WO1999034780A1 - Method and device for capsulating active ingredients - Google Patents

Method and device for capsulating active ingredients Download PDF

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Publication number
WO1999034780A1
WO1999034780A1 PCT/CH1998/000350 CH9800350W WO9934780A1 WO 1999034780 A1 WO1999034780 A1 WO 1999034780A1 CH 9800350 W CH9800350 W CH 9800350W WO 9934780 A1 WO9934780 A1 WO 9934780A1
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WO
WIPO (PCT)
Prior art keywords
vitamins
pharmaceuticals
extruder
active ingredients
flavorings
Prior art date
Application number
PCT/CH1998/000350
Other languages
German (de)
French (fr)
Inventor
Federico Innerebner
Original Assignee
Bühler AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bühler AG filed Critical Bühler AG
Priority to AU86213/98A priority Critical patent/AU8621398A/en
Publication of WO1999034780A1 publication Critical patent/WO1999034780A1/en

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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
    • A61K9/14—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
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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

Definitions

  • the invention relates to a method for encapsulating or blending one or more active ingredients, pharmaceuticals, vitamins, and / or flavorings in a carrier substance.
  • the taste, the application or the delayed action of one or more active ingredients, pharmaceuticals, vitamins, and / or flavorings it is desirable to encapsulate them or to provide them with a coating.
  • This measure is particularly suitable for thermolabile substances.
  • DE 40 02 257 A1 discloses a method for encapsulating or for coating one or more active substances in or with a carrier substance.
  • a mixture of essentially native starch and at least one agent which at least partially swells the starch is used as the encapsulating or coating carrier substance, which is mixed together with the active ingredient and at least one emulsifier for the encapsulation or for the coating.
  • the method proposed above cannot be used for hydrophobic active substances, pharmaceuticals, vitamins and / or flavorings. Furthermore, a targeted setting of parameters such as type of starch, molecular weight, selection and concentration of the emulsifier, type and content of plasticizer etc. (please complete) is not possible or is possible only with great difficulty.
  • the object of the present invention is now to eliminate the disadvantages mentioned above.
  • the method according to the invention is intended to enable encapsulation of thermolabile substances, ie the melting temperatures should be low and the heat load should be short-lived.
  • the object is achieved in that the active ingredients, pharmaceuticals, vitamins and / or flavorings are dispersed and encapsulated in a matrix of thermoplastic starch and an intermediate layer or phase mediator layer by melt extrusion, the substance to be encapsulated or coated at a temperature of 20 ° C to a maximum of 80 ° C, preferably from 30 ° C to 60 ° C is exposed.
  • This process is an encapsulation.
  • the substance to be encapsulated is dispersed in a carrier matrix made of thermoplastic or pregelatinized starch. Between the matrix and the substance to be encapsulated there is an intermediate layer, also called a phase mediator. On the one hand, this intermediate layer takes over the function of the adhesion promoter, so that the material to be encapsulated is integrated as well as possible into the matrix. Furthermore, the encapsulation of pharmaceutical active substances is of therapeutic importance in such a way that the layer thickness and material of this intermediate layer influence the retardation of the pharmaceutical active substance in the human body.
  • the active ingredients, pharmaceuticals, vitamins and / or flavorings are preferably metered into the extruder as an emulsion or natively.
  • Thermoplastic starch for example, is used as the matrix or carrier material.
  • the starch can be in native form, but preferably in a pregelatinized one Condition. Different levels of starch degradation, so-called sugar starches, are also used depending on the requirements.
  • the partial or total metering of the emulsifier or emulsifiers or similar auxiliaries such as.
  • the emulsifiers and / or the auxiliaries can additionally be used as an intermediate layer or phase mediator layer.
  • the emulsifiers and / or the auxiliaries can thus assume a dual role. On the one hand, they serve as a means of lowering the surface tension and thus achieving deep melting temperature control. On the other hand, they can be used simultaneously as an intermediate layer or a phase mediator layer.
