Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2000-10-24
2004-02-03
Page, Thurman K. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S451000, C424S439000, C106S402000
Reexamination Certificate
active
06685961
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to a process for coloring gelatin-based formulations and specifically to a process for preventing the cross-linking between gelatin and the aluminum cations of lake pigments through incorporation of fatty acids.
BACKGROUND OF THE INVENTION
Gelatin, a collagen-derived protein, is used in a variety of commercial products. For example, gelatin capsules generally are comprised of a gelatin sheath encapsulating a fill of pharmaceutical, nutritional, herbal, or personal care products. The fill may be a liquid, suspension, solid, or semi-solid. For example, see commonly-owned U.S. Pat. Nos. 5,146,730 and 5,459,983, each herein incorporated in their entirety, as examples of using gelatin for enrobing solid products. As another example, for soft gelatin capsules or tablets, the gelatin sheath or shell includes a plasticizer, normally glycerin or sorbitol, to control the softness and flexibility of the sheath. The sheath also includes water, and optionally, other additives, such as flavorants or colorants. Gelatin is used for hard shell encapsulation and dipped products as well. Gelatin is also recognized for use in a variety of food products. For example, soups, canned meats and vegetables, jams, jellies, ice cream, marshmallows, and confectionery items may include a gelatin constituent.
Gelatin formulations (gel masses) may be colored using a variety of water-soluble FD&C and D&C dyes and exempt colorants. In production of multi-tone gelatin capsules (or gelatin-coated cores), the water-soluble dyes tend to bleed, smear, or otherwise become tarnished from the darker (“stronger”) color to the lighter (“weaker”) color. Such bleeding particularly occurs across any seam that exists on the gelatin capsule or gelatin-coated core. Similar bleeding problems occur with other gelatin products, as well. Due to the problems associated with certified water-soluble dyes and exempt colorants, lake pigments present a water-insoluble substitute. Lake pigments are known in the art of colorants for edible products. Lake pigments are aluminum or calcium salts of water-soluble FD&C or D&C dyes or exempt colorants, like carmine. The water-soluble dyes and colorants are rendered water insoluble through absorption onto an alumina hydrate substrate. Due to the insolubility of lake pigments in water, the lake pigments color by dispersion. The water-insolubility of lake pigments provides a solution to the aforementioned problems associated with bleeding, smearing, or marking across strong to weak colors.
The use of lake pigments, however, presents other potential negative effects. During manufacturing of gelatin-based formulations and conditioning on heat, aluminum cations (Al
+3
) are released from the lake pigments. The cations interact (cross-link) with the gelatin causing the gelatin to become thick and tough. Specifically, with respect to gelatin-based capsule manufacture, cross-linked gelatin is unmachineable, i.e., difficult to process on an encapsulating machine. The interaction between the cations and the negatively charged sites along gelatin molecules results in the deleterious cross-linking. The cross-linked gelatin is highly viscous and tough, and for example, the cross-linked tough masses are difficult to cut using the rotary die encapsulation machines known in the art of gelatin capsule manufacture. Further, resulting dried gelatin shells produced from the cross-linked gelatin can exhibit unacceptable delayed disintegration.
U.S. Pat. No. 4,500,453 to Shank discloses cross-linked collagen-derived protein compositions as having increased strength and viscosity. Gelatin is specifically reacted with aluminum salts of acetic acid in order to increase the viscosity of the protein. While the '453 patent presents such cross-linking (and the associated increase in viscosity) as beneficial, the present inventors, in fact, seek to prevent such interaction as undesirable due to the highly viscous nature and other resulting deleterious properties of the cross-linked protein product.
The extent to which the aluminum cations release from the lake pigments depends on the particular lake pigment. For example, the present inventors have noted that FD&C Red #40 lake exhibits a greater tendency for aluminum cation release. In turn, therefore, when FD&C Red #40 lake is used to color gelatin-based formulations, the resulting colored gelatin-based formulations often are thick and unmachineable.
One solution to the cross-linking problem has been to add a chelating agent, such as ethylenediaminetetraacetic acid (EDTA). The chelating agent approach, however, has been only partially successful in preventing cross-linking. The costs for such agents, as well, prevent this approach from being a preferable solution.
There is a need therefore, for an economical process for coloring gelatin-based formulations with lake pigments that effectively prevents the undesirable cross-linking that occurs between the gelatin-based formulations and the aluminum cations.
SUMMARY OF THE INVENTION
The present invention is a process for coloring gelatin-based formulations involving adding a saturated fatty acid to the gelatin along with powdered or granular lake pigment or lake pigment pre-dispersed in glycerin, whereby the saturated fatty acid is added in an amount so as to prevent cross-linking between the gelatin and the aluminum cations released by the lake pigments. Preferably, this amount is about 10% to about 300% by weight of the added lake pigment content. With this process, the resulting colored gelatin-based formulations exhibit acceptable machineability characteristics and disintegration. As an example, the colored gelatin formulation produced by this process has a viscosity of less than approximately 10,000 centipoise (cP) at 60° C. Also, specimens (1.5 cm width×1.5 cm length×1.0 cm height) of gelatin-based formulations solidified at ambient temperature disintegrated completely in water (37° C.) using standard laboratory disintegration equipment (with a cylindrical disc) within approximately 25 minutes.
Additionally, the present invention is a gelatin-based formulation made from the above-described process. The gelatin-based formulation includes gelatin, lake pigment(s), and a sufficient amount of fatty acid to prevent cross-linking between the gelatin and the cations released from the lake pigment(s). Further, the present invention includes a dosage form that includes the described gelatin-based formulation as the sheath material. The dosage form may encapsulate a liquid, suspension, semi-solid, or solid pharmaceutical, nutritional, herbal, or personal care product, or combination thereof.
These and other aspects of the present invention as disclosed herein will become apparent to those skilled in the art after a reading of the following description of the preferred embodiments.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The present invention is directed to a process for coloring gelatin-based formulations. As used herein, the term “gelatin” should be considered to include other polymeric substances, either natural or synthetic, that have negative charges capable of interaction with cations, such as the aluminum cations released by lake pigments. Preferably, the present invention is a process for producing colored gelatin-based formulations suitable for use as a gelatin sheath encapsulating a medicament in a liquid, suspension, solid or semi-solid. However, the invention is applicable to coloring gelatin-based formulations in general.
The preferred gelatin-based capsule sheath composition is characterized by flexibility and a non-tacky consistency. These desired physical characteristics are based upon the formation of capsules using encapsulation machinery. While the gelatin-based formulation must be flexible for machineability, the gelatin-based formulation must also exhibit appropriate integrity to enclose a liquid, suspension, paste, or solid fill material for an extended period of time, e.g., up to about two years, without leak
Gennadios Aristippos
Gillette Michelle A.
Gordon Roger E.
Banner Pharmacaps Inc.
Page Thurman K.
Sheikh Humera N.
Womble Carlyle Sandridge & Rice PLLC
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