WO1996008236A1

WO1996008236A1 - Capsules with internal waterproof coating for containing matrix-adsorbed aqueous (radioactive) solutions and method of preparing said capsules

Info

Publication number: WO1996008236A1
Application number: PCT/EP1995/003390
Authority: WO
Inventors: Vaclav Endrst; Burkhard Haase
Original assignee: Nuclear Research Institute Rez Plc
Priority date: 1994-09-13
Filing date: 1995-08-28
Publication date: 1996-03-21
Also published as: DE4432557A1

Abstract

The invention concerns capsules with an internal waterproof coating for containing preferably radioactive solutions, said capsules comprising a lower part (sleeve) and an upper part (cap), the internal surfaces of the capsules being completely covered with a waxy neutral material. The capsules according to the invention are preferably used as drugs containers for aqueous radioactive solutions for diagnostic or therapeutic purposes.

Description

description

Capsules with a hydrophobic coating on the inside for receiving matrix-adsorbed aqueous (radioactive) solutions and process for producing the above capsules

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.

To reduce sensitivity to water, stabilizing substances have been added to the gelatin in the past, i.e. into the capsule wall, which allowed the filling of syrupy and pasty substances. However, even with these capsules, the filling of aqueous solutions is fundamentally at risk of damage to the capsule. This is particularly critical when a particularly tight closure of the capsule is required, e.g. when the actual active substance is volatile or has a high vapor pressure. This is the case with radioactive iodine, for example, which must not evaporate into the environment.

One possibility for taking up 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). In 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).

This situation was in need of improvement since these measures are ineffective for substances with high vapor pressure.

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. For this reason, 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 5ε} (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).

Furthermore, 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. However, 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.

It was surprising that the hard gelatin capsules according to the invention are also gas-tight. Thus, 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. For this purpose, the inside of the capsule halves (sleeve and Cap) with a thin covering, preferably with a thickness of 0.01 to 0.5 mm.

Here, the material, preferably the hard fat, is melted. In particular, 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.

Furthermore, 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.

The above-mentioned, 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.

In the following test series are described, which the suitability of the

Prove invention.

Since 1-131 is very well detectable, all optimization attempts with aqueous l-1 31 solutions without iodine-stabilizing matrix (dosing volume see

Tables). Leaking capsules emerge in the course of a 24-hour or 4-day waiting period after the production of the radioactive ones

Capsules of different amounts of 1-1 31.

The less 1-1 31 emerges from the respective capsule type, the denser it is Capsule. 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 31, 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. It can be seen that 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. In the capsule 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 ^{φ 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:

Preparation of Witepsol hard fat H 1 5 ^*

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.

Coating the capsule halves with Witepsol hard fat H 1 5

Since the hard gelatin capsules are sensitive to moisture, gloves must be worn during all work steps.

Approx. 100 capsule halves are positioned in a suitable holder for the capsule halves. Approx. 25 μ \ of liquid Witepsol hard fat H1 5 are dosed into each capsule cap, and approx. 60 μl into each capsule sleeve. With the preheated heating finger, the Witepsol in the capsule cap is evenly distributed into a thin film. 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). Using 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.

Filling the capsule lower parts (sleeves) with disodium hydrogen phosphate The capsule shell lined with Witepsol hard fat H 1 5 is (bottom part) filled with disodium hydrogen phosphate and compressed. A hollow cone is then punched into the compressed phosphate powder with a stuffing mandrel to ensure faster and more uniform water absorption when filling the 1-131 solution.

Preparations for filling the l-1 31 activity solution

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.

Bottling of the 1- 1 31 activity solution

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.

Close the capsule

After filling the l-1 31 solution into the capsule sleeve (lower part), 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. Table 1

No. dosing volume nominal activity incubation time pulse rate per (in Bq) (in days) minute (Ipm) on the carbon filter plate

1 50 2 x 10 ⁸ 1 x 10 ⁷

2 50 2 x 10 ⁸ 1 x 10 ⁷

3 50 2 x 10 ⁸ 5 x 10 ⁶

4 50 2 x 10 ⁸ 3 x 10 ⁴

5 50 2 x 10 ⁸ 1 x 10 ⁷

6 50 2 x 10 ⁸ 4 5 x 10 ³

7 50 2 x 10 ⁸ 4 5 x 10 ³

8 50 2 x 10 ⁸ 4 3 x 10 ³

9 50 2 x 10 ⁸ 4 3 x 10 ³

10 50 2 x 10 ⁸ 4 8 x 10 ³

Table 2

No. dosing volume nominal activity incubation time pulse rate per (in l) (in Bq) (in days) minute (Ipm) on the carbon filter plate

1 15 7 x 10 ⁷ 4 3 x 10 ³

2 50 3 x 10 ⁸ 4 1 x 10 ³

3 86 4 x 10 ⁸ 4 3 x 10 ²

4 14 6 x 10 ⁸ 4 2 x 10 ³

5 50 2 x 10 ⁹ 4 2 x 10 ³

6 83 4 x 10 ⁹ 4 1 x 10 ³

7 14 7 x 10 ⁷ 4 4 x 10 ²

8 49 3 x 10 ⁸ 4 2 x 10 ²

9 95 5 x 10 ⁸ 4 1 x 10 ³

10 12 6 x 10 ⁸ 4 7 x 10 ²

11 50 2 x 10 ⁹ 4 2 x 10 ²

12 84 4 x 10 ⁸ 4 4 x 10 ²

Table 3

1 83 4x 10 ⁹ 4 1 x 10 ³

2 86 4 x 10 ⁹ 4 7 x 10 ⁴

3 86 4 x 10 ⁹ 4 9 x 10 ²

Claims

claims

1 . Capsules for receiving substances, consisting of a lower part (sleeve) and an upper part (cap), characterized in that the inner surfaces of the capsule are completely covered with a hydrophobic layer.

2. Capsule according to claim 1, characterized in that the hydrophobic layer contains a wax-like neutral material.

3. Capsule according to claim 2, characterized in that the wax-like neutral material has a melting point of below 37 ° C, preferably from 28 ° C to 37 ° C.

4. Capsule according to claims 2 and 3, characterized in that the wax-like neutral material has no significant influence on the bioavailability of a preparation in the capsule.

5. Capsule according to one or more of claims 1 to 4, characterized in that the capsules themselves consist of hard gelatin.

6. Capsule according to one or more of claims 2 to 4, characterized in that the protective layer is compatible with matrix materials and antioxidants.

7. Capsule according to one or more of claims 2 to 4 and 6, characterized in that the wax-like neutral material is applied in a layer thickness of 0.01 to 0.5 mm on the inside of the capsule halves.

8. Capsule according to one or more of claims 1 to 7, characterized in that in the capsule a preparation in the form of powders, Granules or contained as a matrix-adsorbed aqueous solution.

9. Capsule according to claim 8, characterized in that the filled aqueous solution contains 1- 1 31.

10. Capsule according to claims 8 and 9, characterized in that it contains an active ingredient and a matrix.

1 1. A method of coating the capsule according to one or more of claims 1 to 10, characterized in that the capsule halves (sleeve and capsule) are positioned in a suitable holder, a sufficient amount of the wax-like neutral material is applied to the capsule halves and then the excess wax-like material is removed, a uniform thin film of the wax being produced after the material has solidified.

12. Use of the capsule according to claims 1 to 10 as a pharmaceutical container for orally or rectally absorbable substances.

13. Use of the capsule according to claims 1 to 10 as a pharmaceutical container for aqueous, radioactive solutions in diagnostics or therapy.