  • Water and / or low or high molecular weight polyhydric alcohols are preferably used as plasticizers individually or in combination.
  • glycerin, sorbtol etc. can be used as plasticizers individually or in combination.
  • the active ingredients, pharmaceuticals, vitamins and / or flavorings are metered in as shortly as possible before the extruder outlet. Dosing the substances to be encapsulated as late as possible shortens the duration of the heat load in the extruder.
  • the active ingredients, pharmaceuticals, vitamins, and / or flavorings are exposed to a residence time of 5 seconds to a maximum of one minute, preferably 10 to 30 seconds, in the extruder.
  • the active ingredients, pharmaceuticals, vitamins and / or flavorings are preferably exposed to 4 to 8 LJD process lengths in the extruder.
  • the encapsulation and / or the partial blinding is carried out by means of an extruder with at least two screws and the subsequent granulation is carried out by means of a downstream single-shaft extruder.
  • twin-screw or multi-screw extruders are used in this method according to the invention.
  • a small single-screw extruder can be used to produce very small granules, for example with a granule diameter of less than 1 mm.
  • the advantage of the downstream extruder is, in particular, that the low shearing action and possible low temperature control mean that lower melting temperatures can be achieved.
  • FIG. 2 shows an extruder configuration according to Examples 2 and 4.
  • FIG. 1 shows a preferred extruder configuration of a twin-screw extruder with individual housings 1 to 10.
  • Dosages D1 to D4 are shown schematically in different housings. In Figure 1, the dosages on the housings sen 1, 2, 7, and 9 are provided. Dosages on other housings are also mentioned in the examples.
  • a vacuum device 11 for degassing is arranged in the housing 5. The end of the extruder is formed by a nozzle 12. The nozzle can be arranged centrally or decentrally to the extruder axis.
  • FIG. 2 instead of the nozzle 12, a single-shaft extruder 14 is connected via an intermediate section 13. Otherwise, FIG. 2 corresponds to FIG. 1.
  • 15 kg of pregelatinized starch is metered into housing 1.
  • 8 kg of a mixture of 6 parts of water, 1 part of glycerol and 1 part of lecithin are introduced into housing 2.
  • the active ingredient for example 0.5 kg of acetyl-salicylic acid, is added to the extruder via the housing 9.
  • the temperature is controlled in such a way that the product temperatures in the housings 2 to 7 are around 70 ° C, in the housings 8 to 10 around 60 ° C and at the nozzle around 70 ° C
  • the granulation takes place by means of a head granulation known per se after the extruder exit, the granulate size being approximately 2 to 3 mm.
  • 15 kg of pregelatinized starch is metered into housing 1.
  • 2 parts of glycerol are entered and Le ⁇ 2 kg cithin in housing 7.
  • the active ingredient for example 0.5 kg acetylsalicylic acid is added over the housing 9 of the extruder.
  • the twin-screw extruder is followed by a single-screw extruder with subsequent head granulation with a granulate size of approx. 1 mm.
  • the temperature is controlled in such a way that the product temperatures in the housings 2 to 7 at approx. 70 ° C, in the housings 8 to 10 at approx. 50 ° C and on the single-screw extruder approx. 50 °.
  • the nozzle is around 70 ° C
  • 15 kg of pregelatinized starch is metered into housing 1.
  • 6 kg of a mixture of 4 parts of water and 2 parts of glycerin are introduced into housing 2.
  • Another 3 kg of a mixture of 1 part, lecithin, 1.5 parts water and 0.5 parts of an active ingredient, for example acetyl-salicylic acid, is added to the extruder via the housing 8.
  • Example 2 The composition corresponds to that of Example 3.
  • the temperature control, granulation size and the arrangement of a two-screw extruder in connection with a downstream single-shaft extruder corresponds to Example 2.
  • 18 kg of native starch with approx. 18% water is metered into housing 1.
  • 4 kg of a mixture of 3 parts of water and 1 part of glycerol are introduced into housing 2 and 1.5 kg of a mixture of 1 part of lecithin and 0.5 part of glycerol monostearate into housing 7.
  • the active ingredient for example 0.5 kg of acetylsalicylic acid, is added via the Housing 8 added to the extruder.
  • a vacuum device is connected to the housing 5 for degassing.
  • the twin-screw extruder configuration corresponds to that of Example 1.m.
  • the temperature is controlled in such a way that the product temperatures in the housing 2 at approx. 80 ° C, in the housing 3 at approx. 120 °, in the housings 4 and 5 at approx. 100 °, in the housings 6 and 7 at approx 70 ° and in the housings 8 and 9 at approx. 60 ° C

