WO2000023046A1

WO2000023046A1 - Chewable or dissolvable pharmaceutical compositions suitable for oral administration

Info

Publication number: WO2000023046A1
Application number: PCT/US1999/023877
Authority: WO
Inventors: Shan-Shan Sheu
Original assignee: Bush Boake Allen Inc.
Priority date: 1998-10-16
Filing date: 1999-10-16
Publication date: 2000-04-27

Abstract

This invention pertains to chewable or dissolvable pharmaceutical compositions suitable for oral administration. The pharmaceutical compositions comprise (a) a therapeutically effective amount of a pharmaceutical active in the free amine form, which pharmaceutical active is unpleasant tasting in the amine acid salt form; (b) a pharmaceutically acceptable acid; and (c) a pharmaceutically acceptable carrier. The pharmaceutical active, pharmaceutically acceptable acid, and pharmaceutically acceptable carrier are in solid form, and an aqueous mixture of the pharmaceutical composition has a pH value from about 2 to about 7. The pharmaceutical compositions suitable for oral adminstration may be used in a wide variety of solid oral vehicles such as chewable and nonchewable hard and soft confections including lozenges, tablets, and powders. The present invention also provides methods for preparing and using these pharmaceutical compositions and the formulations in which they may be employed.

Description

CHEWABLE OR DISSOLVABLE PHARMACEUTICAL COMPOSITIONS

SUITABLE FOR ORAL ADMINISTRATION

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention pertains to chewable or dissolvable pharmaceutical compositions suitable for oral administration. The pharmaceutical compositions comprise (a) a therapeutically effective amount of a pharmaceutical active in the free amine form, which pharmaceutical active is unpleasant tasting in the amine acid salt form; (b) a pharmaceutically acceptable acid; and (c) a pharmaceutically acceptable carrier. The pharmaceutical active, pharmaceutically acceptable acid, and pharmaceutically acceptable carrier are in solid form, and an aqueous mixture of the pharmaceutical composition has a pH value from about 2 to about 7. The pharmaceutical compositions suitable for oral administration may be used in a wide variety of solid oral vehicles such as chewable and nonchewable hard and soft confections including lozenges, tablets, and powders. The present invention also provides methods for preparing and using these pharmaceutical compositions and the formulations in which they may be employed. 2. Description of the Background

Chewable or dissolvable tablets and lozenges are often preferred by patients who have difficulty swallowing solid medications. A problem arises when the pharmaceutical active in the chewable tablet or lozenge has a strong bitter taste, such as when the pharmaceutical active contains an amine or amide group. Such pharmaceutical products have limited user acceptability and compliance. Sweetening agents, flavoring agents, and various diluents have been used to minimize or mask unpleasant tastes. Other taste modification methods include polymer encapsulation, viscosity increase, and adsorption of the pharmaceutical active onto silicon dioxide.

United States patent no. 5, 196,436 (Smith) discloses an antitussive composition consisting essentially of an effective amount of dextromethorphan and an orally-acceptable pharmaceutical carrier. The pharmaceutical carrier is a buffer system such that the antitussive composition, when mixed with saliva in the mouth, is within the pH range of about 8 to about 11. Because dextromethorphan is relatively insoluble in water at the pH of this composition, Smith states that a sufficient level of a cosolvent, such as ethanol, propylene glycol, polyethylene glycol, glycerin, or sorbitol, should be incorporated in the pharmaceutical carrier to provide for dissolution of the dextromethorphan.

United States patent no. 5,560,913 (Kupper) discloses a pharmaceutical composition comprising from about 1 : 1 to about 90: 1 of an unpleasant tasting pharmaceutical active; an effective amount of an aloe vera component for taste masking the unpleasant tasting pharmaceutical active; and an orally acceptable carrier. The aloe vera component contains no more than about 1 : 1 anthraquinones and the ratio of the unpleasant tasting pharmaceutical active to aloe vera component is at least about 1.5: 1.

While the above pharmaceutical compositions provide some degree of taste masking of pharmaceutically actives, none of the above compositions are entirely satisfactory taste masked pharmaceutical compositions. The present invention provides pharmaceutical compositions suitable for oral administration without the disadvantages which are characteristic of previously known products. The pharmaceutical compositions may be used in a wide variety of solid oral vehicles. The present invention also provides methods for preparing and using these pharmaceutical compositions and the formulations in which they may be employed.

