United States Patent:  6,090,401

Assignee:  McNeil-PPC, Inc. (Skillman, NJ)

Filed:  March 31, 1999

The present invention provides a quick dissolving, readily broken substrate suitable for the addition of pharmaceutical agents for oral administration. A method for making the substrate is also disclosed.

DETAILED DESCRIPTION OF THE INVENTION

Suitable materials for the polymeric foaming agent of the present invention are well known in the art, and include proteins, protein hydrolyzates, cellulose derivatives or naturally occurring macromolecules. Suitable protein hydrolyzates include, casseinate, whey and vegetable proteins; gelatin, egg whites and mixtures thereof. Preferred proteins are casseinates derived from spray dried milk products. Similarly, suitable cellulose derivatives useful in the present invention include methyl cellulose, hydroxymethyl cellulose, hydroxypropylmethylcellulose, hydroxypropyl cellulose and other substituted cellulose derivatives, see for example U.S. Pat. No. 5,576,306, herein incorporated by reference. Naturally occurring macromolecules include albumen and casein. Mixtures of polymeric foaming agents may also be employed.

In a preferred embodiment, the compositions of the present invention also include a non-cellulosic polysaccharide, of either natural or synthetic origin. Natural polysaccharides are preferred including xantham gum, agar and especially preferred is carrageenan.

The level of polymeric foaming agent in the foam tab can be up to essentially the entire weight of the foam tab matrix, greater than 99 weight percent, before additional ingredients such as excipients, preservatives, flavorings etc., are included. More preferably the foam tab matrix is comprised of the polymeric foaming agent and the non-cellulosic polysaccharide. The weight ratio of the polymeric foaming agent to the non-cellulosic polysaccharide is generally greater than about 5.5 to 1; preferably from about 7.5 to about 30 to 1; and most preferably from about from about 9 to about 20 to 1.

The polymeric foaming agent and non-cellulosic polysaccharide are admixed in a solvent. The solvent is any suitable solvent for human consumption, with water, particularly deionized water most preferred. In a preferred embodiment the pharmaceutically active ingredient is not admixed with the polymeric film forming agent and non-cellulosic polysaccharide until the foam tab is formed after drying.

The density of the foam tabs prepared by the present invention range from about 0.15 grams /cubic centimeter (g/cc) to about 0.35 g/cc; preferably from about 0.20 to about 0.30 and most preferably from about 0.22 to about 0.28 g/cc with an average value of about 0.26 g/cc.

The solvent content of the foam tabs after drying is less than about 3 weight percent; preferably less than 2 and most preferably from about 1.0 to about 1.6 weight percent.

One or more pharmaceutical or nutritional materials may be dispersed into this foam. The foam is then dried to yield a dosage form that may be chewed, or that readily dissolves in the mouth without chewing. The foam may be dispensed into molds before drying to yield uniform dosage forms. Alternatively, the foam may be dried in large sheets or blocks, and the dried foam is subsequently subdivided into individual dosage units. Materials useful as pharmaceutical actives or nutritional supplements may be added to the solution that is used to generate the foam, or they may be added to the foam after it is generated. The addition of drugs to the dried dosage forms has several potential advantages. First, the amount of drug added can be carefully controlled. This overcomes potential variations in the weight of the dosage forms produced by the foam generating and dispensing process, which could result in variations in the drug in the amount of drug delivered. Also, this addition of drug as a solution or dispersion in a solvent to the dried foam dosage unit allows the use of drugs that are unstable in water. Finally, the addition of drug directly to the dried foam dosage form allows the production of dosage units containing different levels of drugs, or alternatively, different drugs can be added to various portions of a single batch of dried dosage units.

The pharmaceutical actives or nutritional supplements often have a bitter or unpleasant taste, rendering undesirable products made with these materials that are intended or chewing or dissolving in the mouth. Therefore, some procedure for masking the unpleasant taste of these materials may be incorporated into the current invention. Especially preferred is the incorporation of particulate pharmaceutical actives or particulate nutritional supplements which have been coated with a lipid or polymer film. The lipid or polymer film protects the active or supplement from dissolving in the mouth, thereby masking the taste of the material. These coated particles may be introduced into the foam at any point prior to drying. However, addition of these particles just before the foam is dispensed for drying is preferable, since this minimizes the amount of time that the particles are exposed to high levels of moisture present in the undried foam. These particles are preferably added after the vigorous agitation or mixing process that is needed to entrain gas bubbles in the foam. This agitation or mixing may result in fracture or breakage of the coated particles. Additionally, the longer duration of exposure of the coated particles to the high moisture content of the undried foam increases the amount of material in the coated particles that dissolves and leaches into the liquid foam portion.

A preferred method consists of first drying the foam, and then adding the pharmaceutical or nutritional material as a liquid or solution that does not substantially collapse the foam. This approach is especially preferred for materials that are active at very low doses, or are sufficiently volatile that they would be lost during the process of drying the wet foam. Nicotine is an example of a material that may advantageously be incorporated into the foam in this manner. One additional benefit of adding the active material to the foam after drying is that the dosing amount can be carefully controlled. When active materials are added to the foam before drying, the amount of active material may be affected by variations in the amount of foam that is incorporated into the dosage unit, or by non-uniformity of the active material in the foam before drying.