Abstract

The invention relates to a method for capsulating or blending one or several active ingredients, pharmaceuticals, vitamins and/or flavourings in a carrier substance, according to which method the active ingredients, pharmaceuticals, vitamins and/or flavourings are dispersed in a matrix of thermoplastic starch and an intermediate layer or phase connecting layer by melt extrusion and capsulated and the substance to be capsulated or coated is subjected to temperatures of between 20 °C and no more than 80 °C, but preferably of between 30 °C and 60 °C.

Description

Verfahren und Vorrichtung zum Verkapseln von Wirkstoffen Method and device for encapsulating active substances
Die Erfindung betrifft ein Verfahren zur Einkapselung oder zum Blenden eines oder mehrerer Wirkstoffe, Pharmaka, Vitamine, und/oder Aromastoffe in einer Trägersubstanz.The invention relates to a method for encapsulating or blending one or more active ingredients, pharmaceuticals, vitamins, and / or flavorings in a carrier substance.
Es ist zum Zwecke der Haltbarkeit, des Geschmacks, der Anwendung oder der re- tardierten Wirkung eines oder mehrerer Wirkstoffe, Pharmaka, Vitamine, und/oder Aromastoffe wünschenswert, diese zu verkapseln oder mit einem Überzug zu versehen. Insbesondere ist diese Massnahme für thermolabile Stoffe geeignet.For the purpose of the shelf life, the taste, the application or the delayed action of one or more active ingredients, pharmaceuticals, vitamins, and / or flavorings, it is desirable to encapsulate them or to provide them with a coating. This measure is particularly suitable for thermolabile substances.
Eine Vielzahl von Verfahren zum Verkapseln von Stoffen jeglicher Art ist bekannt. In der DE 40 02 257 A1 ist ein Verfahren zur Einkapselung oder zum Beschichten eines oder mehrerer Wirkstoffe in einer oder mit einer Trägersubstanz bekannt. Hierbei wird als einkapselnde oder beschichtende Trägersubstanz ein Gemisch aus im wesentlichen nativer Stärke und mindestens einem die Stärke mindestens teilweise quellenden Mittel verwendet, das für die Einkapselung oder für das Beschichten zu- sammen mit dem Wirkstoff und mindestens einem Emulgator gemischt wird.A variety of methods for encapsulating substances of any kind are known. DE 40 02 257 A1 discloses a method for encapsulating or for coating one or more active substances in or with a carrier substance. In this case, a mixture of essentially native starch and at least one agent which at least partially swells the starch is used as the encapsulating or coating carrier substance, which is mixed together with the active ingredient and at least one emulsifier for the encapsulation or for the coating.
Das oben vorgeschlagene Verfahren ist nicht anwendbar für hydrophobe Wirkstoffe, Pharmaka, Vitamine, und/oder Aromastoffe. Weiterhin ist eine gezielte Einstellung von Parametern, wie zum Beispiel Stärkeart, Molekulargewicht, Auswahl und Kon- zentration des Emulgators, Weichmacherart und -gehalt etc. (bitte vervollständigen) nicht oder nur sehr erschwert möglich.The method proposed above cannot be used for hydrophobic active substances, pharmaceuticals, vitamins and / or flavorings. Furthermore, a targeted setting of parameters such as type of starch, molecular weight, selection and concentration of the emulsifier, type and content of plasticizer etc. (please complete) is not possible or is possible only with great difficulty.
Die Aufgabe der vorliegenden Erfindung liegt nunmehr darin, die oben genannten Nachteile zu beseitigen. Insbesondere soll durch das erfindungsgemässe Verfahren eine Verkapselung von thermolabilen Stoffen ermöglicht werden, d.h. die Schmelztemperaturen sollen niedrig und die Wärmebelastung von kurzer Dauer sein. Erfindungsgemäss wird die Aufgabe dadurch gelöst, dass die Wirkstoffe, Pharmaka, Vitamine, und/oder Aromastoffe, in einer Matrix aus thermoplastischer Stärke und einer Zwischenschicht oder Phasenvermittlerschicht durch Schmelzextrusion dispergiert und eingekapselt werden, wobei der zu verkapselnde bzw. beschichtende Stoff einer Temperatur von 20°C bis maximal 80°C, vorzugsweise von 30°C bis 60°C ausgesetzt wird.The object of the present invention is now to eliminate the disadvantages mentioned above. In particular, the method according to the invention is intended to enable encapsulation of thermolabile substances, ie the melting temperatures should be low and the heat load should be short-lived. According to the invention, the object is achieved in that the active ingredients, pharmaceuticals, vitamins and / or flavorings are dispersed and encapsulated in a matrix of thermoplastic starch and an intermediate layer or phase mediator layer by melt extrusion, the substance to be encapsulated or coated at a temperature of 20 ° C to a maximum of 80 ° C, preferably from 30 ° C to 60 ° C is exposed.
