WO1994028872A1

WO1994028872A1 - Non-alcoholic cold and sinus medication

Info

Publication number: WO1994028872A1
Application number: PCT/US1994/005812
Authority: WO
Inventors: Charles Pozzi
Original assignee: Warner Lambert Co LLC
Current assignee: Warner Lambert Co LLC
Priority date: 1993-06-04
Filing date: 1994-05-24
Publication date: 1994-12-22
Anticipated expiration: 1995-12-04
Also published as: AU6956494A

Abstract

An improved non-alcoholic aqueous cold and sinus medication provides the same level of efficacy as those formulations known in the art with an acceptable taste and mouthfeel. Otherwise bitter tasting actives consisting of an antihistamine and a decongestant are solubilized and dispersed in the aqueous solution using an emulsifier/surfactant system which incorporates small amounts of flavor compounds that further act to taste mask the bitter medicinal notes.

Description

Non-Alcoholic Cold and Sinus Medication Field of the Invention

The present invention relates to antihistaminic/nasal- decongestant cold/sinus medications which are orally administered in liquid dosage forms that are easy to swallow, taste good and provide immediate and long lasting relief. Such medications generally contain active ingredients such as a decongestant or antihistamine that are otherwise bitter tasting and unpalatable by themselves but are effective in clearing up blocked sinuses, itchy, watery eyes, headache and sore throat and, in so doing, provide relief from nagging coughs that are a direct result of these symptoms. Background of Invention

One of the major problems that exists in the art of pharmacy is that many patients, particularly young children and older adults, are unwilling and/or unable to swallow tablets, capsules or other solid traditional dosage forms of medication. Liquid cold/sinus preparations are admittedly not novel and numerous commercially available formulations exist in the marketplace. Benadryl®, vicks®, Sudafed®, Dimetapp® and others are well known liquid cold remedies that are easily swallowed and do not possess the problems inherent in swallowing a tablet which causes difficulty for young children and older parents. These cold/sinus remedies vary with respect to what actives are present, but may include a decongestant, an antihistamine, an antitussive or expectorant and an analgesic and the like either singly or in combination depending upon the relief sought. United States Patent No. 4,892,877 to Sorrentino discloses a cough-sore throat medication comprising an aqueous-based liquid preparation comprising an antitussive such as destromethorphan and a known topical anesthetic such as pheonol. Although water serves as the main carrier in the formulation, an alcoholic co- solvent is also required up to 25%.

United States Patent 5,112,604 to Beaurline et al. discloses a sustained release oral formulation for an active drug, in particular, theophylline, an anti-asthmatic. The drug is maintained in an aqueous suspension through the use of a hydrocolloid gum/silicone dioxide suspending agent. A polymeric particle system such as polyvinyl pyrrolidone, polyvinylalcohol, acrylic acid and the like are necessary as a dispersing agent in a 70% sorbitol carrier solution.

The problem that exists with respect to many of these actives is that they are generally bitter tasting and therefore require some type of carrier or taste masking agent to render them more palatable, particularly for young children. Flavors and sweeteners are often incorporated in the medication for this purpose but these are not very soluble in water. As a result, an organic solvent such as alcohol is necessary for dissolution and dispersion of the ingredients throughout the liquid formulation. Alcohol also serves to enhance the perception of the flavors and sweeteners and in essence aids in the taste masking function of the bitter testing actives as well.

The need for using high levels of alcohol as a solvent and as a flavor enhancer in the formulation which otherwise serves no therapeutic purpose has recently been questioned in that consumption of alcohol in any form has never been regarded as highly beneficial to ones health. Nevertheless, the conventional carrier for the active and flavor ingredients in most cold/sinus medications is typically a water:alcohol mixture. Generally the ration of water to alcohol is in the range of from about 1:1 to about 20:1 and preferably from about 3:1 to about 10:1. The typical amount of the water:alcohol mixture comprising most cold/sinus formulations range from about 50% to about 99.9% of the entire composition by weight. In light of these amounts of alcohol present in most formulations, it would be obviously beneficial if a non-alcohol based liquid medication was available. Summery of the Invention

