WO1994017787A1 - Capsule filled with a mixture of active ingredient in powder form and highly dispersed silicon dioxide - Google Patents

Capsule filled with a mixture of active ingredient in powder form and highly dispersed silicon dioxide Download PDF

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Publication number
WO1994017787A1
WO1994017787A1 PCT/EP1994/000281 EP9400281W WO9417787A1 WO 1994017787 A1 WO1994017787 A1 WO 1994017787A1 EP 9400281 W EP9400281 W EP 9400281W WO 9417787 A1 WO9417787 A1 WO 9417787A1
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WO
WIPO (PCT)
Prior art keywords
active ingredient
capsule
pharmaceutical preparation
ibuprofen
mixture
Prior art date
Application number
PCT/EP1994/000281
Other languages
German (de)
French (fr)
Inventor
Hans Peter Weckenmann
Hermann Franz
Peter Lembke
Original Assignee
Merck Patent Gmbh
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 Merck Patent Gmbh filed Critical Merck Patent Gmbh
Priority to EP94906190A priority Critical patent/EP0633770A1/en
Publication of WO1994017787A1 publication Critical patent/WO1994017787A1/en

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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the invention relates to a pharmaceutical preparation in the form of a capsule which rapidly releases the active ingredient and which contains the active ingredient in high concentration, and in addition to the active ingredient only a further auxiliary is necessary.
  • active ingredients such as acetylsalicylic acid, ibuprofen racema, S-ibuprofen, ascorbic acid etc.
  • the active ingredient producers endeavor to offer highly concentrated, directly tablettable active ingredient mixtures.
  • the aim is to provide the producers with a mixture that is as easy to handle as possible and that, apart from tableting,
  • Another goal of these mixtures, especially with high-dose active ingredients, is to keep the dosage form as small as possible, since patient compliance suffers when too many 20 or too large forms have to be taken.
  • active ingredients that have a relatively low melting point, e.g. Ibuprofen racemate (75-78 ° C), butibufen (51-53 ° C) or especially S-ibuprofen (52 ° C), however, 25 encounter greater difficulties in the manufacture of tablets.
  • Ibuprofen racemate 75-78 ° C
  • butibufen 51-53 ° C
  • S-ibuprofen 52 ° C
  • S-ibuprofen is the pharmacologically active enantiomer of ibuprofen racemate.
  • Ibuprofen is a well-known non-steroidal substance with anaigetic, anti-inflammatory and antipyretic effects.
  • WO 88/02625 describes the production of a soft gelatin capsule which is filled with dissolved ibuprofen.
  • ibuprofen is dissolved in polyethylene glycol.
  • the solubility in this can be further improved by partially neutralizing ibuprofen with alkalis, such as potassium hydroxide.
  • the conventional matrix tablets claimed in US Pat. No. 5,009,895 are sustained-release formulations which, depending on the mixing ratio used of S-ibuprofen to hydroxypropylmethyl cellulose, lead to tablets with different levels of retardation.
  • EP-OS 0 299 668 describes the production of hard gelatin capsules by filling with melts. Capsules produced in this way dissolve very slowly, however, so that this principle tends to be used for the production of Retarded forms are suitable as of quick release forms. Melt embedding is also considered problematic in that crystal modifications with changed bioavailability often occur during storage.
  • a mechanical filling of the capsules with pure powdered active ingredient, which has a relatively low melting point, is not technically possible with the capsule filling machines commonly used in pharmaceutical production, since S-ibuprofen, for example, has inadequate flow properties due to its needle-shaped crystal structure and therefore not the uniformity of salary required by the pharmacopoeia is achieved. In addition, sticking of the machine through melting active substance can be observed.
  • the object of the invention was therefore to find a pharmaceutical preparation in the form of a capsule which contains the active ingredient in high concentrations and releases it quickly.
  • the invention therefore relates to a pharmaceutical preparation in the form of a capsule which rapidly releases the active ingredient, which is characterized in that it essentially consists of a mixture of powdered active ingredient and highly disperse silicon dioxide as auxiliary, filled into a capsule shell.
