WO2000025759A1 - Orally applicable therapeutic dosage form which spontaneously disintegrates upon contact with a liquid and method for producing the same - Google Patents

Orally applicable therapeutic dosage form which spontaneously disintegrates upon contact with a liquid and method for producing the same Download PDF

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Publication number
WO2000025759A1
WO2000025759A1 PCT/EP1999/007940 EP9907940W WO0025759A1 WO 2000025759 A1 WO2000025759 A1 WO 2000025759A1 EP 9907940 W EP9907940 W EP 9907940W WO 0025759 A1 WO0025759 A1 WO 0025759A1
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Prior art keywords
dosage form
preparation
capsule
protective cover
spontaneously
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PCT/EP1999/007940
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German (de)
French (fr)
Inventor
Frank Becher
Original Assignee
Lts Lohmann Therapie-Systeme Ag
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Priority to AU11528/00A priority Critical patent/AU1152800A/en
Publication of WO2000025759A1 publication Critical patent/WO2000025759A1/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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • 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
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release

Definitions

  • the invention relates to an orally administrable dosage form, containing a preparation which spontaneously disintegrates upon contact with liquid and releases active substance, and a process for its preparation.
  • Capsules filled with an active substance preparation are known which, after reaching the stomach, dissolve quickly under the influence of the gastric fluid, so that a larger amount of active substance is suddenly released. Combinations of such capsule fillings are also known, which initially release a lot of active substance and then implement slower release kinetics to maintain the active substance plasma level which was initially achieved.
  • Such systems have the disadvantage that the active ingredient or the preparation containing the active ingredient must be provided in a special way with properties by means of which it is released spontaneously, for example by freeze-drying or in another manner known to the person skilled in the art via so-called instant preparations.
  • instant preparations can be filled into capsules only with great difficulty because there is a risk that the preparations will be damaged in the process.
  • Another disadvantage is that after the capsule has been filled, a production or quality control is no longer possible.
  • Other preparations in powder form do not exclude with certainty or with absolute certainty the risk that the accessories formation clumps and the spontaneous effect of a release is not achieved.
  • wafers which disintegrate in the oral cavity.
  • the active ingredient released from it is only slowly and not suddenly - if at all - transferred into the stomach.
  • Systems of this type are therefore unsuitable for the desired goal of releasing the active ingredient as quickly as possible.
  • US 5,658,589 describes a capsule-like medicament comprising an underlayer of a mixture of a water-soluble film-forming polymer, for example hydroxypropyl methyl cellulose and a hydrophobic plasticizer, e.g. Castor oil, which favors a smooth, uniform and substantially bubble-free outer layer, for example gelatin; the capsule-like form of the drug can contain a variety of different active ingredients.
  • a water-soluble film-forming polymer for example hydroxypropyl methyl cellulose and a hydrophobic plasticizer, e.g. Castor oil, which favors a smooth, uniform and substantially bubble-free outer layer, for example gelatin
  • a hydrophobic plasticizer e.g. Castor oil
  • WO 97/24109 A describes a bioadhesive composition containing an active ingredient, 80-98.8% by weight of pregelatinized starch, 1-10% by weight of a polymer forming a hydrophilic matrix and 0.2-5% by weight of alkali C 16 _ 22 alkyl fumarate as a lubricant.
  • the dosage form can be used as an active ingredient-containing tablet or capsule for oral, nasal, rectal or vaginal administration.
  • No. 5,296,233 describes a capsule-like medicament, comprising a dual underlayer of a water-soluble film-forming polymer, for example povidone, with * a second underlayer composed of a mixture of two film-forming polymers, for example povidone and hydroxypropyl methylcellulose, and a hydrophobic plasticizer, for example castor oil, which is used for a smooth, uniform and substantially bubble-free outer layer ensures, for example gelatin for a capsule-like medication.
  • a water-soluble film-forming polymer for example povidone
  • a second underlayer composed of a mixture of two film-forming polymers, for example povidone and hydroxypropyl methylcellulose
  • a hydrophobic plasticizer for example castor oil
  • No. 4,983,401 describes a pharmaceutical preparation for long-term release of active substance using a pH-controllable diffusion membrane, consisting of a pH-sensitive film-forming polymer.
  • a pH-sensitive film-forming polymer may contain phthalic acid as a starting polymer with a carboxyl group attached to the starting polymer through an ester bond, while the second carboxyl group remains as a free acid, so that the modified film-forming polymer is hydrophobic at a low pH and hydrophilic at a higher pH.
  • Hydrophobic stearyl side chains are bound to the starting polymer, which means that the pH-controlled diffusion membrane remains insoluble at high pH.