The present invention relates to an improved liquid cold and sinus medication that provides the same level of efficacy as those formulations known in the art with an acceptable taste and mouthfeel. Detailed Description of the Invention

Cold/sinus formulations of the present invention may generally be regarded as improvements over those commercially available in the art known for example as Benadryl® Elixir (Parke-Davis, Morris Plains, New Jersey) Vicks® 44-D (Richardson- Vicks, Shelton, Connecticut) and Dimetapp® Elixir (A.H. Robins, Richmond, Virginia) . These liquid cold/sinus remedies are beneficial in the administration and delivery of antihistamines, decongestants, expectorants and the like in a form that is generally flavored so that it tastes good and is readily swallowable as opposed to tablets and capsules which often pose difficulty for young children, the disabled and older people. Unfortunately, high levels of alcohol are required as a solvent for the actives, the flavors and sweeteners and as a flavor enhancer for these components in order to help taste mask the active drugs which are generally bitter and unpalatable.

The liquid formulations of the present invention provide temporary relief of symptoms such as runny nose, sneezing, itching, watery eyes and other respiratory ailments and allergies and coughs that result therefrom. The active ingredients comprise an antihistamine such as dipenhydramine hydrochloride (2-diphenylmethoxy-N,N-dimethylethananmine hydrochloride) . The antihistamine's chemical characterics and method of preparation is disclosed in U.S. Patent No. 2,427,878 Rieveschal, Jr., which is hereby incorporated by reference.

The amount of antihistamine incorporated in the formulation may vary but generally will comprise from about 0.15% w/v to about 0.5% w/v and preferably from about 0.20% w/v to about 0.30% w/v based upon the total weight of the composition. Most preferably, an amount of about 0.25% w/v will be employed. This will translate in terms of weight per volume to an amount of from about 0.5 mg/ml. solution to about 3.5 mg/ml. solution and preferably from about 2.0 mg/ml. solution to about 3.0 mg/ml. solution and most preferably in an amount of about 2.5 mg/ml. solution.

In one embodiment of the present invention, a decongestant is also included in the present formulation to provide a dual form of relief. While the antihistamine blocks the immuno- response based action of the histamines and thereby dries up much of the watery, fluid excretions (watery eyes, fluid filled sinuses) that are a result of the cold's infection, the decongestant relieves the mucus build-up that occurs in the upper respiratory track and otherwise irritates the throat and lungs thereby causing a cough. A suitable decongestant is pesudoephedrine hydrochloride (d- [1- (me hylamine)ethyl] benzene- methanol hydrochloride) .

The amount of pseudoephedrine hydrochloride incorporated in the formulation may also vary but generally will comprise from about 0.20% w/v to about 0.80% w/v and preferably from about 0.40% w/v to about 0.70% w/v based upon the total weight of the composition. Most preferably, an amount of about 0.60% w/v will be employed. This will translate in terms of weight per volume to an amount of from about 0.2 mg/ml. solution to about 8.0 mg/ml. solution and preferably from about 2.0 mg/ml. solution to about 8.0 mg/ml. solution and most preferably in an amount of about 6.0 mg/ml. solution.

Unlike the cold/sinus preparations of the prior art, the liquid elixirs of the present invention have been surprisingly and unexpectedly prepared using water as the main solvent carrier without the need for alcohol. The amount of water added to the formulation will generally comprise from about 50% w/v to about 99.9% w/v by weight of the entire composition and preferably an amount from about 60% w/v to about 70% w/v by weight is added and most preferably from about 60% w/v to 65% w/v is added by weight of the entire composition. This percentage is then actually decreased to a range from about 80% to 95% since a 70% sorbitol solution is used, thereby adding more water to the final composition.

