The present invention provides a chewing gum composition containing an active ingredient. The preferred chewing gum composition comprises a plurality of granules comprising a mixture of a powdered chewing gum base and a selected amount of a powdered active ingredient, said powdered chewing gum base and powdered active ingredient being mixed together within said granules. Additives may be mixed in the granules or may coat the granules. The preferred form is a tablet containing a controlled dosage form of the active ingredient.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is directed to processes for improved production of pharmaceutical chewing gum dosage forms. The processes of the present invention enable production of chewing gum tablets without the disadvantages of heating the therapeutic agent, and without problems associated with inaccuracy and non-uniformity of therapeutic agent doses characteristic of conventional chewing gum processes. The present invention achieves these and other significant advantages by a process in which a chewing gum composition is cooled to a brittle temperature, ground while at a brittle temperature to form a powder, and formed into a tablet. The pharmaceutical therapeutic agent, or active ingredient, is readily mixed with the powdered gum composition prior to tablet formation, to produce a uniform and accurate mixture, from which a well-defined and precise tablet dosage form can be prepared by tabletization.

In one step of the process of the present invention, a chewing gum composition is cooled to a temperature at which the composition is brittle. The chewing gum composition can be any chewing gum composition, such as conventional compositions known in the art. In general, such compositions include a chewing gum base, to which may be added flavorants, sweeteners, colorants, and other ingredients known in the art. The chewing gum base is typically a natural or synthetic elastomer, such as rubber, chicle, lechi caspi, jelutong, polyisobutylene, an isobutylene-isoprene copolymer, a styrene-butadiene copolymer, or other suitable gum base known in the art. In order to facilitate the subsequent grinding step, the chewing gum composition is preferably in the form of chips, pellets, or other relatively small particles.

The chewing gum composition is cooled to a temperature at which the composition is brittle. It should be appreciated that even a mildly cooled chewing gum composition will possess some degree of brittleness; however, to be suitable for the process of the present invention, the composition is cooled to a temperature at which the composition is sufficiently brittle such that the brittleness is maintained during the subsequent grinding step without adhesion to the grinding apparatus. The appropriate temperature is determined in part by the specific composition of the chewing gum, and is easily determined empirically by observing the properties of the cooled chewing gum composition. Thus, for example, a chewing gum composition cooled to a temperature sufficiently low can be ground in, for example, a mill grinder, without the composition sticking to the grinder parts. Preferably, the temperature will be less than -15.degree. C., more preferably less than -30.degree. C., and still more preferably less than about -40.degree. C.

The cooling can be carried out by any of a variety of cooling processes. The chewing gum composition can be frozen in a conventional freezer apparatus capable of reaching the very low temperatures needed to achieve the requisite brittleness. Preferably, however, the chewing gum composition is cooled by contacting with a coolant. The coolant can be any substance capable of cooling the chewing gum composition to the desired temperature and can be, for example, a cryogenic liquid such as liquid nitrogen, a cold solid such as solid carbon dioxide, or a cold gas such as the gaseous boil-off from a cryogenic liquid. The coolant should be chosen so that the coolant does not interact adversely with the chewing gum composition or with the mixing or grinding apparatuses used in the present process. In addition, the coolant should not produce a substance upon warming that suffers from such adverse interactions, or that leaves a residue that adversely affects subsequent processing or presents potential safety hazards when the chewing gum tablet is chewed. For example, a coolant such as water ice, even if cooled to a sufficiently low temperature, would not be preferred, as any water ice that melts will form liquid water, which is absorbed by the chewing gum composition. Likewise, a coolant such as a hydrocarbon slush would not be preferred, since any hydrocarbon residue remaining in the chewing gum composition would present potential safety hazards when the chewing gum tablet is consumed.

