die oxidations- und temperatur- empfindliche Vitamine, Provitamine oder Vitaminderivate enthal¬ ten. Durch das Einschmelzen der Vitamine in die Polymer-Matix
werden oxidative Zersetzungen (Luftsauerstoff!) minimiert, da die erkaltete Schmelze nicht porös ist.The process according to the invention is particularly suitable for the production of vitamin preparations which contain vitamins, provitamins or vitamin derivatives which are sensitive to oxidation and temperature. By melting the vitamins into the polymer matrix oxidative decomposition (atmospheric oxygen!) is minimized because the cooled melt is not porous.
So läßt sich Ascorbinsäure weitgehend zersetzungsfrei verarbei- 5 ten, was im Hinblick auf die bekannte Temperaturempfindlichkeit dieser Substanz überraschend war. Auch ß-Carotin läßt sich her¬ vorragend verarbeiten, ohne daß eine nennenswerte Isomerisierung stattfindet. Die Lagerstabilitäten der erfindungsgemäßen Formu¬ lierungen waren ebenfalls gut; nach dreimonatiger Lagerung bei 10 30°C waren beispielsweise keine Verluste an Vitaminen festzu¬ stellen.Ascorbic acid can thus be processed largely without decomposition, which was surprising in view of the known temperature sensitivity of this substance. Β-carotene can also be processed excellently without significant isomerization taking place. The storage stabilities of the formulations according to the invention were also good; after three months of storage at 10.degree. C., no losses of vitamins were found, for example.
Die erfindungsgemäß hergestellten Vitaminpräparate können für pharmazeutische oder veterinärmedizinische Zwecke eingesetzt wer-The vitamin preparations produced according to the invention can be used for pharmaceutical or veterinary purposes
15 den. Sie eignen sich auch zum "Vitaminisieren" von Lebensmitteln, beispielsweise als Trinklösung durch Einstreuen entsprechender Granulate oder Pulver in Wasser, andere Getränke oder in Speisen. Weiterhin können Carotinoide enthaltende Zusammensetzungen auch zum Färben von Lebensmitteln eingesetzt werden. Ein weiteres An-15 den. They are also suitable for "vitaminizing" foods, for example as a drinking solution by sprinkling appropriate granules or powders in water, other drinks or in dishes. Compositions containing carotenoids can also be used for coloring foods. Another arrival
20 Wendungsgebiet ist die Tierernährung.20 The area of application is animal nutrition.
Beispiele 1 bis 10Examples 1 to 10
Alle Versuche wurden in einem Doppelschneckenextruder 25 (ZSK-40-Extruder, Fa. Werner und Pfleiderer, Stuttgart) durchge¬ führt. Der Extruder beinhaltete 4 beheizbare Schüsse, auch der Extruderkopf und die Breitschlitzdüse waren separat beheizbar. Die eingestellten Temperaturen sind der Tabelle zu entnehmen. Die extrudierte Schmelze wurde in Form eines 12 bis 14 cm breiten 30 Bandes über eine Breitschlitzdüse ausgetragen und anschließend in einem Formkalander, der aus einem gegenläufig rotierenden Form- walzenpaar (kühlbar) besteht, direkt zu Tabletten gepreßt. Die Tabletten besaßen eine längliche, stäbchenförmige Gestalt (Oblon- Tabletten) . Die in der Tabelle aufgelisteten Rohstoffe wurden zu- 35 vor in einem Rhönradmischer gemischt und als Mischung in den Ex¬ truder über eine Dosierwaage mit Leistungen von 20 bis 30 kg/h eingetragen. Die Drehzahl der Extruder-Förderschnecke lag in al¬ len Fällen bei 100 bis 150 U/min.All experiments were carried out in a twin-screw extruder 25 (ZSK-40 extruder, Werner and Pfleiderer, Stuttgart). The extruder contained 4 heatable sections, the extruder head and the slot die were also separately heatable. The set temperatures can be found in the table. The extruded melt was discharged in the form of a 12 to 14 cm wide 30 tape through a slot die and then pressed directly into tablets in a molding calender consisting of a pair of counter-rotating molding rolls (coolable). The tablets had an elongated, rod-like shape (oblon tablets). The raw materials listed in the table were mixed to-35 present in an adequate mixer and entered h as a mixture in the ex ¬ screw extruder via a weigh feeder with capacities ranging from 20 to 30 kg /. The speed of the extruder screw was in al ¬ len cases from 100 to 150 rev / min.