The non-alcoholic formulations of the present invention are able to employ water as the primary solvent through the unique combination of a surfactant and an emulsifier, together with two flavor compounds, monoammonium glcyrrhizinate and vanillin extract, the emulsifier somehow act in tandem to disperse the flavor ingredients into solution and enhance their taste. The liquid formulations also include a humectant composition to give the liquid greater viscosity and stability. Suitable humectants useful in the formulations of the present invention include glycerin, polyethylene glycol, propylene glycol and mixtures thereof. Preferably, glycerin is used and incorporated in an amount of from about 0.5% w/v to about 15.0% w/v by weight and preferably in an amount of from about 0.75% w/v to about 2.5% w/v by weight of the entire composition and most preferably in an amount of about 1.0% w/v by weight.

The oral liquid compositions of the present invention will also comprise at least one and preferably two emulsifiers or surfactants in amounts of up to about 5.0% w/v and preferably from about 0.02% w/v to about 3.0% w/v of the total formulation. The surfactants useful in the preparation of the cold/sinus formulations of the present invention are generally organic materials which aid in the stabilization and dispersion of the ingredients in aqueous systems for a suitable homogenous composition. Preferably, the surfactants of choice are non-ionic surfactants such as poly(oxyethylene) -poly(oxypropylene) block co-polymers. These are commercially know as poloxamers and are produced in a wide variety of structures and molecular weights with varying contents of ethylene oxide and propylene oxide.

Vanillin extract, sold under the trade name of Van-o-Plus (Bush, Boake and alien Flavor Company, Montvale, New Jersey) is incorporated as a taste masking agent in relatively small amounts of from about 0.002% to about 0.2% by weight of the total syrup composition. Monoammonium glycyrrhizinate, a sweetener, is also incorporated in an equal amount of from about 0.002% to 0.2% by weight of the total syrup composition.

Whereas any one of a number of emulsifier/surfactants may be used, preferably a poloxamer such as Poloxamer 407 is employed which, together with another emulsifier/surfactant, enables the flavor compounds to go into solution in the absence of an of an organic solvent. It is also believed without being bound to any theory, that the polymers may provide a taste masking function as well by binding with the active. Poloxamer 407 has an HLB (hydrophilic/ lipophilic balance) of about 22 and is sold under the trade name Pluoronic-127 (BASF-Wyandotte, Parsippany, New Jersey) . This first emulsifier/surfactant component will comprise from about 0.05% to about 2.0% by weight of the total composition and preferably will comprise about 0.1% of the total weight of the composition.

A second emulsifier/surfactant useful in combination with Poloxamer 407 in the practice of the present invention may be selected from the group comprising polysorbate copolymers (sorbitan-mono-9-octadecenoate*poly(oxy-1,2-ethanediyl) ) . This compound is also added and functions to keep the flavors and sweeteners homogeneously dissolved and dispersed in solution. Suitable polysorbates include polysorbate 20, polysorbate 40, polysorbate 80 and mixtures thereof. Most preferably, two surfactants are employed in equivalent amounts. For example, the Poloxmer 407 and polysorbate 20 may each be employed together at levels of approximately from about 0.02% to about 4.0% w/v of the total weight of the formulation.

In situations where long shelf life requirements may result in further stability problems, additional preservatives, stabilizers, flavor modifiers, acidifiers, other pH adjusters and the like may be incorporated as necessary. The specific agents, such as sodium benzoate as a preservative and monoammonium glycyrrhizinate as a flavor enhancer are well known in the art and may be added in amounts as dictated by standard pharmacological practice.

In order to make the liquid cold/sinus formulations more aesthetically appealing, additional flavors, colorants and sweeteners may also be added according to taste. Suitable sweeteners include water-soluble artificial sweeteners such as saccharin salts, cyclamate salts, acesulfame-K and mixtures thereof. Other suitable sweetening agents include aspartame, sucralose, protein based sweeteners such as thymidine, monellin and the like. In general, the effective amount of sweetener employed will vary accordingly to what type of sweetener is used an dis utilized to provide the level of sweetness desired for a particular flavor of liquid formulation. The amount will normally comprise from about 0.01% w/v to about 5.0% w/v and preferably from about 0.5% w/v to about 1.0% w/v of the weight of the entire composition. Sodium saccharin is the preferred sweetener of choice and will preferably be incorporated in an amount of from about 0.10% w/v to about 0.75% w/v of the weight of the entire composition and most preferably in an amount of about 0.33% w/v of the total weight of the composition.