  • the invention further relates to a method for producing a pharmaceutical preparation, which is characterized in that the powdered active ingredient is mixed with the highly disperse silicon dioxide and filled into a capsule.
  • the filling consists of more than 95% active ingredient and, surprisingly, the usual addition of lubricants or mold release agents can also be dispensed with entirely.
  • This concentrated powder mixture with an active ingredient content of the order of magnitude of at least 95% enables individual doses of up to 600 mg to be filled into capsule sizes which can be used for oral use and which are otherwise only achieved with tablets.
  • silicon dioxide which is commercially available, for example, as Aerosil® or Carbosil®, is admixed to the powdered active ingredient as an auxiliary to improve the flowability and as an anti-adhesive.
  • talc as a mold release agent for low-melting substances recommended in the prior art would be technically feasible, higher amounts of talc based on the active ingredient would be required for this.
  • Talc is an accepted pharmaceutical auxiliary in its use as a mold release agent, but the use of higher amounts is to be viewed rather critically from the point of view of drug safety.
  • the capsules are mechanically filled with the mixture according to the invention using conventional capsule machines without any additional equipment.
  • the production according to this method is particularly simple and economical since, apart from sieving and mixing the capsule filling, no further process steps are required. The manufacturing costs of such a capsule form are therefore very low.
  • the capsule shell material can be hard gelatin or starch, preferably hard gelatin.
  • Capsule shells generally known to those skilled in the art can be used.
  • the use of known capsule disintegrants, such as crosslinked polyvinylpyrrolidone, commercially available as Kollidon® CL or Plasdone® XL, sodium starch glycolate or also crosslinked sodium carboxymethyl cellulose is optional. They bring about a faster disintegration of the capsules in the stomach and can thus contribute to a faster onset of action.
  • the amount of the active ingredient can be varied within a wide range and is preferably between 50 and 600 mg per
  • Capsule Capsules with 100 mg, 200 mg, 300 mg or 600 mg of active ingredient are particularly preferred.
  • the basic mixture according to the invention also offers sufficient formulation scope for less concentrated
  • Capsule forms In the case of capsules for the treatment of headaches, for example, the dosage of 50 mg of active ingredient desired in children can be easily produced by adding other auxiliaries such as lactose, cellulose, calcium hydrogen phosphate or other auxiliaries known to the person skilled in the art using the same process. The admixture of further auxiliaries may also be desirable if, for marketing reasons, different dosages are to be filled into capsules of the same size.
  • auxiliaries such as lactose, cellulose, calcium hydrogen phosphate or other auxiliaries known to the person skilled in the art using the same process.
  • the admixture of further auxiliaries may also be desirable if, for marketing reasons, different dosages are to be filled into capsules of the same size.
  • All low-melting substances can be used as active ingredient, preferably S-ibuprofen or butibufen, but also the ibuprofen racemate.
  • a transferability of the capsule filling according to the invention and its production even to higher-melting active ingredients is also possible due to the simplicity and economy of this method.
  • the pharmaceutical preparation according to the invention and its production therefore make it possible to provide capsules which contain the active ingredient in high doses and release it quickly in a very simple manner on a production scale without the need for active ingredients which have a relatively low melting point Disadvantages described in the literature occur.
  • Aerosil® 200 3.00 mg
  • Hard gelatin capsule 50.00 mg

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention pertains to a pharmaceutical preparation in the form of a quick-release capsule that is filled with a mixture of active ingredient in powder form and highly dispersed silicon dioxide as inactive ingredient, and to a process for producing it.