40 In den Beispielen wurden unter anderem die folgenden Einsatz- Stoffe verwendet:40 The following feedstocks were used in the examples:
a) Klucel® EF. Hydroxypropylcellulose (Fa. Aqualon) , molarer Substitutionsgrad 3,0 - 4,4 45 b) Ascorbinsäure: Vitamin C (kristalline Ware), Fa. BASF AG
c) Tocopherolacetat: Vitamin E-Präparation "SD-50" (Fa. BASF AG; 50 %ige Formulierung von Toxopherolacetat auf wasserlöslichem Träger) d) Betacarotin: Reinsubstanz (Pulver) , Fa. Merck oder 10 Gew. -%ige CWD-Formulierung (BASF AG) e) Mannit: Fa. Merck f) Reinlecithin: Sternpur PM (Fa. Stern) g) Isomalt: Palatinit®, Fa. Palatinit, Mannheima) Klucel® EF. Hydroxypropyl cellulose (Aqualon), molar degree of substitution 3.0 - 4.4 45 b) Ascorbic acid: Vitamin C (crystalline product), BASF AG c) Tocopherol acetate: Vitamin E preparation "SD-50" (from BASF AG; 50% formulation of toxopherol acetate on a water-soluble carrier) d) Beta-carotene: pure substance (powder), from Merck or 10% by weight CWD- Formulation (BASF AG) e) Mannitol: Merck f) Reinlecithin: Sternpur PM (Stern) g) Isomalt: Palatinit®, Palatinit, Mannheim
Beispiel 11Example 11
Der Vitamin-C-Gehalt einer Probe gemäß Beispiel 3 wurde wenige Tage nach der Herstellung mit Hilfe einer HPLC-Methode (isokrati- sches System) analysiert. Der gefundene Istwert betrug 41,46 Gew.-% (Sollwert: 41,66 Gew.-%), es wurden keinerlei Neben¬ produkte beobachtet. Die gefundenen Ist-Werte für das Beta-Caro- tin betrugen 3,8 Gew.-% (Soll: 3,34 Gew.-%), davon waren 90,7 % all-trans-Betacarotin.The vitamin C content of a sample according to Example 3 was analyzed a few days after production using an HPLC method (isocratic system). The actual value found was 41.46% by weight (target value: 41.66% by weight), and no by-products were observed. The actual values found for the beta-carotene were 3.8% by weight (target: 3.34% by weight), of which 90.7% were all-trans-beta-carotene.
Beispiel 12Example 12
Analog zu den Beispielen 1 - 10 wurde die folgende Mischung verarbeitet (die Zahlenangaben zu den Einsatzstoffen bedeuten jeweils Gew. -%) .The following mixture was processed analogously to Examples 1-10 (the figures given for the starting materials in each case mean% by weight).
Im Chromatogramm wurden keine typischen thermischen Vitaminzer¬ setzungsprodukte gefunden.
No typical thermal vitamin decomposition products were found in the chromatogram.
Tabelletable
SS
+» [°C]
+ »[° C]
Claims
1. Verfahren zur Herstellung von vitaminhaltigen Arzneiformen durch Extrusion einer vitaminhaltigen Polymerschmelze und anschließender Formgebung, dadurch gekennzeichnet, daß man als Matrixpolymer eine Hydroxypropylcellulose verwendet.1. A process for the production of vitamin-containing pharmaceutical forms by extrusion of a vitamin-containing polymer melt and subsequent shaping, characterized in that a hydroxypropyl cellulose is used as the matrix polymer.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß man die vitaminhaltige Schmelze bei Temperaturen von 80 bis 110°C erzeugt.2. The method according to claim 1, characterized in that one produces the vitamin-containing melt at temperatures of 80 to 110 ° C.
3. Verfahren nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß man eine Hydroxypropylcellulose mit einem molaren Substitutionsgrad von 3,0 bis 4,4 verwendet.3. The method according to claim 1 or 2, characterized in that one uses a hydroxypropyl cellulose with a molar degree of substitution of 3.0 to 4.4.