  • the pH-sensitive film-forming polymer can be a polymer containing hydrophobic free acid groups, so that the modified film-forming polymer is hydrophobic at low pH and hydrophilic at high pH, but insoluble.
  • the preparation for long-term drug release is applied to drug particles for the production of a pH-controlled diffusion membrane for coating the drug with formation of mi Croparticles for mixing with medication or slow-release medication and introduced into gelatin capsules or tableted.
  • the invention has for its object to provide an orally administrable therapeutic dosage form of the type mentioned in the preamble of claim 1, which is suitable for a • drug after oral administration while preventing a premature dissolution on the way from the oral cavity via release the esophagus into the stomach only spontaneously after reaching the stomach, but then in larger amounts of active substance.
  • the invention proposes that an orally administrable dosage form containing a preparation which spontaneously disintegrates and releases active substance upon contact with liquid, in particular gastric liquid, to prevent premature dissolution on the way from the oral cavity via the esophagus into the stomach is surrounded with a protective cover.
  • the protective cover is an extremely thin capsule made of gelatin-like polymer.
  • the protective cover can consist of pH-sensitive material, which is released in the acidic environment of the gastric juice and releases the preparation spontaneously and allows it to disintegrate.
  • the protective cover can consist of a mixture of a water-soluble film-forming polymer, for example of hydroxyporpylmethyl cellulose and a hydrophobic plasticizer, for example castor oil.
  • a water-soluble film-forming polymer for example of hydroxyporpylmethyl cellulose
  • a hydrophobic plasticizer for example castor oil.
  • the protective casing contains corn starch. This has the advantage that when dry it results in a comparatively dimensionally stable shell, which, however, immediately loses this shape upon contact with gastric fluid and releases the contents of the capsule.
  • the dosage form is characterized in that it is a sheet-like, active substance-containing structure made of film-forming polymer and is present in the cover as a roll or folded body.
  • the casing for the spontaneous release of the preparation in the stomach has a tear-open aid in the form of a line of weakness running in the transverse or longitudinal direction thereof.
  • a method for producing the orally administrable, sheet-like dosage form which comprises a preparation which spontaneously disintegrates and releases active substance upon contact with liquid, in particular gastric juice, can advantageously be used, this being introduced as a roll or folded body into a casing to form a capsule, come to use, which is characterized in that after the completion of the dosage form using a laser beam is provided with the tear-open aid in the form of a line of weakness.
  • the weakening line can advantageously be formed from perforation lines or from embrittlement lines.
  • the tear-open aid can also be designed with two intersecting lines of weakness.
  • Section a section line B-B of FIG.lb an orally administrable therapeutic dosage form in the form of an oval capsule 5
  • FIG. 1b the capsule 5 in the section of the sectional plane A-A of FIG.la, containing the preparation in the form of a folding body
  • FIG.lc in section A-A in FIG.la containing the preparation in the form of a roll.
  • the orally administrable dosage form shown in FIG.la containing a preparation 6 which spontaneously disintegrates upon contact with liquid and releases active substance, is characterized in that it is in the form of a to prevent premature release on the way from the oral cavity via the esophagus into the stomach Capsule 5 is surrounded by a protective cover 1.
  • the protective cover 1 can be an extremely thin capsule 5 on gelatin-like polymer.
  • the protective sheath 1 can advantageously also consist of pH-sensitive material, which dissolves faster in the acidic environment of the gastric juice and spontaneously releases the preparation 6 and allows it to disintegrate.
  • the protective cover 1 consists of a mixture of a water-soluble film-forming polymer, for example hydroxypropylmethyl cellulose, and a hydrophobic plasticizer, e.g. Castor oil.
  • the protective cover can also contain 1 corn starch.
  • the preparation 6 contained in the capsule 5 is a leaf-shaped Total, active substance-containing structure made of film-forming polymer and contained in the shell 1 as a roll 3 (FIG.lc) or as a folded body 2 (FIG.lb).
  • FIGS. 1 a and 1 b show an embodiment of the casing 1 with a tear-open aid in the form of a weakening line 4 or 4 ′ running in the transverse or longitudinal direction.
  • These weakening lines 4, 4 ' are designed either as a perforation line or as an embrittlement line and are produced in accordance with the method according to the invention after the protective casing 1 or the thin capsule 5 formed therefrom using a laser beam.
  • the tear-open aid can preferably be designed with two intersecting lines of weakness 4, 4 ′.
  • the production using a laser beam is economical and uncomplicated and can be carried out, for example, with the aid of a pulsating laser beam in the form of tiny perforations lying next to one another in a line, or the envelope 1 for the weakening line 4 or 4 "can be carried out with the aid of the laser beam thermal embrittlement of the material of the shell 1 are produced.
  • 5 gas formers can be added to the capsule according to the method in an amount sufficient to expand and destroy the capsule along the tear aids 4, 4 '.