Durch die Auswahl und die Kombination von geeigneten Stärkearten, Emulgatoren, Hilfsstoffen, Prozessführung, Parameter und Extruder- und Gerätekonfigurationen wird es ermöglicht die gewünschten tiefen Schmelztemperaturen unter 80° C zu erreichen. Die zu verkapselnden Stoffe werden darüber hinaus während nur einer kurzen Zeit von maximal einer Minute einer Wärmebelastung bei relativ niedrigen Temperaturen ausgesetzt.The selection and combination of suitable starch types, emulsifiers, auxiliaries, process control, parameters and extruder and device configurations make it possible to achieve the desired low melting temperatures below 80 ° C. In addition, the substances to be encapsulated are exposed to thermal stress at relatively low temperatures for only a short time of up to one minute.
Es wird weiterhin vorgeschlagen als Verkapselungsstoff pregelatinisierte Stärke zu verwenden.It is also proposed to use pregelatinized starch as an encapsulant.
Bei diesem Verfahren handelt es sich um eine Blendkapselung. Dabei wird der zu verkapselnde Stoff in einer Trägermatrix aus thermoplastischer oder pregelatinisier- ter Stärke dispergiert. Zwischen der Matrix und dem zu verkapselnden Stoff kommt eine Zwischenschicht, oder auch Phasenvermittler genannt, hinzu. Einerseits übernimmt diese Zwischenschicht die Funktion des Haftvermittlers, damit eine möglichst gute Einbindung des zu verkapselnden Stoffes in die Matrix gewährleistet ist. Weiterhin kommt bei der Verkapselung von Pharmawirkstoffen eine therapeutische Be- deutung in der Weise hinzu, wobei die Schichtdicke und der - stoff dieser Zwischenschicht die Retardation des Pharmawirkstoffes im menschlichen Körper beeinflusst.This process is an encapsulation. The substance to be encapsulated is dispersed in a carrier matrix made of thermoplastic or pregelatinized starch. Between the matrix and the substance to be encapsulated there is an intermediate layer, also called a phase mediator. On the one hand, this intermediate layer takes over the function of the adhesion promoter, so that the material to be encapsulated is integrated as well as possible into the matrix. Furthermore, the encapsulation of pharmaceutical active substances is of therapeutic importance in such a way that the layer thickness and material of this intermediate layer influence the retardation of the pharmaceutical active substance in the human body.
Bevorzugt werden die Wirkstoffe, Pharmaka, Vitamine, und/oder Aromastoffe als Emulsion oder nativ in den Extruder eindosiert.The active ingredients, pharmaceuticals, vitamins and / or flavorings are preferably metered into the extruder as an emulsion or natively.
Als Matrix oder Trägerwerkstoff kommt beispielsweise thermoplastische Stärke zum Einsatz . Die Stärke kann in nativer Form, bevorzugt aber in einem pregelatinisierten Zustand vorliegen. Verschiedene Abbaustufen der Stärken, sogenannten Zuckerstärken werden ebenfalls je nach Anforderung eingesetzt.Thermoplastic starch, for example, is used as the matrix or carrier material. The starch can be in native form, but preferably in a pregelatinized one Condition. Different levels of starch degradation, so-called sugar starches, are also used depending on the requirements.
Um eine möglichst tiefe Schmelztemperatur vor dem Eindosieren der Wirkstoffe, Pharmaka, Vitamine, und/oder Aromastoffe zu erreichen, werden Nach einem weiteren bevorzugten Verfahrensschritt mit oder nach der Eindosierung der Stärke Weichmacher, Emulgatoren und/oder Hilfsstoffe aber vor dem Eindosieren der Wirkstoffe, Pharmaka, Vitamine, und/oder Aromastoffe in die Stärke teilweise oder ganz eindosiert und eingearbeitet.In order to achieve the lowest possible melting temperature before metering in the active ingredients, pharmaceuticals, vitamins, and / or flavorings, plasticizers, emulsifiers and / or auxiliaries, but before metering in the active ingredients, pharmaceuticals, are used in a further preferred process step with or after metering in the starch , Vitamins, and / or flavorings are partially or completely metered into the starch and incorporated.
Die teilweise oder gesamte Eindosierung des Emulgators oder der Emulgatoren oder ähnlicher Hilfsstoffe, wie z. B. Kalziumstearat oder Fettsäure, vor er Eindosierung der zu verkapselnden Stoffe bewirkt eine Abnahme der Oberflächenspannung der thermoplastischen Stärke und ermöglicht eine sehr tiefe Schmelztemperaturführung der Stärke.The partial or total metering of the emulsifier or emulsifiers or similar auxiliaries, such as. As calcium stearate or fatty acid, before metering in the substances to be encapsulated causes a decrease in the surface tension of the thermoplastic starch and enables a very low melting temperature control of the starch.
Weiterhin können zusätzlich die Emulgatoren und/oder die Hilfsstoffe als Zwischenschicht oder Phasenvermittlerschicht eingesetzt werden.Furthermore, the emulsifiers and / or the auxiliaries can additionally be used as an intermediate layer or phase mediator layer.
Die Emulgatoren und/oder die Hilfsstoffe können somit eine Doppelrolle übernehmen. Sie dienen einerseits als Mittel zur Erniedrigung der Oberflächenspannung und damit zur Erlangung einer tiefen Schmelztemperaturführung. Andererseits können sie gleichzeitig als Zwischenschicht oder Phasenvermittlerschicht eingesetzt werden.The emulsifiers and / or the auxiliaries can thus assume a dual role. On the one hand, they serve as a means of lowering the surface tension and thus achieving deep melting temperature control. On the other hand, they can be used simultaneously as an intermediate layer or a phase mediator layer.