4. Vitaminhaltige Arzneiformen, erhältlich nach dem Verfahren gemäß einem der Ansprüche 1 bis 3. 4. Vitamin-containing pharmaceutical forms, obtainable by the process according to one of claims 1 to 3.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU72833/96A AU7283396A (en) | 1995-09-29 | 1996-09-30 | Process for producing solid vitamin preparations |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19536387A DE19536387A1 (en) | 1995-09-29 | 1995-09-29 | Process for the preparation of vitamin-containing solid preparations |
| DE19536387.6 | 1995-09-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1997012604A1 true WO1997012604A1 (en) | 1997-04-10 |
Family
ID=7773627
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1996/004272 WO1997012604A1 (en) | 1995-09-29 | 1996-09-30 | Process for producing solid vitamin preparations |
Country Status (5)
| Country | Link |
|---|---|
| AU (1) | AU7283396A (en) |
| DE (1) | DE19536387A1 (en) |
| HR (1) | HRP960436A2 (en) |
| WO (1) | WO1997012604A1 (en) |
| ZA (1) | ZA968134B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003505410A (en) * | 1999-07-23 | 2003-02-12 | バイエル アクチェンゲゼルシャフト | Immediate release extrudate, method for producing the same and preparation obtained from the extrudate |
| EP1836902A1 (en) * | 2006-03-23 | 2007-09-26 | Firmenich Sa | Extruded glassy vitamin C particles |
| EP2925880B1 (en) * | 2012-11-27 | 2020-07-01 | DSM IP Assets B.V. | Process for the production of discrete solid extruded particles |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19943501A1 (en) | 1999-09-10 | 2001-03-15 | Basf Ag | Underwater granulation of melts containing active ingredients |
| DE10026698A1 (en) * | 2000-05-30 | 2001-12-06 | Basf Ag | Self-emulsifying active ingredient formulation and use of this formulation |
| US8377952B2 (en) | 2003-08-28 | 2013-02-19 | Abbott Laboratories | Solid pharmaceutical dosage formulation |
| US8025899B2 (en) | 2003-08-28 | 2011-09-27 | Abbott Laboratories | Solid pharmaceutical dosage form |
| EP2463327A3 (en) | 2010-12-10 | 2015-06-03 | Basf Se | Method for producing granulates containing at least one water-soluble component |
| KR101847947B1 (en) | 2013-03-15 | 2018-05-28 | 옵코 아이피 홀딩스 Ⅱ 인코포레이티드 | Stabilized modified release vitamin d formulation |
| US10022337B2 (en) | 2013-11-15 | 2018-07-17 | Dsm Ip Assets B.V. | Formulation of sparingly soluble compounds by hot-melt extrusion |
| CN108135849A (en) * | 2015-10-07 | 2018-06-08 | 帝斯曼知识产权资产管理有限公司 | Multivitamin extrudate |
| CN111836556B (en) * | 2018-03-15 | 2022-08-19 | 帝斯曼知识产权资产管理有限公司 | Production of extrudates with improved microbiological quality |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0465338A1 (en) * | 1990-06-29 | 1992-01-08 | Rhone-Poulenc Nutrition Animale | Process for the preparation of granulates of actives through extrusion |
| WO1996025149A1 (en) * | 1995-02-14 | 1996-08-22 | Basf Aktiengesellschaft | Solid active agent preparations containing hydroxypropyl cellulose |
| WO1996025151A1 (en) * | 1995-02-14 | 1996-08-22 | Basf Aktiengesellschaft | Solid active agent preparations |
-
1995
- 1995-09-29 DE DE19536387A patent/DE19536387A1/en not_active Withdrawn
-
1996
- 1996-09-26 HR HR19536387.6A patent/HRP960436A2/en not_active Application Discontinuation
- 1996-09-27 ZA ZA9608134A patent/ZA968134B/en unknown
- 1996-09-30 WO PCT/EP1996/004272 patent/WO1997012604A1/en active Application Filing
- 1996-09-30 AU AU72833/96A patent/AU7283396A/en not_active Abandoned
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0465338A1 (en) * | 1990-06-29 | 1992-01-08 | Rhone-Poulenc Nutrition Animale | Process for the preparation of granulates of actives through extrusion |
| WO1996025149A1 (en) * | 1995-02-14 | 1996-08-22 | Basf Aktiengesellschaft | Solid active agent preparations containing hydroxypropyl cellulose |
| WO1996025151A1 (en) * | 1995-02-14 | 1996-08-22 | Basf Aktiengesellschaft | Solid active agent preparations |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003505410A (en) * | 1999-07-23 | 2003-02-12 | バイエル アクチェンゲゼルシャフト | Immediate release extrudate, method for producing the same and preparation obtained from the extrudate |
| EP1836902A1 (en) * | 2006-03-23 | 2007-09-26 | Firmenich Sa | Extruded glassy vitamin C particles |
| EP2925880B1 (en) * | 2012-11-27 | 2020-07-01 | DSM IP Assets B.V. | Process for the production of discrete solid extruded particles |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA968134B (en) | 1998-03-27 |
| DE19536387A1 (en) | 1997-04-03 |
| AU7283396A (en) | 1997-04-28 |
| HRP960436A2 (en) | 1998-02-28 |
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