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WO1996008236A1 - Capsules a revetement interne hydrophobe, destinees a contenir des solutions aqueuses (radioactives) adsorbees par une matrice et procede de fabrication de telles capsules - Google Patents

Capsules a revetement interne hydrophobe, destinees a contenir des solutions aqueuses (radioactives) adsorbees par une matrice et procede de fabrication de telles capsules Download PDF

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Publication number
WO1996008236A1
WO1996008236A1 PCT/EP1995/003390 EP9503390W WO9608236A1 WO 1996008236 A1 WO1996008236 A1 WO 1996008236A1 EP 9503390 W EP9503390 W EP 9503390W WO 9608236 A1 WO9608236 A1 WO 9608236A1
Authority
WO
WIPO (PCT)
Prior art keywords
capsule
capsules
capsule according
wax
matrix
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP1995/003390
Other languages
German (de)
English (en)
Inventor
Vaclav Endrst
Burkhard Haase
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nuclear Research Institute Rez PLC
Hoechst AG
Original Assignee
Nuclear Research Institute Rez PLC
Hoechst 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 Nuclear Research Institute Rez PLC, Hoechst AG filed Critical Nuclear Research Institute Rez PLC
Publication of WO1996008236A1 publication Critical patent/WO1996008236A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1262—Capsules
    • 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
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells