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  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

The invention relates to an orally applicable therapeutic dosage form containing a preparation that spontaneously disintegrates upon contact with a liquid and releases an active substance. The inventive therapeutic dosage form is characterized in that it is embedded in a protective coating in the form of a capsule to prevent it from prematurely disintegrating on the way from the mouth cavity via the esophagus to the stomach.

Description

Oral applizierbare, mit Flüssigkeit spontan zerfallende therapeutische Darreichungsform und Verfahren zu ihrer HerstellungOral application, spontaneously disintegrating with liquid, therapeutic dosage form and process for its preparation
Die Erfindung betrifft eine oral applizierbare therapeutische Darreichungsform, enthaltend eine bei Kontakt mit Flüssigkeit spontan zerfallende und Wirkstoff freisetzende Zubereitung, sowie ein Verfahren zu ihrer Herstellung.The invention relates to an orally administrable dosage form, containing a preparation which spontaneously disintegrates upon contact with liquid and releases active substance, and a process for its preparation.
Bei einer Anzahl von Indikationen besteht das Erfordernis vorrangig darin, ein Arzneimittel im Magen möglichst schnell, praktisch schlagartig freizusetzen. Bekannt sind mit einer WirkstoffZubereitung gefüllte Kapseln, welche sich nach Erreichen des Magens unter dem Einfluß der Magenflüssigkeit schnell auflösen, so daß eine größere Menge von Wirkstoff schlagartig freigesetzt wird. Bekannt sind auch Kombinationen von solchen Kapselfüllungen, welche anfangs eine Menge Wirkstoff freisetzen und anschließend eine langsamere Freisetzungskinetik zur Erhaltung des anfangs erreichten Wirkstoff-Plasmapegels verwirklichen.For a number of indications, the primary requirement is to release a drug in the stomach as quickly as possible, practically suddenly. Capsules filled with an active substance preparation are known which, after reaching the stomach, dissolve quickly under the influence of the gastric fluid, so that a larger amount of active substance is suddenly released. Combinations of such capsule fillings are also known, which initially release a lot of active substance and then implement slower release kinetics to maintain the active substance plasma level which was initially achieved.
Solche Systeme haben den Nachteil, daß Wirkstoff bzw. die wirkstoffhaltige Zubereitung in besonderer Weise mit Eigenschaften versehen werden muß, durch welche sie spontan freigesetzt werden, beispielsweise durch Gefriertrocknung oder in einer anderen, dem Fachmann bekannten Art und Weise über sogenannte Instant-Zubereitungen. Solche Instant- Zubereitungen lassen sich jedoch nur unter größeren Schwierigkeiten in Kapseln füllen, weil die Gefahr besteht, daß die Zubereitungen dabei beschädigt werden. Von Nachteil ist auch, daß nach der Kapselbefüllung eine Herstellungs- oder Qualitätskontrolle nicht mehr möglich ist. Andere Zubereitungen in Pulverform lassen nicht mit Sicherheit oder mit letzter Sicherheit die Gefahr ausschließen, daß die Zube- reitung Klumpen bildet und somit der Spontaneffekt einer Freisetzung nicht erreicht wird.Such systems have the disadvantage that the active ingredient or the preparation containing the active ingredient must be provided in a special way with properties by means of which it is released spontaneously, for example by freeze-drying or in another manner known to the person skilled in the art via so-called instant preparations. However, such instant preparations can be filled into capsules only with great difficulty because there is a risk that the preparations will be damaged in the process. Another disadvantage is that after the capsule has been filled, a production or quality control is no longer possible. Other preparations in powder form do not exclude with certainty or with absolute certainty the risk that the accessories formation clumps and the spontaneous effect of a release is not achieved.
Bekannt sind weiterhin schnell zerfallende flächige Darrei- chungsformen, sogenannte Obletten, die in der Mundhöhle zerfallen. Dies hat zur Folge, daß der daraus freigesetzte Wirkstoff nur langsam und nicht schlagartig - sofern überhaupt - in den Magen überführt wird. Derartige Systeme eignen sich daher nicht für das angestrebte Ziel einer möglichst raschen Wirkstofffreisetzung.Also known are rapidly disintegrating forms of administration, so-called wafers, which disintegrate in the oral cavity. The result of this is that the active ingredient released from it is only slowly and not suddenly - if at all - transferred into the stomach. Systems of this type are therefore unsuitable for the desired goal of releasing the active ingredient as quickly as possible.
Zum Stand der Technik betreffend Überzugsschichten von therapeutischen Dosierungsformen ist weiterhin auf die folgenden Veröffentlichungen hinzuweisen:With regard to the state of the art regarding coating layers of therapeutic dosage forms, reference should also be made to the following publications:
1) Porter, Stuart C, "Coating of Pharmaceutical Dosage Forms", 17th Edition, Mack Publishing Co., 1985; sowie auf1) Porter, Stuart C, "Coating of Pharmaceutical Dosage Forms", 17 th Edition, Mack Publishing Co., 1985; as well as on
2) Pharmaceutical Dosage Forms: Tablets, H. A. Liebermann, L. Lachmann and J. B. Schwartz, vol.3 pp. 108-113, Se- cond Edition, 1990.2) Pharmaceutical Dosage Forms: Tablets, H. A. Liebermann, L. Lachmann and J. B. Schwartz, vol. 3 pp. 108-113, Second Edition, 1990.