SUMMARY OF THE INVENTION

The present invention is directed at a chewable or dissolvable pharmaceutical composition suitable for oral administration which comprises: (a) a therapeutically effective amount of a pharmaceutical active in the free amine form, which pharmaceutical active is unpleasant tasting in the amine acid salt form;

(b) a pharmaceutically acceptable acid; and

(c) a pharmaceutically acceptable carrier; wherein the pharmaceutical active, pharmaceutically acceptable acid, and pharmaceutically acceptable carrier are in solid form, and an aqueous mixture of the pharmaceutical composition has a pH value from about 2 to about 7.

The present invention is also directed at a method for treating an ailment in a human which comprises orally administering to a human, in need thereof, a chewable or dissolvable pharmaceutical composition which comprises:

(a) a therapeutically effective amount of a pharmaceutical active in the free amine form, which pharmaceutical active is unpleasant tasting in the amine acid salt form; (b) a pharmaceutically acceptable acid; and

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed at chewable or dissolvable pharmaceutical compositions in which the unpleasant taste of a pharmaceutical active is reduced thus rendering the pharmaceutical compositions suitable for oral administration. Many poorly soluble pharmaceutical actives containing an amine group are converted to the amine acid salt form to increase the water-solubility, dissolution, and bioavailability of the active. Pharmaceutical actives in the amine acid salt form, however, often have unpleasant tastes. The pharmaceutical compositions of the present invention comprise a pharmaceutical active in the free amine form, a pharmaceutically acceptable acid, and a pharmaceutically acceptable carrier, all in solid form. The pharmaceutical active is employed in the substantially water-insoluble free amine form to minimize the bitter taste of the active. During oral ingestion of the pharmaceutical composition, the pharmaceutically acceptable acid can slowly react with the pharmaceutical active in the free amine form converting the active to the water-soluble amine acid salt form. The otherwise unpleasant taste of a pharmaceutical active can thus be reduced in accordance with the present invention rendering the pharmaceutical compositions suitable for oral administration. The present invention also provides methods for preparing and using these pharmaceutical compositions and the formulations in which they may be employed.

The terms "ingestible" and "edible", as used herein, refer to all materials and compositions which can be safely taken into the body whether or not they perform a function in the body. These materials and compositions include those which are adsorbed, and those which are not absorbed as well as those which are digestible and non-digestible. The term "chewable or dissolvable" pharmaceutical composition, as used herein, refers to a pharmaceutical composition which may be chewed or dissolved in the mouth to obtain the desired pharmacological result without the need to swallow the entire tablet or capsule.

In accord with the present invention, the chewable or dissolvable pharmaceutical compositions suitable for oral administration comprise:

(c) a pharmaceutically acceptable carrier; wherein the pharmaceutical active, pharmaceutically acceptable acid, and pharmaceutically acceptable carrier are all in solid form, and an aqueous mixture of the pharmaceutical composition has a pH value from about 2 to about 7.

The pharmaceutical active in the present invention may be selected from a wide variety of pharmaceutical actives which contain an amine group, are unpleasant tasting in the water-soluble amine acid salt form, but are sufficiently water-insoluble so as not to be unpleasant tasting in the free amine form. The pharmaceutical active must have a pharmacological action and must be suitable for oral administration. Preferred pharmaceutical actives are may be selected from the group consisting of dextromethorphan, pseudoephedrine, and diphenhydramine. More preferably, the pharmaceutical active is dextromethorphan.

Dextromethorphan is an antitussive agent used in cough syrups and hard and chewable tablets. Because the free base form of dextromethorphan is practically insoluble in water, the acid salts of dextromethorphan are often used, especially dextromethorphan hydrobromide (dextromethorphan HBr). The water- solubility of dextromethorphan hydrobromide at 25 °C is 1.5% and the pH of a 1 % aqueous solution is 5.2-6.5. Dextromethorphan hydrobromide has an unpleasant bitter taste with an associated burning sensation and numbing feel.

Diphenhydramine (2-diphenylmethoxy-N,N-dimethylethanamine) is an antihistamine agent. The hydrochloride salt of diphenhydramine has a bitter taste. One gram of diphenhydramine hydrochloride dissolves in one gram of water and the pH of a 1 % solution is about 5.5.

