WO2008079963A2

WO2008079963A2 - Pharmaceutical compositions comprising ionic complexes of active pharmaceutical ingredients

Info

Publication number: WO2008079963A2
Application number: PCT/US2007/088354
Authority: WO
Inventors: Erik T. Michalson; Brian T. Becicka; Paul A. Jass; Rachel N. Catherman
Original assignee: Cambrex Charles City Inc
Current assignee: Cambrex Charles City Inc
Priority date: 2006-12-22
Filing date: 2007-12-20
Publication date: 2008-07-03
Anticipated expiration: 2009-06-22
Also published as: WO2008079963A3

Abstract

The present invention relates to pharmaceutical compositions comprising ionic complexes of anion-containing APIs as new chemical entities. Such ionic complexes of the anion-containing APIs have utility for preparing oral delivery forms of the respective APIs. The invention further provides methods for the preparation and oral delivery of ionic complexes of APIs having an amine functionality.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING IONIC COMPLEXES QF ACTIVE PHARMACEUTICAL INGREDIENTS

[01] This application claims benefit of U.S. Provisional Patent Application 60/871,476 filed December 22, 2006, the entirety of which is incorporated herein by reference.

FIELD OF THE INVENTION

[02] The present invention relates to pharmaceutical compositions comprising ionic complexes of APIs as new chemical entities. Such ionic complexes of the APIs have utility for preparing oral delivery forms of the respective APIs. The invention further provides methods for the preparation and oral delivery of ionic complexes of active pharmaceutical ingredients (hereafter APIs) having an amine functionality.

BACKGROUND OF THE INVENTION

[03] The preparation of a palatable dosage form of an active pharmaceutical ingredient (API) has long been an approach for helping to ensure patient compliance with a prescribed oral drug treatment regimen. Taste masking of an API, particularly those APIs which have an extremely unpleasant taste, has generally been attempted by some combination of (i) coating the API with a film, or (ii) forming a complex of the API with an ion-exchange matrix material.

[04] For example, U.S. 5,075,1 14 describes a fluidized bed method of coating a pharmaceutical agent for taste-masking purposes. The patent describes the coating as a blend of cellulosic materials, i.e., hydroxypropyl cellulose and either cellulose acetate, cellulose acetate butyrate, or both. A number of drugs are mentioned, including ibuprofen, loperamide, famotidine, cimetidine, and ranitidine.

[05] U.S. 5,082,669 describes ethyl cellulose coatings for bitter-tasting drugs. A number of drugs are mentioned as possibilities (at column 3, lines 13-31). The coating is prepared using either a film-forming solution or dispersion, or a spraying technique (column 5, lines 36-50). [06] Based on its Abstract, it appears that JP 57058631 describes coating a granulated API using a combination of an insoluble polymer coating agent, such as ethyl cellulose, and several polymer coating agents of varying solubility characteristics as a way of masking a bitter taste of a drug.

[07] U.S. 5,032,393 suggests that the bitter taste of ranitidine can be masked by absorbing ranitidine hydrochloride onto a sulfonated styrene resin crosslinked with divinylbenzene or a methacrylic acid-divinylbenzene resin.

[08] U.S. 3,594,470 and the related publication, Borodkin and Sundberg, J. of Pharmaceutical Sciences, 60(10): 1523- 1527 (1971), describe coating weak ion exchange resins previously complexed with basic-reacting APIs, such as dextromethorphan, with a mixture of ethylcellulose and hydroxypropylmethyl cellulose as a prelude to making chewable tablets.

[09] Example XII of U.S. 4,851,226 describes a coating formulation for taste-masking loperamide, supplied as the HCl salt presumably in the form of granules having a particle size of 40-60 mesh, comprising a blend of cellulose acetate and polyvinylpyrrolidone.

[10] In U.S. 5,075,114, loperamide, supplied as the HCl salt presumably in the form of granules having a particle size of 40-80 mesh, is taste-masked in Example X by a coating comprising a blend of cellulose acetate and hydroxypropyl cellulose.

[11] U.S. 5,215,755 describes in Example VIII a coating formulation for taste-masking loperamide, supplied as the HCl salt presumably in the form of a powder having a particle size of 40-80 mesh, comprising a blend of hydroxyethyl cellulose and hydroxypropyl cellulose.

[12] U.S. 5,489,436 describes a coating formulation for taste-masking loperamide in Example VIII comprising a mixture of cellulose acetate, polyvinylpyrrolidone and a copolymer of dimethylaminoethyl methacrylate and neutral methacrylic acid ester.

[13] The art continues to explore new ways for taste masking APIs. SUMMARY OF THE INVENTION

[14] The invention provides a pharmaceutical composition comprising an ionic complex of an active pharmaceutical ingredient (API) and a member selected from the group consisting of a sweetener, an acid salt, a polymer, and combinations thereof. The invention provides a pharmaceutical composition comprising an ionic complex of an anionic API and a member selected from the group consisting of a sweetener, an acid salt, a polymer, and combinations thereof. The invention provides a pharmaceutical composition wherein the API comprises an anionic group which is a member selected from the group consisting of carboxyl, carboxylate, sulfonate, sulfate, phosphate, phosphonate, amines, amides, and functional groups that can form a salt or complex.

[15] The invention provides a pharmaceutical composition comprising an ionic complex of an anion-containing API and a member selected from the group consisting of a sweetener, an acid salt, a polymer, and combinations thereof. The invention provides a pharmaceutical composition comprising an ionic complex of an anion-containing API and a taste masking agent which is a member selected from the group consisting of a sweetener, an acid salt, a polymer, and combinations thereof.

[16] The invention provides a pharmaceutical composition comprising an ionic complex of an anion-containing API and a sweetener. The invention provides a pharmaceutical composition comprising an ionic complex of an anion-containing API and a taste masking sweetener. The invention further provides a pharmaceutical composition, wherein the sweetener is a member selected from the group consisting of aspartame, saccharin, saccharin sodium, sodium cyclamate, xylitol, mannitol, sorbitol, lactose, sucrose, and acesulfame K. The invention further provides a method of preparing the pharmaceutical composition comprising combining an anion-containing API and a sweetener. The invention further provides a pharmaceutical composition wherein the sweetener is a member selected from the group consisting of aspartame, saccharin, saccharin sodium, sodium cyclamate, xylitol, mannitol, sorbitol, lactose, sucrose, and acesulfame K. [17] The invention provides a pharmaceutical unit dosage form comprising an ionic complex of an anion-containing API and a sweetener, wherein the dosage form is coated with a pharmaceutically acceptable coating. The invention further provides a pharmaceutical unit dosage form, wherein the sweetener is a member selected from the group consisting of sucrose, sorbitol, mannitol, saccharin, aspartame, acesulfame K, and the like. The invention further provides a pharmaceutical unit dosage form wherein the pharmaceutically acceptable coating is a member selected from the group consisting of polyethylene glycols, waxes, cellulose derivatives, polyacrylate derivatives, and the like. The invention further provides a method of preparing the pharmaceutical unit dosage form comprising combining an anion-containing API and a sweetener.

[18] The invention provides an oral dosage form comprising an ionic complex of an anion-containing API and a sweetener. The invention further provides an oral dosage form wherein the oral dosage form is a member selected from the group consisting of a capsule, a tablet, a wafer, a chewable tablet, a buccal tablet, a sub lingual tablet, a quick-dissolve tablet, an effervescent tablet, a granule, a gum, a pellet, a bead, a pill, a sachet, a sprinkle, a syrup, a dry syrup, a reconstitutable solid, a suspension, a lozenge, a troche, an oral suspension, a lozenge, an implant, a powder, a triturate, an enteric/controlled release coated tablet, a thin film, or a strip. The invention further provides a method of preparing the oral dosage form comprising combining an anion-containing API and a sweetener. The invention provides a controlled-release pharmaceutical formulation comprising an ionic complex of an anion-containing API and a sweetener.

[19] The invention provides a pharmaceutical composition comprising an ionic complex of an anion-containing API and a polymer. The invention provides a pharmaceutical composition comprising an ionic complex of an anion-containing API and a taste masking polymer. The invention further provides a pharmaceutical composition wherein the polymer is a member selected from the group consisting of carboxymethyl cellulose, sulfopropyl cellulose polymaleic acid, lignosulfonic acid, pharmaceutically acceptable salts thereof, and combinations thereof. The invention further provides a method of preparing the pharmaceutical composition, comprising combining an anion-containing API and a polymer.

[20] The invention provides a pharmaceutical composition comprising an ionic complex of an anion-containing API and a taste masking polymer, further comprising a sweetener. The invention provides a pharmaceutical unit dosage form comprising an anion-containing API and a polymer, wherein the dosage form is coated with a pharmaceutically acceptable coating. The invention further provides a pharmaceutical unit dosage form wherein the polymer is a member selected from the group consisting of carboxymethyl cellulose, sulfopropyl cellulose polymaleic acid, lignosulfonic acid, and pharmaceutically acceptable salts thereof. The invention further provides a pharmaceutical unit dosage form wherein the pharmaceutically acceptable coating is a member selected from the group consisting of polyethylene glycols, waxes, cellulose derivatives, and polyacrylate derivatives. The invention further provides a method of preparing the pharmaceutical unit dosage form comprising combining an anion-containing API and a polymer.

