Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2002-05-15
2004-02-10
Azpuru, Carlos A. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C400S400000, C400S451000
Reexamination Certificate
active
06689382
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to stable soft gelatine capsules (hereinafter softgel) containing non-steroidal anti-inflammatory agents (NSAID's) including both cyclooxygenase 1 (Cox1) and cyclooxygenase 2 (Cox2) inhibitors and to a process for the preparation of therapeutically useful, highly stable, soft gelatine capsules, containing non-steroidal anti-inflammatory agents including both cyclo-oxygenase 1 (Cox1) and cyclooxygenase 2 (Cox2) inhibitors as active ingredients as well as mixtures thereof. The present invention also relates to soft gelatin capsules with a gelatin shell, at least one plasticizer and a capsule filling which contains at least one pharmacologically-active substance and a solvent, as well as processes for their manufacture.
The present invention further relates to a process for solubilizing at least one difficulty soluble pharmaceutical active in a mixture of glycofurol and glycerol and optionally polyvinylpyrrolidone. In further embodiments, the present invention also relates to a process for encapsulating these solubilized pharmaceutical compositions within soft gelatin shells, which are optionally transparent. Both the resulting compositions and their capsules provide an effective means for oral delivery of a wide variety of difficulty soluble pharmaceutical actives.
The instant invention also relates to a liquid softgel fill formulation containing a NSAID and a solvent system containing glycofurol, glycerin, water, optionally polyvinylpyrrolidone and optionally from 0.1 to 1 equimolar amounts of alkaline hydroxide to neutralize the NSAI) when said NSAID contains an acidic moiety.
BACKGROUND OF THE INVENTION AND DESCRIPTION OF THE PRIOR ART
It is well known that liquid, and especially concentrated liquid pharmaceutical compositions offer many advantages over solid compositions. Liquids are easy to swallow and provide an excellent vehicle for the uniform delivery of pharmaceutical actives. Liquids provide a rapid onset of pharmacologic action, since the composition does not first have to disintegrate and dissolve in the gastrointestinal tract. Concentrated liquid compositions are ideally suited for encapsulation within a soft gelatin shell, to provide a portable and easy-to-swallow soft, flexible capsule. Encapsulation would also permit the accurate and uniform delivery of a unit dose of a pharmaceutical active, an advantage which becomes especially important when relatively small amounts of an active are to be delivered. Additionally, soft gelatin capsules are aesthetically appealed (especially when filled with a transparent liquid) and can be manufactured in a wide variety of sizes, shapes, and colors.
Gelatin capsules, especially soft gelatin capsules, have become increasingly important as a medical dosage form since it became feasible, in the 1930′s, to manufacture them by making and filling the capsules in one operation. Compared to other medical dosage forms they show many advantages such as being odorless and tasteless, they can be taken easily and, owing to their swelling capability and water solubility, the drugs are readily liberated in the stomach. Numerous drugs which, on account of their instability such as sensitivity to oxidation and to light, their thermal stability or their hygroscopicity, may not be easily processed into other medicinal forms, can be encapsulated without impairment of their function.
The need for encapsulation of pharmaceutically active dosage forms such as liquids, semi-solids, and pastes within a gelatin shell in such a way as to prevent uncontrolled leakage has resulted in the development of a very fundamental pharmaceutical dosage form: the soft gelatin capsule. While a difficult and not particularly accurate process initially, current manufacturing processes for softgels are fully automated, with a high degree of precision.
The softgel (the currently accepted nomenclature adopted by the SoftGel Association) is a one-piece, hermetically sealed soft gelatin shell containing a liquid, a suspension, or a semi-solid.
The most common modern production method involved in the preparation of softgels is a continuous method whereby two gelatin ribbons pass between twin rotating dies. As the ribbons meet, the liquid to be encapsulated is precisely injected between them. The capsule halves are sealed and ejected by the continuous rotation of the dies. See P. Tyle, Specialized Drug Delivery Systems, Marcel Dekker, Inc. (1990) for a general discussion of softgel manufacturing and production technology, in particular, Chapter 10 by Paul K. Wilkinson and Foo Song Hom.
Various gelatin shell masses may be prepared, depending on the fill properties, climatic conditions, and end use. Typically, gelatin formulations include the same basic ingredients, namely, gelatin, plasticizers such as glycerin, water, and optionally preservatives as well as other optimizing ingredients. The formulations of gelatins are well known to those of ordinary skill in the art.
In most cases, the typical rotary die process requires a flowable liquid or fill containing a bio-active ingredient. The fill may be a single phase liquid active, a mixture of miscible liquids, or a solution or a suspension of solids and liquids. Generally, the fill contains glycerin and a medicament. The liquids to be encapsulated in a gelatin shell are also well known to those of ordinary skill in the art.
Many shell and fill formulations are discussed in Van Hostetler and J. Q. Bellard noted below as well as in “Advances in Softgel Formulation Technology”, M. S. Patel, F. S. S. Morton and H. Seager, Manufacturing Chemists, July 1989; “Soft Elastic Gelatin Capsules: A Unique Dosage Form”, William R. Ebert, Pharmaceutical Technology, October 1977; “Soft gelatin capsules: a solution to many tableting problems”, H. Seager, Pharmaceutical Technology, September 1985; U.S. Pat. No. 4,067,960 to Fadda; U.S. Pat. No. 4,198,391 to Grainger; U.S. Pat. No. 4,744,988 to Brox; and U.S. Pat. No. 4,780,316 to Brox. All of the above references are incorporated herein by reference.
Subsequent to the rotary die process used to produce the gelatin shells having a medicament fill therein, the resulting capsules are typically washed with a solvent that evaporates easily. Thereafter, the capsules are typically tumble dried in a series of hollow drums with perforated walls. Heated dry air is continuously pumped through the rotating drums at an air temperature typically less than 35° C. The warm air blown into the capsules appears to penetrate the shell and cause it to dry from the inside by moving the water outward to the surface of the capsule. By the time the capsules exit this process, all of the solvent used in washing has typically been evaporated, and a large proportion (50-60%) of the water from the gelatin shell has been removed. Recent developments in drying include bypassing the drum drying stage and having the capsules dried in a drying tunnel or room as further discussed below.
After the capsules exit the last drying drum, the capsules are typically spread on drying trays. The final drying phase for softgels is typically accomplished by passing the drying trays through drying tunnels or into drying rooms. Stacks of trays are inserted into drying tunnels or drying rooms, in which controlled temperature air (21°-24° C.) and low relative humidity (20-30%) is continuously circulated. Although additional water may be removed from dry capsules by further heating, for example at 40° C., such a procedure has not been found to be practical or necessary. See Van Hostetler and J. Q. Bellard in The Theory and Practice of Industrial Pharmacy, “Capsules”, (1970), Chapter 13 at pages 346-383, and in particular at page 380.
The drying time, for most softgels, is 16-24 hours, but may be slightly longer if the softgels are over 20 minims in size or if the softgels contain a non-oily type liquid base. Softgels permitted to come to water equilibrium in this controlled environment are considered “dry”. The gelatin fill and shell of such “dry” softgels contain 6-10% water depending on
Berthel Alfredo
Gomez Jorge
Angres Issac A.
Azpuru Carlos A.
Oh Simon J.
Procaps S.A.
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