In accordance with the present invention, and in a particularly preferred aspect, it has been surprisingly found that by mixing a chewing gum composition with solid carbon dioxide (dry ice), the chewing gum composition can be cooled to a brittle temperature without the undesirable effects discussed above. At the sublimation temperature, -78.5.degree. C., solid carbon dioxide is sufficiently cold to ensure that the chewing gum composition is suitably brittle. Of course, the solid carbon dioxide can be cooled to an even lower temperature, if desired. Upon warming, the solid carbon dioxide sublimes to form carbon dioxide gas, which does not react with the chewing gum composition, is not absorbed by the composition, and does not interact adversely with processing apparatuses. Further, the gaseous, non-reactive nature of the sublimation product ensures that no undesirable and potentially hazardous residue of the coolant remains in the chewing gum tablet product. Preferably, the solid carbon dioxide coolant is provided in pelletized form to facilitate further processing steps.

Alternatively, the steps of cooling the chewing gum composition and grinding the composition can be combined into a single step by, for example, cooling the grinding apparatus itself, such as by contacting the grinding apparatus with a coolant. For example, in this alternative aspect, the grinding apparatus can be placed in a cooling jacket of liquid nitrogen or other cold liquid. For more efficient cooling, in this embodiment, the chewing gum composition is preferably pre-cooled, although the pre-cooling need not be to a temperature as low as the brittle temperature. It should be appreciated that even in the preferred embodiment, wherein the chewing gum composition is cooled my mixing with a coolant, it may also be advantageous to cool the grinding apparatus as well.

If desired, the chewing gum composition can be mixed with an anti-caking agent prior to the grinding step, and the use of an anti-caking agent is preferred. Such anti-caking agents are known in the art. A preferred anti-caking agent is precipitated silicon dioxide. In a preferred embodiment in which the chewing gum composition is mixed with solid carbon dioxide and an anti-caking agent prior to grinding, the anti-caking agent helps to prevent agglomeration of the subsequently ground chewing gum particles, upon sublimation of the solid carbon dioxide.

If a coolant, such as solid carbon dioxide, and other components, such as an anti-caking agent are used, the chewing gum composition and other substances can be combined using a conventional mixing apparatus, such as a vented V-blender.

The chewing gum composition, and other components such as coolant and anti-caking agent, are ground to form a fine powder. The grinding can be carried out using any conventional grinding apparatus, such as a mill grinder. In a preferred embodiment, a mixture of a chewing gum composition, solid carbon dioxide, and precipitated silica is provided, and the mixture is introduced into a mill grinder. In this embodiment, the mixture is ground to a fine powder, and the solid carbon dioxide remains present during the grinding process. It has been surprisingly found that by co-grinding the chewing gum composition and solid carbon dioxide, the chewing gum composition can be ground into a fine powder, without any adverse adhesion to the grinding apparatus.

The desired properties of the ground chewing gum composition are better achieved when the composition is kept at a very low temperature throughout the grinding process. Thus, in a particularly preferred process, a mixture of chewing gum composition, solid carbon dioxide and precipitated silica is ground in a mill grinder in a first grinding step, additional solid carbon dioxide and precipitated silica are added to the ground composition, and the composition is further ground in a second grinding step. This two-step grinding process advantageously keeps the chewing gum composition at a very low temperature. Although not wishing to be bound by theory, it is further believed that the presence of the solid carbon dioxide particles, in addition to providing the necessary cooling, also serves to enhance the efficiency of the grinding process. It should be appreciated that although a two-step grinding process is described herein, the number of steps is not particularly limited. Thus, a process in which additional solid carbon dioxide and/or precipitated silica are added in multiple steps, or even in a slow, continuous stream, may also be used if desired.

After the composition is ground to a powder, the coolant can be removed by, for example, allowing the coolant to evaporate. Using the preferred coolant of solid carbon dioxide, the coolant is removed simply by allowing the solid carbon dioxide to sublime, releasing harmless carbon dioxide gas and leaving no undesirable contaminants. The ground composition can be stored such that the carbon dioxide gas can escape, as for example in loosely closed plastic bags. Alternatively, the carbon dioxide can be removed more rapidly by processing the ground composition in a fluidized bed reactor.

