Process for manufacturing a pharmaceutical chewing gum

Details Process for manufacturing a pharmaceutical chewing gum Process for manufacturing a pharmaceutical chewing gum

1999-09-13

2001-11-27

Corbin, Arthur L. (Department: 1761)

Food or edible material: processes, compositions, and products

Normally noningestible chewable material or process of...

C424S048000, C424S440000, C424S441000, C426S285000, C426S454000

Reexamination Certificate

active

06322828

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to processes for producing chewing gum tablets as dosage forms for pharmaceutical therapeutic agents, and in particular to a process for making a pharmaceutical chewing gum dosage form having a more accurate and uniform dose of the pharmaceutical active ingredient.
BACKGROUND
Pharmaceutical therapeutic agents, such as drugs, are formulated in a variety of dosage forms, depending upon the target absorption site of the drug, the intended time profile for absorption, the solubility characteristics of the drug, the susceptibility of the drug to various forms of attack in vivo, such as enzymatic degradation and organ uptake, and other considerations well-known to those skilled in the art. A large number of drugs are formulated in orally ingestible dosage forms for delivery into the gastrointestinal tract, where they are absorbed into the blood stream and carried to various organs or tissues where the pharmacological action is exerted. Typically, such dosage forms are capsules or tablets, which may further be provided with various coatings, to assist in passage through the gastrointestinal tract, or to provide a delayed or extended release profile. When more rapid therapeutic action is desired, or when the therapeutic agent is particularly susceptible to chemical or enzymatic attack in the gastrointestinal tract, a preferred route of delivery is injection into the blood stream, and the corresponding dosage form is an injectable liquid or solution. Still other drugs are delivered topically to the skin, eyes, and various mucosal tissues, in dosage forms such as ointments, creams, gels and lotions.
A number of therapeutically useful drugs are capable of buccal absorption; i.e., absorption in the oral cavity, either sublingually or throughout the oral mucosal wall, or by dissolution in the saliva and absorption in the throat, esophagus, or upper gastrointestinal tract. For drugs having significant buccal and/or upper and lower gastrointestinal tract absorption, oral dosage forms taking advantage of the absorption, such as lozenges, chewable tablets, and chewing gum, are particularly advantageous. Such dosage forms permit more rapid therapeutic action compared to per-oral (swallowed) dosage forms, and the topically absorbed therapeutic agent also partially escapes liver metabolism.
The chewing gum dosage form is particularly attractive due to its ease of administration and the generally acceptable or even pleasant qualities of chewing gum. These attractive properties can significantly improve patient compliance with the dosage regimen. Thus, for example, U.S. Pat. No. 4,971,079 is directed to chewing gum compositions having an anti-nicotine therapeutic effect, for use in facilitating cessation of smoking. Likewise, U.S. Pat. No. 5,922,347 is directed to chewing gum compositions containing acetylsalicylic acid, a well-known anti-inflammatory and analgesic compound.
The conventional chewing gum processing technology involves melting a gum base in, for example, a sigma blender, and adding components such as sweeteners and flavorants to the melt. The melted mass is then extruded, rolled into sheets, and cut to the desired shape on the rollers. This conventional technology, however, suffers from several disadvantages, when applied to the preparation of pharmaceutical chewing gum dosage forms. For example, the elevated temperatures used in the melt can adversely affect the chemical stability of the therapeutic agent contained therein. In addition, the melting and mixing process of the highly viscous gum mass makes controlling the accuracy and uniformity of the drug dose difficult, and this difficulty is further exacerbated by the lack of a precise form, shape or weight of the dosage form. Further, the gum processing technology is not easily adapted to incorporate the stringent sanitary manufacturing conditions required for production of pharmaceutical products, and the concomitant process validation and control measures. In addition, conventional gum processing technology is generally poorly suited for high-speed, more economical, production.
Several patents are directed to improved methods of processing chewing gums, in order to overcome some of the disadvantages described above. U.S. Pat. No. 4,000,321, for example, is directed to a process for preparing chewing gum, in which a chewing gum composition is cooled to −15° C. to facilitate fragmentation, and the cooled composition is pulverized with a crusher, hammer mill, pelletizer or turbomill. The pulverized product is then melted to cause the pulverized pieces to co-adhere, forming a chewing gum reportedly having low specific gravity and a soft chewing texture. The process, however, suffers from all of the disadvantages associated with heating, process speed, poorly defined dosage forms and weights described above, and is not well-suited for making a pharmaceutical chewing gum dosage form.
U.S. Pat. No. 4,753,805 is directed to a chewing gum composition in the form of a tablet having a low moisture content. The tablet is produced by grinding a chewing gum composition, blending the ground composition with a compression aid, and compressing the granulated product to form a tablet. Grinding of the chewing gum composition, typically a difficult process because of the tendency for the gum to stick to the grinding apparatus, is accomplished by the use of 2-8% by weight of a grinding aid such as an alkaline metal phosphate, an alkaline earth metal phosphate, or a maltodextrin. The use of such grinding aids, however, is disadvantageous. The metal phosphate salts are highly alkaline, and such alkalinity may be incompatible with acidic ionizable therapeutic agents, for example. In addition, the grinding aid remains in the composition and ultimately in the chewing gum tablet, and the presence of a large amount of metal phosphate in the dosage form is potentially problematic from therapeutic and safety perspectives.
Thus, there is a need for processes to produce dosage forms of buccally absorbable therapeutic agents which do not suffer from the disadvantages of conventional pharmaceutical chewing gum formulations.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a process for preparing chewing gum dosage forms of therapeutic agents topically effective toward the gastrointestinal tract having improved dose accuracy and uniformity.
It is also an object of the present invention to provide a process for preparing chewing gum dosage forms of therapeutic agents topically effective toward the gastrointestinal tract having a precise and well-defined form, shape and weight.
It is also an object of the present invention to provide a process for preparing chewing gum dosage forms of therapeutic agents topically effective toward the gastrointestinal tract, wherein the therapeutic agent is not subjected to elevated temperatures.
It is further an object of the present invention to provide processes for preparing chewing gum dosage forms of therapeutic agents topically effective toward the gastrointestinal tract capable of being carried out in high-speed, efficient manufacturing processes.
It is still a further object of the present invention to provide chewing gum dosage forms of therapeutic agents topically effective toward the gastrointestinal tract.
The foregoing objects and other advantages are achieved by the process of the present invention, in which a chewing gum composition is cooled to a temperature at which the composition is brittle, and the composition is ground while brittle to form a fine powder. In a preferred process, the composition is cooled by mixing with a coolant, such as solid carbon dioxide, and the mixture is ground to a powder. The powder can be mixed with a pharmaceutical active ingredient capable of buccal and/or upper or lower gastrointestinal tract topical absorption (i.e., topically effective toward the gastrointestinal tract), and formed into a tablet. Preferably, the mixture of the powder, pharmaceutical active ingredient, and other additives such

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