[21] The invention provides an oral dosage form comprising an ionic complex of an anion-containing API and a polymer. The invention further provides an oral dosage form wherein the oral dosage form is a member selected from the group consisting of a capsule, a tablet, a wafer, a chewable tablet, a buccal tablet, a sub lingual tablet, a quick-dissolve tablet, an effervescent tablet, a granule, a gum, a pellet, a bead, a pill, a sachet, a sprinkle, a syrup, a dry syrup, a reconstitutable solid, a suspension, a lozenge, a troche, an oral suspension, a lozenge, an implant, a powder, a triturate, an enterics/controlled release coated tablet, a thin film, or a strip. The invention further provides a method of preparing the oral dosage form comprising combining an anion-containing API and a polymer. The invention further provides an oral dosage form wherein the oral dosage form is enteric coated, coated for fast disintegration, seal coated, film coated, barrier coated, compress coated, or coated with an enzyme- degradable coating. The invention provides a controlled-release pharmaceutical formulation comprising an ionic complex of an anion-containing API and a polymer. [22] The invention provides a pharmaceutical composition comprising an ionic complex of an anion-containing API and a taste masking acid. The invention provides a pharmaceutical composition comprising an ionic complex of an anion-containing API and a taste masking acid, wherein the taste masking acid is a member selected from the group consisting of d-aspartate, 1-aspartate, d,l-aspartate, acetate, lactate, citrate, taurine, glutamic acid, saccharic acid, salicylic acid, glycine, tartaric acid, ascorbic acid, and saccharin salt. The invention further provides a method of preparing the pharmaceutical composition comprising combining an anion- containing API and a taste masking acid.

[23] The invention provides a pharmaceutical composition comprising an ionic complex of an anion-containing API and a taste masking acid, further comprising a sweetener. The invention provides a pharmaceutical unit dosage form comprising an ionic complex of an anion-containing API and a taste masking acid, wherein the dosage form is coated with a pharmaceutically acceptable coating. The invention further provides a pharmaceutical unit dosage form wherein the taste masking acid is a member selected from the group consisting of d-aspartate, 1-aspartate, d,l-aspartate, acetate, lactate, citrate, taurine, glutamic acid, saccharic acid, salicylic acid, glycine, tartaric acid, ascorbic acid, and saccharin salt. The invention further provides a pharmaceutical unit dosage form wherein the pharmaceutically acceptable coating is a member selected from the group consisting of polyethylene glycols, waxes, cellulose derivatives, and polyacrylate derivatives. The invention further provides a method of preparing the pharmaceutical unit dosage form comprising combining an anion-containing API and a taste masking acid.

[24] The invention provides an oral dosage form comprising an ionic complex of an anion-containing API and a taste masking acid. The invention further provides an oral dosage form wherein the oral dosage form is a member selected from the group consisting of a capsule, a tablet, a wafer, a chewable tablet, a buccal tablet, a sub lingual tablet, a quick-dissolve tablet, an effervescent tablet, a granule, a gum, a pellet, a bead, a pill, a sachet, a sprinkle, a syrup, a dry syrup, a reconstitutable solid, a suspension, a lozenge, a troche, an oral suspension, a lozenge, an implant, a powder, a triturate, an enterics/controlled release coated tablet, a thin film, or a strip. The invention further provides a method of preparing the oral dosage form comprising combining an anion-containing API and a taste masking acid. The invention provides a controlled-release pharmaceutical formulation comprising an ionic complex of an anion-containing API and a taste-masking acid.

[25] The invention provides a method of administering a pharmaceutical composition comprising an ionic complex of an anion-containing API and a sweetener to a patient in need thereof, the method comprising providing a unit dosage comprising the pharmaceutical composition comprising an ionic complex of an anion-containing API and a sweetener, administering to the patient the unit dosage form, further wherein the patient is a mammal, and further wherein the patient is a human.

[26] The invention provides a method of administering a pharmaceutical composition comprising an ionic complex of an anion-containing API and a taste masking acid to a patient in need thereof, the method comprising providing a unit dosage comprising the pharmaceutical composition comprising an anion-containing API and a taste masking acid, and administering to the patient the unit dosage form, further wherein the patient is a mammal, and further wherein the patient is a human.

The invention provides a method of administering a pharmaceutical composition comprising an ionic complex of an anion-containing API and a polymer to a patient in need thereof, the method comprising providing a unit dosage comprising the pharmaceutical composition comprising an ionic complex of an anion-containing API and a polymer, and administering to the patient the unit dosage form, further wherein the patient is a mammal, and further wherein the patient is a human.

DETAILED DESCRIPTION OF THE INVENTION

[27] The invention provides a pharmaceutical composition comprising an ionic complex of an active pharmaceutical ingredient (API) and a member selected from the group consisting of bivalent alkaline earth metals, a sweetener, an acid salt, a polymer, combinations thereof, and polymorphic forms thereof. The invention provides a pharmaceutical composition comprising an ionic complex of an anion-containing active pharmaceutical ingredient (API) and a member selected from the group consisting of bivalent alkaline earth metals, a sweetener, an acid salt, a polymer, combinations thereof, and polymorphic forms thereof. The invention provides a pharmaceutical composition comprising an ionic complex of an active pharmaceutical ingredient (API) and a member selected from the group consisting of bivalent alkaline earth metals, a sweetener, an acid salt, a polymer, combinations thereof, and polymorphic forms thereof, wherein the API comprises an anionic group. Examples of anionic groups include, but are not limited to, carboxyl, carboxylate, sulfonate, sulfate, phosphate, phosphonate, amines, amides, and functional groups that can form a salt or complex. The invention provides a pharmaceutical composition comprising an ionic complex of an anion-containing active pharmaceutical ingredient (API) and a taste masking agent wherein the taste masking agent is a member selected from the group consisting of bivalent alkaline earth metals, a sweetener, an acid salt, a polymer, combinations thereof, and polymorphic forms thereof.

[28] The invention provides a pharmaceutical composition comprising an ionic complex of an active pharmaceutical ingredient (API) and a bivalent alkaline earth metal. The invention provides a pharmaceutical composition comprising an ionic complex of an anion-containing API and a taste masking bivalent alkaline earth metal. The invention provides a pharmaceutical composition comprising an ionic complex of an anion-containing API and a bivalent alkaline earth metal, wherein the bivalent alkaline earth metal is a member selected from the group consisting of calcium and magnesium

[29] The invention provides a pharmaceutical unit dosage form comprising an ionic complex of an anion-containing API and a bivalent alkaline earth metal, wherein the dosage form is coated with a pharmaceutically acceptable coating. The invention provides a pharmaceutical unit dosage form comprising an ionic complex of an anion-containing API and a bivalent alkaline earth metal, wherein the alkaline earth metal is selected from the group consisting of Ca++ and Mg++. The invention provides a pharmaceutical unit dosage form comprising an ionic complex of an anion-containing API and a bivalent alkaline earth metal, wherein the dosage form is coated with a pharmaceutically acceptable coating.

[30] The invention provides an oral dosage form comprising an ionic complex of an anion-containing API and a bivalent alkaline earth metal. The invention provides an oral dosage form comprising an ionic complex of an anion-containing API and a bivalent alkaline earth metal, wherein the bivalent alkaline earth metal is a member selected from the group consisting of calcium and magnesium. The invention provides a method of preparing an oral dosage form comprising an ionic complex of an anion-containing API and a bivalent alkaline earth metal, comprising combining an anion-containing API and a bivalent alkaline earth metal into an oral dosage form.

[31] The invention provides an oral dosage form comprising an ionic complex of an anion-containing API and a polymer. The invention provides a method of preparing an oral dosage form comprising an ionic complex of an anion-containing API and a polymer.

[32] The invention provides an oral dosage form, wherein the oral dosage form is a member selected from the group consisting of a capsule, a tablet, a wafer, a chewable tablet, a buccal tablet, a sub lingual tablet, a quick-dissolve tablet, an effervescent tablet, a granule, a gum, a pellet, a bead, a pill, a sachet, a sprinkle, a syrup, a dry syrup, a reconstitutable solid, a suspension, a lozenge, a troche, an oral suspension, a lozenge, an implant, a powder, a triturate, an enterics/controlled release coated tablet, a thin film, or a strip.

[33] The invention provides an oral dosage form, wherein the oral dosage form is enteric coated, coated for fast disintegration, seal coated, film coated, barrier coated, compress coated, or coated with an enzyme-degradable coating.

[34] The invention provides a method of administering a pharmaceutical composition comprising an ionic complex of an anion-containing API and a bivalent alkaline earth metal to a patient in need thereof, the method comprising providing a unit dose comprising the pharmaceutical composition comprising an ionic complex of an anion-containing API and a bivalent alkaline earth metal, and administering to the patient the unit dosage form, wherein the patient is a mammal, and wherein the patient is a human.

[35] The invention provides the use of a pharmaceutical composition comprising an ionic complex of an anion-containing API and a sweetener for the preparation of a medicament for administration to a patient, further wherein the patient is a mammal, and further wherein the patient is a human.

[36] The invention provides the use of a pharmaceutical composition comprising an ionic complex of an API and a sweetener for the preparation of a medicament for administration to a patient, further wherein the patient is a mammal, and further wherein the patient is a human.

[37] The invention provides the use of a pharmaceutical composition comprising an ionic complex of an anion-containing API and a taste masking acid for the preparation of a medicament for administration to a patient, further wherein the patient is a mammal, and further wherein the patient is a human.

[38] The invention provides the use of a pharmaceutical composition comprising an ionic complex of an API and a taste masking acid for the preparation of a medicament for administration to a patient, further wherein the patient is a mammal, and further wherein the patient is a human.

[39] The invention provides the use of a pharmaceutical composition comprising an ionic complex of an anion-containing API and a taste masking polymer for the preparation of a medicament for administration to a patient, further wherein the patient is a mammal, and further wherein the patient is a human.