The flavoring (flavoring agents) that may be used include those known to the skilled artisan, such as natural and artificial flavors. These flavorings may be chosen from synthetic flavor oils and flavoring aromatics, and/or oils, oleo resins and extracts derived from plants, leaves, flowers, fruits and so forth, and combinations thereof. Representative flavor oils include: spearmint oil, cinnamon oil, oil of wintergreen (methyl salicylate) , peppermint oil, clove oil, bay oil, eucalyptus oil, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, and oil of bitter almond. Also useful are artificial, natural or synthetic fruit flavors such as vanilla, and citrus oil, including lemon, orange, grape, lime and grapefruit and fruit essences including apple, pear, peach, strawberry, raspberry, cherry, plus, pineapple, apricot and so forth. These flavorings may be used individually or in admixture. Commonly used flavors include mints such as peppermint, menthol, artificial vanilla, cinnamon, derivatires, and various fruit flavors whether employed individually or in admixture.

Flavorings such as aldehydes and esters including cinnamyl acetate, cinnamaldehyde, citral, dielthylacetal, dihydrocarvyl acetate, eugenyl formate, p-methylanisoke, and so forth may also be used. Generally, any flavoring or food additive such as those described in "Chemicals Used in Food Processing" pub. 1274 by the National Academy of Sciences, pages 63-258 may be used.

Further examples of aldehyde flavorings include but are not limited to acetaldehyde (apple) ; benzaldehyde (cherry, almond) ; cinnamic aldehyde (cinnamon); citral, i.e., alpha citral (lemon, lime); neral, i.e. beta citral (lemon, lime); decanal (orange, lemon); ethyl vanillin (vanilla, cream); heliotropine, i.e. peperonal (vanilla, cream) ; alpha-amyl cinnamaldehyde (spicy fruity flavors) ; butyraldehyde (butter, cheese) ; valeraldehyde (butter, cheese); citronella (modifies, many types); decanal (citrus fruits) ; aldehyde C-9 (citrus fruits) ; aldehyde C-12 (citrus fruits); 2-ethyl butyraldehyde (berry fruits); nexenal, i.e. trans-2 (berry fruits); tolyl aldehyde (cherry, almond); veratraldehyde (vanilla); 2,6-dimethyl-5-heptenal, i.e. melonal (melon); 2,6-dimenthyloctanal (green fruit); and 2-dodecenal (citrus, mandarin); cherry; grape; mixtures thereof and the like.

The amount of flavoring employed is normally a matter of preference subject to such factors as flavor type, individual flavor, and strength desires. Thus, the amoung may be varied in order to obtain the result desired in the final elixir product. Such variations are within the capabilities of those skilled in the art without the need for undue experimentation. In general, amounts of about 0.05% to about 2.0% by weight of the composition are useable with amount of about 0.05% TO 1.5% being preferred.

The following examples are provided to more specifically teach and better define the formulations of the present invention, they are for illustrative purposes only and it is realized that minor changes and variations can be made that are not disclosed therein. Such alternatives are still to be considered as falling within the spirit and scopt of the present invention as recited by the claims that follow. Example I