Pseudoephedrine (d-2-(methylamino)-l-phenylpropan-l-ol) is a decongestant agent. One gram of the hydrochloride salt of ephedrine dissolves in 4 ml of water with a pH about 6.

The pharmaceutical compositions of the present invention may be used in many distinct physical forms well known in the pharmaceutical art to provide an initial dosage of the pharmaceutical active and/or a further time-release form of the pharmaceutical active. Without being limited thereto, such physical forms include free forms and encapsulated forms, and mixtures thereof.

The amount of the pharmaceutical active employed in the inventive oral compositions is a therapeutically effective amount to provide a pharmaceutical composition that provides a known pharmacological effect. The exact amount of pharmaceutical active may vary depending upon the type of pharmaceutical active employed, the type of oral vehicle employed, and the level of pharmacological action desired. In general, the amount of pharmaceutical active present is the ordinary dosage required to obtain the desired result. Such dosages are known to the skilled practitioner in the pharmacological arts and are not a part of the present invention. In a preferred embodiment, the pharmaceutical active in the pharmaceutical composition is present in an amount from about 0.01 % to about 20%, preferably from about 0.1 % to about 10%, and more preferably from about 0.2% to about 5%, by weight.

The pharmaceutically acceptable acid in the present invention is an acid in solid form that is generally regarded as safe for human consumption, does not interfere with the pharmacological activity of the pharmaceutical active, and can lower the pH of the pharmaceutical composition to a value from about 2 to about 7. Nonlimiting suitable pharmaceutically acceptable acids may be selected from the group consisting of fumaric acid, adipic acid, citric acid, lactic acid, maleic acid, ascorbic acid, succinic acid, tartaric acid, sorbic acid, and malic acid. Preferred pharmaceutically acceptable acids may be selected from the group consisting of fumaric acid, adipic acid, and sorbic acid. More preferably, the pharmaceutically acceptable acid is fumaric acid.

The amount of the pharmaceutically acceptable acid employed in the inventive compositions is an amount such that an aqueous mixture of the pharmaceutical composition has a pH value from about 2 to about 7. The exact amount of pharmaceutically acceptable acid may vary depending upon the type of pharmaceutically acceptable acid employed, the type of pharmaceutical active employed, the type of oral vehicle employed, and the level of pharmacological action desired. In a preferred embodiment, the pharmaceutically acceptable acid is present in amount to lower the pH of a 10% aqueous mixture of the pharmaceutical composition to a value from about 2 to about 7, preferably from about 3 to about 7, and more preferably from about 4 to about 7.

The pharmaceutically acceptable carrier in the present invention may be used in a wide variety of oral vehicles. Nonlimiting examples of suitable pharmaceutically acceptable carriers or oral vehicles include hard and soft confections, lozenges, tablets, and powders.

The present invention extends to methods for preparing the pharmaceutical compositions. In such a method- the pharmaceutical composition is prepared by admixing the pharmaceutical active, pharmaceutically acceptable acid, and pharmaceutically acceptable carrier, all in solid form, together with any optional ingredients, to form a uniform mixture. The final compositions are readily prepared using standard methods and apparatus generally known by those skilled in the confectionery arts. The apparatus useful in accordance with the present invention comprises mixing apparatus well known in the confectionery arts, and therefore the selection of the specific apparatus will be apparent to the artisan. In a specific embodiment, the present invention is directed to a method for making a chewable or dissolvable pharmaceutical composition which comprises admixing: (a) a therapeutically effective amount of a pharmaceutical active in the free amine form, which pharmaceutical active is unpleasant tasting in the amine acid salt form;

(b) a pharmaceutically acceptable acid; and

In another embodiment, the present invention is directed at a method for treating an ailment in a human which comprises orally administering to a human, in need thereof, a chewable or dissolvable pharmaceutical composition which comprises:

(a) a therapeutically effective amount of a pharmaceutical active in the free amine form, which pharmaceutical active is unpleasant tasting in the amine acid salt form;

(b) a pharmaceutically acceptable acid; and

An important aspect of the present invention includes a confectionery composition incorporating the inventive pharmaceutical compositions suitable for oral administration and a method for preparing the confectionery compositions. The preparation of confectionery formulations is historically well known and has changed little through the years. Confectionery items have been classified as either "hard" confectionery or "soft" confectionery. The pharmaceutical compositions suitable for oral administration of the present invention can be incorporated into the confections by admixing the inventive composition into the conventional hard and soft confections.