Definitions

  • the invention relates to capsules for receiving radioactive substances, possibly matrix-adsorbed aqueous radioactive solutions.
  • Capsules of this type consist of a lower part (sleeve) and a cap and are used to hold pharmaceutically active substances which are intended for oral or rectal use.
  • the material of the capsules must be biologically harmless and must dissolve in aqueous solutions to release the pharmaceutically active substances. They are preferably made of hard gelatin. This means that only non-aqueous substances can be introduced into these capsules, usually in the form of powders or granules, since otherwise the capsule wall is deformed and destroyed (dissolved) under the action of water.
  • aqueous solutions in a hard gelatin capsule is to fill a matrix before filling the aqueous solution to add that absorbs water.
  • Any water-absorbing, chemically inert and biologically harmless substance can be used as a matrix, such as, for example, anhydrous, neutral, acidic or alkaline phosphate, which may be diluted with small amounts of highly disperse silicon dioxide (eg Aerosil).
  • silicon dioxide eg Aerosil
  • WO 93/1 4 788 such and other matrix materials are used in combination with antioxidants (eg thiosulfate, ascorbic acid, reducing sugars) in order to prevent the evaporation of activity (eg 1-1 31).
  • the object was therefore to make hard gelatin capsules more dense in order to prevent volatile radioactivity from evaporating off in the case of corresponding preparations, in particular when aqueous solutions are filled into the capsules.
  • Particularly vaporizing, radioactive iodine is a problem during the packaging, storage and preparation of the therapeutic measures in the nuclear medicine clinic.
  • the development of a practically gastight sealable hard gelatin capsule that does not require the addition of radioactive iodine-stabilizing chemical reducing agents also desirable.
  • the solution to the problem is that the inner surfaces of the capsules, both the sleeve and the cap, are completely coated with a hydrophobic layer.
  • the hydrophobic layer consists essentially of a wax-like, neutral material (eg hard fat). Its melting point is preferably below 37 ° C., further preferably 28 ° C. to 37 ° C., particularly preferably 33 ° C. to 36 ° C. This ensures that the protective layer formed by the wax-like, neutral material is solid at room temperature and thus acts as a seal, while at body temperature (approx. 37 ° C) this layer melts and the absorption of the drug after dissolving the hard gelatin - Capsule can use.
  • the hard fat is not soluble in water, is hardly soluble in anhydrous ethanol, but is slightly soluble in diethyl ether. When heated above the melting point, the white, brittle hard fat should melt into a colorless, possibly slightly yellowish liquid.
  • a hard fat is preferred here, which can be characterized individually and / or in combination with one another by the following parameters: acid number 0.5 g, saponification number 225-245, hydroxyl number ⁇ 50, iodine number ⁇ 3 iodine color number ⁇ 3, unsaponifiable fraction ⁇ 0.5% .
  • the hard fat Witepsol H 1 5 ⁇ (DAB9, Ph. Eur. 2. USP XXI, manufacturer Dynamit Nobel AG, Witten) is particularly preferred.
  • the advantages of the hard gelatin capsules according to the invention with the hydrophobic layer are that the layer has no significant influence on the bioavailability of the preparation (pharmaceuticals).
  • aqueous solutions in hard gelatin capsules can now also be filled with this protective layer, the aqueous solution being absorbed by the Metrix.
  • the capsule wall therefore no longer deforms in the presence of the protective layer.
  • the protective layer is compatible with all common matrix materials and antioxidants, so that even if a hydrophobic protective layer is present, the matrix can be filled in the capsule next to the preparation.
  • hard gelatin capsules according to the invention are also gas-tight.
  • no noticeable amounts of 1-1 31 emerge from commercially available hard gelatin capsules, which have the hydrophobic protective layer according to the invention, provided preparations with 1-131 are contained.
  • the tightness of such a capsule corresponds to at least one that contains the same preparation in an iodine-stabilizing matrix.
  • the invention further relates to a method with which commercially available capsules for storing pharmaceutical preparations have been provided with the hydrophobic layer.
  • the material preferably the hard fat
  • the hard fat is reduced to approx. Heated 50 ° C and coated the inside of the capsule with the melt.
  • the melt can be applied by spraying, brushing, painting and pouring. If the capsule halves are poured with the melt of the hard fat, the excess fat is sucked off again before cooling.
  • the hard gelatin capsule halves are ready for use immediately after the protective layer has solidified, i.e. for filling with the respective preparations or matrices.
  • the invention relates to the use of the capsules according to the invention with a hydrophobic protective layer as a drug container, the tightness of which has to be guaranteed without the bioavailability being significantly impaired.
  • the encapsulation of malodorous substances, oxidation-sensitive substances, substances with higher vapor pressure, radioactive substances are particularly important and highlight aqueous solutions.
  • the capsules according to the invention can contain both orally and rectally absorbable substances, since they can be used orally and rectally.
  • coated capsule is of particular importance as a container for aqueous, radioactive solutions which are used for diagnostics or therapy, for. B. for the l-1 31 therapy capsule for the treatment of thyroid carcinoma and similar diseases.
  • the individual capsules were stored in closed lead containers containing an activated carbon plate. After the respective incubation time, 24 hours or 4 days, the activity on the activated carbon slide, which absorbs the emerging 1-131 activity well, was determined by measuring the pulse rates in a borehole.
  • the results of this series of experiments with or without pretreatment of the capsules according to the invention can be found in Table 1.
  • the capsules 1 -5 were produced without the hydrophobic layer according to the invention.
  • the capsules 6-20 are made with the layer according to the invention, their 1-1 31 losses are about 1000 times less. In absolute terms, the 1-131 evaporation rate within the 4-day incubation period is only 0.001% of the nominal radioactivity of the capsules
  • Table 2 shows the results of the 1-31 losses in a series of 1-31 therapy capsules from routine production. The evaporation rates are only 0.001% of the nominal activity. The capsules are all lined with the hydrophobic protective layer according to the invention.
  • Table 3 shows a comparison between the currently customary formulations of commercially available preparations of the l-1 31 therapy capsule with the l-1 31 therapy capsule according to the invention.
  • Capsule 1 is made according to the invention.
  • Capsule 2 contains 10% sodium thiosulfate as a reducing agent, which is to prevent the formation of free 1- 1
  • capsule 3 contains 10% sodium thiosulfate and 10% sucrose, in each case based on the basic matrix of di-sodium hydrogen phosphate, to increase the I-1 31 - Stability.
  • the iodine evaporation rate of the commercial capsules containing a reducing agent is equal to or higher than that of the capsule which has been produced according to the invention.
  • the addition of reducing agents in the matrix can be completely eliminated.
  • Hard gelatin capsules were used in all cases (type Con. Snap. Gr. 1, from Capsugel).
  • Witepsol H 1 5 ⁇ was used as hard fat only in the capsule according to the invention.
  • the respective layer thickness averaged 0.1 to 0.3 mm, preferably approximately 0.2 mm.
  • the capsules according to the invention were produced as follows:
  • Both halves of the hard gelatin capsules are lined with Witepsol hard fat H1 5 from the inside to protect the hard gelatin from moisture and to ensure an almost gas-tight seal of the capsule halves.
  • the Witepsol is first heated in a glass storage vessel on a heating block or in a drying cabinet to approx. 60 ° C (1 5 minutes preparation time). At the same time, a heating finger is activated within approx. 1 0 minutes preheated to its operating temperature, approx. 50 ° C.
  • Approx. 100 capsule halves are positioned in a suitable holder for the capsule halves.
  • Approx. 25 ⁇ ⁇ of liquid Witepsol hard fat H1 5 are dosed into each capsule cap, and approx. 60 ⁇ l into each capsule sleeve.
  • the capsule sleeves are positioned in a special device with horizontally rotating sleeve holders (speed approx. 25-40 rpm; up to 10 capsule sleeves can be coated at the same time).
  • a heating finger a uniform, thin Witepsol film is created in the capsule shells. After a short rotation time (approx. 3 minutes) the Witepsol solidifies to a matt-appearing layer.
  • the further steps for the production of the l-1 31 therapy capsule take place in a suitably shielded lead castle, which is equipped with long-distance grippers.
  • the capsules are loaded with I-1 31 activity in specially developed locking receptacles (take up the sleeve and cap), which enable exact positioning to close the two capsule halves.
  • Both parts of the closure receptacles, each equipped with the corresponding capsule halves, are introduced into the lead castle.
  • the capsule sleeves are then mixed with the required volume of activity.
  • the closure receptacles are now put together.
  • the capsule is sealed gas-tight by a locking pin.
  • the closing pressure is about 2 kpm.
  • the sealed capsule is transferred from the closure holder into a measuring glass vial, the radioactivity of the respective 1-1 31 capsule is measured in an ionization chamber and then transferred to a suitable transport shield.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Dispersion Chemistry (AREA)
  • Optics & Photonics (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des capsules à revêtement interne hydrophobe, destinées à contenir des solutions de préférence radioactives, constituées respectivement par une partie inférieure (manchon) et par une partie supérieure (coiffe), les surfaces intérieures desdites capsules étant complètement enduites d'un matériau neutre de type cireux. Les capsules selon l'invention sont utilisées de préférence comme récipients pour médicaments pour des solutions aqueuses radioactives à usage thérapeutique ou diagnostique.
PCT/EP1995/003390 1994-09-13 1995-08-28 Capsules a revetement interne hydrophobe, destinees a contenir des solutions aqueuses (radioactives) adsorbees par une matrice et procede de fabrication de telles capsules Ceased WO1996008236A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4432557.6 1994-09-13
DE19944432557 DE4432557A1 (de) 1994-09-13 1994-09-13 Kapseln mit innenseitig hydrophober Beschichtung zur Aufnahme von matrixadsorbierten wäßrigen (radioaktiven) Lösungen und Verfahren zur Herstellung obiger Kapseln

