One of the most common dosage forms for pharmaceuticals is the tablet. However, tablets are not limited to pharmaceuticals and have been applied in areas as diverse as detergents, beverages and sweeteners. Tablets are successful devices for delivering intended ingredients because of their wide consumer acceptance, convenience, ease of use and economy. In common tableting processes, material which is to be tableted is deposited into a cavity, and one or more punch members are then advanced into the cavity and brought into intimate contact with the material to be pressed, whereupon compressive force is applied. The material is thus forced into conformity with the shape of the punches and the cavity. Hundreds, and even thousands, of tablets per minute can be produced in this fashion. Various tableting methods, well known to those skilled in the art, are comprehensively discussed in Lieberman, Pharmaceutical Dosaqe Forms: Tablets Volume 1, Second Edition, Revised and Expanded Copyright 1989 by Marcel Dekker, Inc.
These basic compression steps are common to most tableting operations including methods known as direct dry compression, wet granulation, and dry granulation. See European patent application 0,127,400.
The term "direct compression" was historically used to describe compression of a single crystalline compound into a compact tablet form without the use of additional ingredients. However, few compounds posses the necessary properties to make such compaction possible. The term has more recently evolved such that it now defines processes by which tablets are compressed directly from powder blends of active or intended ingredients and suitable excipients.
Where direct compaction is not possible, granulation techniques may also be used as a pre-treatment. Most powders cannot be compressed directly into tablets because they lack the proper characteristics. These characteristics include a lack of *compressibility and a lack of necessary lubrication. See Lieberman, supra at page 148. For these reasons materials to be delivered are often pretreated either alone or in combination with other fillers to form granules that readily lend themselves to tableting. This process is known as granulation. As commonly defined, "granulation" is any process of size enlargement whereby small particles are gathered together into larger, permanent aggregates to yield a free-flowing composition having a consistency similar to that of dry sand. This may be accomplished by agitation in mixing equipment or by compaction, extrusion or globulation. In granulation, active or intended ingredients are generally admixed with a compression vehicle. The compression vehicle or filler must have good compressibility, good flowability and stability under normal ambient conditions as well as being low in cost and satisfactory in both texture and appearance. In addition to compression vehicles, tablet formulations typically include other additives such as diluents, flavors, colors disintegrating agents and lubricants, all of which may be added during granulation or thereafter.
Lubricant, as used herein, refers to a material which can reduce the friction between the tablet, the die walls and the punch faces, which occurs during the compression and ejection of a tablet. Lubricants, in general, prevent sticking of tablet material to the punch faces and die walls. The term "antiadherents" is sometimes used to refer to substances which in some formulations are needed to aid the lubricant and prevent films from forming on the punch faces. However, as used in the present disclosure, the term "lubricant" is used generically and includes "antiadherents". Tablet sticking during formation and/or ejection may pose serious production problems such as reduced efficiency, irregularly formed tablets, and non-uniform distribution of intended agents or intended ingredients to be delivered thereby. These problems are particularly severe with high speed tableting approaches and methods.
Lubricants may be intrinsic or extrinsic. A lubricant which is directly applied to the tableting tool surface in the form of a film, as by spraying onto the die cavity and/or punch surfaces, is known as an extrinsic lubricant. Although extrinsic lubricants can provide effective lubrication, their use requires complex application equipment and methods which add cost and reduce productivity. Therefore, extrinsic lubricants generally are considered to be undesirable. See Leal, et al., U.S. Pat. No. 3,042,531 which describes another form of extrinsic lubrication by disclosing the compression of a lubricant tablet just prior to the tableting of the desired composition. After compaction of the lubricant tablet, a lubricated residue remains in the punch and cavity walls such that a subsequent tablet is lubricated. This obviously cuts tableting efficiency in half, raises cost and yields unwanted waste; namely the lubricant tablets.
Intrinsic lubricants are incorporated in the material to be tableted. Magnesium, calcium and zinc stearates and stearic acid have long been regarded as the most efficient intrinsic lubricants in common use. Concentrations of 0.3% to 2.0% are usually effective. Unfortunately, metallic stearates and stearic acid are not water soluble. This fact can seriously hinder tablet disintegration. Additionally, when these materials are used in products which are reconstituted into a solution prior to use, they leave an objectionable "scum" on the surface of the resulting solution.
To attempt to remedy this situation, a number of water soluble or water dispersible lubricants may be used. Unfortunately what these substances gain in water solubility, they sacrifice in lubrication efficiency. Other traditional intrinsic lubricants include hydrogenated and partially hydrogenated vegetable oils, animal fats, polyethyleneglycol, polyoxyethylene monostearate, talc, light mineral oils, sodium benzoate, sodium lauryl sulphate, and the like. See European Patent Application No. 0,275,834, the disclosure of which is incorporated by reference. See also Leal et al., U.S. Pat. No. 3,042,531.