Hard confectionery may be processed and formulated by conventional means. In general, a hard confectionery has a base composed of a mixture of sugar and other carbohydrate bulking agents kept in an amorphous or glassy condition. The hard confectionery may also be sugarless. This form is considered a solid syrup of sugars generally having from about 0.5% to about 1.5% moisture. Such materials normally contain up to about 92% sugar, up to about 55% corn syrup and from about 0.1 % to about 5% water, by weight of the final composition. The syrup component is generally prepared from sucrose and corn syrups, but may include other materials. Further ingredients such as flavorings, sweetening agents, acidulants, colorants and so forth may also be added.

Such confectionery may be routinely prepared by conventional methods such as those involving fire cookers, vacuum cookers, and scraped-surface cookers also referred to as high speed atmospheric cookers.

Fire cookers involve the traditional method of making a candy base. In this method, the desired quantity of carbohydrate bulking agent is dissolved in water by heating the agent in a kettle until the bulking agent dissolves. Additional bulking agent may then be added and cooking continued until a final temperature of 140° C. to 156° C. is achieved. The batch is then cooled and worked as a plasticlike mass to incorporate additives such as flavoring agents, colorants and the like.

A high-speed atmospheric cooker uses a heat-exchanger surface which involves spreading a film of candy on a heat exchange surface, the candy is heated to 165° C. to 170° C. in a few seconds. The confectionery is then rapidly cooled to 100° C. to 120° C. and worked as a plastic-like mass enabling incorporation of the additives, such as flavoring agents, colorants and the like.

In vacuum cookers, the carbohydrate bulking agent is boiled to 125° C. to 132° C , vacuum is applied and additional water is boiled off without extra heating. When cooking is complete, the mass is a semi-solid and has a plastic-like consistency. At this point, flavoring agents, colorants, and other additives are admixed in the mass by routine mechanical mixing operations.

The optimum mixing required to uniformly mix the flavoring agent, colorants and other additives during conventional manufacturing of hard confectionery is determined by the time needed to obtain a uniform distribution of the materials. Normally, mixing times of from 2 to 10 minutes have been found to be acceptable.

Once the candy mass has been properly tempered, it may be cut into workable portions or formed into desired shapes. A variety of forming techniques may be utilized depending upon the shape and size of the final product desired. A general discussion of the composition and preparation of hard confections may be found in H.A. Lieberman, Pharmaceutical Dosage Forms: Tablets, Volume 1 (1989), 3rd edition, Marcel Dekker, Inc. , New York, N.Y. at pages 419 to 582, which disclosure is incorporated herein by reference.

The apparatus useful in accordance with the present invention comprises cooking and mixing apparatus well known in the confectionery manufacturing arts, and therefore the selection of the specific apparatus will be apparent to the artisan.

In contrast, compressed tablet confections contain particular materials and are formed into structures under pressure. These confections generally contain sugars in amounts up to about 95%, by weight of the composition, and typical tablet excipients such as binders and lubricants as well as flavoring agents, colorants and so forth. These confections may also be sugarless.

Similar to hard confectionery, soft confectionery may be utilized in this invention. The preparation of soft confections, such as nougat, involves conventional methods, such as the combination of two primary components, namely

(1) a high boiling syrup such as a corn syrup, or the like, and (2) a relatively light textured frappe, generally prepared from egg albumin, gum arabic, gelatin, vegetable proteins, such as soy derived compounds, sugarless milk derived compounds, such as milk proteins, and mixtures thereof. The frappe is generally relatively light, and may, for example, range in density from about 0.5 to about

0.7 gram/cc.

The high boiling syrup, or "bob syrup" of the soft confectionery is relatively viscous and has a higher density than the frappe component, and frequently contains a substantial amount of carbohydrate bulking agent.

Conventionally, the final nougat composition is prepared by the addition of the "bob syrup" to the frappe under agitation, to form the basic nougat mixture. Further ingredients such as flavoring, additional carbohydrate bulking agent, colorants, preservatives, medicaments, mixtures thereof and the like may be added thereafter also under agitation. Soft confectioneries may also be prepared sugarless.

