AU725108B2 - Soft gelatin capsule manufacture - Google Patents

Description

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

(ORIGINAL)

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a a a a Name of Applicant: Actual Inventors: Address for Service: Invention Title: Novartis AG AND R.P. Scherer GmbH Werner BROX Armin MEINZER Horst ZANDE DAVIES COLLISON CAVE, Patent Attorneys, 1 Little Collins Street, Melbourne, 3000 Soft gelatin capsule manufacture The following statement is a full description of this invention, including the best method of performing it known to us: Q:\OPER\PDB\2065618.189 8f7198 1A SOFT GELATIN CAPSULE MANUFACTURE This application is derived from application number 9419353.9.

This invention relates to a process for manufacturing soft gelatin capsules.

In EP-B-0 121 321 there have been disclosed soft gelatin capsules wherein at least one pharmacologically active substance has been dissolved or suspended in a liquid polyethyleneglycol, the capsule comprising gelatin, a plasticizer therefor and a compound for preventing embrittlement which compound is a mixture comprising sorbitol and at least one sorbitan. If so desired, alcohols having several hydroxyl groups are added to the capsule shell as the embrittlement-preventing compound. As polyhydric alcohols suitable for this purpose there have been mentioned glycerol, sorbitol and propyleneglycol.

Furthermore this patent specification mentions that the capsule filling may also contain such alcohols comprising several hydroxyl groups. Again glycerol, sorbitol and propyleneglycol have been described. However, it is conspicuous that in the examples glycerol has been exclusively used for the capsule filling as well as for the capsule shell. This may be due to the fact that the attempts to substitute propyleneglycol for glycerol in the capsule shell failed. Although propyleneglycol is basically suitable as a plasticizer for gelatin, in the large scale commercial manufacture of such soft gelatin capsules according to the so-called Rotary Die Process the gelatin bands, once poured onto the cooling drums, may be removed only with difficulty from the cooling drums and passed to the molding rolls where the encapsulation is effected. The reason therefor is that the gelatin bands containing propyleneglycol as the plasticizer are substantially more tacky than those containing glycerol or sorbitol as the plasticizer. This is why soft gelatin capsules having a capsule shell comprising gelatin and propyleneglycol as a plasticizer have never been introduced into practice.

In EP-B-0 257 386 there have been disclosed gelatin capsules which, in the capsule filling, contain a solvent mixture which contains at least 5% by weight of ethanol and at least 2by weight of one or more partial glycerides of fatty acids having from 6 to 18 carbon atoms.

In the description there has been mentioned that the capsule shell may contain glycerol, propyleneglycol, sorbitol and sorbitans as the plasticizer. However, again just glycerol, sorbitol and sorbitans were used in the capsule shell, because propylene glycol results in the above-described undesirable tackiness.

Since the use as a plasticizer of propyleneglycol in the capsule shell results in difficulties in the manufacture of soft gelatin capsules according to the Rotary Die Process, there was a further need for developing a process wherein the manufacture of soft gelatin capsules according to the Rotary Die Process is possible even in the case where the capsule shell contains a component which leads to tackiness, e.g. 1,2-propyleneglycol.

We have found surprisingly by cooling the cooling drum with a liquid coolant it is possible to eliminate or at least to suppress the troublesome tackiness observed, and a commercially feasible manufacture of such soft gelatin capsules is possible.

In one aspect the present invention provides a process for manufacturing soft gelatin :::::capsules having a capsule shell comprising gelatin and a component which leads to tackiness, wherein the gelatin is in the form of bands, wherein cooling of the gelatin bands to form the capsule shell is effected using a liquid coolant. Preferably, but not necessarily, g" the component which leads to tackiness is a migrateable component.

Typical migrateable components include non-volatile pharmaceutically acceptable solvents which are capable of mixing with, or forming a solid solution with, the gelatine. As mentioned above glycerol is mentioned in the above EP-B-0-121321. However, glycerol is not a particularly good solvent, and in general does not lead to tackiness. Glycerol may of course also be present as described hereinafter.

Typical migrateable solvents include tetrahyrofurylalcohol ethers, e.g. glycofurol diethylene glycol mono ethyl ether, e.g. transcutol, 1,3-dimethyl-2-imidazolidinone, dimethylisosorbide, polyethylene glycol of molecular weight from 200 to 600) and preferably propylene glycol or solvents having similar migration capability. Preferably, the concentration of the migrateable component in the capsule shell is chosen to be so high that an approximately stable equilibrium of the concentrations between the capsule shell and the capsule filling is established soon after encapsulation. During the equilibration phase the migrateable component may migrate from the capsule shell into the capsule filling (thereby increasing its concentration in the capsule filling and decreasing it in the gelatine shell), but migration of the migrateable component into the capsule shell from the capsule filling is significantly reduced.

In one embodiment of the invention the carrier filling at least partially is 1,2propyleneglycol, but not predominantly polyethyleneglycol.

S In another aspect this invention provides a process for manufacturing soft gelatin capsules having a capsule shell comprising gelatin, plasticizers and, if desired or required, further auxiliary agents, and a capsule filling containing a solvent, wherein the solvent at least partially is 1,2propyleneglycol, but not predominantly polyethyleneglycol, the capsule shell contains 1,2propyleneglycol, and a drum is adapted for guiding and cooling the bands, wherein the drum contains a liquid coolant.

