WO2012016181A2

WO2012016181A2 - Anti-allergy lozenges

Info

Publication number: WO2012016181A2
Application number: PCT/US2011/045959
Authority: WO
Inventors: Mario W. Medri
Original assignee: Bestsweet, Inc.
Priority date: 2010-07-30
Filing date: 2011-07-29
Publication date: 2012-02-02
Also published as: WO2012016181A3

Abstract

A lozenge preparation comprising an anti-allergy agent and optionally menthol as an active ingredient is provided. The preparation may comprise sugar or may be sugar free. Also provided are methods for producing said lozenges and uses for modulating allergic reactions in subject in need thereof.

Description

ANTI-ALLERGY LOZENGES TECHNICAL FIELD

Disclosed herein is a lozenge preparation for taste masking comprising an anti- allergy agent and optionally menthol as an active ingredient. The preparation may comprise sugar or may be sugar free. BACKGROUND ART

Pharmaceutically active ingredients may be delivered orally via a number of means. These include a liquid, tablets (chewable and non-chewable), comestible solids, capsules, pills, granules, powder and lozenges. A lozenge is a solid preparation containing one or more pharmaceutically active ingredients which is intended to dissolve slowly in the mouth.

The pharmaceutically active ingredients often have a bitter taste. Therefore, attempts have been made to mask such taste. Strategies that have been used include (1) flavors, sweeteners and/or amino acids; (2) lipophilic vehicles; (3) hydrophilic vehicles; (4) inclusion complexes (e.g., cyclodextin); (5) ion exchange resins; (6) effervescent agents; (7) viscosity modifiers; (8) freeze-drying; (9) solid dispersions; (10) spray drying. Examples of these various strategies are provided in Saigal et al., 2008, Expert Opin. Ther. Patents

18:769-781; Douroumis, 2007, Expert Opin. Drug Deliv. 4:417-426; Sohi et al., 2004, Drug Development and Industrial Pharmacy 30:429-448; US Patent No. 6,923,988; US Patent No. 6,165,512; US Patent No. 4,983,394; US Patent No. 4,935,243; US Patent No.

4,632,821; US Patent No. 4,642,231; US Patent No. 4,643,892; US Patent No. 3,085, 942; US 2009/0060983; US 2006/0018961; WO/1995/033446.

One group of such pharmaceutically active ingredients are anti- allergy agents such as antihistamines. Taste masking agents have been used with antihistamines. Generally antihistamines are formulated as liquids, tablets or effervescents (see S Douroumis, 2007, Expert Opin. Drug Deliv. 4:417-426; US Patent No. 6,923,988; US Patent No. 6,165,512; US Patent No. 4,983,394; US 2009/0060983; US 2006/0018961; WO/1995/033446).

SUMMARY Provided herein is a lozenge comprising (a) an anti-allergy agent as an active pharmaceutical ingredient and (b) one or more reagents which masks the taste of said anti- allergy agent and (c) optionally menthol as another active ingredient. The anti-allergy agent may be present in a pediatric dose (6-12 years old) or an adult dose within federal register guidelines with respect. The anti-allergy agent may be an antihistamine. The antihistamine may include but is not limited to triprolidine, fexofenadine, hydroxyzine,

diphenyhydramine, brompheneramine, chlorpheniramine, loratidine, dimenhydrinate, tripelenamine, cyproheptadine, promethazine, phenyltoloxamine, terfenadine, acrivastine, clemastine, doxylamine, cetirizine. In a particular embodiment, the anti-allergy agent is diphenyhydramine or chlorpheniramine.

The active ingredient may be present in the amount of about 0.01 to about 1.0 % (by weight). Further, the active ingredient may be in its pure state or may be encapsulated, particularly with, for example, magnesium silicate, guar gum, xantham gum, and/or gum arabic.

As noted above, the lozenge may comprise one or more agents which mask the taste of the anti-allergy agent and may alternatively be referred to as "taste masking agents". In a particular embodiment, the agent may be a sugar and glucose syrup (e.g., corn syrup) composition. In another embodiment, the taste masking agent may be one or more polyols and free of sugar. Thus provided is a sugar free lozenge comprising (a) an anti-allergy agent as an active pharmaceutical ingredient; (b) one or more polyols which masks the taste of said anti-allergy agent and (c) optionally menthol.