A general discussion of the composition and preparation of nougat confections may be found in B.W. Minifie, Chocolate, Cocoa and Confectionery: Science and Technology, 3rd edition, AVI Publishing Co. , Inc., Westport. Conn. (1989), at pages 576-580, which disclosure is incorporated herein by reference. The procedure for preparing the soft confectionery involves known procedures. In general, the frappe component is prepared first and thereafter the syrup component is slowly added under agitation at a temperature of at least about 65° C , and preferably at least about 100° C. The mixture of components is continued to be mixed to form a uniform mixture, after which the mixture is cooled to a temperature below 80° C, at which point, the flavor may be added. The mixture is further mixed for an additional period until it is ready to be removed and formed into suitable confectionery shapes.

In accordance with this invention, therapeutically effective amounts of the pharmaceutical compositions suitable for oral administration of the present invention may be admixed into the hard and soft confections. The exact amount of pharmaceutical composition employed is normally a matter of preference subject to such factors as the particular type of confection being prepared, the type of bulking agent or carrier employed, the type of flavor employed and the intensity of breath freshening perception desired. Thus, the amount of pharmaceutical composition may be varied in order to obtain the result desired in the final product and such variations are within the capabilities of those skilled in the art without the need for undue experimentation. In general, the amount of pharmaceutical composition normally present in a hard or soft confection will be from about 0.01 % to about 20%, preferably from about 0.1 % to about 10%, and more preferably from about 0.25% to about 5%, by weight of the confection.

In a preferred embodiment, the present invention is directed to a confectionery composition comprising:

(i) a confectionery bulking agent; and

(ii) a chewable or dissolvable pharmaceutical composition suitable for oral administration which comprises: (a) a therapeutically effective amount of a pharmaceutical active in the free amine form, which pharmaceutical active is unpleasant tasting in the amine acid salt form;

(b) a pharmaceutically acceptable acid; and

(c) a pharmaceutically acceptable carrier; wherein the pharmaceutical active, pharmaceutically acceptable acid, and pharmaceutically acceptable carrier are in solid form, and an aqueous mixture of the pharmaceutical composition has a pH value from about 2 to about 7. The present invention extends to methods for making the improved confections. The pharmaceutical compositions may be incorporated into an otherwise conventional hard or soft confection composition using standard techniques and equipment known to those skilled in the art. The apparatus useful in accordance with the present invention comprises mixing and heating apparatus well known in the confectionery manufacturing arts, and therefore the selection of the specific apparatus will be apparent to the artisan.

In such a method, a composition is made by admixing the inventive pharmaceutical composition into the confectionery composition along with the other ingredients of the final desired composition. Other ingredients will usually be incorporated into the composition as dictated by the nature of the desired composition as well known by those having ordinary skill in the art. The ultimate confectionery compositions are readily prepared using methods generally known in the food technology and pharmaceutical arts. Thereafter the confectionery mixture may be formed into desirable confectionery shapes.

The pharmaceutical compositions may be formulated with conventional ingredients which offer a variety of textures to suit particular applications. Such ingredients may be in the form of hard and soft confections, tablets, toffee, nougat, chewy candy, chewing gum and so forth, center filled candies, both sugar and sugarless. The acceptable ingredients may be selected from a wide range of materials. Without being limited thereto, such materials include diluents, binders and adhesives, lubricants, disintegrants, bulking agents, humectants, buffers, and adsorbents. The preparation of such confections and chewing gum products is well known.

The pharmaceutical compositions of this invention may also be in chewable form. To achieve acceptable stability and quality as well as good taste and mouth feel in a chewable formulation several considerations are important.

These considerations include the amount of active substance per tablet, the flavoring agent employed, the degree of compressibility of the tablet and the organoleptic properties of the composition.

Chewable pharmaceutical composition candy is prepared by procedures similar to those used to make soft confectionery. In a typical procedure, a boiled sugar-corn syrup blend is formed to which is added a frappe mixture. The boiled sugar-corn syrup blend may be prepared from sugar and corn syrup blended in parts by weight ratio of about 90: 10 to about 10:90. The sugar-corn syrup blend is heated to temperatures above about 120° C. to remove water and to form a molten mass. The frappe is generally prepared from gelatin, egg albumin, milk proteins such as casein, and vegetable proteins such as soy protein, and the like, which is added to a gelatin solution and rapidly mixed at ambient temperature to form an aerated sponge like mass. The frappe is then added to the molten candy mass and mixed until homogeneous at temperatures between about 65° C. and about 120° C.