[40] The invention provides the use of a pharmaceutical composition comprising an ionic complex of an API and a taste masking polymer for the preparation of a medicament for administration to a patient, further wherein the patient is a mammal, and further wherein the patient is a human. [41] The invention provides a taste masking agent selected from the group consisting of bivalent alkaline earth metals, a sweetener, an acid salt, a polymer, combinations thereof, and polymorphic forms thereof.

[42] The invention provides ionic complexes comprising APIs and agents in a reversible association of molecules, atoms, or ions through weak non-covalent chemical bonds.

[43] The present invention is directed to methods for the preparation of taste-masked active pharmaceutical ingredients (APIs) for oral delivery. Taste masking can be defined as the perceived reduction of an undesirable taste commonly associated with a particular API. One of the most common tastes that must be masked in APIs is bitterness.

[44] The present invention provides methods for taste masking APIs having, for example, an amine functional group. The methods of the invention are premised on the discovery that it is possible to taste mask such anion-containing APIs either by forming certain ionic complexes with the API.

[45] Examples of anionic substituents include, but are not limited to, carboxyl, carboxylate, sulfonate, sulfate, phosphate, phosphonate, amines, amides groups, and functional groups that can form a salt or complex.

[46] The invention also provides the ionic complexes of the anion-containing APIs themselves as new chemical entities. Such ionic complexes of the anion-containing APIs have utility for preparing oral delivery forms of the respective APIs.

[47] In particular, the ionic complexes of these APIs can then be used to prepare a final pharmaceutical formulation using conventional oral dosage forms, such as a capsule, a tablet, a wafer, a chewable tablet, a buccal tablet, a sub lingual tablet, a quick- dissolve tablet, an effervescent tablet, a granule, a gum, a pellet, a bead, a pill, a sachet, a sprinkle, a syrup, a dry syrup, a reconstitutable solid, a suspension, a lozenge, a troche, an oral suspension, a lozenge, an implant, a powder, a triturate, an enterics/controlled release coated tablet, a thin film, or a strip, and other suitable pharmaceutical formulation techniques. [48] The invention provides a method for taste masking APIs by forming an acid salt or an acid complex between the API and a taste masking acid. Examples of taste masking acids include, but are not limited to, d-aspartate, 1-aspartate, d,l-aspartate, acetate, lactate, citrate, taurine, glutamic acid, saccharic acid, salicylic acid, glycine, tartaric acid, ascorbic acid, saccharin salt, aspartic acid, saccharin, taurine and carboxymethylcellulose, acetic acid, aconitic acid, adipic acid, alginic acid, anisic acid, ascorbic acid, 1-aspartic acid, benzoic acid, cholic acid, citric acid, desoxycholic acid, erythorbic acid, folic acid, fumaric acid, geranic acid, gibberellic acid & potassium gibberellate, D-gluconic acid, 1-glutamic acid, glycocholic acid, lactic acid, Laurie acid, 1-malic acid, malic acid, oleic acid, palmitic acid, salicylic acid, sorbic acid, stearic acid, succinic acid, sulfamic acid, tannic acid, tartaric acid, 1-taurine, taurocholic acid, vanillic acid, and/or from pharmaceutically acceptable salts of these taste masking acids.

[49] The invention provides a method for taste masking such amine function-containing APIs by forming a API-ionic complex between the API and a taste masking agent, wherein the taste masking agent is selected from the group consisting of bivalent alkaline earth metals, a sweetener, an acid salt, a polymer, combinations thereof, and polymorphic forms thereof.

[50] The invention also provides the API - ionic complexes themselves produced in accordance with the first and second aspects of the invention as described above. In this regard, the present invention is directed to compositions containing, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of an API-ionic complex produced in accordance with the first and second aspects, respectively described above. The invention provides taste masked compositions containing a substantially pure preparation of an API-ionic complex.

[51] As used throughout the specification and the claims the phrase "a substantially pure preparation" means, for example, that the API is greater than about 95 weight percent pure, i.e., it contains less than about five weight percent, generally between about one and about four weight percent, of impurity, by weight of the API.

[52] The API may comprise one or more anionic groups. Examples of anionic groups include, but are not limited to, carboxyl, carboxylate, sulfonate, sulfate, phosphate, phosphonate, amines, amides, sulfonamides, and groups that can be converted into the these groups by salt formation. Examples of anion-containing API are APIs having a primary, secondary or tertiary amine group, as part of its structure. The API may have a secondary or tertiary amine group, and examples include, but are not limited to, such APIs as dextromethorphan, diphenhydramine, phenylephrine, loperamide, cetirizine, Zolpidem, chlorpheniramine, loratadine, and desloratadine.

[53] In preparing a composition of an anion-containing API in accordance with the present invention, one can start with the API either in its acid salt form or in its free base form. In a preferred method, before contacting the respective API with either an appropriate taste masking acid or an appropriate taste masking calcium salt, the API is first converted to its free base form. Alternatively, in some circumstances the API in its acid salt form can be reacted with a basic (e.g., salt) form of the taste masking acid to produce a taste masked composition of the present invention. One embodiment of this technique is illustrated in the following examples by the taste masking of API acid salts using sodium carboxymethylcellulose (sodium CMC).

[54] In accordance with the invention, an API having an amine function and present in its free base form, such as dextromethorphan free base, diphenhydramine free base, phenylephrine free base, loperamide free based, cetirizine free base, Zolpidem free base, chlorpheniramine free base, loratadine free base, or desloratadine free base is contacted in an aqueous solution with a taste masking acid selected from, for example, the group consisting of aspartic acid, a pharmaceutically acceptable salt of aspartic acid, saccharine, a pharmaceutically acceptable salt of saccharine, taurine, a pharmaceutically acceptable salt of taurine, carboxymethylcellulose and a pharmaceutically acceptable salt of carboxymethylcellulose. [55] The taste masking acid may contact the API in solution. Preferably the API and the taste masking acid are contacted in an aqueous solution.

[56] In order to fully taste mask a particular quantity of an anion-containing API by the technique of forming a taste masked acid salt or a taste masked ionic complex, it is necessary that the taste masking acid be provided in substantially a stoichiometric equivalent amount relative to the API. A skilled worker will recognize the appropriate stoichiometry between any specific API and any particular taste masking agent based on their respective structures and in many cases it may not be a one-to- one mole ratio of API to acid. Preferably, the taste masking agent is provided in at least a small stoichiometric excess relative to the API. As used herein, the phrase "a small stoichiometric excess" means no more than about a 1.25 times the stoichiometric amount, i.e., no more than a 25% excess. Use of an even higher stoichiometric excess is possible and is considered to be included within the broad aspects of the present invention, but is less favored as these higher excesses often will result in higher costs either because of the added efforts to recover the excess material or because of the unnecessary waste of taste masking agent.

[57] If the taste masking agent is provided in less than a substantially stoichiometric equivalent amount, then all of the API may not be converted to the taste masked acid salt, or taste masked ionic complex form. API not so-converted must either be removed from the successfully taste masked API - ionic complex, so that the taste masked composition does not exhibit the undesired taste of the original API, or an alternative form of taste masking may be needed to mask the taste of the unconverted API in the composition. While these approaches are considered to be within the scope of the present invention, considerations of cost and simplicity suggest that the best approach is to convert the entire quantity of API to the desired taste masked complex.

[58] Examples of preferred taste masking agents are D-aspartic acid, DL-aspartic acid, saccharin, sodium saccharin, taurine, carboxymethylcellulose and sodium carboxymethylcellulose. [59] The API-ionic complex made in accordance with the present invention can be isolated as a substantially pure preparation by precipitation from solution with or without addition of an anti-solvent, or by evaporating the solvent from the reaction (salt-forming) mixture. The resulting solids can be dried, milled and sieved to the desired particle size. Alternatively, additional ingredients can be added to the mixture, before the isolation of the API - ionic complex, in order to produce directly a taste masked granule without first isolating the API - ionic complex. In this regard, a granulating adjuvant such as a polyethylene glycol (approximate M.W. of 3000), macrocrystalline cellulose, hydroxypropyl cellulose; hydroxypropyl methylcellulose; hydroxyethyl cellulose; polyvinyl alcohol; polyvinylpyrrolidone; carboxymethylcellulose, and silica combinations thereof, may be added to the API — ionic complex, or API - ionic complex solution before isolating the salt or complex, or otherwise removing the solvent, e.g., by evaporation. In this way, a taste masked composition or preparation containing from 10 to 100% by weight of the taste masked API acid salt, or acid complex can be recovered. Again, the resulting granular solids can be dried, milled and sieved to the desired particle size.

[60] The API-ionic complex made in accordance with the invention also can be isolated as a substantially pure preparation simply by filtering the so-formed solid API-ionic complex from the reaction solvent mixture and then dried to the desired moisture content. An anti-solvent may be used to reduce the solubility of the API-ionic complex prior to filtration. The resulting solids can be dried, milled and sieved to the desired particle size. Alternatively, additional ingredients can be added to the mixture before the isolation of the API-ionic complex, in order to produce directly a taste masked granule without first isolating the taste masked API-ionic complex. In this regard, a granulating adjuvant such as a polyethylene glycol (approximate M.W. of 3000), macrocrystalline cellulose, hydroxypropyl cellulose; hydroxypropyl methylcellulose; hydroxyethyl cellulose; polyvinyl alcohol; polyvinylpyrrolidone; carboxymethylcellulose, silica, and combinations thereof may be added to the API- ionic complex slurry before isolating the API-ionic complex, e.g., by removing the solvent such as by evaporation, as the evolving solids are granulated. In this way, a taste masked composition or preparation containing from 10 to 100% by weight of the taste masked API-ionic complex can be recovered. Again, the resulting granular solids can be dried, milled and sieved to the desired particle size.