In another embodiment, the taste masking agent may contain in addition to the sugar and corn syrup composition, vegetable oil and gelatin and thus may be a combination comprising (a) the sucrose and corn syrup composition or (b) one or more polyols and (c) a vegetable oil and (d) gelatin. Thus provided in a particular embodiment is a lozenge comprising (a) an anti-allergy agent as an active pharmaceutical ingredient; (b) menthol as an active pharmaceutical agent; (c) at least one of (i) a glucose syrup (e.g., corn syrup) and sugar composition; (B) one or more polyols and (d) optionally a vegetable oil and gelatin.

Further provided is a method for modulating an allergic reaction in a subject in need thereof comprising administering the lozenges disclosed herein in an amount effective to modulate said allergic reaction.

Additionally provided are methods for obtaining the lozenges set forth above. In one embodiment, the method comprises comprising (a) Providing a taste masking agent, wherein said taste masking agent is a composition comprising a glucose syrup (e.g., corn syrup) and sugar or one or more polyols:

(b) adding anti-allergy agent and optionally vegetable oil and gelatin to and mixing with said taste masking agent of (a) to obtain an anti-allergy composition and

(c) solidifying the composition of (b) to obtain said lozenge.

In another embodiment, the method comprises:

(a) providing one or more polyols;

(b) adding an anti-allergy agent and optionally menthol to the polyols of (a) to

obtain an anti-allergy composition and

(c) solidifying the composition of (b) to obtain said lozenge.

In yet another embodiment, the method comprises:

(a) providing a composition comprising a glucose syrup (e.g., corn syrup) and

sugar;

(b) adding anti-allergy agent and menthol to and mixing with said composition of (a) to obtain an anti-allergy composition and

(c) solidifying the composition of (b) to obtain said lozenge.

Further provided is the use of anti-allergy agent, a taste masking agent(s) and optionally menthol to obtain said lozenge set forth above. As noted above, the taste masking agent may be a composition comprising corn syrup and sugar or one or more polyols or may additionally be in the form of a combination comprising said corn syrup and sugar composition or one or more polyols and a vegetable oil and gelatin.

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described.

It must be noted that as used herein and in the appended claims, the singular forms "a," "and" and "the" include plural references unless the context clearly dictates otherwise.

Lozenge Preparations

The lozenge may, as noted above, contain in addition to the active ingredient(s) sugar, such as sucrose, polysaccharides, oligosaccharides, hydrogenated saccharides, rice syrup, a glucose syrup such as corn syrup, maltodextrin, gelatin or protein fractions thereof, glycerin, botanical extracts, artificial sweeteners, such as sucralose, coloring and flavor ingredients. Sugars, in a specific embodiment, may be present as the largest percent ingredient ranging from about 30 to 99% and preferably from about 40 to 95% by weight. A glucose syrup such as corn syrup (e.g., corn syrup 36-65 DE (dextrose equivalents) or more particularly, corn syrup 42-43 DE), commercially found at 80% solids, also being a significant ingredient as well can range from 30 to 99% and preferably from about 40 to 95% by weight. The ratio of a glucose syrup such as corn syrup to sugar is from about 1:10 to about 10:1 by weight. All other ingredients such as sweeteners (e.g., sucralose), botanicals etc. as well as the active ingredient in an encapsulated or pure state are ranging from about 0.01 to 10% (w/v) .

Polyols such as maltitol, mannitol, isomalt, xylitol and various types of HSH hydrolysates (e.g., HYSTAR© 3375, 4075, 6075), can replace sucrose and/or corn syrup, in part and or completely. Hydrogenated starch hydrolysate and may be defined as a broad group of polyols that contain substantial quantities of hydrogenated oligo- and

polysaccharides in addition to any monomelic or dimeric polyols. The broad term HSH does not differentiate polyols having, for example, different levels of sweetness nor does it identify the principle polyol in the HSH. Common names for major HSH subgroups have, therefore, been developed. Examples of products called by the general term HSH include Roquette's 75/400 and Com Products Specialty Ingredients' HYSTAR® 3375 and Liquid HSH (STAB iLITE® ) and a powdered HSH (STABILITE® SD). Polyols may be present in the amount of about 30-99% either singly or in combination.

The lozenges may also comprise hydrogenated or partially hydrogenated vegetable oil or fractions thereof. These include but are not limited to palm oil (e.g, PARAMOUNT C®, PARAMOUNT B®, PARAMOUNT X®, PARAMOUNT XX®, all from Loders Croklaan, Channahon, IL), corn oil, coconut oil, soy oil, peanut oil, cottonseed oil, sunflower seed oil. Vegetable oil may be present in the amount of about 0.01-10% by weight.