Description

Kapsel, die mit einer Mischung aus gepulvertem Wirkstoff und hochdispersemCapsule made with a mixture of powdered active ingredient and highly disperse
Siliciumdioxid gefuellt istSilicon dioxide is filled
Die Erfindung betrifft eine pharmazeutische Zubereitung in Form einer den Wirkstoff schnell freisetzenden Kapsel, welche 5 den Wirkstoff in hoher Konzentration enthält, und neben dem Wirkstoff nur ein weiterer Hilfsstoff notwendig ist.The invention relates to a pharmaceutical preparation in the form of a capsule which rapidly releases the active ingredient and which contains the active ingredient in high concentration, and in addition to the active ingredient only a further auxiliary is necessary.
Im Falle von hochdosierten Wirkstoffen, wie Acetylsalicyl- säure, Ibuprofen-Racema , S-Ibuprofen, Ascorbinsäure etc.In the case of high-dose active ingredients, such as acetylsalicylic acid, ibuprofen racema, S-ibuprofen, ascorbic acid etc.
10 sind die Wirkstoffproduzenten bemüht, neben dem reinen Wirk¬ stoff möglichst hochkonzentrierte, direkt tablettierbare Wirkstoffmischungen anzubieten. Damit wird die Zielsetzung verfolgt, den Produzenten eine möglichst einfach handhabbare Mischung zu liefern, die außer der Tablettierung keine weite-In addition to the pure active ingredient, the active ingredient producers endeavor to offer highly concentrated, directly tablettable active ingredient mixtures. The aim is to provide the producers with a mixture that is as easy to handle as possible and that, apart from tableting,
15 ren Herstellschritte erfordert.15 ren manufacturing steps required.
Ein weiteres Ziel dieser Mischungen, gerade bei hochdosierten Wirkstoffen ist es, die Arzneiform möglichst klein zu halten, da die Patientencompliance darunter leidet, wenn zu viele 20 oder zu große Formen eingenommen werden müssen.Another goal of these mixtures, especially with high-dose active ingredients, is to keep the dosage form as small as possible, since patient compliance suffers when too many 20 or too large forms have to be taken.
Bei Wirkstoffen, die einen relativ niedrigen Schmelzpunkt besitzen, wie z.B. Ibuprofen-Racemat (75-78 °C) , Butibufen (51-53 °C) oder vor allem S-Ibuprofen (52 °C) , treten jedoch 25 bei der Herstellung von Tabletten größere Schwierigkeiten auf.For active ingredients that have a relatively low melting point, e.g. Ibuprofen racemate (75-78 ° C), butibufen (51-53 ° C) or especially S-ibuprofen (52 ° C), however, 25 encounter greater difficulties in the manufacture of tablets.
30 Aber gerade pharmazeutische Zubereitungen dieser Wirkstoffe mit hoher Konzentration sind beispielsweise in der Rheuma¬ therapie sehr gefragt.30th But pharmaceutical preparations of these active ingredients with a high concentration are very much in demand, for example, in rheumatism therapy.
S-Ibuprofen ist das pharmakologisch wirksame Enantiomer des Ibuprofen-Racemats. Ibuprofen ist eine allgemein bekannte nicht steroidale Substanz mit anaigetischer, antiinflam a- torischer und antipyretischer Wirkung.S-ibuprofen is the pharmacologically active enantiomer of ibuprofen racemate. Ibuprofen is a well-known non-steroidal substance with anaigetic, anti-inflammatory and antipyretic effects.
Es hat sich gezeigt, daß die Verabreichung nur der S-Form anstelle des Racemats einen wesentlichen therapeutischen Vorteil darstellt. Dies wird z.B. in den Dokumenten EP-OS 0 267 321 oder WO 89/00421 beschrieben.It has been shown that the administration of only the S form instead of the racemate is an essential therapeutic advantage. This will e.g. described in documents EP-OS 0 267 321 or WO 89/00421.
Die niedrigen Schmelzpunkte dieser Wirkstoffe machen dieThe low melting points of these active ingredients make them
Anwendung konventioneller Granuliertechniken bei der Herstel¬ lung von Granulaten nahezu unmöglich, da durch die beim Trocknen erforderliche Wärmezufuhr der Wirkstoff anschmilzt bzw. sintert. Es ist jedoch aus der Literatur bekannt, daß während der Verarbeitung geschmolzene oder gesinterte Wirk¬ stoffe beispielsweise eine verschlechterte in vivo Bioverfüg¬ barkeit zeigen.Use of conventional granulation techniques in the manufacture of granules is almost impossible, since the active ingredient melts or sinters as a result of the heat input required during drying. However, it is known from the literature that melted or sintered active substances during processing, for example, show a deteriorated in vivo bioavailability.