The composition of the instant invention can then be added to the homogeneous mixture as the temperature is lowered to about 65° C.-95⁰ C. whereupon additional ingredients can then be added such as flavoring agents and coloring agents. The formulation is further cooled and formed into pieces of desired dimensions.

A general discussion of the lozenge and chewable tablet forms of confectionery may be found in H.A. Lieberman and L. Lachman, Pharmaceutical Dosage Forms: Tablets Volume 1, Marcel Dekker, Inc., New York, N.Y. (1989) at pages 367 to 418, which disclosure is incorporated herein by reference.

In accordance with this invention, therapeutically effective amounts of the pharmaceutical compositions of the present invention may be admixed into the hard and soft confectionery products. These amounts are readily determined by those skilled in the art without the need for undue experimentation. In a preferred embodiment, the pharmaceutical composition will comprise the pharmaceutical composition in an amount from about 0.25% to about 2% and an ingestible vehicle, that is a pharmaceutically acceptable carrier, in a quantity sufficient to bring the total amount of composition to 100%, by weight.

Throughout this application, various publications have been referenced. The disclosures in these publications are incorporated herein by reference in order to more fully describe the state of the art.

The present invention is further illustrated by the following examples which are not intended to limit the effective scope of the claims. All parts and percentages in the examples and throughout the specification and claims are by weight of the final composition unless otherwise specified. Example 1

This example illustrates the preparation of the free base of the pharmaceutical active, dextromethorphan.

Material Amount

Dextromethorphan HBr, m.w. 352.3 40.00 g

NaOH, m.w. 40.00, 10% solution 52.20 g

Na2CO3 (1 % solution) 1250.00 g

Dextromethorphan HBr and the 10% NaOH solution were mixed in a beaker until white crystals formed. The white crystals were then transferred to a tared filter paper, washed several times with sodium bicarbonate solution, and then air dried. The yield was : 271.4/352.4 = 77.03%.

Example 2

This example illustrates the preparation of hard candies containing the pharmaceutical active, dextromethorphan. The composition of the candies is set out below.

with OJ %

with 0.2%

Ingredient Blank Control Base Acid** Acid

Candy Base* 100.000 99.333 99.487 99.387 99.287

Flavor and Color — — — — —

Dextromethoφhan — 0.667 — — — HBr

Free Base — — 0.513 0.513 0.513

Fumaric Acid — — — 0.100 0.200

Total % 100.000 100.000 100.000 100.000 100.000

*Candy Base (35/65 solid ratio from com syrup [80% solid] and sugar) **Acid (typically 0 to 1.0% for hard candy)

Procedure

1. Weigh com syrup, sugar, and water (sufficient to dissolve sugar) in a 1 quart pot. Heat to 144°C. 2. Remove pot from heat source.

3. When temperature drops to 125°C, add Dextromethoφhan HBr or Base. Mix well.

4. Add flavor, acid, and color at 118°C.

5. Pour candy mass to a cooling table. 6. Fold into suitable shape and run through a candy drop roller.

7. Shake off candy flash pieces in a sieve to smooth the surfaces and store in a plastic bag.

8. Each 3.0 g piece contains 20 mg salt or 15.4 mg base.

Taste evaluations of the hard candies containing the pharmaceutical active, dextromethoφhan, are set out in Example 5. Example 3

This example illustrates the preparation of pressed tablets containing the pharmaceutical active, dextromethoφhan. The composition of the tablets is set out below.

Ingredient Test Control

Dipac Sugar 95.99 95.48

Dextromethoφhan HBr — 2.22

Dextromethoφhan Free Base 1.71 —

T/S Art. Cherry Flavor #34443 0.50 0.50

Adipic Acid 0.80 0.80

Magnesium Stearate 1.00 1.00

Total % 100.00 100.00

Procedure:

1. Mix all ingredients except Magnesium Stearate in a beaker.

2. Add Magnesium Stearate and mix for 1 minute.

3. Press into 900 mg tablet using a lab scale press. (Stokes Pennwalt Model 511-6)

4. Each tablet contains 20 mg salt or 15.4 mg base.

Taste evaluations of the pressed tablets containing the pharmaceutical active, dextromethoφhan, are set out in Example 5.