Als Weichmacher werden bevorzugt Wasser und/oder niedrig oder hochmolekulare mehrwertige Alkohole einzeln oder in Kombination verwendet.Water and / or low or high molecular weight polyhydric alcohols are preferably used as plasticizers individually or in combination.
Beispielsweise kommen Glyzerin, Sorbtol etc. als Weichmacher einzeln oder in Kombination in Betracht.For example, glycerin, sorbtol etc. can be used as plasticizers individually or in combination.
Gemass eines bevorzugten Verfahrensschrittes werden die Wirkstoffe, Pharmaka, Vitamine, und/oder Aromastoffe möglichst kurz vor dem Extruderausgang eindosiert. Die möglichst späte Eindosierung der zu verkapselnden Stoffe verkürzt die Dauer der Wärmebelastung im Extruder.According to a preferred process step, the active ingredients, pharmaceuticals, vitamins and / or flavorings are metered in as shortly as possible before the extruder outlet. Dosing the substances to be encapsulated as late as possible shortens the duration of the heat load in the extruder.
Die Wirkstoffe, Pharmaka, Vitamine, und/oder Aromastoffe sind einer Verweilzeit von 5 Sekunden bis maximal einer Minute, vorzugsweise 10 bis 30 Sekunden im Extruder ausgesetzt.The active ingredients, pharmaceuticals, vitamins, and / or flavorings are exposed to a residence time of 5 seconds to a maximum of one minute, preferably 10 to 30 seconds, in the extruder.
Vorzugsweise sind die Wirkstoffe, Pharmaka, Vitamine, und/oder Aromastoffe 4 bis 8 LJD Verfahrenslängen im Extruder ausgesetzt.The active ingredients, pharmaceuticals, vitamins and / or flavorings are preferably exposed to 4 to 8 LJD process lengths in the extruder.
Die Verkapselung und/oder das teilweise Blenden erfolgt mittels eines Extruders mit mindestens zwei Schnecken und die anschliessende Granulation mittels eines nachgeschalteten Einwellenextruders.The encapsulation and / or the partial blinding is carried out by means of an extruder with at least two screws and the subsequent granulation is carried out by means of a downstream single-shaft extruder.
In der Regel werden bei diesem erfindungsgemässen Verfahren Zwei- oder Mehrwellenextruder eingesetzt. Durch einen nachgeschalteten Einwellenextruder können sehr kleine Granulate hergestellt werden, beispielsweise mit einem Granulatdurchmesser von kleiner 1 mm. Der Vorteil des nachgeschalteten Extruders liegt insbesondere auch darin, dass durch die geringe Schereinwirkung und mögliche niedrige Temperaturführung geringere Schmelztemperaturen zu erreichen.As a rule, twin-screw or multi-screw extruders are used in this method according to the invention. A small single-screw extruder can be used to produce very small granules, for example with a granule diameter of less than 1 mm. The advantage of the downstream extruder is, in particular, that the low shearing action and possible low temperature control mean that lower melting temperatures can be achieved.
Anschliessend wird die Erfindung anhand von Zeichnungen und Beispielen näher erläutert.The invention is then explained in more detail with reference to drawings and examples.
Es zeigen:Show it:
Figur 1 eine Extruderkonfiguration gemass der Beispiele 1 , 3 und 5 und1 shows an extruder configuration according to Examples 1, 3 and 5 and
Figur 2 eine Extruderkonfiguration gemass der Beispiele 2, und 4.FIG. 2 shows an extruder configuration according to Examples 2 and 4.
Die Figur 1 zeigt eine bevorzugte Extruderkonfiguration eines Zweiwellenextruders mit einzelnen Gehäusen 1 bis 10. In verschiedenen Gehäusen sind Dosierungen D1 bis D4 schematisch dargestellt. In der Figur 1 sind die Dosierungen an den Gehäu- sen 1 , 2, 7, und 9 vorgesehen. In den Beispielen sind auch Dosierungen an anderen Gehäusen genannt. Im Gehäuse 5 ist eine Vakuumeinrichtung 1 1 zur Entgasung angeordnet. Den Abschluss des Extruders bildet eine Düse 12. Die Düse kann zentrisch oder dezentrisch zur Extruderachse angeordnet sein.FIG. 1 shows a preferred extruder configuration of a twin-screw extruder with individual housings 1 to 10. Dosages D1 to D4 are shown schematically in different housings. In Figure 1, the dosages on the housings sen 1, 2, 7, and 9 are provided. Dosages on other housings are also mentioned in the examples. A vacuum device 11 for degassing is arranged in the housing 5. The end of the extruder is formed by a nozzle 12. The nozzle can be arranged centrally or decentrally to the extruder axis.
In der Figur 2 ist anstelle der Düse 12 ein Einwellenextruder 14 über einen Zwischenabschnitt 13 nachgeschaltet. Ansonsten ist stimmt die Figur 2 mit der Figur 1 überein.In FIG. 2, instead of the nozzle 12, a single-shaft extruder 14 is connected via an intermediate section 13. Otherwise, FIG. 2 corresponds to FIG. 1.
Beispiel 1 :Example 1 :