Der Schmelzpunkt stellt selbst bei der Herstellung von Film- tabletten mit dem höher schmelzenden Ibuprofen-Racemat ein Problem dar. So ist bekannt, daß bei zu heiß lackierten Filmtabletten sich die Bioverfügbarkeit ebenfalls verschlech¬ tert. Verschiedene Darreichungsformen wurden bisher im Stand der Technik für solche relativ niedrig schmelzende Wirkstoffe beschrieben. Beispielsweise wird in der WO 88/02625 die Herstellung einer Weichgelatinekapsel beschrieben, die mit gelöstem Ibuprofen befüllt wird. Hierbei wird Ibuprofen in Polyethylenglykol gelöst. Die Löslichkeit darin kann noch verbessert werden, indem Ibuprofen partiell mit Laugen, wie Kaliumbydroxid, neutralisiert wird. Diese Art der Darreichung ist jedoch nicht für das S-Ibuprofen geeignet, da es entweder bei dieser Art der Lösung des Wirkstoffs allgemein durch Veresterungsreaktionen von S-Ibuprofen mit Alkoholen zu unerwünscht hohen Gehaltsabnahmen kommt, oder aber - was gravierender ist - durch den Zusatz von Kaliumhydroxid eine Racemisierung des S-Ibuprofens eintritt.The melting point is a problem even in the production of film tablets with the higher melting ibuprofen racemate. It is known, for example, that film tablets coated too hot also deteriorate the bioavailability. Various dosage forms have hitherto been described in the prior art for such relatively low-melting active ingredients. For example, WO 88/02625 describes the production of a soft gelatin capsule which is filled with dissolved ibuprofen. Here, ibuprofen is dissolved in polyethylene glycol. The solubility in this can be further improved by partially neutralizing ibuprofen with alkalis, such as potassium hydroxide. However, this type of administration is not suitable for S-ibuprofen, since either with this type of solution of the active ingredient there is generally an undesirably high decrease in content due to esterification reactions of S-Ibuprofen with alcohols, or - what is more serious - through the addition of Potassium hydroxide causes racemization of S-ibuprofen.
Bei den im US-Patent 5,009,895 beanspruchten konventionellen Matrixtabletten handelt es sich um Retardformulieruiigen, die je nach eingesetztem Mischungsverhältnis von S-Ibuprofen zu Hydroxypropylmethylcellulose zu unterschiedlich stark retar- dierten Tabletten führen.The conventional matrix tablets claimed in US Pat. No. 5,009,895 are sustained-release formulations which, depending on the mixing ratio used of S-ibuprofen to hydroxypropylmethyl cellulose, lead to tablets with different levels of retardation.
Da die Herstellung von Tabletten jedoch, wie vorher beschrie¬ ben, einige Schwierigkeiten bereitet, eignen sich als hoch konzentrierte Darreichungsform die Hartkapseln am besten.However, since the manufacture of tablets, as previously described, presents some difficulties, the hard capsules are best suited as a highly concentrated dosage form.
In der EP-OS 0 299 668 wird die Herstellung von Hartgelatine¬ kapseln durch Befüllung mit Schmelzen beschrieben. Derart hergestellte Kapseln lösen sich allerdings nur sehr langsam wieder auf, so daß dieses Prinzip eher zur Herstellung von Retardformen als von schnellfreisetzenden Formen geeignet ist. Schmelzeinbettungen gelten auch insofern als problema¬ tisch, als während der Lagerung häufig Kristallmodifikationen mit geänderter Bioverfügbarkeit auftreten.EP-OS 0 299 668 describes the production of hard gelatin capsules by filling with melts. Capsules produced in this way dissolve very slowly, however, so that this principle tends to be used for the production of Retarded forms are suitable as of quick release forms. Melt embedding is also considered problematic in that crystal modifications with changed bioavailability often occur during storage.