[61] In the broad practice of the present invention, the anion-containing API to be taste- masked may belong to any class of therapeutic agents which can be administered orally, i.e., by mouth. Thus, the designation "API" as used herein, is meant to include any therapeutic or otherwise active agent, preferably a pharmaceutical compound or chemical that is capable of being orally administered. Generally, the APIs used in conjunction with the present invention are those APIs having an amine function, which are bitter or otherwise unpleasant-tasting and thus in need of taste masking.

[62] The invention provides polymorphic forms of the API-ionic complex. Polymorphism is the ability of a drug substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice. Polymorphism refers to the occurrence of different crystalline forms of the same drug substance. The invention provides amorphous forms of the API - ionic complex. Amorphous solids consist of disordered arrangements of molecules and do not possess a distinguishable crystal lattice. The invention provides solvates of the API - ionic complex. Solvates are crystalline solid adducts containing either stoichiometric or nonstoichiometric amounts of a solvent incorporated within the crystal structure. The invention provides hydrates of the API-ionic complex. If the incorporated solvent is water, the solvates are also commonly known as hydrates.

[63] The kinds of APIs that may benefit from the present invention include, without being limiting, antibiotics, antiviral agents, analgesics, anesthetics, anorexics, antiarthritics, antiasthmatic agents, anticonvulsants, antidepressants, antidiabetic agents, antidiarrheals, antihistamines, anti-inflammatory agents, antinauseants, antineoplastics, antiparkinsonism drugs, antipruritics, antipsychotics, antipyretics, antispasmodics, H₂ antagonists, antitussives, cardiovascular drugs, antiarrhythmics, antihypertensives, ACE inhibitors, diuretics, vasodilators, hormones, hypnotics, immunosuppressives, muscle relaxants, parasympatholytics, parasympathomimetics, psychostimulants, sedatives, antimigrane agents antituberculosis agents, tranquilizers vitamins and mineral supplements.

[64] Examples of antibiotic APIs that may benefit from the present invention include, without being limiting, tetracycline, penicillin V, or neomycin; hypnotics such as the barbiturates, methaqualone or mecloqualone; oral antidiabetics such as sulfamides or biguanides; antihistamines such as chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate, or promethazine; bronchodilators such as theophylline or hydroxyethyl theophylline; vasoconstrictors such as ephedrine or isoprenaline or naphazoline; and antitussants such as dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentane citrate, and chlophedianol hydrochloride. As noted above, the following anion-containing APIs, dextromethorphan, diphenhydramine, phenylephrine, loperamide, cetirizine, Zolpidem, chlorpheniramine, loratadine, and desloratadine, Chlorpropamide, Tromadol, Famotadine, Glipizide, Chlorpheniramine, Brompheniramine, Doxylamine, Fexofenadine, Lamotrigine, Resperdone, Meloxicam, Olanzapine, Toperimate, Paxil, Topamax.

[65] In the embodiments of the present invention which include active ingredients, the active ingredients suitable for use in the pharmaceutical compositions and methods of the present invention are not particularly limited, as the compositions are surprisingly capable of effectively delivering a wide variety of active ingredients. The active ingredient can be hydrophilic, lipophilic, amphophilic or hydrophobic, and can be solubilized, dispersed, or partially solubilized and dispersed. Such active ingredients can be any compound or mixture of compounds having therapeutic or other value when administered to an animal, particularly to a mammal, such as drugs, nutrients, cosmeceuticals, diagnostic agents, nutriceuticals, nutritional agents, and the like.

[66] Suitable APIs are not limited by therapeutic category, and can be, for example, analgesics, anti-inflammatory agents, antihelmimthics, anti-arrhythmic agents, antibacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti- malariale, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, .beta.-Blockers, cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastro-intestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, cox-2 inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti- obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, non-essential fatty acids, and mixtures thereof.

[67] Specific, non-limiting examples of suitable APIs for use according to the present invention are: acetretin, albendazole, albuterol, aminoglutethimide, amiodarone, amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone, azithromycin, baclofen, beclomethasone, benezepril, benzonatate, betamethasone, bicalutanide, budesonide, bupropion, busulfan, butenafine, calcifediol, calcipotriene, calcitriol, camptothecin, candesartan, capsaicin, carbamezepine, carotenes, celecoxib, cerivastatin, cetirizine, chlorpheniramine, cholecalciferol, cilostazol, cimetidine, cinnarizine, ciprofloxacin, cisapride, clarithromycin, clemastine, clomiphene, clomipramine, clopidogrel, codeine, coenzyme QlO, cyclobenzaprine, cyclosporin, danazol, dantrolene, dexchlorpheniramine, diclofenac, dicoumarol, digoxin, dehydroepiandrosterone, dihydroergotamine, dihydrotachy sterol, dirithromycin, dimenhydrinate, donezepil, docusate, efavirenz, eposartan, ergocalciferol, ergotamine, essential fatty acid sources, etodolac, etoposide, escitalopram, famotidine, fenofibrate, fentanyl, fexofenadine, finasteride, fluconazole, flurbiprofen, fluvastatin, fosphenytoin, frovatriptan, furazolidone, gabapentin, gemfibrozil, glibenclamide, glipizide, glyburide, glimepiride, griseofulvin, halofantrine, ibuprofen, irbesartan, irinotecan, isosorbide dinitrate, isotretinoin, itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine, lansoprazole, leflunomide, lisinopril, loperamide, loratadine, lovastatin, L-thryroxine, lutein, lycopene, medroxyprogesterone, mifepristone, mefloquine, megestrol acetate, methadone, methoxsalen, metronidazole, miconazole, midazolam, miglitol, minoxidil, mitoxantrone, montelukast, nabumetone, nalbuphine, naratriptan, nelfinavir, nifedipine, nilsolidipine, nilutanide, nitrofurantoin, nizatidine, omeprazole, oprevelkin, oestradiol, ondransetron, oxaprozin, paclitaxel, paracalcitol, paroxetine, pentazocine, pioglitazone, pizofetin, pravastatin, prednisolone, probucol, progesterone, pseudoephedrine, pyridostigmine, rabeprazole, raloxifene, rofecoxib, repaglinide, rifabutine, rifapentine, rimexolone, ritanovir, rizatriptan, rosiglitazone, saquinavir, scopolamine, sertraline, sibutramine, sildenafil citrate, simvastatin, sirolimus, spironolactone, sumatriptan, tacrine, tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene, telmisartan, teniposide, terbinafine, terazosin, tetrahydrocannabinol, tiagabine, ticlopidine, tirofibran, tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin, troglitazone, trovafloxacin, ubidecarenone, valsartan, venlafaxine, verteporfin, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K, zafirlukast, zileuton, zolmitriptan, Zolpidem, and zopiclone. Of course, salts, isomers and derivatives of the above-listed hydrophobic active ingredients may also be used, as well as mixtures, and polymorphic forms.

[68] Further suitable APIs are not limited by therapeutic category, and can be, for example, analgesics, anti-inflammatory agents, antihelminthics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, antidiabetics, an ti -epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosuppressants, antiprotozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, .beta.-Blockers, cardiac inotropic agents, corticosteroids, diuretics, antiparkinsonian agents, gastro-intestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, cox-2 inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, nonessential fatty acids, and mixtures thereof, and polymorphic forms. [69] Furthermore, the API can be a cytokine, a peptidomimetic, a peptide, a protein, a toxoid, a serum, an antibody, a vaccine, a nucleoside, a nucleotide, a portion of genetic material, a nucleic acid, or a mixture thereof.