15 kg pregelatinisierte Stärke wird in Gehäuse 1 eindosiert. In Gehäuse 2 werden 8 Kg einer Mischung von 6 Teilen Wasser, 1 Teil Glyzerin und 1 Teil Lecithin eingege- ben. Der Wirkstoff, beispielsweise 0,5 kg Acetyl-salizylsäure wird über das Gehäuse 9 dem Extruder zugegeben.15 kg of pregelatinized starch is metered into housing 1. 8 kg of a mixture of 6 parts of water, 1 part of glycerol and 1 part of lecithin are introduced into housing 2. The active ingredient, for example 0.5 kg of acetyl-salicylic acid, is added to the extruder via the housing 9.
Die Temperaturführung geschieht in der Weise, dass die Produkttemperaturen in den Gehäusen 2 bis 7 bei ca. 70° C, in den Gehäusen 8 bis 10 bei ca. 60° C und an der Düse bei ca. 70° C liegenThe temperature is controlled in such a way that the product temperatures in the housings 2 to 7 are around 70 ° C, in the housings 8 to 10 around 60 ° C and at the nozzle around 70 ° C
Die Granulation erfolgt mittels einer an sich bekannten Kopfgranulation nach dem Extruderausgang, wobei die Granulatgrösse bei ca. 2 bis 3 mm liegt.The granulation takes place by means of a head granulation known per se after the extruder exit, the granulate size being approximately 2 to 3 mm.
Beispiel 2:Example 2:
15 kg pregelatinisierte Stärke wird in Gehäuse 1 eindosiert. In Gehäuse 2 werden 6 Kg einer Mischung von 4 Teilen Wasser, 2 Teilen Glyzerin eingegeben und 2 kg Le¬ cithin in Gehäuse 7. Der Wirkstoff, beispielsweise 0,5 kg Acetylsalizylsäure wird über das Gehäuse 9 dem Extruder zugegeben. Dem Zweiwellenextruder ist anstelle der Düse ein Einwellenextruder mit anschlie- ssender Kopfgranulation nachgeschaltet mit einer erreichten Granulatgrösse von ca. 1 mm.15 kg of pregelatinized starch is metered into housing 1. In case 2 6 kg of a mixture of 4 parts water, 2 parts of glycerol are entered and Le ¬ 2 kg cithin in housing 7. The active ingredient, for example 0.5 kg acetylsalicylic acid is added over the housing 9 of the extruder. Instead of the nozzle, the twin-screw extruder is followed by a single-screw extruder with subsequent head granulation with a granulate size of approx. 1 mm.
Die Temperaturführung geschieht in der Weise, dass die Produkttemperaturen in den Gehäusen 2 bis 7 bei ca. 70° C, in den Gehäusen 8 bis 10 bei ca. 50° C und an dem Einwellenextruder ca. 50°. Düse bei ca. 70° C liegenThe temperature is controlled in such a way that the product temperatures in the housings 2 to 7 at approx. 70 ° C, in the housings 8 to 10 at approx. 50 ° C and on the single-screw extruder approx. 50 °. The nozzle is around 70 ° C
Beispiel 3:Example 3:
15 kg pregelatinisierte Stärke wird in Gehäuse 1 eindosiert. In Gehäuse 2 werden 6 Kg einer Mischung von 4 Teilen Wasser, 2 Teilen Glyzerin eingegeben. Weitere 3 kg einer Mischung aus 1 Teil, Lecithin, 1 ,5 Teilen Wasser und 0,5 Teilen eines Wirk- Stoffes, beispielsweise Acetyl-salizylsäure, wird über das Gehäuse 8 dem Extruder zugegeben.15 kg of pregelatinized starch is metered into housing 1. 6 kg of a mixture of 4 parts of water and 2 parts of glycerin are introduced into housing 2. Another 3 kg of a mixture of 1 part, lecithin, 1.5 parts water and 0.5 parts of an active ingredient, for example acetyl-salicylic acid, is added to the extruder via the housing 8.
Alles andere entspricht dem Beispiel 1.Everything else corresponds to example 1.
Beispiel 4:Example 4:
Die Zusammensetzung entspricht der von Beispiel 3. Die Temperaturführung, Gra- nulationsgrösse und die Anordnung Zweiwelienextruder in Verbindung mit einem nachgeschalteten Einwellenextruder entspricht Beispiel 2.The composition corresponds to that of Example 3. The temperature control, granulation size and the arrangement of a two-screw extruder in connection with a downstream single-shaft extruder corresponds to Example 2.
Beispiel 5:Example 5:
18 kg native Stärke mit ca. 18% Wasser wird in Gehäuse 1 eindosiert. In Gehäuse 2 werden 4 kg einer Mischung aus 3 Teilen Wasser und 1 Teil Glyzerin eingegeben und 1 ,5 kg einer Mischung aus 1 Teil Lecithin und 0,5 Teilen Glyzerinmonostearat in Gehäuse 7. Der Wirkstoff, beispielsweise 0,5 kg Acetylsalizylsäure wird über das Gehäuse 8 dem Extruder zugegeben. Zur Entgasung ist bei diesem Beispiel am Gehäuse 5 eine Vakuumeinrichtung angeschlossen. Die Zweiwellenextruderkonfiguration entspricht der von Beispiel 1.m.18 kg of native starch with approx. 18% water is metered into housing 1. 4 kg of a mixture of 3 parts of water and 1 part of glycerol are introduced into housing 2 and 1.5 kg of a mixture of 1 part of lecithin and 0.5 part of glycerol monostearate into housing 7. The active ingredient, for example 0.5 kg of acetylsalicylic acid, is added via the Housing 8 added to the extruder. In this example, a vacuum device is connected to the housing 5 for degassing. The twin-screw extruder configuration corresponds to that of Example 1.m.
Die Temperaturführung geschieht in der Weise, dass die Produkttemperaturen in dem Gehäuse 2 bei ca. 80° C, im Gehäuse 3 bei ca. 120°, in den Gehäusen 4 und 5 bei ca. 100°, in den Gehäusen 6 und 7 bei ca. 70° und in den Gehäusen 8 und 9 bei ca. 60° C liegen The temperature is controlled in such a way that the product temperatures in the housing 2 at approx. 80 ° C, in the housing 3 at approx. 120 °, in the housings 4 and 5 at approx. 100 °, in the housings 6 and 7 at approx 70 ° and in the housings 8 and 9 at approx. 60 ° C