The process of this invention may be employed to produce a capsule having a capsule filling which comprises a cyclosporin, e.g. cyclosporin A, or a macrolide as pharmaceutically active substance.

4 The term gelatin as used herein includes not only unmodified gelatin as in the European Pharmacopeia and NF but also modified gelatin such as succinated gelatin.

The process according to the invention is basically carried out in the same manner as usual in accordance with the Rotary Die Process as described in greater detail, inter alia, in Lachmann et al., "The Theory and Practice of Industrial Pharmacy", 2nd Edition, pages 404-419. It is apparent from Figure 13-9 and its description in page 414, right column, last paragraph, that the gelatin band is passed over an air-dried rotating drum. The temperature of the cold air was reported to be 56 °F to 58 corresponding to 13.3 °C to 14.4 but this only inefficiently cools the gelatine.

*In the accompanying Figure 1 A represents a cooling apparatus for the cooling medium B shows the feed flow of the cooling medium C represents gelatine D represents the spreader box E represents the cooling drum F represents the gelatine band G indicates the direction of rotation of the cooling drum 5 H represents the gelatine band take-off, and I shows the return flow of the spent cooling medium In another aspect the invention provides a cooling drum for cooling gelatin bands to form soft gelatine capsule shells wherein the drum is adapted with means for cooling the drum surface using a liquid coolant e.g. water. The cooling drum may be in association with a machine for producing soft gelatine capsules.

According to the invention, the cooling drum as shown in the attached schematic figure is cooled with a liquid coolant, with water being particularly preferred as the coolant, and being administered at such a rate that it can remove large quantities of heat quickly to provide a rapid and thorough cooling of the gelatin bands.

The gelatine bands conveniently have a temperature of about 65°C when they contact the cooling drum. The bands may be better and more evenly cooled by the cooling drum according to the invention than an air-cooled cooling drum.

The gelatine bands stick less strongly to the cooling drum according to the invention and after the bands have been cooled to about 20*C they may be easily removed from the cooling drum.

This results not only in a better, but also in a more uniform cooling of the gelatin bands.

The preferred temperature of the coolant water, may be about 15 to 20'C, in comparison with from 20 *C to 22 *C for gelatin bands in the absence of 1,2-propyleneglycol. For example gelatin bands comprising 10% of such a component, e.g. 1,2-propyleneglycol (corresponding to Examples 1 and 3 hereinafter) preferred temperatures are from 18 *C to 'C and for gelatin bands comprising 21% of such a component (corresponding to Example 2) it is even lower, i.e. from 16 *C to 18 *C.

The temperature of the cooling medium may be thermostatically controlled precisely e.g.

with a cryostat.

P:\OPER\PDB\75112-98.202.doc-20/07/00 -6- Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

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Claims (10)

1. A process for manufacturing soft gelatin capsules having a capsule shell comprising gelatin and a component which leads to tackiness, wherein the gelatin is in the form of bands, wherein cooling of the gelatin bands to form the capsule shell is effected using a liquid coolant.

2. A process according to claim 1 wherein the component which leads to tackiness is a migrateable component. I 3. A process according to claim 2 wherein the migrateable component comprises tetrahydrofurfurylalcohol ethers, 1,3-dimethyl-2-imidazolidinone, dimethylisosorbide, polyethylene glycol and propylene glycol.

4. A process according to claim 3 wherein the migrateable component comprises propylene glycol.

5. A process according to any one of claims 2 to 4 for producing a capsule having a capsule filling wherein the concentration of the migrateable component in the capsule shell is chosen to be so high that an approximately stable equilibrium of the concentrations -between the capsule shell and the capsule filling is established soon after encapsulation.

6. A process according to claim 5 wherein the filling is at least partially 1,2- propyleneglycol, but not predominantly polyethyleneglycol.

7. A process according to claim 1 for manufacturing soft gelatin capsules having a capsule shell comprising gelatin, plasticizers and, if desired or required, further auxiliary agents, and a capsule filling containing a solvent, wherein the solvent at least partially is 1,2-propyleneglycol, but not predominantly polyethyleneglycol, the capsule shell contains 1,2-propyleneglycol, and a drum is adapted for guiding and cooling the bands, wherein the S drum contains a liquid coolant. P:\OPER\PDB\75112-98.202.doc.21/0700 -8-

8. A process as claimed in any preceding claim for producing a capsule having a capsule filling which comprises a cyclosporin or macrolide as pharmaceutically active substance.

9. A process as claimed in claim 8 wherein the cyclosporin is cyclosporin A. A process according to any preceding claim wherein water is used as the coolant.

11. A process according to claim 7 wherein the gelatine bands have a temperature of about 65 0 C when they contact the cooling drum. 12 Capsules produced by the process of any preceding claim.

13. A process according to claim 1 substantially as hereinbefore described with reference to the drawing. DATED this 2 0 th day of July 2000 R. P. Scherer GmbH and Novartis AG by their Patent Attorneys DAVIES COLLISON CAVE