[70] Specific, non-limiting examples of suitable APIs also include: acarbose; acyclovir; acetyl cysteine; acetylcholine chloride; alatrofloxacin; alendronate; aglucerase; amantadine hydrochloride; ambenomium; amifostine; amiloride hydrochloride; aminocaproic acid; amphotericin B; antihemophilic factor (human), antihemophilic factor (porcine); antihemophilic factor (recombinant), aprotinin; asparaginase; atenolol; atracurium besylate; atropine; azithromycin; aztreonam; BCG vaccine; bacitracin; becalermin; belladona; bepridil hydrochloride; bleomnycin sulfate; calcitonin human; calcitonin salmon; carboplatin; capecitabine; capreomycin sulfate; cefamandole nafate; cefazolin sodium; cefepime hydrochloride; cefixime; cefonicid sodium; cefoperazone; cefotetan disodium; cefotaxime; cefoxitin sodium; ceftizoxime; ceftriaxone; cefuroxime axetil; cephalexin; cephapirin sodium; cholera vaccine; chorionic gonadotropin; cidofovir; cisplatin; cladribine; clidinium bromide; clindamycin and clindamycin derivatives; ciprofloxacin; clodronate; colistimethate sodium; colistin sulfate; corticotropin; cosyntropin; cromolyn sodium; cytarabine; dalteparin sodium; danaparoid; desferrioxamine; denileukin diflitox; desmopressin; diatrizoate meglumine and diatrizoate sodium; dicyclomine; didanosine; dirithromycin; dopamine hydrochloride; dornase alpha; doxacurium chloride; doxorubicin; etidronate disodium; enalaprilat; enkephalin; enoxaparin; enoxaprin sodium; ephedrine; epinephrine; epoetin alpha; erythromycin; esmolol hydrochloride; factor IX; famciclovir; fludarabine; fluoxetine; foscarnet sodium; ganciclovir; granulocyte colony stimulating factor, granulocyte-macrophage stimulating factor; growth hormones— recombinant human; growth hormone—bovine; gentamycin; glucagon; glycopyrolate; gonadotropin releasing hormone and synthetic analogs thereof; GnRH; gonadorelin; grepafloxacin; haemophilus B conjugate vaccine; Hepatitis A virus vaccine inactivated; Hepatitis B virus vaccine inactivated; heparin sodium; indinavir sulfate; influenza virus vaccine; interleukin-2; interleukin- 3; insulin-human, insulin lispro; insulin procine; insulin NPH; insulin aspart; insulin glargine; insulin detemir; interferon alpha; interferon beta; ipratropium bromide; ifosfamide; Japanese encephalitis virus vaccine; lamivudine; leucovorin calcium; leuprolide acetate, levofloxacin; lincomycin and lincomycin derivatives; lobucavir; lomefloxacin; loracarbef; mannitol; is measles virus vaccine; meningococcal vaccine; menotropins; mepenzolate bromide; mesalamine; methenamine; methotrexate; methscopolamine; metformin hydrochloride; metoprolol; mezocillin sodium; mivacurium chloride; mumps viral vaccine; nedocromil sodium; neostigmine bromide; neostigmine methyl sulfate; neurontin; norfloxacin; octreotide acetate; ofloxacin; olpadronate; oxytocin; pamidronate disodium; pancuronium bromide; paroxetine; perfloxacin; pentamidine isethionate; pentostatin; pentoxifylline; periciclovir; pentagastrin; pentholamine mesylate; phenylalanine; physostigmine salicylate; plague vaccine; piperacillin sodium; platelet derived growth factor-human; pneumococcal vaccine polyvalent; polio virus vaccine inactivated; poliovirus vaccine live (OPV); polymyxin B sulfate; pralidoxime chloride; pramlintide, pregabalin; propafenone; propenthaline bromide; pyridostigmine bromide; rabies vaccine; residronate; ribavarin; rimantadine hydrochloride; rotavirus vaccine; salmeterol xinafoate; sinealide; small pox vaccine; solatol; somatostatin; sparfloxacin; spectinomycin; stavudine; streptokinase; streptozocin; suxamethonium chloride; tacrine hydrochloride; terbutaline sulfate; thiopeta; ticarcillin; tiludronate; timolol; tissue type plasminogen activator; TNFR:Fc; TNK-tPA; trandolapril; trimetrexate gluconate; trospectinomycin; trovafloxacin; tubocurarine chloride; tumor necrosis factor; typhoid vaccine live; urea; urokinase; vancomycin; valacyclovir; valsartan; varicella virus vaccine live; vasopressin and vasopressin derivatives; vecuronium bromide; vinblastine; vincristine; vinorelbine; vitamin B 12; warfarin sodium; yellow fever vaccine; zalcitabine; zanamivir; zolendronate; zidovudine; pharmaceutically acceptable salts, isomers and derivatives thereof; and mixtures thereof, and polymorphic forms.

[71] Examples of taste masked pharmaceutical complexes include, but are not limited to, dextromethorphan calcium acetate complex; dextromethorphan calcium saccharate complex; dextromethorphan aspartate salt; dextromethorphan salt of a mixture of aspartic acid and saccharin; dextromethorphan taurine salt; dextromethorphan carboxymethylcellulose complex; loperamide calcium acetate complex; loperamide calcium saccharate complex; loperamide aspartate salt; loperamide salt of a mixture of aspartic acid and saccharin; loperamide taurine salt; loperamide carboxymethylcellulose complex; Alendronate calcium acetate complex; Alendronate calcium saccharate complex; Alendronate aspartate salt; Alendronate salt of a mixture of aspartic acid and saccharin; Alendronate taurine salt; Alendronate carboxymethylcellulose complex; Brompheniramine calcium acetate complex; Brompheniramine calcium saccharate complex; Brompheniramine aspartate salt; Brompheniramine salt of a mixture of aspartic acid and saccharin; Brompheniramine taurine salt; Brompheniramine carboxymethylcellulose complex; Cetirizine calcium acetate complex; Cetirizine calcium saccharate complex; Cetirizine aspartate salt; Cetirizine salt of a mixture of aspartic acid and saccharin; Cetirizine taurine salt; Cetirizine carboxymethylcellulose complex; Chlorpheniramine calcium acetate complex; Chlorpheniramine calcium saccharate complex; Chlorpheniramine aspartate salt; Chlorpheniramine salt of a mixture of aspartic acid and saccharin; Chlorpheniramine taurine salt; Chlorpheniramine carboxymethylcellulose complex; Diphenhydramine calcium acetate complex; Diphenhydramine calcium saccharate complex; Diphenhydramine aspartate salt; Diphenhydramine salt of a mixture of aspartic acid and saccharin; Diphenhydramine taurine salt; Diphenhydramine carboxymethylcellulose complex; Loperamide calcium acetate complex; Loperamide calcium saccharate complex; Loperamide aspartate salt; Loperamide salt of a mixture of aspartic acid and saccharin; Loperamide taurine salt; Loperamide carboxymethylcellulose complex; ondansetron calcium acetate complex; ondansetron calcium saccharate complex; ondansetron aspartate salt; ondansetron salt of a mixture of aspartic acid and saccharin; ondansetron taurine salt; ondansetron carboxymethylcellulose complex; Phenylephrine calcium acetate complex; Phenylephrine calcium saccharate complex; Phenylephrine aspartate salt; Phenylephrine salt of a mixture of aspartic acid and saccharin; Phenylephrine taurine salt; Phenylephrine carboxymethylcellulose complex; Pseudoephedrine calcium acetate complex; Pseudoephedrine calcium saccharate complex; Pseudoephedrine aspartate salt; Pseudoephedrine salt of a mixture of aspartic acid and saccharin; Pseudoephedrine taurine salt; Pseudoephedrine carboxymethylcellulose complex; Zolpidem calcium acetate complex; Zolpidem calcium saccharate complex; Zolpidem aspartate salt; Zolpidem salt of a mixture of aspartic acid and saccharin; Zolpidem taurine salt; Zolpidem carboxymethylcellulose complex; Dimenhydrinate calcium acetate complex; Dimenhydrinate calcium saccharate complex; Dimenhydrinate aspartate salt; Dimenhydrinate salt of a mixture of aspartic acid and saccharin; Dimenhydrinate taurine salt; Dimenhydrinate carboxymethylcellulose complex; Ranitidine calcium acetate complex; Ranitidine calcium saccharate complex; Ranitidine aspartate salt; Ranitidine salt of a mixture of aspartic acid and saccharin; Ranitidine taurine salt; Ranitidine carboxymethylcellulose complex; Escitalopram calcium acetate complex; Escitalopram calcium saccharate complex; Escitalopram aspartate salt; Escitalopram salt of a mixture of aspartic acid and saccharin; Escitalopram taurine salt; Escitalopram carboxymethylcellulose complex; Fexofenadine calcium acetate complex; Fexofenadine calcium saccharate complex; Fexofenadine aspartate salt; Fexofenadine salt of a mixture of aspartic acid and saccharin; Fexofenadine taurine salt; Fexofenadine carboxymethylcellulose complex; Ofloxacin calcium acetate complex; Ofloxacin calcium saccharate complex; Ofloxacin aspartate salt; Ofloxacin salt of a mixture of aspartic acid and saccharin; Ofloxacin taurine salt; Ofloxacin carboxymethylcellulose complex; Docusate calcium acetate complex; Docusate calcium saccharate complex; Docusate aspartate salt; Docusate salt of a mixture of aspartic acid and saccharin; Docusate taurine salt; Docusate carboxymethylcellulose complex; Paroxetine calcium acetate complex; Paroxetine calcium saccharate complex; Paroxetine aspartate salt; Paroxetine salt of a mixture of aspartic acid and saccharin; Paroxetine taurine salt; Paroxetine carboxymethylcellulose complex; Scopolamine calcium acetate complex; Scopolamine calcium saccharate complex; Scopolamine aspartate salt; Scopolamine salt of a mixture of aspartic acid and saccharin; Scopolamine taurine salt; Scopolamine carboxymethylcellulose complex; Zolmitriptan calcium acetate complex; Zolmitriptan calcium saccharate complex; Zolmitriptan aspartate salt; Zolmitriptan salt of a mixture of aspartic acid and saccharin; Zolmitriptan taurine salt; Zolmitriptan carboxymethylcellulose complex; and polymorphs thereof.

[72] In most cases, standard granulating equipment and drying apparatus can be used to produce pharmaceutical compositions of the API - ionic complex, or taste masked API - ionic complexes of the present invention. Such equipment and apparatus are well known to those skilled in the art. For example, pan granulators and rotor granulators along with spray drying and drum drying procedures may be suitable. Preferred ways of performing the original salt/complex formation and subsequent granulation thereof may include use of paddle dryers or fluidized bed plow mixers. As one suitable piece of equipment one can use the Tilt-A-Mix mixer available from Processall, Inc.

[73] An advantage of the techniques used in practicing the present invention is that one can produce granules having a uniform distribution of the API - ionic complex, or the taste masked API-ionic complex. In this way, one can be confident that when these granules are used to prepare the ultimate oral dosage form, whether in the form of a film (such as a fast melt film), a tablet (including chewable tablets and fast dissolving tablets), a capsule, an oral suspension, a gum, a lozenge, or the like dosage forms, one is precisely providing the desired quantity of the API, and not an undesired lower or higher amount of the API. The invention provides an oral dosage form which may be a capsule, a tablet, a wafer, a chewable tablet, a buccal tablet, a sub-lingual tablet, a quick-dissolve tablet, an effervescent tablet, a granule, a gum, a pellet, a bead, a pill, a sachet, a sprinkle, a syrup, a dry syrup, a reconstitutable solid, a suspension, a lozenge, a troche, an oral suspension, a lozenge, an implant, a powder, a triturate, an enterics/controlled release coated tablet, a thin film, or a strip.

