Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2000-10-17
2003-04-29
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S452000, C424S455000, C424S456000, C424S458000, C514S183000, C514S291000
Reexamination Certificate
active
06555132
ABSTRACT:
The present invention relates to soft gelatin capsules having a capsule shell made of gelatin, plasticizing agents, in particular 1,2-propylene glycol, and optionally further auxiliary materials, and a capsule filling containing solvent, adjuvants and one or more pharmacologically active substances. The invention further relates to a process for preparing such soft gelatin capsules.
Some pharmacologically active substances may have biopharmaceutical and/or physicochemical properties which make them difficult to formulate into commercially acceptable formulations. Such substances may however be conveniently administered in liquid form, e.g. in a complex carrier medium made up of several components. Solvents such as 1,2-propylene glycol and dimethyl isosorbide have great potential in such carrier media. The carrier medium may be designed to form an emulsion in the stomach thereby facilitating absorption of the pharmacologically active substance. The carrier medium may have to be accurately prepared and even slight variations in the composition cannot be tolerated without irreversibly upsetting the system, and destroying its beneficial properties. Thus the solubilizing properties of the capsule filling may be changed and the active substance precipitates out. This precipitation process may be irreversible, and the patient is under-dosed. The emulsifying properties of the capsule filling may be changed, and, upon administration, an emulsion may not be formed in the stomach and the pharmacologically active substance is not correctly or reproducibly absorbed.
Encapsulation of such liquid formulations in soft gelatine capsules potentially offers a very convenient way of administering such pharmacologically active substances. However the manufacture of commercially acceptable liquid filled soft gelatine capsules is fraught with difficulties which restricts the availability of this approach. Thus, during manufacture, the capsule shell is formed from wet gelatine bands and the resultant wet capsules are dried. During this stage or even afterwards, we have found that components in the capsule filling may migrate into the capsule shell, and vice versa, thereby changing the composition of the capsule filling at least in the boundary region near the interface of the capsule filling and the capsule shell, with the result that the beneficial properties of the capsule filling are lost.
In recent years microemulsion pre-concentrates have been developed as carrier media for active substances which are sparingly soluble in water, which microemulsion pre-concentrates exhibit a distinct improvement in the bioavailability. Examples of such microemulsion pre-concentrates have been described, for example, in the UK patent application No 2 222 770 A (equivalent to DE-A-39 30 928) for the active substance cyclosporin. Microemulsion pre-concentrates consist of a hydrophilic phase, a lipophilic phase and a surface-active agent. As the hydrophilic phase there has been expressly mentioned and also used in the examples propyleneglycol, and more specifically 1,2-propylene-glycol. UK patent application No 2 222 770 A mentions, as an application form of the microemulsion pre-concentrates in addition to hard gelatin capsules, also soft gelatin capsules as well as other parenteral or topically applicable forms; cf. page 13, lines 16-25. We have found that microemulsion pre-concentrates comprising 1,2-propyleneglycol as the hydrophilic phase in soft gelatin capsules are prone to the migration of the 1,2-propyleneglycol into the capsule shell from the capsule filling. Not only softening of the capsule shell occurred, but also a destruction of the microemulsion pre-concentrates, because the hydrophilic component was withdrawn therefrom.
Since propyleneglycol, and more specifically 1,2-propyleneglycol, is a good hydrophilic solvent, it would be desirable to employ this solvent also for the preparation of capsule fillings. It is true, it is readily possible to produce such gelatin capsules wherein, for example, glycerol or sorbitol are used as the plasticizer for the capsule shell. However, such soft gelatin capsules are not stable, since with the lapse of time the propyleneglycol migrates into the capsule shell from the capsule filling so that the capsules will become weak.
Furthermore, such softened capsules will undergo deformation, because due to the migration of part of the solvent into the capsule shell from the capsule filling there will be a decrease in volume and a reduction in pressure in the interior of the capsule.
We have now found that the migration of, e.g. 1,2-propyleneglycol, may be hindered by using this component in the gelatine band composition with the result that it is present in the capsule shell. However we also experienced difficulties in the commercial manufacture of soft gelatine capsules containing 1,2,propylene glycol.
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 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 20% by 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.
Therefore, the present invention provides soft gelatin capsules which include a capsule shell comprising gelatin, plasticizers and, if desired or required, further auxiliary mate
Brox Werner
Meinzer Armin
Zande Horst
Haghighatian M.
Hartley Michael G.
Novartis AG
Thallemer John D.
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