Publications (1)

Publication Number Publication Date
WO1996008236A1 true WO1996008236A1 (fr) 1996-03-21

Family

ID=6528086

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1995/003390 Ceased WO1996008236A1 (fr) 1994-09-13 1995-08-28 Capsules a revetement interne hydrophobe, destinees a contenir des solutions aqueuses (radioactives) adsorbees par une matrice et procede de fabrication de telles capsules

Country Status (2)

Country Link
DE (1) DE4432557A1 (fr)
WO (1) WO1996008236A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115813878A (zh) * 2022-12-09 2023-03-21 浙江省食品药品检验研究院 一种隔水涂层溶液及制备隔水胶囊的应用

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996040083A2 (fr) * 1995-06-07 1996-12-19 R.P. Scherer Corporation Procedes et compositions pour preparer des gelules molles de gelatine presentant des enveloppes resistant a l'infiltration par des substances de remplissage

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2140177A1 (de) * 1971-08-11 1973-02-22 Hoechst Ag Oral applizierbare, radioaktives jod enthaltende kapsel zur schilddruesenfunktionsdiagnostik und verfahren zu ihrer herstellung
JPS62263128A (ja) * 1986-05-08 1987-11-16 Freunt Ind Co Ltd 腸内有用細菌含有カプセル

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2140177A1 (de) * 1971-08-11 1973-02-22 Hoechst Ag Oral applizierbare, radioaktives jod enthaltende kapsel zur schilddruesenfunktionsdiagnostik und verfahren zu ihrer herstellung
JPS62263128A (ja) * 1986-05-08 1987-11-16 Freunt Ind Co Ltd 腸内有用細菌含有カプセル

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch Week 8751, Derwent World Patents Index; Class B04, AN 87-359742 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115813878A (zh) * 2022-12-09 2023-03-21 浙江省食品药品检验研究院 一种隔水涂层溶液及制备隔水胶囊的应用

Also Published As

Publication number Publication date
DE4432557A1 (de) 1996-03-14

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