The lozenges may also comprise gelatin or protein fractions thereof. The gelatin may be selected from the group consisting of animal-derived gelatin, chemically modified gelatin, physically modified gelatin, and combinations thereof. A particularly suitable animal-derived gelatin may be derived from pigskin or alternatively bovine bone. Gelatin may be present in the amount of about 0.1-10% by weight.

Other ingredients that may be present include but are not limited to pectin, sweeteners, in particular, artificial sweeteners such as sucralose, flavors, such as cherry flavor, dyes such as red dye, particularly red azo dye (e.g., FD&C red#40) or blue dye, particularly, brilliant blue FCF (e.g., FD&C Blue#l) and pigment such as titanium dioxide. Each of these ingredients are in the amount of about 0.1-10% by weight.

Production Methods

The candy base or candy vehicle, containing ingredients such as sucrose, corn syrup, processing water, active ingredients in encapsulated form or in a pure state, of mineral nature and optionally starches, HSH, oligosaccharides, isomalt and/or sorbitol, or other complex hydrogenated or non-hydrogenates saccharides are cooked by the means of conventional heat exchanger, continuous or interrupted, to a final cook temperature of about 280 to 360F, preferably about 285 to 320F, for the purpose of removing process water, with and without the aid of vacuum and to result with a cooked sugar or sugar-free candy mass with a residual moisture content ranging from 0.02 to 5.0% and preferably from .0.08 to 3.0% to deliver the 0.01-3% active ingredient. Other ingredients such as color, sweeteners, botanical flavoring etc., are added and dispersed to the molten candy mass. The candy mass is than cooled, by any conventional means, to an operating temperature of 160 to 190, preferably 170 to 180F prior to forming. Pieces of a specific weight are than formed by the means of forming/stamping machines. Uniform pieces at consistent weights are then obtained for this type of hard candy drug manufacturing.

Uses This type of vehicle allows the production of a pleasant tasting product for the delivery of unpleasant tasting actives such as anti-allergy agents. The unique properties of this vehicle are preserved in the final form while containing active ingredients which modifies the stimulation of taste receptors in the oral cavity to the extent of suppressing bitterness and other forms of unpleasant taste imparted by actives. Actives, beside being made palatable due to the intimate presence of fats and hydrogenated fats, oil and gelatin, in this slow dissolving taste modifying vehicles, are also favored in the induced pre laryngeal adsorption in the oral cavity especially when combined with a topical remedy of the Menthol type. This novel product which is recognized to be unique in its delivery system and made easy and convenient to take by the consumer for fast allergy relief once compared to tablets or liquid preparations providing an anywhere easy to take very palatable, non bitter and pleasant tasting medicated preparation for allergy relief of the systemic and topical benefit. This is valid for adults and children as an Over the Counter Drugs (OTC) preparations. EXAMPLES

The examples set forth herein disclose various specific embodiments of lozenges and methods of production.

Example 1: Chlorpheniramine 2.0 mg/Drop (Corn/Sugar Base)

Cook A to a residual moisture of 1-3%. Add B, C, D, and E to A and mix thoroughly before extruding onto cooling surface prior to forming individual pieces.

Example 2: Chlorpheniramine 2.0mg/Drop 50/50 Isomalt/Maltitol Base

Cook A to a residual moisture of less than 2%. Add B, C, D and E to A and mix thoroughly before extruding onto cooling surface prior to forming into individual pieces.

Example 3: Chlorpheniramine 2.0mg/Drop 100% Isomalt Base

Example 4: Diphenhydramine 12.5mg/Drop-Corn/Sugar Base

Cook A to a residual moisture of 1-3%. Add B, C, D, E and F to A and mix thouroughly before extruding onto cooling surface.

Example 5: Diphenhydramine 12.5mg/Drop-50/50 Isomalt/Maltitol Base

Cook A to a residual moisture of less than 2%. Add B, C, D, E and F to A and mix thoroughly before extruding onto cooling surface.

Example 6: Diphenhydramine 12.5mg/Drop-100% Isomalt Base

Cook A to a residual moisture of less than 2%. Add B, C, D and E to A and mix thoroughly before extruding onto cooling surface prior to forming into individual pieces. Example 7: Chlorpheniramine 2.0mg/Drop: Corn Syrup/Sugar Base + Gelatin + Palm Oil

Cook A to a residual moisture of 1-3%. Add B, C, D and E to A and mix thoroughly before extruding onto cooling surface prior to forming into individual pieces.