Examples of pharmaceutical actives that may be advantageously incorporated as coated particles include acetaminophen, ibuprofen, ketoprofen, naproxen, loperamide, famotidine, cimetidine, ranitidine, diphenydramine, pseudoephedrine, loratidine, aspirin, and ebastine, and pharmaceutically acceptable salts thereof. Other pharmaceutical actives are disclosed in U.S. Pat. No. 5,446,070, the contents of which are hereby incorporated by reference. Examples of nutritional supplements that may be advantageously incorporated as coated particles include niacin, B vitamins, decosahexaenoic acid, conjugated linoleic acid, phytosterols, iron salts, and salts of other essential minerals. Numerous other drugs may be applied to the foam dosage forms in this manner. Drugs that have relatively low therapeutic doses are preferred. Also preferred are drugs that are relatively tasteless, since this approach does not provide taste-masking of the unpleasant taste of the drugs.

The process of preparing foams by mixing a polymer or a mixture of polymers with air or other gas under conditions of vigorous agitation so that gas is entrained as small bubbles is well known. The foams may be created by vigorous agitation of a polymer solution in the presence of air, inert gases and mixtures of gases such as nitrogen, carbon dioxide, helium and the like may be incorporated into the foam. Alternatively, a commercially available foam generating unit may be used. An example are the foamers made by the Oakes Corporation

The degree of agitation and gas entrainment must be carefully controlled so as to provide foams of appropriate density. This density control is important in maintaining a uniform weight of the dosage forms created by drying. Drying of the foam results in the creation of a stable solid material. Drying may occur by atmospheric exposure at room temperature or at elevated temperatures in an oven, at temperatures preferably less than 70^o, most preferably less than 50^oC. Alternatively, drying may be carried out by lyophilization. Foams may be molded or cast into precise shapes before drying. Also, some foams are sufficiently stable so that they can be cut into uniform sections after drying.

Additionally, a sugar or other carbohydrate material may be dissolved in the foam. The sugar or carbohydrate adds additional bulk to the foam after drying, furthermore, the drying and crystallization of the sugar or other carbohydrate provides additional strength to the dried foam. The sugar or other carbohydrate can add sweetness to the dried foam or otherwise improve the organoleptic qualities of the foam. Examples of sugars which may be used include maltose, lactose, sucrose, dextrose, and trehalose, as well as sugar-alcohols, such as mannitol, sorbitol, xylitol, maltitol, and the like. Examples of other carbohydrates include maltodextrin, corn syrup solids, soluble starches and the like.

Other materials may be added to improve the taste or physical properties of the dried foam. Flavor may be added; examples of flavors are vanilla, orange, orange cream, strawberry, and raspberry. Additionally, natural or artificial colors may be added. Also, artificial sweeteners may be added; these sweeteners may increase the level of sweetness beyond that obtained by adding sugar to the foam. Examples of artificial sweeteners include sucralose, aspartame, cyclamate, saccharin, and acesulfame and their salts. Various acids may be added to provide a pleasant tartness to the foam. Examples of acids that may be used include citric, malic, tartaric, and 2,4-dihydroxybenzoic acids. Additionally, the incorporation of these acids may be used to decrease the pH of the foam. This is especially desirable for materials such as ibuprofen that are relatively insoluble under acidic conditions. This decreased solubility decreases the amount of ibuprofen that dissolves into the foam, thereby improving the taste of the dried foam.

Additionally, humectant materials may be added to improve the aesthetic properties of the dried foam and decrease the friability of the dried foam. Examples of humectants include glycerol, propylene glycol, and polyglycerol esters. Also, surfactant materials may be added to improve the stability of the foam before or after drying. Examples of desirable surfactants include the TWEEN (ICI Americas) series of substituted sorbitan derivatives.

A large variety of molding materials may be used for the production of uniform foam tabs. In addition to metal molds or trays, conventional blister package materials such as, but not limited to, polyvinyl chloride (PVC) or polyvinylidiene chloride (PVDC) or fluorohalocarbon film (ACLAR available from Allied-Signal) may be used. The interior of the blister cavities may be coated with a release agent such as a silicone preparation. Other suitable surfaces for drying foam tablets include TEFLON-coated sheets, POREX polyethylene sheets, and polystyrene plastic sheets or molds. Release of the dried foam tablets may be enhanced by coating the surfaces with a silicone mold release agent, vegetable oils, lecithin, glycerin or talc prior to deposition of the foam onto these surfaces. Materials such as glycerin serve the purposes of lubricating and softening the foam and conferring flexibility and resistance to friability to the dried dosage forms.

As used throughout the specification liquid forms is understood to include without limitation neat liquids, solutions, suspensions, emulsions, dispersions and the like.

The following examples are provided as specific embodiments of the present invention. Other modifications of this invention will be readily apparent to those skilled in these arts without departing from the scope of the present invention. Unless noted to the contrary all measurements are weight and g is understood to be grams.

Claim 1 of 24 Claims

1. A method of preparing an edible comestible suitable for human consumption, comprising:

providing a polymeric foaming agent; optionally a non-cellulosic polysaccharide, a solvent and a therapeutically effective dose of a pharmaceutically active ingredient; admixing said polymeric foaming agent, non-cellulosic polysaccharide, solvent and pharmaceutically active ingredient; forming a foam dispersion from the admixed mixture; drying said foam dispersion to provide a dried foam with a density of less than about 0.40 grams/cubic centimeter.

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