US 5,658,589 beschreibt ein kapselartiges Medikament, umfassend eine Unterschicht aus einer Mixtur eines wasserlöslichen fumbildenden Polymers, beispielsweise Hydroxypro- pylmethylcellulose und einen hydrophoben Weichmacher, z.B. Rizinusöl, welches eine glatte, uniforme und substantiell blasenfreie Außenschicht begünstigt, beispielsweise Gelatine; die kapselartige Form des Medikaments kann eine Vielzahl verschiedener Wirkstoffe enthalten.US 5,658,589 describes a capsule-like medicament comprising an underlayer of a mixture of a water-soluble film-forming polymer, for example hydroxypropyl methyl cellulose and a hydrophobic plasticizer, e.g. Castor oil, which favors a smooth, uniform and substantially bubble-free outer layer, for example gelatin; the capsule-like form of the drug can contain a variety of different active ingredients.
WO 97/24109 A beschreibt eine bioadhäsive Zusammensetzung enthaltend einen aktiven Wirkstoff, 80-98,8 Gew.% vorgela- tinisierte Stärke, 1-10 Gew.% eines eine hydrophile Matrix ausbildenden Polymers und 0,2-5 Gew.% Alkali- C16_22-alkyl- fumarat als Gleitmittel. Die Dosierform kann als wirkstoffhaltige Tablette oder Kapsel für orale, nasale, rektale oder vaginale Administration verwendet werden.WO 97/24109 A describes a bioadhesive composition containing an active ingredient, 80-98.8% by weight of pregelatinized starch, 1-10% by weight of a polymer forming a hydrophilic matrix and 0.2-5% by weight of alkali C 16 _ 22 alkyl fumarate as a lubricant. The dosage form can be used as an active ingredient-containing tablet or capsule for oral, nasal, rectal or vaginal administration.
US 5,296,233 beschreibt ein kapselartig ausgebildetes Medikament, umfassend eine duale Unterschicht eines wasserlöslichen Filmbildner-Polymers, beispielsweise Povidon, mit* einer zweiten Unterschicht aus einer Mischung zweier filmbildender Polymere, beispielsweise Povidon und Hydroxypro- pylmethylcellulose, und einem hydrophoben Weichmacher, z.B. Rizinusöl, welches für eine glatte, gleichmäßige und substantiell blasenfreie Außenschicht sorgt, z.B. Gelatine für ein kapselartiges Medikament.No. 5,296,233 describes a capsule-like medicament, comprising a dual underlayer of a water-soluble film-forming polymer, for example povidone, with * a second underlayer composed of a mixture of two film-forming polymers, for example povidone and hydroxypropyl methylcellulose, and a hydrophobic plasticizer, for example castor oil, which is used for a smooth, uniform and substantially bubble-free outer layer ensures, for example gelatin for a capsule-like medication.
US 4,983,401 beschreibt ein pharmazeutisches Präparat zur längerfristigen Wirkstofffreisetzung unter Verwendung einer pH-kontrollierbaren Diffusionsmembran, »bestehend aus einem pH-sensitiven Filmbildner-Polymer. Dieses kann als Ausgangspolymer Phthalsäure mit einer Carboxylgruppe enthalten, gebunden an das Ausgangspolymer durch eine Ester- Bindung, während die zweite Carboxylgruppe als freie Säure übrigbleibt, so daß das modifizierte Filmbildnerpolymer bei niedrigem pH-Wert hydrophob und bei einem höheren pH-Wert hydrophil ist. Hydrophobe Stearyl-Seitenketten sind an das Ausgangspolymer gebunden, wodurch die pH-kontrollierte Diffusionsmembran bei hohem pH-Wert unlöslich bleibt. Alternativ kann das pH-sensitive Filmbildnerpolymer ein Polymer, enthaltend hydrophobe freie Säure-Gruppen sein, so daß das modifizierte Filmbildnerpolymer bei niedrigem pH-Wert hydrophob, und bei hohem pH-Wert hydrophil, jedoch unlöslich ist.No. 4,983,401 describes a pharmaceutical preparation for long-term release of active substance using a pH-controllable diffusion membrane, consisting of a pH-sensitive film-forming polymer. This may contain phthalic acid as a starting polymer with a carboxyl group attached to the starting polymer through an ester bond, while the second carboxyl group remains as a free acid, so that the modified film-forming polymer is hydrophobic at a low pH and hydrophilic at a higher pH. Hydrophobic stearyl side chains are bound to the starting polymer, which means that the pH-controlled diffusion membrane remains insoluble at high pH. Alternatively, the pH-sensitive film-forming polymer can be a polymer containing hydrophobic free acid groups, so that the modified film-forming polymer is hydrophobic at low pH and hydrophilic at high pH, but insoluble.
In bevorzugter Ausbildung ist das Präparat zur längerfristigen Wirkstof freisetzung aufgebracht auf Wirkstoffpartikel zur Herstellung einer pH-kontrollierten Diffusionsmembran zur Umhülllung des Wirkstoffs unter Ausbildung von Mi- kropartikeln zur Mischung mit Arznei oder Retard-Arznei und in Gelatinekapseln eingebracht oder tablettiert.In a preferred embodiment, the preparation for long-term drug release is applied to drug particles for the production of a pH-controlled diffusion membrane for coating the drug with formation of mi Croparticles for mixing with medication or slow-release medication and introduced into gelatin capsules or tableted.
Ausgehend vom vorgenannten Stand der Technik liegt der Erfindung die Aufgabe zugrunde, eine oral applizierbare therapeutische Darreichungsform der im Oberbegriff von Anspruch 1 genannten Art anzugeben, die geeignet ist, ein • Arzneimittel nach oraler Einnahme unter Verhinderung einer vorzeitigen Auflösung auf dem Weg von der Mundhöhle über die Speiseröhre in den Magen erst nach Erreichen des Magens, dann aber in größerer Wirkstoffmenge, spontan freizusetzen.Starting from the aforementioned prior art, the invention has for its object to provide an orally administrable therapeutic dosage form of the type mentioned in the preamble of claim 1, which is suitable for a • drug after oral administration while preventing a premature dissolution on the way from the oral cavity via release the esophagus into the stomach only spontaneously after reaching the stomach, but then in larger amounts of active substance.