Eine maschinelle Befüllung der Kapseln mit reinem gepulverten Wirkstoff, der einen relativ niedrigen Schmelzpunkte besitzt, ist mit den üblicherweise in der pharmazeutischen Produktion verwendeten Maschinen zu Kapselbefüllung technisch nicht möglich, da beispielsweise S-Ibuprofen wegen seiner nadei¬ förmigen Kristallstruktur unzureichende Fließeigenschaften besitzt und somit nicht die vom Arzneibuch geforderte Gehaltseinheitlichkeit erreicht wird. Daneben ist ein Ver¬ kleben der Maschine durch anschmelzenden Wirkstoff zu beob- achten.A mechanical filling of the capsules with pure powdered active ingredient, which has a relatively low melting point, is not technically possible with the capsule filling machines commonly used in pharmaceutical production, since S-ibuprofen, for example, has inadequate flow properties due to its needle-shaped crystal structure and therefore not the uniformity of salary required by the pharmacopoeia is achieved. In addition, sticking of the machine through melting active substance can be observed.
Der Erfindung lag daher die Aufgabe zugrunde, eine pharmazeu¬ tische Zubereitung in Form einer Kapsel zu finden, die den Wirkstoff in hohen Konzentrationen enthält und schnell frei- setzt.The object of the invention was therefore to find a pharmaceutical preparation in the form of a capsule which contains the active ingredient in high concentrations and releases it quickly.
Überraschenderweise wurde nun gefunden, daß sich eine Mischung, alleine bestehend aus dem Wirkstoff und hochdis¬ persem Siliciumdioxid als Hilfsstoff, hervorragend ohne Schwierigkeiten bei der Produktion in Kapseln abfüllen läßt. Der Wirkstoff wird nach der Einnahme schnell freigesetzt.Surprisingly, it has now been found that a mixture consisting solely of the active ingredient and highly disperse silicon dioxide as auxiliary can be filled into capsules without difficulty during production. The active ingredient is released quickly after ingestion.
Gegenstand der Erfindung ist daher eine pharmazeutische Zubereitung in Form einer den Wirkstoff schnell freisetzenden Kapsel, die dadurch gekennzeichnet ist, daß sie im wesent¬ lichen aus einer Mischung aus gepulvertem Wirkstoff und hochdispersem Siliciumdioxid als Hilfsstoff, abgefüllt in eine Kapselhülle, besteht. Weiterhin ist Gegenstand der Erfindung ein Verfahren zur Herstellung einer pharmazeutischen Zubereitung, das dadurch gekennzeichnet ist, daß man den gepulverten Wirkstoff mit dem hochdispersen Siliciumdioxid mischt und in eine Kapsel abfüllt.The invention therefore relates to a pharmaceutical preparation in the form of a capsule which rapidly releases the active ingredient, which is characterized in that it essentially consists of a mixture of powdered active ingredient and highly disperse silicon dioxide as auxiliary, filled into a capsule shell. The invention further relates to a method for producing a pharmaceutical preparation, which is characterized in that the powdered active ingredient is mixed with the highly disperse silicon dioxide and filled into a capsule.
Bei den erfindungsgemäßen Kapseln besteht die Füllung zu über 95 % aus Wirkstoff und überraschenderweise kann darüber hinaus auf den üblichen Zusatz von Schmiermitteln oder For- mentrennmitteln völlig verzichtet werden.In the capsules according to the invention, the filling consists of more than 95% active ingredient and, surprisingly, the usual addition of lubricants or mold release agents can also be dispensed with entirely.
Diese konzentrierte Pulvermischung mit einem Wirkstoffanteil in der Größenordnung von mindestens 95 % erlaubt es Einzel- dosierungen von bis zu 600 mg in die zur oralen Anwendung nutzbaren Kapselgrößen abzufüllen, die ansonsten nur mit Tabletten erreicht werden.This concentrated powder mixture with an active ingredient content of the order of magnitude of at least 95% enables individual doses of up to 600 mg to be filled into capsule sizes which can be used for oral use and which are otherwise only achieved with tablets.
Dies ist im Fall von hochdosierten Wirkstoffen, wie z.B. S-Ibuprofen, auch von therapeutischem Interesse, da bei rheumatischen Erkrankungen Tageεdosen von bis zu 1200 mg zu erwarten sind.This is the case in the case of high-dose active ingredients, e.g. S-ibuprofen, also of therapeutic interest, since daily doses of up to 1200 mg can be expected in rheumatic diseases.