[74] When making a final dosage form using the API-ionic complex containing granules of the present invention any of the wide variety of excipients commonly used in making pharmaceutical preparations can be used. For example, disintegrants, coloring agents, flavoring agents, lubricants, fillers and the like materials can be employed with the inventive granular composition of this invention. The present invention is not to be limited to any specific set of excipients. Suitable pharmaceutical excipients include but are not limited to, polymers, resins, plasticizers, fillers, binders, lubricants, glidants, disintegrants, solvents, co-solvents, buffer systems, surfactants, preservatives, sweetening agents, flavoring agents, pharmaceutical grade dyes or pigments, and viscosity agents, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, lactose, mannitol, sorbitol, tribasic calcium phosphate, dibasic calcium phosphate, compressible sugar, starch, calcium sulfate, dextro and microcrystalline cellulose, acacia, tragacanth, hydroxypropylcellulose, pregelatinized starch, gelatin, povidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, sugar solutions, such as sucrose and sorbitol, and ethylcellulose, and the like.

[75] The invention provides extended release formulations for the therapeutically active agent. For example, the pharmaceutical composition of the invention includes a controlled release, sustained release, or timed release dosage formulation for the therapeutically active agent. The extended release formulation as described herein can provide continuous and non-pulsating therapeutic levels of the therapeutically active agent to a mammal in need of such treatment over a period of time, such as a six-hour period or longer, e.g., a twelve-hour to twenty-four hour period. Such an extended release, controlled release, sustained release, or timed release dosage formulation employs a mixture of an organic acid and water-soluble polymers, e.g., a high molecular weight hydroxypropyl methylcellulose and polyvinylpyrrolidone.

[76] The invention provides extended release formulations having, for example, a core of a pharmaceutical mixture, and a coating layer of a pharmaceutically acceptable coating material. The pharmaceutical mixture may further include pharmaceutically acceptable excipients, fillers, binders and blending agents, such as hydrous or anhydrous form of lactose, starches, glucose, sucrose, mannitol, sorbitol, silicic acid, microcrystalline celluloses, sodium carboxymethylcelluloses, sodium starch glycolate, and derivatives and mixtures thereof.

[77] The pharmaceutical mixture may further include pharmaceutically acceptable excipients, fillers, binders and blending agents, such as hydrous or anhydrous form of lactose, starches, glucose, sucrose, mannitol, sorbitol, silicic acid, microcrystalline cellulose, sodium carboxymethylcellulose, sodium starch glycolate, and derivatives and mixtures thereof. [78] The core of the pharmaceutical mixture can be prepared in a form of granules, particles, beads, spherical beads, pellets, coated beads, coated pellets, coated particles, and other pharmaceutically acceptable shapes and sizes. This can be done by various granulation methods and other methods, such as wet and dry granulations. Wet granulation is prepared by mixing required components with various conventional well-known solvents to form granules. Alternatively, dry granulation techniques may be used to prepare the pharmaceutical composition. The mixture of the core of the pharmaceutical composition can then be incorporated into solid dosage forms, such as tablets and others, and an optional external coating is applied. For making compressed tablets, a conventional tabletting machine may be used to compress a granulated mixture of the components of the present invention into a tablet. In an alternative embodiment, the invention provides a method for preparing an extended release formulation by preparing a pharmaceutical mixture into a core and coating the core with a pharmaceutically acceptable coating material. The coated core is then incorporated into solid dosage forms.

[79] The invention provides pharmaceutical unit dosage forms, wherein the dosage form is coated with a pharmaceutically acceptable coating. The pharmaceutically acceptable coating material includes, but is not limited to, a rapid-disintegrating coating material, a colorant, an enteric polymer, a plasticizer, a water-soluble polymer, a water-insoluble polymer, a dye, a pigment, other disintegrants, combinations thereof, and polymorphic forms thereof, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose succinate, carboxymethylethylcellulose, cellulose acetophthalate. In addition, examples of plasticizers include polyethylene glycol (PEG), propylene glycol, and others, water-soluble polymers include hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene oxide, and others.

[80] In yet another embodiment, a method of administering an extended release pharmaceutical composition is provided. The method includes administering the pharmaceutical composition of the invention having a therapeutically active agent in an effective amount to treat, for example, a mammal. [81] The invention provides pharmaceutically acceptable coating of bulk active material. The invention provides pharmaceutically acceptable coating of bulk material comprising ionic complexes of anion-containing APIs. The invention provides pharmaceutically acceptable coating of bulk active material, wherein the material is taste masked. The invention provides pharmaceutically acceptable coating of bulk material comprising ionic complexes of anion-containing APIs, wherein the material is taste masked. The pharmaceutically acceptable coating material includes, but is not limited to, a rapid-disintegrating coating material, a colorant, an enteric polymer, a plasticizer, a water-soluble polymer, a water-insoluble polymer, a dye, a pigment, other disintegrants, combinations thereof, and polymorphic forms thereof, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose succinate, carboxymethylethylcellulose, cellulose acetophthalate. In addition, examples of plasticizers include polyethylene glycol (PEG), propylene glycol, and others, water-soluble polymers include hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene oxide, and others.

[82] The step of providing the pharmaceutically active agent with the coating includes a treatment for coating onto portions of the pharmaceutically active agent. The drying includes applying heat to the bottom of the carrier surface. Moreover, the drying may include applying microwave energy to the film. Useful methods for providing the pharmaceutically active agent with the coating include fluidized bed coating, spray congealing coating, agglomeration or granulation coating, entrapment coating, coaccervation coating, infusion coating, spin coating, and ion exchange coating of the pharmaceutically active agent.

[83] The pharmaceutically acceptable polymers of the instant invention include, but are not limited to, water-soluble hydrophilic polymers, maltodextrin, natural gums, arabic gum, guar gum, xanthan gum, tragacanth gum, agar, gellan gum, kayara gum, alginic acids, pectins, pre-gelatinized starch, dextrin, maltodextrin, and blends of these polymers, combinations thereof, and polymorphic forms thereof. Examples of water-soluble polymers include polyvinylpyrrolidone, hydroxypropyl cellulose (HPC; Klucel), hydroxypropyl methylcellulose (HPMC; Methocel), nitrocellulose, hydroxypropyl ethylcellulose, hydroxypropyl butylcellulose, hydroxypropyl pentylcellulose, methyl cellulose, ethylcellulose (Ethocel), hydroxyethyl cellulose, various alkyl celluloses and hydroxyalkyl celluloses, various cellulose ethers, cellulose acetate, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, vinyl acetate/crotonic acid copolymers, poly-hydroxyalkyl methacrylate, hydroxymethyl methacrylate, methacrylic acid copolymers, polymethacrylic acid, polymethylmethacrylate, maleic anhydride/methyl vinyl ether copolymers, poly vinyl alcohol, sodium and calcium polyacrylic acid, polyacrylic acid, acidic carboxy polymers, carboxypolymethylene, carboxyvinyl polymers, polyoxyethylene polyoxypropylene copolymer, polymethylvinylether co-maleic anhydride, carboxymethylamide, potassium methacrylate divinylbenzene copolymer, polyoxyethyleneglycols, polyethylene oxide, and derivatives, salts, and mixtures thereof.

[84] Routine organoleptic screening can be used to identify satisfactorily taste masked compositions from those that are not. In particular, a suitable screening test for evaluating the suitability of the methods of the present invention for taste masking a specific , anion-containing API involves preparing a solution or suspension of about 4 mmol of the taste masked API in 13 ml of water. The mixture is then agitated for about 1-2 hours and then an approximate 5μL sample of the mixture is tasted. The taste of an aqueous solution or suspension of the untreated API at the same concentration should be evaluated contemporaneously. The relative taste of the taste masked API can be rated on a scale of 1 to 4, where 4 signifies that the taste of the untreated API is the same as the taste masked sample and 1 signifies that the taste masked API has no significant taste. By having the taste masked APIs considered by a panel of tasters (preferably three or more), an average level of taste masking can be determined. While any rating below 4 indicates a level of taste masking, satisfactory taste masking is usually considered when an average of 2 or lower is attained, which is indicative of a significantly reduced negative taste.

[85] Organoleptic screening can utilize, for example, an electronic tongue (e.g. α-Astree Electronic Tongue, Alpha-MOS), which is an instrument used to detect chemical analytes in solutions. In certain instances, the electronic tongue is used to simulate a mammalian organoleptic system. In general, an electronic tongue is a system having an array of sensors that are used in conjunction with pattern-recognition algorithms. Using the combination of chemical sensors, which produce a fingerprint of the analyte, the recognition algorithms can identify and/or quantify the analytes of interest. The electronic tongue is thus capable of recognizing chemical analytes,. The effectiveness of the taste masking of the formulations of the invention can be assessed by comparison to their relative placebo. The placebo contains all ingredients of the formulation except the active principle. Alternatively, the effectiveness of the taste masking of the formulations of the invention can be assessed by comparison to, for example, the free base of the API, or a pharmaceutical salt of the API.

