Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
1999-11-16
2002-03-05
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S455000, C424S456000
Reexamination Certificate
active
06352717
ABSTRACT:
BACKGROUND OF THE INVENTION
Owing to their special properties and advantages, gelatin capsules are used widely in the pharmaceutical industry. They can be applied as an oral dosage form, as a suppository dosage form for rectal use or for vaginal use, as a specialty package in tube form, for human and veterinary single dose application, in the cosmetic industry etc. Their capsule shell is basically composed of gelatin and water; it may contain additional ingredients such as plasticisers, preservatives, colouring and opacifying agents, flavouring, sugars, acids, and medicaments to achieve desired effects.
Gelatin capsules can be used to dispense a variety of different active compounds. Several advantages of gelatin capsules derive from the fact that the drug may be a liquid or at least dissolved, solubilised, or suspended in a liquid vehicle. Since the capsule fill mass is metered into individual capsules by a positive-displacement pump, a much higher degree of reproducibility is achieved than is possible with powder or granule feed in the manufacture of tablets and powder or granule filled hard gelatin capsule products. The biopharmaceutical availability of drugs formulated as liquid filled gelatin capsules, as measured by disintegration time or dissolution rate, often shows an advantage over other solid dosage forms. The biopharmaceutical characteristics of such formulations can be altered or adjusted more easily than those of other dosage forms. Through the selection and use of liquids and combinations of liquids that range from water immiscible through emulsifiable to completely water-miscible, and by altering the type or quantity of thickening or suspending agents, capsule formulations allow more flexibility in the design of a dosage form to fit biopharmaceutical specifications of a particular therapeutic agent.
Mainly, two different kinds of gelatin capsules are commonly used, i.e. soft and hard gelatin capsules.
Several processes are known in the art for producing soft gelatin capsules. The most important is the rotary die process, which is a continuous flow process developed by Scherer first in 1933 (J. P. Stanley,
The Theory and Practice of Industrial Pharmacy,
3
rd
Ed., 1986, p 398-412).
According to this process, the gelatin mass is fed by gravity to a metering device (spreader box), which controls the flow of the mass onto air-cooled rotating drums. Gelatin ribbons of controlled thickness are therefore formed. The ribbons are fed through a lubricating bath, over guide rolls, and then down between an injection wedge (for the fill material) and die rolls. The material to be encapsulated, which has been previously mixed and stored, flows by gravity into a positive displacement pump. The pump accurately meters the material through a leads and the wedge and into the gelatin ribbons between the die rolls. The capsule is about half sealed when the pressure of the pumped material forces the gelatin into the die pockets, where the capsules are simultaneously filled, shaped, hermetically sealed and cut from the gelatin ribbon. The sealing of the capsule is achieved by mechanical pressure on the die rolls and the heating of the ribbons by the wedge. All fill masses (e.g. liquids, solutions, and suspensions) for encapsulation should preferably flow at room temperature and in any case at a temperature not exceeding 35° C. at the point of encapsulation, since the sealing temperature of the gelatin films must remain below this temperature.
Several types of filling machines for hard gelatin capsules are known in the pharmaceutical industry (Larry L. Augsburger, Hard and Soft Shell Capsules, Modern Pharmaceutics, G. S. Banker, C. T. Rhodes (Eds.), Third Edition, Marcel Dekker Inc. (1996), 395-428).
The liquid fill mass can be prepared as described for the soft gelatin capsules process. The empty capsules, comprising a cap and a body portion, are oriented so that all point in the same direction (i.e. body-end downward). In general the capsules pass one-at-a-time through a channel just wide enough to provide a frictional grip at the cap end. A specially designed blade pushes against the capsule and causes it to rotate about its cap end as a fulcrum. After two pushes (one horizontally and one vertically downward), the capsules will always be aligned body-end downward, regardless of which end entered the channel first. At this point the caps are separated from the bodies. Here, the rectified capsules are delivered body-end first into the upper portion of split bushings or split filling rings. A vacuum applied from below pulls the bodies down into the lower portion of the split bushing. The diameter of the caps is too large to allow them to follow the bodies into the lower bushing portion. The split bushings are then separated to expose the bodies for filling. The body portion of the capsule can be thus filled with the fill mass which cannot exceed a temperature of 60° C. The cap and body bushing portions are rejoined wherein pins are used to push the filled bodies up into the caps for closure, and to push the closed capsules out of the bushings. Compressed air also may be used to eject the capsules. If necessary, hard gelatin capsules may be made hermetically by e.g. banding (i.e. layering down a film of gelatin, often distinctively colored, around the seam of the cap and body).
Using the above mentioned processes, however, it has been unfortunately found that shear sensitive fill masses can totally or partially solidify before being encapsulated, or even in the capsules upon storage. The solidification of the fill mass or of one or more components thereof is due to mechanical phenomena, such as the shear stress, which occurs at various points of the manufacturing process. The most critical points of the process involve the mixing vessels and the pumps, wherein the shear stress dramatically increases with increasing viscosity of the fill mass.
This total or partial solidification can cause significant and unacceptable changes in the pharmaceutical quality of the product like, for example, reduction and variability of the capsules dissolution rate, and hence the bioavailability of the drug substance and the therapeutic effects of the drug.
SUMMARY OF THE INVENTION
The present invention provides a process for encapsulating a shear sensitive fill mass into a capsule, comprising the following steps in order:
a) providing a shear sensitive fill mass comprising an agent taken from the group consisting of pharmaceutical active agents and nutrients;
b) heating the fill mass;
c) cooling the fill mass; and
d) encapsulating the fill mass into the capsule essentially immediately after said cooling.
The present invention provides a capsule containing a shear sensitive fill mass which comprises an agent selected from the group fo pharmaceutically active agents and nutrients, wherein the fill mass is encapsulated in accordance with the above process.
The present invention also provides a capsule containing a shear sensitive fill mass which comprises an agent selected from the group of pharmaceutically active agents and nutrients, wherein the capsule has a constant dissolution rate of at least 70% of the pharmaceutically active agent within 30 minutes after administration.
REFERENCES:
patent: 2692404 (1954-10-01), Plourde et al.
patent: 5723452 (1998-03-01), Chan
patent: 5876749 (1999-03-01), Al-Razzak et al.
patent: 85 36 337 (1986-02-01), None
patent: 0 040 840 (1981-12-01), None
patent: 0 227 060 (1987-07-01), None
J. P. Stanley, The Theory and Practice of Industrial Pharmacy, pp. 398-412 (1986).
L. L. Augsburger, Hard and Soft Shell Capsules, pp. 395-428 (1996).
Alex Rainer
Gerhards Jürgen
Kraemer-Pittrof Ingeborg
Oeschger Richard
Rades Thomas
Ebel Eileen M.
Hoffman-La Roche Inc.
Johnston George W.
Page Thurman K.
Rocha-Tramaloni Patricia S.
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