Claims

Patentansprüche claims
1 . Verfahren zur Einkapselung oder zum Blenden eines oder mehrerer Wirkstoffe, Pharmaka, Vitamine, und/oder Aromastoffe in einer Trägersubstanz, dadurch gekennzeichnet, dass die Wirkstoffe, Pharmaka, Vitamine, und/oder Aromastoffe, in einer Matrix aus thermoplastischer Stärke und einer Zwischenschicht oder Phasenvermittlerschicht durch Schmelzextrusion dispergiert und eingekapselt werden, wobei der zu verkapselnde bzw. beschichtende Stoff einer Temperatur von 20°C bis maximal 80°C, vorzugsweise von 30°C bis 60°C ausgesetzt wird.1 . Process for encapsulation or for blinding one or more active substances, pharmaceuticals, vitamins, and / or flavoring substances in a carrier, characterized in that the active substances, pharmaceuticals, vitamins, and / or flavoring substances, in a matrix of thermoplastic starch and an intermediate layer or phase mediator layer are dispersed and encapsulated by melt extrusion, the substance to be encapsulated or coated being exposed to a temperature of from 20 ° C. to a maximum of 80 ° C., preferably from 30 ° C. to 60 ° C.
2. Verfahren nach Anspruch 1 , dadurch gekennzeichnet, dass als Verkap- selungsstoff pregelatinisierte Stärke verwendet wird.2. The method according to claim 1, characterized in that pregelatinized starch is used as the encapsulant.
3. Verfahren nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass die Wirkstoffe, Pharmaka, Vitamine, und/oder Aromastoffe als Emulsion oder nativ in den Extruder eindosiert werden.3. The method according to claim 1 or 2, characterized in that the active ingredients, pharmaceuticals, vitamins, and / or flavorings are metered into the extruder as an emulsion or natively.
4. Verfahren nach mindestens einem der Ansprüche 1 , 2 oder 3, dadurch gekennzeichnet, dass mit oder nach der Eindosierung der Stärke Weichmacher, Emulgatoren und/oder Hilfsstoffe aber vor dem Eindosieren der Wirkstoffe, Pharmaka, Vitamine, und/oder Aromastoffe in die Stärke teilweise oder ganz eindosiert und eingearbeitet werden, um eine möglichst tiefe Schmelztemperatur vor dem Eindosieren der Wirkstoffe, Pharmaka, Vitamine, und/oder Aromastoffe zu erreichen.4. The method according to at least one of claims 1, 2 or 3, characterized in that with or after the metering in of the starch plasticizers, emulsifiers and / or auxiliaries but before metering in the active ingredients, pharmaceuticals, vitamins, and / or flavorings into the starch partially or completely metered in and incorporated in order to achieve the lowest possible melting temperature before metering in the active ingredients, pharmaceuticals, vitamins and / or flavorings.
5. Verfahren nach mindestens einem der vorherigen Ansprüche, dadurch gekennzeichnet, dass zusätzlich die Emulgatoren und/oder die Hilfsstoffe als Zwi- schenschicht oder Phasenvermittlerschicht eingesetzt werden. 5. The method according to at least one of the preceding claims, characterized in that the emulsifiers and / or the auxiliaries are additionally used as an intermediate layer or phase mediator layer.
6. Verfahren nach mindestens einem der vorherigen Ansprüche, dadurch gekennzeichnet, dass als Weichmacher Wasser und/oder niedrig oder hochmolekulare mehrwertige Alkohole einzeln oder in Kombination verwendet werden.6. The method according to at least one of the preceding claims, characterized in that water and / or low or high molecular weight polyhydric alcohols are used individually or in combination as plasticizers.
7. Verfahren nach mindestens einem der vorherigen Ansprüche, dadurch gekennzeichnet, dass die Wirkstoffe, Pharmaka, Vitamine, und/oder Aromastoffe möglichst kurz vor dem Extruderausgang eindosiert werden-7. The method according to at least one of the preceding claims, characterized in that the active ingredients, pharmaceuticals, vitamins, and / or flavorings are metered in as shortly as possible before the extruder outlet.
8. Verfahren nach mindestens einem der vorherigen Ansprüche, dadurch gekennzeichnet, dass die Wirkstoffe, Pharmaka, Vitamine, und/oder Aromastoffe einer Verweilzeit von 5 Sekunden bis maximal einer Minute, vorzugsweise 10 bis 30 Sekunden im Extruder ausgesetzt sind.8. The method according to at least one of the preceding claims, characterized in that the active ingredients, pharmaceuticals, vitamins, and / or flavorings are exposed to a residence time of 5 seconds to a maximum of one minute, preferably 10 to 30 seconds.
9. Verfahren nach mindestens einem der vorherigen Ansprüche, dadurch gekennzeichnet, dass die Wirkstoffe, Pharmaka, Vitamine, und/oder Aromastoffe 4 bis 8 L/D Verfahrenslängen im Extruder ausgesetzt sind ( L= Länge des Extruders, D= Aussendurchmesser der Extruderschnecke).9. The method according to at least one of the preceding claims, characterized in that the active ingredients, pharmaceuticals, vitamins, and / or flavorings are exposed to 4 to 8 L / D process lengths in the extruder (L = length of the extruder, D = outer diameter of the extruder screw).
10. Verfahren nach mindestens einem der vorherigen Ansprüche, dadurch gekennzeichnet, dass die Verkapselung und/oder das teilweise Blenden mittels eines10. The method according to at least one of the preceding claims, characterized in that the encapsulation and / or the partial blinding by means of a
Extruders mit mindestens zwei Schnecken und die anschliessende Granulation mittels eines nachgeschalteten Einwellenextruders erfolgt. Extruder with at least two screws and the subsequent granulation is carried out using a downstream single-shaft extruder.
PCT/CH1998/000350 1998-01-12 1998-08-19 Method and device for capsulating active ingredients WO1999034780A1 (en)