Lubricants can be particularly important when compounding an effervescent tablet. According to the aforementioned Lieberman text, effervescent tablets could not be produced on high speed equipment without a suitable lubricant. Effervescent granulations are inherently difficult to lubricate partly because of the nature of the raw materials used and partly because of the requirement for rapid disintegration of the tablet. Typical intrinsic lubricants sacrifice either lubrication efficiency or desirable disintegration properties.
For example, while magnesium stearate used in conventional amounts is an effective lubricant, it may actually retard disintegration. This is not a generally insurmountable problem in effervescent formulations because of the disintegrating action of the effervescents. It may, however, slow disintegration sufficiently to reduce the commercial appeal of a tablet so formulated. Furthermore, where larger quantities of lubricant are required by the difficulty of tableting certain ingredients, the long disintegration time caused by the lubricant may become significant.
The retardation of disintegration caused by conventional lubricants is a particularly severe problem with non-effervescent tablets. Disintegration in the non-effervescent context generally refers to the break up of a tablet after administration. Obviously, the success of, for example, a drug may depend upon its complete and controlled administration. However, lubricants and disintegrants generally functionally oppose each other. See Lieberman, supra at pg. 108. In fact, conventional disintegrants possess binding and or adhesive properties which inhibit the lubrication efficiency of a lubricant.
Thus, it is a difficult task to produce a tablet formulation which will dissolve and disintegrate in a controlled and timely fashion, but which can be lubricated sufficiently to render high speed manufacturing possible.
An additional problem often encountered in forming a tablet is the inclusion of flavor. Flavors may be added in an attempt to mask objectionable tastes, or merely to make the taking the medicine more pleasurable. Doran et al., U.S. Pat. No. 4,352,821 is directed to a flavored compressible tableting agent formed from fructose and a carrier therefore. The carrier is preferably an edible substantially water insoluble inorganic salt and may include tri-calcium phosphate, di-calcium phosphate anhydrous, magnesium carbonate and mixtures thereof.
Similarly, in European Patent Application 0,275,834, the continuous process for the production of a comestible tablet is disclosed which comprises continuously contacting different ingredients together at high shear while atomizing a solvent of at least one ingredient into the mix. The atomized solvent may include water soluble sweetening agents, water soluble artificial sweetening agents, dipeptide base sweeteners and mixtures thereof.
Levin, U.S. Pat. No. 2,147,743 discloses the use of normal magnesium carbonate and a fruit acid to provide a dry effervescent composition. In one embodiment, a lemon oil flavoring is blended with the dry powder incorporating a minor amount of magnesium carbonate together with sugar and citric acid. This is said to yield a non-caking powder.
As the references cited herein indicate, no single solution to the problems discussed has been completely satisfactory. In fact, despite all of the attention devoted to tableting lubricants and tableting disintegrants in the prior art, there still remains a need and a strong desire amongst those in the tableting industry for a dry free-flowing tableting aid which overcomes or mitigates the disadvantages of the lubricants discussed above.
In particular, there is a need for a dry free-flowing tableting aid which provides suitable lubrication while tableting, which is water dispersible, and which does not have a substantial adverse effect on the compaction process or upon disintegration and dissolution times.
There is a further need for enhanced methods and materials for flavoring tablets.
The need for enhanced methods and materials for flavoring is not, however, limited to tablets. Flavor oils are widely used to flavor consumable products such as foods and beverages, and even other pharmaceutical dosage forms. Unfortunately, flavor oils are generally difficult to incorporate into these consumable products directly, and therefore must generally be spray-dried onto carriers such as dextrose, mannitol or other sugars to form fine, flowable powders. These fine powders can then be easily handled and incorporated as needed.
Unfortunately, spray-drying is not a completely satisfactory technique. Some flavor oils, for example, are very volatile and the spray-drying of these flavor oils generally results in a high oil loss rate. This dramatically effects the cost of the finished product. Furthermore, additives are also required to facilitate the spray-drying process such as antioxidants which are commonly added to preserve the integrity of the spray-dried flavor oil.
Another problem with regard to delivery of flavor oils is the carrier. Sugars may be used, however, the added caloric value of the sugar may render these flavor carriers unattractive for numerous applications. This is particularly true when attempting to market consumable products to today's more health-conscious consumers. Other carriers could be envisioned such as those described in Gioffre, et al., U.S. Pat. No. 4,818,518. Specifically, Gioffre, et al. suggests the mixing of a flavored oil with solid particulate carrier materials such as starch, calcium carbonate, paraffin, vegetable wax, fat, or higher fatty acids. However, even these potential carrier substances are not without problems. For example, calcium carbonate can only handle a rather low loading factor of flavored oil. Furthermore, calcium carbonate, for example, when coated with about 11 weight percent flavored oil, produces a clumpy agglomerate which is not free-flowing and, therefore, difficult to use and to homogeneously incorporate into products.
Therefore, there remains a need for improved flavor delivering agents in general, for more efficient methods of manufacturing these materials and for their use.