Example 4

This example illustrates the measurement of the pH values of the tablets and hard candies containing the pharmaceutical active, Dextromethoφhan HBr or Dextromethoφhan free base, prepared in Examples 2-3. The tablets and hard candies were dissolved in water to form a 10% solution and the pH was measured using an ORION RESEARCH Digital pH/millivolt meter 611 logR Compensation. The pH values obtained are set out below. Tablet pH of 10% solution

Dextromethoφhan HBr 2.22%, adipic acid 0.80% 4.58

free base 1.71 %, adipic acid 0.80% 5.89

Candy pH of 10% solution

Lab water 8.15

blank candy 7.23

Dextromethoφhan HBr 0.67% , 20 mg/3 O g pc 7.13

free base 0.513 %, 15.4 mg/3.0 g pc 8.67

free base 0.513%, fumaric acid 0.10% 6.96

free base 0.513%, fumaric acid 0.20% 4.58

Example 5

This example illustrates taste evaluations of the tablets and hard candies containing the pharmaceutical active, Dextromethoφhan HBr or Dextromethoφhan free base, prepared in Examples 2 and 3.

Bitterness on a scale from 1 (no bitterness) to 7 (very high bitterness) was rated with comments on tolerability by 5 lab panels. Hard candies prepared in Example 2 were tasted for 1 minute without swallowing the active. Tablets prepared in Example 3 were chewed and spit out.

The bitter taste of dextromethoφhan, in the formulations prepared in accordance with the present invention, was found to be reduced when compared to the control samples tested by the lab panels. The method of using the free base for its low solubility and slow reaction with acids made it possible to have a taste- acceptable Dextromethoφhan solid product. The application shows promising improvement in both chewable tablets and in hard candy and can be used in other solid dosage forms. The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the following claims.

Claims

I claim:

1. A chewable or dissolvable pharmaceutical composition suitable for oral administration which comprises: (a) a therapeutically effective amount of a pharmaceutical active in the free amine form, which pharmaceutical active is unpleasant tasting in the amine acid salt form;

(b) a pharmaceutically acceptable acid; and

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical active is selected from the group consisting of dextromethoφhan, pseudoephedrine, and diphenhydramine.

3. The pharmaceutical composition according to claim 2, wherein the pharmaceutical active is dextromethoφhan.

4. The pharmaceutical composition according to claim 1, wherein the pharmaceutical active is present in an amount from about 0.01 % to about 20%, by weight of the pharmaceutical composition.

5. The pharmaceutical composition according to claim 1 , wherein the pharmaceutically acceptable acid is selected from the group consisting of fumaric acid, adipic acid, citric acid, lactic acid, maleic acid, ascorbic acid, succinic acid, tartaric acid, sorbic acid, and malic acid.

6. The pharmaceutical composition according to claim 5, wherein the pharmaceutically acceptable acid is fumaric acid.

7. The pharmaceutical composition according to claim 1, wherein an aqueous mixture of the pharmaceutical composition has a pH value from about 3 to about 7.

8. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable carrier is selected from the group consisting of hard and soft confections, lozenges, tablets, and powders.

9. The pharmaceutical composition according to claim 8, wherein the pharmaceutically acceptable carrier is a tablet.

10. A method for treating an ailment in a human which comprises orally administering to a human, in need thereof, a chewable or dissolvable pharmaceutical composition which comprises:

(b) a pharmaceutically acceptable acid; and

11. The method according to claim 10, wherein the pharmaceutical active is selected from the group consisting of dextromethoφhan, pseudoephedrine, and diphenhydramine.

12. The method according to claim 11, wherein the pharmaceutical active is dextromethoφhan.

13. The method according to claim 10, wherein the pharmaceutical active is present in an amount from about 0.01 % to about 20%, by weight of the pharmaceutical composition.

14. The method according to claim 10, wherein the pharmaceutically acceptable acid is selected from the group consisting of fumaric acid, adipic acid, citric acid, lactic acid, maleic acid, ascorbic acid, succinic acid, tartaric acid, sorbic acid, and malic acid.

15. The method according to claim 14, wherein the pharmaceutically acceptable acid is fumaric acid.

16. The method according to claim 10, wherein an aqueous mixture of the pharmaceutical composition has a pH value from about 3 to about 7.

17. The method according to claim 10, wherein the pharmaceutically acceptable carrier is selected from the group consisting of hard and soft confections, lozenges, tablets, and powders.

18. The method according to claim 17, wherein the pharmaceutically acceptable carrier is a tablet.