Once the coolant has been removed from the powder, the powder can be mixed with other ingredients as desired, before forming the powder into a tablet. Such ingredients can be any ingredient known to be incorporated into chewing gum and not incompatible with tablet formation, such as coating agents, binders, lubricants, sweeteners and the like. Preferably, a pharmaceutical active ingredient topically effective toward the gastrointestinal tract is added in an amount such that the tablet ultimately formed includes a therapeutically effective dose of the active ingredient. As used herein, the term "topically effective toward the gastrointestinal tract" means having significant absorption in the buccal cavity and/or the mucous layer of the upper and/or lower gastrointestinal tract. The active ingredient can be any active ingredient having such topical absorption, such as, for example, gastrointestinal anti-infective drugs, anti-diarrheal drugs, anti-cholic drugs, cardiovascular drugs such as nitroglycerin, and calcium channel blocking agents such as nifedipine.

Such ingredients can be combined with the powder by blending, in for example, a sigma mill, or a high shear mixer. If a conventional blending apparatus is used, the powder mixture should include sufficient amounts of binder to enable effective processing of the mixture. Such binders, well-known in the art, are typically aqueous, and the large amounts of aqueous binder necessary to enable tabletization from a blended mixture are not preferred, as the mixture tends to swell and to develop a disadvantageous stickiness that makes tabletization less efficient. However, although not preferred, such blending processes can still be used in the process of the present invention.

In a preferred process, it has been surprisingly found that the powdered chewing gum composition produced by the process described above can be combined with other ingredients, such as coating agents, binders, sweeteners and active ingredients, in a fluidized bed reactor. The use of a fluidized bed reactor is particularly advantageous, as the process partially rebuilds the powder into granules, as well as coats the powder particles and/or granules with a coating agent, thereby minimizing undesired particle agglomeration. In this embodiment, the temperature of the process should be controlled. If the temperature is too low, the mixture (the "blend") will stick because of a low evaporation rate as the binding solution is sprayed on the blend. The granules that develop are then too large for subsequent tabletization. If the temperature is too high, the blend can soften, with the same disadvantageous results. With these considerations in mind, one skilled in the art can readily determine the appropriate process temperature by observing and optimizing the properties of the granules produced. To reduce the processing time, the fluid bed granulator can be pre-heated to the chosen processing temperature prior to adding the powder mixture. After granulation, the granulate can be discharged onto screens, and any granules that are too large can be removed.

In a preferred process, the powder mixture, containing the powdered chewing gum composition, active ingredient, and other additives, is weighed into individual "charges" for the fluid bed granulator. After processing as described above, and screening, the individual charges are then preferably recombined and mixed in a V-blender, and the resultant "cross-blend" is then discharged across a screen to again remove any granules that are too large. It is particularly advantageous to sample the cross-blend discharge by taking multiple samples from the discharge stream, for analysis of the active ingredient. Thus, the discharge mixture can be stored while the multiple samples are analyzed, to insure that the desired level and uniformity of level of active ingredient are present. If necessary, additional active ingredient can then be added.

The discharge mixture is again placed in a V-blender, and any additional active ingredient added. In addition, an anti-adherent is preferably added at this time, along with any other desired excipients or inactive ingredients. A preferred anti-adherent is talc. The mixture can then be discharged, again screened, and staged for compression.

Compression to form tablets can be carried out by any conventional process, such as a punching process. Of course, the punching process should be monitored for signs of sticking to the punches, and the apparatus cleaned, and/or coated with additional anti-adherent as needed.

In another aspect, the present invention is directed to chewing gum dosage forms of a pharmaceutical active ingredient topically effective toward the gastrointestinal tract, the dosage form being a tablet formed of compressed granules of a gum base and the active ingredient. The granules forming the tablet can be of a size convenient for tabletization, typically from about 15 to about 30 mesh size, and preferably about 20 to about 25 mesh size. The tablets can be produced by any of the methods described above. Advantageously, the tablet does not contain any residue of a grinding aid, such as an alkaline phosphate.
 

Claim 1 of 20 Claims

1. A chewing gum composition comprising: a plurality of granules, each granule comprising a uniform mixture of a powdered chewing gum base and a selected amount of a powdered therapeutic active ingredient, said powdered chewing gum base and powdered active ingredient being mixed together within said granules.

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