Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
1999-03-01
2001-02-27
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S489000, C424S451000, C424S454000, C424S452000, C424S455000, C424S439000
Reexamination Certificate
active
06193999
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the field of soft gelatin capsules for oral delivery of pharmaceutical substances, nutritional supplements and the like. More particularly, it relates to soft gelatin capsule shell compositions that include gum acacia (gum arabic) as a partial substitute for gelatin. Such soft gelatin capsules may be manufactured in a conventional rotary die encapsulation machine.
BACKGROUND OF THE INVENTION
Gelatin is an animal-derived protein that finds a wide array of food, pharmaceutical, photographic, and technical applications. It has been used to manufacture various types of capsules for more than a hundred years, and those capsules have been utilized in a wide variety of industrial and commercial applications. Softgels (soft gelatin capsules) are a common dosage form for the administration of liquid, semi-solid and solid fills, and soft gelatin capsules embody a distinct classification of properties within the gelatin art. The typical softgel manufacturing process uses the rotary die encapsulation system, and such a general manufacturing process is described by Wilkinson, P. K. and Hom, F. S., 1990, “Softgels: manufacturing considerations.” In:
Specialized Drug Delivery Systems,
P. Tyle (Ed.), pp. 409-449, Marcel Dekker, Inc., New York.
The primary components of the conventional capsule shell are gelatin, plasticizers and water. Several other minor shell additives may be present, such as coloring, opacifying, flavoring and antimicrobial agents. Extenders have been used in gelatin shell compositions to reduce the cost of materials within the shell and adjust the physical or chemical properties of the shell.
Gelatin is manufactured by controlled hydrolysis of collagen, which is present in the bones, skins, and white connective tissues of animals. Gelatin obtained from acid hydrolysis of collagen is known as Type A gelatin, whereas gelatin obtained from alkali hydrolysis of collagen is known as Type B gelatin. Commercially, the primary raw materials for gelatin manufacturing are pigskins, and bones and skins from bovine animals. The softgel industry mainly uses gelatin derived from bovine bones.
In recent years, a bovine spongiform encephalopathy (BSE), or “mad cow disease” outbreak in Europe (particularly in the United Kingdom) has affected the meat, rendering and gelatin manufacturing industries using bovine animals. BSE-infected cattle have been implicated, although not conclusively, in transmission of the neurodegenerative variant Creutzfeldt-Jacob disease (CJD) to humans. The suspicion centers on 21 variant CJD cases in the United Kingdom and one variant CJD case in France (Pang, D. C., 1998, “Transmissible spongiform encephalopathies.”
AAPS Newsletter,
April 1998).
In response to the situation, certain bovine bones (e.g., skull and spinal column) are now classified as specified risk materials and are excluded from the raw material supply for gelatin (Anonymous, 1998, “EU proposes new health rules for bovine-sourced materials.”
Chemical Market Reporter,
Mar. 16, 1998).
Also, the sun-dried bones of cattle dying from natural causes in India and Pakistan have lost some level of commercial acceptance due to lack of traceability. As a result, bone supplies for gelatin production have tightened up and prices have increased. Additionally, the potential for continued downturns in the consumption of beef or the reduction in beef production because of reduced profitability would portend for additional upward pressure on the price of bovine gelatin. There is also the probability of additional uses for gelatin which could further support higher prices. Overall, gelatin is a biopolymer in high demand and its market is expected to keep growing in the near future. Therefore, there is an apparent need for identifying inexpensive gelatin extenders that can partially replace gelatin in some of its commercial uses, such as in shell formulations of capsules. In addition to the obvious economical benefits, use of such gelatin extenders in capsules may also be accompanied by functional improvements.
U.S. Pat. No. 3,959,540 discloses an outer coating made of an acrylic polymer that renders softgels resistant to gastric juices and suitable for enteric release. The gelatin capsules comprise three layers: an inner gelatin shell, an intermediate layer comprising a cationic polymerizate of di-lower alkylamino lower alkylmethacrylate, and outer gastric juice resistant coating of an anionic polymerizate of methacrylic acid and acrylic acid esters.
Coating of softgel capsules with an acrylic film that possesses enteric release properties also is discussed by Felton, L. A., Shah, N. H., Zhang, G., Infeld, M. H., Malick, A. W. and McGinity, J. W. 1996. “Physical-mechanical properties of film-coated soft gelatin capsules.”
International Journal of Pharmaceutics,
127:203-211. The article describes that storage at low relative humidity causes an increase in the Young's Modulus for the capsules over time.
U.S. Pat. No. 4,816,259 discloses the application of a hydroxypropyl methylcellulose subcoating to the outer surface of a softgel. This subcoating improves the mechanical strength of the capsule and the capsule surface adheres better to known enteric coating compositions.
U.S. Pat. No. 4,350,679 discloses the application of a carnauba wax coating on a softgel. The functionality of the wax coating is to improve shell strength and moisture resistance.
All of the aforementioned systems involve coating finished (dried softgels in a “post-processing” step). It is preferable that polymeric additives of natural or synthetic origin that impart certain functionalities or are inexpensive gelatin extenders are incorporated into shell formulations during the gel mass preparation stage and prior to capsule formation, as increasing the number of manufacturing steps increases the time needed for manufacture and increases the cost of manufacture.
U.S. Pat. No. 4,055,554 discloses the use of chemically modified dialdehyde polysaccharides as gel strength enhancers for gelatin compositions. Such compositions may be used for manufacturing capsules.
U.S. Pat. No. 4,804,542 discloses a softgel wherein the capsule shell contains (at least 1% by weight) an additive capable of absorbing water in an amount of at least 10% by weight of its own weight. Such additives include starches, starch derivatives, celluloses, cellulose derivatives, and milk powder. Some non-hygroscopic materials such as mono-, di-, and oligosacchrides, lactose, magnesium trisilicate, and colloidal silica also are described as useful.
U.S. Pat. No. 5,554,385 discloses a softgel wherein the dry capsule shell is comprised of 3-60% starch having a high amylose content. This invention involves preparation of gel mass by combining gelatin, high amylose starch, plasticizers, water, and other minor additives. The gel mass is then processed with the rotary die encapsulation machine to manufacture softgels. The capsules of this invention have textured frosted or satin finish.
U.S. Pat. No. 5,614,217 discloses a softgel that has increased brittleness and can be broken with manual pressure. The shell formulation of such a capsule contains a non-hygroscopic plasticizer and an elasticity reducing extender. The extender is selected from a number of natural and synthetic polymers. The capsule of this invention cannot be plasticized with a conventional hygroscopic polyol such as glycerin or sorbitol. Instead, a non-hygroscopic plasticizer is used such as maltitol, maltitol syrup, partially dehydrated hydrogenated glucose syrup, and hydrogenated starch hydrolysate. Although brittle soft gelatin capsules may be desirable for some particular uses, it is desirable for many uses to be able to change from one composition of soft gelatin capsules having one feel (flexibility, texture, brittleness, etc.) to another soft gelatin capsule having a different composition but the same feel. This is particularly important in the commercial pharmaceutical industry where a change in the physical properties of a commercial item can lead t
Banner Pharmacaps Inc.
Fubara Blessing
Page Thurman K.
Rhodes & Mason PLLC
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