Zur Lösung der Aufgabe wird mit der Erfindung vorgeschlagen, daß eine oral applizierbare therapeutische Darreichungsform, enthaltend eine bei Kontakt mit Flüssigkeit, insbesondere Magenflüssigkeit, spontan zerfallende und Wirkstoff freisetzende Zubereitung zur Verhinderung einer vorzeitigen Auflösung auf dem Weg von der Mundhöhle über die Speiseröhre in den Magen mit einer Schutzhülle umgeben ist.To achieve the object, the invention proposes that an orally administrable dosage form containing a preparation which spontaneously disintegrates and releases active substance upon contact with liquid, in particular gastric liquid, to prevent premature dissolution on the way from the oral cavity via the esophagus into the stomach is surrounded with a protective cover.
Weitere Ausgestaltungen der Darreichungsform nach Anspruch 1 sehen in vorteilhafter Ausgestaltung vor, daß die Schutzhülle eine extrem dünne Kapsel aus gelatineartigem Polymer ist.Further embodiments of the dosage form according to claim 1 provide in an advantageous embodiment that the protective cover is an extremely thin capsule made of gelatin-like polymer.
Beispielsweise kann die Schutzhülle aus pH-sensitivem Material bestehen, welches sich im sauren Milieu des Magensaftes beschleunigt auslöst und die Zubereitung spontan freigibt und zerfallen läßt.For example, the protective cover can consist of pH-sensitive material, which is released in the acidic environment of the gastric juice and releases the preparation spontaneously and allows it to disintegrate.
In einer bevorzugten Ausführungsform kann dabei die Schutzhülle aus einer Mischung eines wasserlöslichen filmbildenden Polymers, beispielsweise aus Hydroxyporpylmethylcellu- lose und einem hydrophoben Weichmacher, z.B. Rizinusöl, bestehen. In einer weiteren vorteilhaften Ausgestaltung kann vorgesehen sein, daß die Schutzhülle Maisstärke enthält. Diese hat den Vorteil, daß sie in trockenem Zustand eine vergleichsweise formstabile Hülle ergibt, die jedoch bei Kontakt mit Magenflüssigkeit sofort diese Form verliert und den Inhalt der Kapsel freigibt.In a preferred embodiment, the protective cover can consist of a mixture of a water-soluble film-forming polymer, for example of hydroxyporpylmethyl cellulose and a hydrophobic plasticizer, for example castor oil. In a further advantageous embodiment it can be provided that the protective casing contains corn starch. This has the advantage that when dry it results in a comparatively dimensionally stable shell, which, however, immediately loses this shape upon contact with gastric fluid and releases the contents of the capsule.
Die Darreichungsform ist nach einer weiteren Ausgestaltung dadurch gekennzeichnet, daß sie ein blattförmiges, wirk- stoffhaltiges Gebilde aus fumbildendem Polymer ist und in der Hülle als Rolle oder Faltkörper vorliegt. Mit Vorteil kann weiterhin von der Maßnahme Gebrauch gemacht sein, daß die Hülle zur spontanen Freigabe der Zubereitung im Magen eine Aufreißhilfe in Form einer in Quer- oder Längsrichtung derselben verlaufenden Schwächungslinie aufweist.According to a further embodiment, the dosage form is characterized in that it is a sheet-like, active substance-containing structure made of film-forming polymer and is present in the cover as a roll or folded body. Advantageously, use can also be made of the measure that the casing for the spontaneous release of the preparation in the stomach has a tear-open aid in the form of a line of weakness running in the transverse or longitudinal direction thereof.
Dabei kann mit Vorteil ein Verfahren zur Herstellung der oral ..applizierbaren, blattförmigen Darreichungsform, umfassend eine bei Kontakt mit Flüssigkeit, insbesondere Magensaft, spontan zerfallende und Wirkstoff freisetzende Zubereitung, wobei diese als Rolle oder Faltkörper in eine Hülle unter Ausbildung einer Kapsel eingebracht wird, zur Anwendung kommen, welches dadurch gekennzeichnet ist, daß die Hülle nach Fertigstellung der Darreichungsform unter Verwendung eines Laserstrahles mit der Aufreißhilfe in Form einer Schwächungslinie versehen wird.A method for producing the orally administrable, sheet-like dosage form, which comprises a preparation which spontaneously disintegrates and releases active substance upon contact with liquid, in particular gastric juice, can advantageously be used, this being introduced as a roll or folded body into a casing to form a capsule, come to use, which is characterized in that after the completion of the dosage form using a laser beam is provided with the tear-open aid in the form of a line of weakness.
Dabei kann vorteilhaft die Schwächungslinie aus Perforationslinien oder aus Versprödungslinien ausgebildet werden. Auch kann die Aufreißhilfe mit zwei sich kreuzenden Schwächungslinien ausgebildet werden.The weakening line can advantageously be formed from perforation lines or from embrittlement lines. The tear-open aid can also be designed with two intersecting lines of weakness.
Weiter Einzelheiten, Merkmale und Vorteile der Erfindung ergeben sich aus der nachstehenden Erläuterung eines in den Zeichnungen schematisch dargestellten Ausführungsbeispieles. Es zeigen:Further details, features and advantages of the invention result from the following explanation of an exemplary embodiment shown schematically in the drawings. Show it:
FIG.la rechtsseitig in Ansicht und linksseitig imFIG.la right side in view and left side in