Erfindungsgemäß wird dem gepulverten Wirkstoff also nur hochdisperses Siliciumdioxid, das beispielsweise als Aerosil® oder Carbosil® im Handel erhältlich ist, als Hilfsstoff zur Verbesserung der Fließfähigkeit und als Antiklebe ittel zugemischt.According to the invention, only highly disperse silicon dioxide, which is commercially available, for example, as Aerosil® or Carbosil®, is admixed to the powdered active ingredient as an auxiliary to improve the flowability and as an anti-adhesive.
Die Tatsache, daß auf den Zusatz von Schmiermitteln oder Formentrennmitteln völlig verzichtet werden kann, bringt unerwartete Vorteile. Problematik der konventionellen Schmiermittel (wie z.B. Magnesiumstearat) ist hinlänglich bekannt. So können diese aufgrund ihrer hydrophoben Eigenschaften zu einer verzögerten Wirkstoffauflösung führen. Dieser Effekt ist besonders bei Substanzen mit problematischer Bioverfügbarkeit von Bedeutung und kann zu einer verschlechterten Resorption führen.The fact that the addition of lubricants or mold release agents can be completely dispensed with brings unexpected advantages. The problem of conventional lubricants (such as magnesium stearate) is well known. Because of their hydrophobic properties, these can lead to a delayed drug dissolution. This effect is particularly important for substances with problematic bioavailability and can lead to deteriorated absorption.
Der im Stand der Technik empfohlene Zusatz von Talkum als Formentrennmittel bei niedrig schmelzenden Substanzen wäre zwar technisch machbar, es würden jedoch hierzu höhere Mengen an Talkum bezogen auf den Wirkstoff benötigt. Talkum ist zwar in der Anwendung als Formentrennmittel ein akzeptierter Pharmahilfsstoff, jedoch ist die Verwendung höherer Mengen unter dem Aspekt der Arzneimittelsicherheit eher kritisch zu beurteilen.Although the addition of talc as a mold release agent for low-melting substances recommended in the prior art would be technically feasible, higher amounts of talc based on the active ingredient would be required for this. Talc is an accepted pharmaceutical auxiliary in its use as a mold release agent, but the use of higher amounts is to be viewed rather critically from the point of view of drug safety.
Die maschinelle Befüllung der Kapseln mit der erfindungs¬ gemäßen Mischung erfolgt mit konventionellen Kapselmaschinen ohne weitere Zusatzausrüstung. Die Herstellung nach dieser Methode ist besonders einfach und ökonomisch, da außer Sieben und Mischen der Kapselfüllung keine weiteren Prozeßschritte erforderlich sind. Die Herstellkosten einer derartigen Kap¬ selform liegen daher sehr günstig.The capsules are mechanically filled with the mixture according to the invention using conventional capsule machines without any additional equipment. The production according to this method is particularly simple and economical since, apart from sieving and mixing the capsule filling, no further process steps are required. The manufacturing costs of such a capsule form are therefore very low.
Das Kapselhüllmaterial kann Hartgelatine oder Stärke sein, vorzugsweise ist es Hartgelatine. Es können die dem Fachmann auf diesem Gebiet allgemein bekannten Kapselhüllen eingesetzt werden. Der Einsatz von bekannten KapselSprengmitteln, wie z.B. quervernetztes Polyvinylpyrrolidon, als Kollidon® CL oder Plasdone® XL im Handel erhältlich, Natrium-stärkeglykolat oder auch quervernetzte Natriumcarboxymethylcellulose, ist optional. Sie bewirken einen schnelleren Zerfall der Kapseln im Magen und können somit zu einem schnelleren Wirkungsein¬ tritt beitragen.The capsule shell material can be hard gelatin or starch, preferably hard gelatin. Capsule shells generally known to those skilled in the art can be used. The use of known capsule disintegrants, such as crosslinked polyvinylpyrrolidone, commercially available as Kollidon® CL or Plasdone® XL, sodium starch glycolate or also crosslinked sodium carboxymethyl cellulose is optional. They bring about a faster disintegration of the capsules in the stomach and can thus contribute to a faster onset of action.