[86] Suitable examples of pharmaceutically acceptable sweeteners for the oral formulations include, but are not limited to, aspartame, saccharin, saccharin sodium, sodium cyclamate, xylitol, mannitol, sorbitol, lactose, sucrose, Acesulfame potassium, Alitame, Aspartame, and Aspartame-Acesulfame Salt, Cyclamate, Neohesperidine dihydrochalcone, Neotame, Saccharin, Sucralose, Stevia, Tagalose. Suitable sweeteners include both natural and artificial sweeteners. Non-limiting examples of suitable sweeteners include, e.g.: water-soluble sweetening agents such as monosaccharides, disaccharides and polysaccharides such as xylose, ribose, glucose (dextrose), mannose, galactose, fructose (levulose), sucrose (sugar), maltose, invert sugar (a mixture of fructose and glucose derived from sucrose), partially hydrolyzed starch, corn syrup solids, dihydrochalcones, monellin, steviosides, and glycyrrhizin; water-soluble artificial sweeteners such as the soluble saccharin salts, i.e., sodium or calcium saccharin salts, cyclamate salts, the sodium, ammonium or calcium salt of 3, 4-dihydro-6-methyl-l, 2,3-oxathiazine-4-one-2, 2-dioxide, the potassium salt of 3, 4-dihydro-6-methyl-l, 2,3-oxathiazine-4-one-2, 2-dioxide (acesulfame-K), the free acid form of saccharin and the like; dipeptide based sweeteners, such as L-aspartic acid derived sweeteners, such as L-aspartyl-L- phenylalanine methyl ester (aspartame), L-alpha-aspartyl-N- (2, 2,4, 4- tetramethyl- 3-thietanyl)-D-alaninamide hydrate, methyl esters of L-aspartyl-L- phenylglycerin and L-aspartyl-L-2, 5, dihydrophenylglycine, L-aspartyl-2,5-dihydro-L- phenyl alanine, L-aspartyl-L- (l-cyclohexyen)-alanine, and the like; d. water-soluble sweeteners derived from naturally occurring water-soluble sweeteners, such as a chlorinated derivatives of ordinary sugar (sucrose), known, for example, under the product description of sucralose; and protein based sweeteners such as thaurnatoccous danielli (Thaumatin I and II).

[87] As used in this specification and in the appended claims, the singular forms "a", "an" and "the" also are intended to include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "an API" includes reference to one or more APIs (drugs), and the like.

[88] The invention is further illustrated by the following examples, which are not to be construed as limiting.

Example 1

[89] Dextromethorphan Aspartic acid salt: An aqueous mixture is prepared from dextromethorphan free base (5.4 parts by weight) and a molar excess of racemic aspartic acid (DL-aspartic acid) (2.7 parts by weight) in 70 parts by weight water. The solution is prepared by mixing these ingredients with slight heating. The noted acid salt can be isolated for later use, or can be used directly to produce taste masked granules, for example by mixing the acid salt solution with 13 parts by weight of a 23% by weight aqueous solution of polyethylene glycol (M.W. 3350) and then 6 parts microcrystalline cellulose. The homogeneous mixture is then concentrated under vacuum (Rotovap) at 65⁰C to produce a solid granular product containing over 45% of dextromethorphan aspartate.

Example 2

[90] Dextromethorphan Aspartic Acid/Saccharin salt (90/10): An aqueous mixture is prepared from dextromethorphan free base (5.4 parts by weight) and a molar excess of a combination of racemic aspartic acid and saccharin (2.4 parts by weight and 0.4 parts by weight respectively) in 70 parts by weight water. The solution is prepared by mixing these ingredients with slight heating. The noted mixed acid salt can be isolated for later use, or can be used directly to produce taste masked granules, for example by mixing the acid salt solution with 13 parts by weight of a 23% by weight aqueous solution of polyethylene glycol (M.W. 3350) and then 6 parts macrocrystalline cellulose. The homogeneous mixture is then concentrated under vacuum (Rotovap) at 65°C to produce a solid granular product containing over 45% of an approximately 90:10 by weight mixture of dextromethorphan aspartate and dextromethorphan saccharine salt.

Example 3

[91] Diphenhydramine Aspartic Acid salt: An aqueous mixture is prepared from a diphenhydramine acid salt (the HCl salt). First, the free base of diphenhydramine HCl is prepared by adding 1.48 parts by weight of a 50% by weight sodium hydroxide solution to diphenhydramine HCl (5.4 parts by weight) and 70 parts by weight water. A molar excess of racemic aspartic acid (2.68 parts by weight) then is added. The solution is prepared by mixing these ingredients with a slight heating as needed. The noted acid salt can be isolated for later use, or can be used directly to produce taste masked granules, for example by mixing the acid salt solution with 13 parts by weight of a 23% by weight aqueous solution of polyethylene glycol (M.W. 3350) and then 6 parts macrocrystalline cellulose. The homogeneous mixture is concentrated under vacuum (Rotovap) at 65°C to produce a solid granular product containing over 40% of diphenhydramine aspartate.

Example 4

[92] Dextromethorphan Sodium Carboxymethylcellulose salt: An aqueous mixture is prepared from a dextromethorphan acid salt (the HCl salt). First, the free base of dextromethorphan (2.7 parts by weight) is neutralized with IN HCl (20 mLs) in 140 parts by weight water. Following the application of heat (heating the acid salt solution to 75 to 80 ⁰C), a molar excess (7.3 parts by weight) of sodium carboxymethylcellulose (Na CMC) is mixed with slight heating as needed. The above-noted NaCMC-acid salt of dextromethorphan can be isolated by concentrating under vacuum (Rotovap) at 65⁰C to produce a solid granular product.

Example 5

[93] Diphenhydramine Sodium Carboxymethylcellulose salt: : An aqueous mixture is prepared from a diphenhydramine acid salt (the HCl salt). A solution of diphenhydramine HCl is prepared by stirring, with heat to a temperature of 75-80 0C, 2.9 parts of diphenhydramine HCl and 140.3 parts by weight water. A molar excess of sodium carboxymethylcellulose (Na CMC) (7.3 parts by weight) then is added. A homogeneous mixture is prepared by mixing these ingredients with slight heating as needed. The above-noted acid salt is isolated for later use by concentrating it under vacuum (Rotovap) at 65°C to produce a solid granular product.

Example 6

[94] Phenylephrine Sodium Carboxymethylcellulose salt: An aqueous mixture is prepared from a phenylephrine acid salt (the HCl salt). A solution of phenylephrine HCl is prepared by stirring, with heat to a temperature of 75-80 ⁰C, 2.0 parts of phenylephrine HCl and 140.3 parts by weight water. A molar excess of sodium carboxymethylcellulose (Na CMC) (7.3 parts by weight) then is added. A homogeneous mixture is prepared by mixing these ingredients with slight heating as needed. The above-noted acid salt is isolated for later use by concentrating it under vacuum (Rotovap) at 65°C to produce a solid granular product.

Example 7

[95] Dextromethorphan Calcium Acetate Complex: An aqueous mixture is prepared by stirring at room temperature for one hour a mixture of dextromethorphan free base (20 parts by weight); 296.3 parts by weight water and a stoichiometric excess of calcium acetate (11.7 parts by weight). The above-noted acid salt is isolated for later use by filtering the so-formed solids and oven drying the solids to produce a solid granular product. Alternatively, the solid salt also can be used directly to produce taste masked granules, for example by mixing the acid salt slurry with 43 parts by weight of a 15% by weight aqueous solution of polyethylene glycol (M.W. 3350) and then 13.7 parts macrocrystalline cellulose. The homogeneous mixture is then concentrated under vacuum (Rotovap) at 65°C to produce a solid granular product.

Example 8

[96] Dextromethorphan Calcium Saccharate Complex: An aqueous mixture is prepared by stirring with heating a mixture of dextromethorphan free base (5.4 parts by weight); 70 parts by weight water and a stoichiometric excess of calcium saccharate (2.7 parts by weight). The above-noted complex can be isolated for later use by filtering the so-formed solids and oven drying the solids to produce a solid granular product. Alternatively, the complex (the resulting mixture) also can be used directly to produce taste masked granules, for example by mixing the resulting mixture with 13 parts by weight of about a 23% by weight aqueous solution of polyethylene glycol and then 6 parts microcrystalline cellulose. The homogeneous mixture is then concentrated under vacuum (Rotovap) at 65°C to produce a solid granular product.

Example 9

[97] Bitterness Evaluation Using the α-Astree Electronic Tongue: A quantitative evaluation of bitterness reduction can be achieved through sample analysis using the α-Astree Electronic Tongue. Three samples are prepared to allow comparison of bitterness: 1) untreated API 2) Taste-masked API 3) Placebo of water and/or inert ingredients. Sample 1 and 2 are prepared as aqueous solutions or suspensions equivalent to 4 mg API/ml of water. The samples are analyzed using an array of seven potentiometric sensors capable of providing a numerical value for bitterness response. Based upon these results, the distance between the placebo, taste-masked API, and untreated API (Control) can be determined and a percent reduction in bitterness can be determined. Increased distance from the placebo indicates increased bitterness. An illustrative example of taste-masked Diphenhydramine in the form of Diphenhydramine Aspartate is provided below. Table 1

Based upon the data in the table above, formation of the diphenhydramine aspartate salt provides a 39% reduction in bitterness from commercially available diphenhydramine HCl. Using the α-Astree electronic tongue, several examples of taste-masked APIs were evaluated, and the results are set forth in Table 2.

Table 2

Based upon the data in Table 2, formation of the phenylephrine Ca complex resulted in a 100% reduction in bitterness, formation of phenylephrine Ca granules resulted in a 100% reduction in bitterness, and formation of chlorpheniramine Ca granules resulted in a 37% reduction in bitterness.