Schnitt eine Schnittlinie B-B von FIG.lb eine oral applizierbare therapeutische Darreichungs- for in Gestalt einer ovalen Kapsel 5,Section a section line B-B of FIG.lb an orally administrable therapeutic dosage form in the form of an oval capsule 5,
FIG.lb die Kapsel 5 im Schnitt der Schnittebene A-A von FIG.la, enthaltend die Zubereitung in Form eines Faltkörpers,FIG. 1b the capsule 5 in the section of the sectional plane A-A of FIG.la, containing the preparation in the form of a folding body,
FIG.lc im Schnitt der Schnittebene A-A in FIG.la, enthaltend die Zubereitung in Form einer Rolle.FIG.lc in section A-A in FIG.la, containing the preparation in the form of a roll.
Die in FIG.la gezeigte oral applizierbare therapeutische Darreichungsform, enthaltend eine bei Kontakt mit Flüssigkeit spontan zerfallende und Wirkstoff freisetzende Zubereitung 6 ist dadurch gekennzeichnet, daß sie zur Verhinderung einer vorzeitigen Auslösung auf dem Wege von der Mundhöhle über die Speiseröhre in den Magen in Form einer Kapsel 5 mit einer Schutzhülle 1 umgeben ist.The orally administrable dosage form shown in FIG.la, containing a preparation 6 which spontaneously disintegrates upon contact with liquid and releases active substance, is characterized in that it is in the form of a to prevent premature release on the way from the oral cavity via the esophagus into the stomach Capsule 5 is surrounded by a protective cover 1.
Die Schutzhülle 1 kann eine extrem dünne Kapsel 5 auf gelatineartigem Polymer sein.The protective cover 1 can be an extremely thin capsule 5 on gelatin-like polymer.
Mit Vorteil kann die Schutzhülle 1 auch aus pH-sensitivem Material bestehen, welches sich im sauren Milieu des Magensaftes beschleunigt auflöst und die Zubereitung 6 spontan freigibt und zerfallen läßt.The protective sheath 1 can advantageously also consist of pH-sensitive material, which dissolves faster in the acidic environment of the gastric juice and spontaneously releases the preparation 6 and allows it to disintegrate.
In einer anderen Ausgestaltung kann von der Maßnahme Gebrauch gemacht sein, daß die Schutzhülle 1 aus einer Mi- chung eines wasserlöslichen fumbildenden Polymers, beispielsweise aus Hydroxypropylmethylcellulose, und einem hydrophoben Weichmacher, z.B. Rizinusöl, besteht. Auch kann die Schutzhülle 1 Maisstärke enthalten.In another embodiment, use can be made of the measure that the protective cover 1 consists of a mixture of a water-soluble film-forming polymer, for example hydroxypropylmethyl cellulose, and a hydrophobic plasticizer, e.g. Castor oil. The protective cover can also contain 1 corn starch.
Wie hierzu aus den Figuren lb und lc ersichtlich, ist die in der Kapsel 5 enthaltende Zubereitung 6 ein blattförmi- ges, Wirkstoffhaltiges Gebilde aus filmbildendem Polymer und in der Hülle 1 als Rolle 3 (FIG.lc) oder als Faltkörper 2 (FIG.lb) enthalten.As can be seen from FIGS. 1b and 1c, the preparation 6 contained in the capsule 5 is a leaf-shaped Total, active substance-containing structure made of film-forming polymer and contained in the shell 1 as a roll 3 (FIG.lc) or as a folded body 2 (FIG.lb).
Weiterhin zeigen die Figuren la und lb eine Ausbildung der Hülle 1 mit einer Aufreißhilfe in Form einer in Quer- oder Längsrichtung verlaufenden Schwächungslinie 4 bzw. 4 ' . Diese Schwächungslinien 4, 4' sind entweder als Perforationslinie oder als Versprödungslinie ausgebildet und werden entsprechend dem Verfahren nach der Erfindung nach Fertigstellung der Schutzhülle 1 bzw. der daraus gebildeten dünnen Kapsel 5 unter Verwendung eines Laserstrahles hergestellt.Furthermore, FIGS. 1 a and 1 b show an embodiment of the casing 1 with a tear-open aid in the form of a weakening line 4 or 4 ′ running in the transverse or longitudinal direction. These weakening lines 4, 4 'are designed either as a perforation line or as an embrittlement line and are produced in accordance with the method according to the invention after the protective casing 1 or the thin capsule 5 formed therefrom using a laser beam.
Bevorzugt kann die Aufreißhilfe gemäß Darstellung in den Figuren la und lb mit zwei sich kreuzenden Schwächungslinien 4, 4' ausgebildet sein. Dabei ist die Herstellung mittels Laserstrahl wirtschaftlich und unkompliziert und kann beispielsweise mit Hilfe eines pulsierenden Laserstrahles in Form von winzigen, in einer Linie nebeneinander liegenden Perforationen durchgeführt werden, oder es kann mit Hilfe des Laserstrahles die Hülle 1 für die Schwächungslinie 4 bzw. 4" durch thermische Versprödung des Materials der Hülle 1 hergestellt werden.As shown in FIGS. 1 a and 1 b, the tear-open aid can preferably be designed with two intersecting lines of weakness 4, 4 ′. The production using a laser beam is economical and uncomplicated and can be carried out, for example, with the aid of a pulsating laser beam in the form of tiny perforations lying next to one another in a line, or the envelope 1 for the weakening line 4 or 4 "can be carried out with the aid of the laser beam thermal embrittlement of the material of the shell 1 are produced.
Darüber hinaus kann nach dem Verfahren der Kapsel 5 Gas- bildner in einer Menge beigegeben werden, die zum Blähen und zerstören der Kapsel entlang der Aufreißhilfen 4, 4' reicht .In addition, 5 gas formers can be added to the capsule according to the method in an amount sufficient to expand and destroy the capsule along the tear aids 4, 4 '.
Die Erfindung ist unkompliziert und zweckmäßig und löst in optimaler Weise die eingangs gestellte Aufgabe. The invention is straightforward and expedient and optimally achieves the object stated at the outset.