Die Menge des Wirkstoffs kann in weiten Bereichen variiert werden und liegt vorzugsweise zwischen 50 und 600 mg proThe amount of the active ingredient can be varied within a wide range and is preferably between 50 and 600 mg per
Kapsel. Besonders bevorzugt sind Kapseln mit 100 mg, 200 mg, 300 mg oder 600 mg Wirkstoff.Capsule. Capsules with 100 mg, 200 mg, 300 mg or 600 mg of active ingredient are particularly preferred.
Die erfindungsgemäße Grundmischung bietet auch einen ausrei- chenden Formulierungsspielraum für weniger konzentrierteThe basic mixture according to the invention also offers sufficient formulation scope for less concentrated
Kapselformen. So kann beispielsweise bei Kapseln zur Behand¬ lung von Kopfschmerzen die bei Kindern gewünschte Dosierung von 50 mg Wirkstoff durch Zu ischung von weiteren Hilfsstof¬ fen wie Lactose, Cellulose, Calciumbydrogenphosphat oder anderen, dem Fachmann bekannten Hilfsstoffen problemlos nach demselben Verfahren hergestellt werden. Die Zumischung weite¬ rer Hilfsstoffe kann auch erwünscht sein, wenn aus Marketing¬ überlegungen heraus verschiedene Dosierungen in gleichgroße Kapseln gefüllt werden sollen.Capsule forms. In the case of capsules for the treatment of headaches, for example, the dosage of 50 mg of active ingredient desired in children can be easily produced by adding other auxiliaries such as lactose, cellulose, calcium hydrogen phosphate or other auxiliaries known to the person skilled in the art using the same process. The admixture of further auxiliaries may also be desirable if, for marketing reasons, different dosages are to be filled into capsules of the same size.
Als Wirkstoff können alle niedrig schmelzenden Substanzen eingesetzt werden, vorzugsweise werden S-Ibuprofen oder Butibufen, aber auch das Ibuprofen-Racemat eingesetzt.All low-melting substances can be used as active ingredient, preferably S-ibuprofen or butibufen, but also the ibuprofen racemate.
Eine Ubertragbarkeit der erfindungsgemäßen Kapselfüllung und deren Herstellung auch auf höher schmelzende Wirkstoffe ist jedoch aufgrund der Einfachheit und Ökonomie dieser Methode ebenfalls möglich. Durch die erfindungsgemäße pharmazeutische Zubereitung und deren Herstellung ist es also möglich, Kapseln, die den Wirkstoff in hohen Dosen enthalten und ihn schnell freiset¬ zen, auf einfachste Art und Weise im Produktionsmaßstab zur Verfügung zu stellen, ohne daß die, für relativ niedrig schmelzende Wirkstoffe in der Literatur beschriebenen Nach¬ teile auftreten.A transferability of the capsule filling according to the invention and its production even to higher-melting active ingredients is also possible due to the simplicity and economy of this method. The pharmaceutical preparation according to the invention and its production therefore make it possible to provide capsules which contain the active ingredient in high doses and release it quickly in a very simple manner on a production scale without the need for active ingredients which have a relatively low melting point Disadvantages described in the literature occur.
Beispiel 1example 1
Herstellung von Hartgelatinekapseln enthaltend 200 mg S-IbuprofenProduction of hard gelatin capsules containing 200 mg of S-ibuprofen
10 kg S-Ibuprofen, 150 g Aerosil® 200 (Fa. Degussa, Si02, hochdispers) und 300 g Kollidon® CL (Fa. BASF) werden gesiebt und in einer Mischtrommel in einem Turbula-Mischer 20 Minuten gemischt.10 kg of S-ibuprofen, 150 g of Aerosil® 200 (from Degussa, Si0 2 , highly dispersed) and 300 g of Kollidon® CL (from BASF) are sieved and mixed in a mixing drum in a Turbula mixer for 20 minutes.
Anschließend werden in einer üblichen Kapselmaschine 50 000 Kapseln abgefüllt.Then 50,000 capsules are filled in a conventional capsule machine.
Daten der einzelnen Kapseln:Data of the individual capsules:
Gesamtgewicht: 259,00 mg S-Ibuprofen: 200,00 mgTotal weight: 259.00 mg S-ibuprofen: 200.00 mg
Kollidon® CL: 6,00 mgKollidon® CL: 6.00 mg
Aerosil® 200: 3,00 mgAerosil® 200: 3.00 mg
Hartgelatinekapsel: 50,00 mg Hard gelatin capsule: 50.00 mg