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Cited By (5)

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Publication number Priority date Publication date Assignee Title
KR100432282B1 (en) * 2000-07-14 2004-05-20 주식회사 오리온 Method for microcapsulating α-tocopherol and improving the storage stability thereof
WO2004091770A1 (en) * 2003-04-17 2004-10-28 Innogel Ag Encapsulation system
EP1839651A1 (en) * 1999-04-22 2007-10-03 Euro-Celtique S.A. Method for producing a water-insoluble amorphous or partially amorphous controlled release matrix
US8753705B2 (en) 2005-06-07 2014-06-17 Mgpi Processing, Inc. Mineral-bound starch compositions and methods of making the same
CN110227036A (en) * 2019-05-21 2019-09-13 南京神奇科技开发有限公司 A kind of raw material used for cosmetic and preparation method thereof

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EP0580860A1 (en) * 1991-04-16 1994-02-02 Nippon Shinyaku Company, Limited Method of manufacturing solid dispersion
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FR2179044A1 (en) * 1972-04-03 1973-11-16 Scherer Corp R P
EP0240906A2 (en) * 1986-04-11 1987-10-14 BASF Aktiengesellschaft Continuous pelleting-process
DE3830749A1 (en) * 1987-09-11 1989-03-30 Squibb & Sons Inc MEDICAMENT IN THE FORM OF HIGH MEDICAL CONCENTRATED CONCENTRATES AND METHOD FOR THE PRODUCTION THEREOF
WO1992000140A1 (en) * 1990-06-25 1992-01-09 The United States Of America, As Represented By The Secretary, U.S. Department Of Commerce Starch encapsulation of biologically active agents by a continuous process
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Publication number Priority date Publication date Assignee Title
EP1839651A1 (en) * 1999-04-22 2007-10-03 Euro-Celtique S.A. Method for producing a water-insoluble amorphous or partially amorphous controlled release matrix
KR100432282B1 (en) * 2000-07-14 2004-05-20 주식회사 오리온 Method for microcapsulating α-tocopherol and improving the storage stability thereof
WO2004091770A1 (en) * 2003-04-17 2004-10-28 Innogel Ag Encapsulation system
US8753705B2 (en) 2005-06-07 2014-06-17 Mgpi Processing, Inc. Mineral-bound starch compositions and methods of making the same
CN110227036A (en) * 2019-05-21 2019-09-13 南京神奇科技开发有限公司 A kind of raw material used for cosmetic and preparation method thereof

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