Claims

A N S P R U C H E EXPECTATIONS
1. Oral applizierbare therapeutische Darreichungsform, enthaltend eine bei Kontakt mit Flüssigkeit spontan zerfallende und Wirkstoff freisetzende Zubereitung (6), dadurch gekennzeichnet, daß sie zur Verhinderung einer vorzeitigen Auflösung auf dem Wege von der Mundhöhle über die Speiseröhre in den Magen in Form einer Kapsel (5) mit einer Schutzhülle (1) umgeben ist.1. Orally administrable dosage form, containing a preparation which spontaneously disintegrates upon contact with liquid and releases active substance (6), characterized in that it is in the form of a capsule to prevent premature dissolution on the way from the oral cavity via the esophagus into the stomach ( 5) is surrounded by a protective cover (1).
2. Darreichungsform nach Anspruch 1, dadurch gekennzeichnet, daß die Schutzhülle (1) eine extrem dünne Kapsel (5) aus gelatineartigem Polymer ist.2. Dosage form according to claim 1, characterized in that the protective cover (1) is an extremely thin capsule (5) made of gelatin-like polymer.
3. Darreichungsform nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß die Schutzhülle (1) aus pH-sensitivem Material besteht, welches sich im sauren Milieu des Magensaftes beschleunigt auflöst und die Zubereitung (6) spontan freigibt und zerfallen läßt.3. Dosage form according to claim 1 or 2, characterized in that the protective cover (1) consists of pH-sensitive material which accelerates in the acidic environment of the gastric juice and the preparation (6) releases and disintegrates spontaneously.
4. Darreichungsform nach einem oder mehreren der Ansprüche 1 bis 3, dadurch gekennzeichnet, daß die Schutzhülle (1) aus einer Mixtur eines wasserlöslichen filmbildenden Polymers, beispielsweise Hydroxypropylmethylcellulose, und einem hydrophoben Weichmacher, z.B. Rizinusöl, besteht.4. Dosage form according to one or more of claims 1 to 3, characterized in that the protective cover (1) from a mixture of a water-soluble film-forming polymer, for example hydroxypropylmethyl cellulose, and a hydrophobic plasticizer, e.g. Castor oil.
5. Darreichungsform nach einem oder mehreren der Ansprüche 1 bis 4, dadurch gekennzeichnet, daß die Schutzhülle (1) Maisstärke enthält.5. Dosage form according to one or more of claims 1 to 4, characterized in that the protective cover (1) contains corn starch.
6. Darreichungsform nach einem oder mehreren der Ansprüche 1 bis 5, dadurch gekennzeichnet, daß die darin enthaltene Zubereitung (6) ein blattförmiges, wirkstoffhaltiges Gebilde aus filmbildendem Polymer ist und in der Hülle (1) als Rolle (3) oder Faltkörper (2) vorliegt. 6. Dosage form according to one or more of claims 1 to 5, characterized in that the preparation contained therein (6) is a sheet-like, active substance-containing structure made of film-forming polymer and in the shell (1) as a roll (3) or folded body (2) is present.
7. Darreichungsform nach einem oder mehreren der Ansprüche 1 bis 6, dadurch gekennzeichnet, daß die Hülle (1) zur spontanen Freigabe der Zubereitung (6) im Magen eine Aufreißhilfe in Form einer in Quer- oder Längsrichtung derselben verlaufenden Schwächungslinie (4) aufweist.7. Dosage form according to one or more of claims 1 to 6, characterized in that the envelope (1) for spontaneous release of the preparation (6) in the stomach has a tear-open aid in the form of a transverse or longitudinal direction of the same weakening line (4).
8. Verfahren zur Herstellung einer oral applizierbaren, blattförmigen Darreichungsform, umfassend eine bei Kontakt mit Flüssigkeit, insbesondere Magensaft, spontan zerfallende und Wirkstoff freisetzende Zubereitung, wobei diese als Rolle (3) oder Faltkörper (2) in eine Hülle (1) unter Ausbildung einer Kapsel (5) eingebracht wird, dadurch gekennzeichnet, daß die Hülle (1) nach Fertigstellung der Darreichungsform unter Verwendung eines Laserstrahls mit einer Aufreißhilfe in Form von wenigstens einer Schwächungslinie8. A method for producing an orally administrable, sheet-like dosage form, comprising a preparation which spontaneously disintegrates and releases active substance upon contact with liquid, in particular gastric juice, said preparation being in the form of a roll (3) or folded body (2) in a casing (1) Capsule (5) is introduced, characterized in that the shell (1) after completion of the dosage form using a laser beam with a tear-open aid in the form of at least one line of weakness
(4) versehen wird.(4) is provided.
9. Verfahren nach Anspruch 8, dadurch gekennzeichnet, daß die Schwächungslinie (4) als Perforationslinie oder Ver- sprödungslinie ausgebildet wird.9. The method according to claim 8, characterized in that the weakening line (4) is designed as a perforation line or embrittlement line.
10. Verfahren nach Anspruch 8 oder 9, dadurch gekennzeichnet, daß die Aufreißhilfe mit zwei sich kreuzenden Schwächungslinien (4, 4") ausgebildet wird.10. The method according to claim 8 or 9, characterized in that the tear-open aid with two crossing lines of weakness (4, 4 ") is formed.
11. Verfahren nach einem der Ansprüche 8 bis 10, dadurch gekennzeichnet, daß der Kapsel (5) Gasbildner in einer solchen Menge beigegeben wird, die zum Blähen und Zerstören der Kapsel entlang der Aufreißlinien (4, 4*) reicht. 11. The method according to any one of claims 8 to 10, characterized in that the capsule (5) gas generator is added in an amount sufficient to expand and destroy the capsule along the tear lines (4, 4 *).
PCT/EP1999/007940 1998-10-29 1999-10-19 Orally applicable therapeutic dosage form which spontaneously disintegrates upon contact with a liquid and method for producing the same WO2000025759A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109601670A (en) * 2019-01-22 2019-04-12 海南钟晨生物工程有限责任公司 The preparation method of aloe effervescent tablet