Claims

PatentaπSprüche Patent claims
1. Pharmazeutische Zubereitung in Form einer den Wirkstoff schnell freisetzenden Kapsel, dadurch gekennzeichnet, daß sie im wesentlichen aus einer Mischung aus gepulvertem Wirkstoff und hochdispersem Siliciumdioxid als Hilfs¬ stoff, abgefüllt in eine Kapselhülle, besteht.1. Pharmaceutical preparation in the form of a capsule which releases the active ingredient quickly, characterized in that it consists essentially of a mixture of powdered active ingredient and highly disperse silicon dioxide as auxiliary substance, filled into a capsule shell.
2. Pharmazeutische Zubereitung nach Anspruch 1, dadurch gekennzeichnet, daß das Kapselhüllmaterial Hartgelatine oder Stärke ist.2. Pharmaceutical preparation according to claim 1, characterized in that the capsule shell material is hard gelatin or starch.
3. Pharmazeutische Zubereitung nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß die Mischung zu mindestens 95 % aus dem Wirkstoff besteht.3. Pharmaceutical preparation according to claim 1 or 2, characterized in that the mixture consists of at least 95% of the active ingredient.
4. Pharmazeutische Zubereitung nach mindestens einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, daß als Wirk¬ stoff Ibuprofen, S-Ibuprofen oder Butibufen enthalten ist.4. Pharmaceutical preparation according to at least one of claims 1 to 3, characterized in that it contains ibuprofen, S-ibuprofen or butibufen as active ingredient.
5. Pharmazeutische Zubereitung nach mindestens einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, daß zusätzlich ein Sprengmittel enthalten ist.5. Pharmaceutical preparation according to at least one of claims 1 to 4, characterized in that an explosive is additionally contained.
Pharmazeutische Zubereitung nach mindestens einem der Ansprüche 1, 2, 4 oder 5, dadurch gekennzeichnet, daß weitere Hilfsstoffe zugemischt werden, um eine weniger konzentrierte Form zu erhalten. 7. Verfahren zur Herstellung einer pharmazeutischen Zuberei¬ tung nach einem der Ansprüche 1 bis 6, dadurch gekenn¬ zeichnet, daß man die gepulverten Bestandteile mischt und in eine Kapsel abfüllt. Pharmaceutical preparation according to at least one of Claims 1, 2, 4 or 5, characterized in that further auxiliaries are mixed in in order to obtain a less concentrated form. 7. A method for producing a pharmaceutical preparation according to one of claims 1 to 6, characterized gekenn¬ characterized in that the powdered components are mixed and filled into a capsule.
PCT/EP1994/000281 1993-02-10 1994-02-01 Capsule filled with a mixture of active ingredient in powder form and highly dispersed silicon dioxide WO1994017787A1 (en)

Priority Applications (1)

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EP94906190A EP0633770A1 (en) 1993-02-10 1994-02-01 Capsule filled with a mixture of active ingredient in powder form and highly dispersed silicon dioxide

Applications Claiming Priority (2)

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DE19934303844 DE4303844A1 (en) 1993-02-10 1993-02-10 Pharmaceutical preparation
DEP4303844.1 1993-02-10

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Publication number Priority date Publication date Assignee Title
DE19849848A1 (en) * 1998-10-29 2000-05-04 Lohmann Therapie Syst Lts Oral application, spontaneous disintegration with liquid and dosage form and process for its preparation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2302087A1 (en) * 1975-02-28 1976-09-24 Juste Sa Compsns. contg. 2-(4-isobutylphenyl) butyric acid - useful as nonulcerogenic analgesic, antiinflammatory and antipyretic
EP0172014A2 (en) * 1984-08-17 1986-02-19 The Upjohn Company Formulations of ibuprofen
US5191114A (en) * 1991-10-09 1993-03-02 Sage Pharmaceuticals, Inc. Process for enhancing the flow characteristics of ibuprofen

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2302087A1 (en) * 1975-02-28 1976-09-24 Juste Sa Compsns. contg. 2-(4-isobutylphenyl) butyric acid - useful as nonulcerogenic analgesic, antiinflammatory and antipyretic
EP0172014A2 (en) * 1984-08-17 1986-02-19 The Upjohn Company Formulations of ibuprofen
US5191114A (en) * 1991-10-09 1993-03-02 Sage Pharmaceuticals, Inc. Process for enhancing the flow characteristics of ibuprofen

Also Published As

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DE4303844A1 (en) 1994-08-11

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