[98] The present invention has been described with reference to specific embodiments. However, this application is intended to cover those changes and substitutions that may be made by those skilled in the art without departing from the spirit and the scope of the invention. Unless otherwise specifically indicated, all percentages are by weight. Throughout the specification and in the claims the term "about" is intended to encompass + or - 5% and preferably is only about + or - 2%.

Claims

1. A pharmaceutical composition comprising an ionic complex of an active pharmaceutical ingredient (API) and a member selected from the group consisting of a sweetener, an acid salt, a polymer, and combinations thereof.

2. A pharmaceutical composition comprising an ionic complex of an anionic API and a member selected from the group consisting of a sweetener, an acid salt, a polymer, and combinations thereof.

3. The pharmaceutical composition of claim 1, wherein the API comprises an anionic group which is a member selected from the group consisting of carboxyl, carboxylate, sulfonate, sulfate, phosphate, phosphonate, amines, amides, and functional groups that can form a salt or complex.

4. A pharmaceutical composition comprising an ionic complex of an anion-containing API and a member selected from the group consisting of a sweetener, an acid salt, a polymer, and combinations thereof.

5. A pharmaceutical composition comprising an ionic complex of an anion-containing API and a taste masking agent which is a member selected from the group consisting of a sweetener, an acid salt, a polymer, and combinations thereof.

6. A pharmaceutical composition comprising an ionic complex of an anion-containing API and a sweetener.

7.A pharmaceutical composition comprising an ionic complex of an anion-containing API and a taste masking sweetener.

8. The pharmaceutical composition of claim 6, wherein the sweetener is a member selected from the group consisting of aspartame, saccharin, saccharin sodium, sodium cyclamate, xylitol, mannitol, sorbitol, lactose, sucrose, and acesulfame K.

9. A method of preparing the pharmaceutical composition of claim 6, comprising combining an anion-containing API and a sweetener.

10. The pharmaceutical composition of claim 7 wherein the sweetener is a member selected from the group consisting of aspartame, saccharin, saccharin sodium, sodium cyclamate, xylitol, mannitol, sorbitol, lactose, sucrose, and acesulfame K.

I L A pharmaceutical unit dosage form comprising an ionic complex of an anion-containing API and a sweetener, wherein the dosage form is coated with a pharmaceutically acceptable coating.

12. The pharmaceutical unit dosage form of claim 11, wherein the sweetener is a member selected from the group consisting of sucrose, sorbitol, mannitol, saccharin, aspartame, acesulfame K, and the like.

13. The pharmaceutical unit dosage form of claim 11, wherein the pharmaceutically acceptable coating is a member selected from the group consisting of polyethylene glycols, waxes, cellulose derivatives, polyacrylate derivatives, and the like.

14. A method of preparing the pharmaceutical unit dosage form of claim 11, comprising combining an anion-containing API and a sweetener.

15. An oral dosage form comprising an ionic complex of an anion-containing API and a sweetener.

16. The oral dosage form of claim 15, wherein the oral dosage form is a member selected from the group consisting of a capsule, a tablet, a wafer, a chewable tablet, a buccal tablet, a sub lingual tablet, a quick-dissolve tablet, an effervescent tablet, a granule, a gum, a pellet, a bead, a pill, a sachet, a sprinkle, a syrup, a dry syrup, a reconstitutable solid, a suspension, a lozenge, a troche, an oral suspension, a lozenge, an implant, a powder, a triturate, an enteric/controlled release coated tablet, a thin film, or a strip.

17. A method of preparing the oral dosage form of claim 15, comprising combining an anion-containing API and a sweetener.

18. A controlled-release pharmaceutical formulation comprising an ionic complex of an anion-containing API and a sweetener.

19. A pharmaceutical composition comprising an ionic complex of an anion-containing API and a polymer.

20. A pharmaceutical composition comprising an ionic complex of an anion-containing API and a taste masking polymer.

21. The pharmaceutical composition of claim 20, wherein the polymer is a member selected from the group consisting of carboxymethyl cellulose, sulfopropyl cellulose polymaleic acid, lignosulfonic acid, pharmaceutically acceptable salts thereof, and combinations thereof.

22. A method of preparing the pharmaceutical composition of claim 20, comprising combining an anion-containing API and a polymer.

23. A pharmaceutical composition comprising an ionic complex of an anion-containing API and a taste masking polymer, further comprising a sweetener.

24. A pharmaceutical unit dosage form comprising an anion-containing API and a polymer, wherein the dosage form is coated with a pharmaceutically acceptable coating.

25. The pharmaceutical unit dosage form of claim 24, wherein the polymer is a member selected from the group consisting of carboxymethyl cellulose, sulfopropyl cellulose polymaleic acid, lignosulfonic acid, and pharmaceutically acceptable salts thereof.

26. The pharmaceutical unit dosage form of claim 24, wherein the pharmaceutically acceptable coating is a member selected from the group consisting of polyethylene glycols, waxes, cellulose derivatives, and polyacrylate derivatives.

27. A method of preparing the pharmaceutical unit dosage form of claim 24, comprising combining an anion-containing API and a polymer.

28. An oral dosage form comprising an ionic complex of an anion-containing API and a polymer.

29. The oral dosage form of claim 28, wherein the oral dosage form is a member selected from the group consisting of a capsule, a tablet, a wafer, a chewable tablet, a buccal tablet, a sub lingual tablet, a quick-dissolve tablet, an effervescent tablet, a granule, a gum, a pellet, a bead, a pill, a sachet, a sprinkle, a syrup, a dry syrup, a reconstitutable solid, a suspension, a lozenge, a troche, an oral suspension, a lozenge, an implant, a powder, a triturate, an enterics/controlled release coated tablet, a thin film, or a strip.

30. A method of preparing the oral dosage form of claim 28, comprising combining an anion-containing API and a polymer.

31. The oral dosage form of claim 28, wherein the oral dosage form is enteric coated, coated for fast disintegration, seal coated, film coated, barrier coated, compress coated, or coated with an enzyme-degradable coating.

32. A controlled-release pharmaceutical formulation comprising an ionic complex of an anion-containing API and a polymer.

33. A pharmaceutical composition comprising an ionic complex of an anion-containing API and a taste masking acid.

34. A pharmaceutical composition comprising an ionic complex of an anion-containing API and a taste masking acid, wherein the taste masking acid is a member selected from the group consisting of d-aspartate, 1-aspartate, d,l-aspartate, acetate, lactate, citrate, taurine, glutamic acid, saccharic acid, salicylic acid, glycine, tartaric acid, ascorbic acid, and saccharin salt.

35. A method of preparing the pharmaceutical composition of claim 33, comprising combining an anion-containing API and a taste masking acid.

36. A pharmaceutical composition comprising an ionic complex of an anion-containing API and a taste masking acid, further comprising a sweetener.

37. A pharmaceutical unit dosage form comprising an ionic complex of an anion-containing API and a taste masking acid, wherein the dosage form is coated with a pharmaceutically acceptable coating.

38. The pharmaceutical unit dosage form of claim 37, wherein the taste masking acid is a member selected from the group consisting of d-aspartate, 1-aspartate, d,l-aspartate, acetate, lactate, citrate, taurine, glutamic acid, saccharic acid, salicylic acid, glycine, tartaric acid, ascorbic acid, and saccharin salt.

39. The pharmaceutical unit dosage form of claim 37, wherein the pharmaceutically acceptable coating is a member selected from the group consisting of polyethylene glycols, waxes, cellulose derivatives, and polyacrylate derivatives.

40. A method of preparing the pharmaceutical unit dosage form of claim 33, comprising combining an anion-containing API and a taste masking acid.

41. An oral dosage form comprising an ionic complex of an anion-containing API and a taste masking acid.

42. The oral dosage form of claim 41, wherein the oral dosage form is a member selected from the group consisting of a capsule, a tablet, a wafer, a chewable tablet, a buccal tablet, a sub lingual tablet, a quick-dissolve tablet, an effervescent tablet, a granule, a gum, a pellet, a bead, a pill, a sachet, a sprinkle, a syrup, a dry syrup, a reconstitutable solid, a suspension, a lozenge, a troche, an oral suspension, a lozenge, an implant, a powder, a triturate, an enterics/controlled release coated tablet, a thin film, or a strip.

43. A method of preparing the oral dosage form of claim 41, comprising combining an anion-containing API and a taste masking acid.

44. A controlled-release pharmaceutical formulation comprising an ionic complex of an anion-containing API and a taste -masking acid.

45. A method of administering a pharmaceutical composition comprising an ionic complex of an anion-containing API and a sweetener to a patient in need thereof, the method comprising:

- providing a unit dosage comprising the pharmaceutical composition comprising an ionic complex of an anion-containing API and a sweetener;

- administering to the patient the unit dosage form.

46. The method of claim 45, wherein the patient is a mammal.

47. The method of claim 45, wherein the patient is a human.

48. A method of administering a pharmaceutical composition comprising an ionic complex of an anion-containing API and a taste masking acid to a patient in need thereof, the method comprising:

- providing a unit dosage comprising the pharmaceutical composition comprising an anion-containing API and a taste masking acid; and

- administering to the patient the unit dosage form.

49.The method of claim 48, wherein the patient is a mammal.

50. The method of claim 48, wherein the patient is a human.

51. A method of administering a pharmaceutical composition comprising an ionic complex of an anion-containing API and a polymer to a patient in need thereof, the method comprising

- providing a unit dosage comprising the pharmaceutical composition comprising an ionic complex of an anion-containing API and a polymer; and

- administering to the patient the unit dosage form.

52.The method of claim 51, wherein the patient is a mammal.

53. The method of claim 51 , wherein the patient is a human.