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITBO20110233A1 (en) * 2011-04-29 2012-10-30 I M A Ind Macchine Automatic He S P A PROCEDURE AND EQUIPMENT FOR REALIZING A SOLID FORM OF MATERIAL
WO2021198353A1 (en) * 2020-03-31 2021-10-07 Danmarks Tekniske Universitet A flexible foil for the delivery of therapeutic cargos

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3444290A (en) * 1965-02-15 1969-05-13 Biorex Laboratories Ltd Dosage unit forms for the administration of medicaments
FR2170751A5 (en) * 1972-02-03 1973-09-14 Parke Davis & Co
US3952741A (en) * 1975-01-09 1976-04-27 Bend Research Inc. Controlled release delivery system by an osmotic bursting mechanism
US4128445A (en) * 1975-12-15 1978-12-05 Hoffmann-La Roche Inc. Manufacture of pharmaceutical unit dosage forms
DE4419818A1 (en) * 1994-06-07 1995-12-14 Lohmann Therapie Syst Lts Drug carrier for the controlled release of active substances in the gastrointestinal tract with delayed pyloric passage
WO1997031747A1 (en) * 1996-02-29 1997-09-04 Merck & Co., Inc. Laser drilling process for producing a plurality of holes in chemical dosage forms using acousto-optic deflector
DE19800523A1 (en) * 1997-01-14 1998-07-30 Lohmann Therapie Syst Lts Device for controlled release of active agent in the stomach

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4339428A (en) * 1980-08-18 1982-07-13 Bristol-Myers Company Capsule product containing high dosage of aspirin in powder or granulated form and alkaline tablet or pellet comprising magnesium carbonate, calcium carbonate and a magnesium dry component
NZ233403A (en) * 1989-04-28 1992-09-25 Mcneil Ppc Inc Simulated capsule-like medicament
US5198227A (en) * 1990-01-22 1993-03-30 Mcneil-Ppc, Inc. Dual subcoated simulated capsule medicament
DE4219702A1 (en) * 1992-06-16 1993-12-23 Roemmers Sa Pharmaceutical soft capsules containing lysine clonixinate and a process for the production thereof
DE4303844A1 (en) * 1993-02-10 1994-08-11 Merck Patent Gmbh Pharmaceutical preparation
DE19500977C2 (en) * 1995-01-14 1999-01-07 Lohmann Therapie Syst Lts Solid drug form with active ingredient distributed in polymeric material
DE19648576C2 (en) * 1996-11-23 1999-08-12 Lohmann Therapie Syst Lts Lozenge for modified release of active substances in the gastrointestinal tract
FR2757173A1 (en) * 1996-12-17 1998-06-19 Warner Lambert Co POLYMERIC COMPOSITIONS OF NON-ANIMAL ORIGIN FOR FILM FORMATION

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3444290A (en) * 1965-02-15 1969-05-13 Biorex Laboratories Ltd Dosage unit forms for the administration of medicaments
FR2170751A5 (en) * 1972-02-03 1973-09-14 Parke Davis & Co
US3952741A (en) * 1975-01-09 1976-04-27 Bend Research Inc. Controlled release delivery system by an osmotic bursting mechanism
US3952741B1 (en) * 1975-01-09 1983-01-18
US4128445A (en) * 1975-12-15 1978-12-05 Hoffmann-La Roche Inc. Manufacture of pharmaceutical unit dosage forms
DE4419818A1 (en) * 1994-06-07 1995-12-14 Lohmann Therapie Syst Lts Drug carrier for the controlled release of active substances in the gastrointestinal tract with delayed pyloric passage
WO1997031747A1 (en) * 1996-02-29 1997-09-04 Merck & Co., Inc. Laser drilling process for producing a plurality of holes in chemical dosage forms using acousto-optic deflector
DE19800523A1 (en) * 1997-01-14 1998-07-30 Lohmann Therapie Syst Lts Device for controlled release of active agent in the stomach

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109601670A (en) * 2019-01-22 2019-04-12 海南钟晨生物工程有限责任公司 The preparation method of aloe effervescent tablet
CN109601670B (en) * 2019-01-22 2021-06-08 海南钟晨生物工程有限责任公司 Preparation method of aloe effervescent tablet

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