Example 8: Chlorpheniramine 2.0mg/Drop-50/50 Isomalt/Maltitol Base

Cook A to a residual moisture of less than 2% . Add B , C, D and E to A and mix thoroughly before extruding onto cooling surface prior to forming into individual pieces.

Example 9: Chlorpheniramine 2.0mg/Drop -100% Isomalt Base + Menthol + Gelatin + Palm Oil

The invention described and claimed herein is not to be limited in scope by the specific embodiments herein disclosed, since these embodiments are intended as illustrations of several aspects of the invention. Any equivalent embodiments are intended to be within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.

Various references are cited herein, the disclosures of which are incorporated by reference in their entireties.

Claims

WHAT IS CLAIMED IS:

1. A lozenge comprising (a) an anti-allergy agent as an active pharmaceutical ingredient and (b) a combination which masks the taste of said anti-allergy agent, said combination comprising (i) a vegetable oil, (ii) gelatin and (iii) at least one of (A) a glucose syrup and sugar composition; (B) one or more polyols; and (c) optionally menthol.

2. The lozenge according to claim 1 , wherein said combination which masks the taste of said anti-allergy agent comprises (i) a vegetable oil, (ii) gelatin and (iii) a glucose syrup and sugar composition, wherein the ratio of corn syrup to sugar is from about 1:10 and 10:1 (w/w).

3. The lozenge according to claim 1 , wherein said vegetable oil is present in the amount of about 0.01-10% by weight and/or said gelatin is present in the amount of about 0.1-10% by weight.

4. A lozenge comprising (a) an anti-allergy agent as an active pharmaceutical ingredient; (b) menthol as an active pharmaceutical agent; (c) at least one of (i) a glucose syrup and sugar composition; (B) one or more polyols and (d) optionally a vegetable oil and gelatin.

5. The lozenge according to claim 1 or 4, wherein said vegetable oil is selected from the group consisting of palm oil, coconut oil, partially hydrogenated cottonseed oil, soybean oil, peanut oil, sunflower seed oil and corn oil.

6. A sugar free lozenge comprising (a) an anti-allergy agent as an active pharmaceutical ingredient; (b) one or more polyols which masks the taste of said anti-allergy agent and (c) optionally menthol.

7. The lozenge according to claim 1 , 4 or 6 wherein said anti-allergy agent is an antihistamine selected from the group consisting of triprolidine, fexofenadine, hydroxyzine, diphenyhydramine , brompheneramine , chlorpheniramine , loratidine , dimenhydrinate , tripelenamine, cyproheptadine, promethazine, phenyltoloxamine, terfenadine, acrivastine, clemastine, doxylamine, cetirizine.

8. The lozenge according to claim 7, wherein said anti-allergy agent, is present in an amount of about 0.01 to about 10% w/v.

9. The lozenge according to claim 1 , 4 or 6, wherein said polyol is selected from the group consisting of erythritol, hydrogenated starch hydrolysate, maltitol, mannitol, isomalt sorbitol, isomalt and xylitol.

10. The lozenge according to claim 9. wherein said polyol is present in the amount of about 30-99% by weight either singly or in combination.

11. The lozenge according to claim 1 , 4 or 6, wherein said active ingredient is in an encapsulated form.

12. A method of modulating an allergic reaction in a subject in need thereof comprising administering the lozenge of claim 1 , 4 or 6 in an amount effective to modulate said allergic reaction.

13. A method for obtaining the lozenge of claim 1 comprising:

(a) Providing a taste masking agent, wherein said taste masking agent is a composition comprising a glucose syrup and sugar or one or more polyols:

(b) adding vegetable oil, anti-allergy agent and gelatin to and mixing with said taste masking agent of (a) to obtain an anti- allergy composition and

(c) solidifying the composition of (b) to obtain said lozenge.

14. A method for obtaining the lozenge of claim 4 comprising

(a) providing one or more polyols;

(b) adding an anti-allergy agent and optionally menthol to the polyols of (a) to obtain an anti-allergy composition and (c) solidifying the composition of (b) to obtain said lozenge.

15. A method for obtaining the lozenge of claim 6 comprising:

(a) providing a composition comprising a glucose syrup and sugar:

(c) solidifying the composition of (b) to obtain said lozenge.