Water (900 mis.), Poloxamer 407, (2.0 gms.), sodium citrate (5.4 gms.), sodium chloride (2.2 gms.), citric acid (3.4 gms.) and sodium saccharin (6.6 gms.) were mixed in a first flask at room temperature until the solid components were dissolved. Sodium benzoate (6.0 gms.) was also then added and mixed until dissolved. Diphenhydramine hydrochloride (5.0 gms.) and pesudeophedrine hydrochloride (12.0 grams) were added and dissolved in the first mixture which was then thoroughly blended together with 1000 gms. of 70% sorbitol solution. Polysorbate 20 (Tween 20) (4.0 gms.), grape flavoring (5.72 gms.) were added to the main reaction vessel and mixed until thoroughly homogenized. Van-O-Plus vanillin extract (0.4 gms.) was added to this mixture and blended until uniform. Monoammonium glycyrrhizinate (0.4 gms.) was first mixed with glycerin (20 gms.) until uniform prior to adding it to the main reaction vessel and food colorings (F.D. & C. Red #40, (0.046 gms.); and F.D. & C. Blue #1 (0.01 gms.) were added with additional water to bring the total volume of the cold/sinus preparation to two (2.0) liters.

The grape flavored sinus-cough liquid composition thus prepared was of the same viscosity and clarity and color as those liquid cherry sinus/couth preparations currently available on the market such as Benadryl® Elixir. Teaspoon samples given to an expert taste panel were found to possess no noticeable differences in taste or mouthfeel as well and possessed a defined, distinctive grape taste. Example II

Water (1.2 liters), sodium citrate (1.0 gms.), citric acid (1.48 gms.) and sodium saccharin (0.54 gms.) were mixed in a first flask at room temperature until the solid components were dissolved. Sodium benzoate (10.0 gms.) and sucrose (600 gms.) were also then added and mixed until dissolved. Two (2.0) grams of Poloxamer 407 were dissolved in a second, separate flask of water (40 mis.) and this was heated to 40'C to reach complete dissolution. Diphenhydramine hydrochloride (5.0 gms.) was added to and dissolved in the first mixture which was then thoroughly blended with the Poloxamer 407 solution. Polysorbate 20 (2.0 gms.), cherry flavoring (12.0 gms.) and glycerin (120 gms.) as a binder were added to the main reaction vessel and mixed until thoroughly homogenized. Monoammonium glycyrrhizinate (0.8 gms.) and food color (D. & C. #33, 0.1 gms.; and F.D. & C. red 40, 0.01 gms.) were added with additional water to bring the total volume of the cold/sinus preparation to two (2.0) liters. The cold/sinus liquid composition thus prepared was of the same viscosity, clarity and color as those liquid cherry cold/since preparation currently available on the market such as Benadryl® Elixir. Teaspoon samples given to an expert taste panel were found to possess no noticeable differences in taste or mouthfeel as well.

Claims

What Claim I is:

1. An aqueous, non-alcoholic cold and sinus medication consisting essentially of an antihistamine, at least one emulsifier/surfactant, a humectant, flavor compounds and water.

2. The cold and sinus medication of Claim 1 further consisting of a decongestant.

3. The cold and sinus medication of claim 2 wherein said antihistamine is present in an amount of from about 0.15% w/v by weight to about 0.5% w/v by weight of the entire composition.

4. The cold and sinus medication of claim 3 wherein said antihistamine is present in an amount of from abut 0.2% w/v by weight to about 0.3% w/v by weight of the entire composition.

5. The cold and sinus medication of claim 4 wherein said antihistamine is selected from the group consisting of diphenhydramine hydrochloride.

6. The cold and sinus medication of claim 5 wherein said decongestant is present in an amount of from about 0.15% w/v by weight to about 0.5% w/v by weight of the entire composition.

7. The cold and sinus medication of claim 6 wherein said decongestant is present in an amount of from about 0.2% w/v by weight to about 0.3% w/v by weight of the entire composition.

8. The cold and sinus medication of claim 7 wherein said decongestant is selected from the group consisting of psyeodoephedrine hydrochloride.

9. The cold and sinus medication of claim 8 wherein said humectant is selected from the group consisting of polyethylene glycol, polypropylene glycol, glycerin and mixtures thereof.

10. The cold and sinus medication of claim 9 wherein said humectant is glycerin.

11. The cold and sinus medication of claim 10 wherein said humectant is present in an amount of from about 0.5% w/v to about 15.0% w/v by weight of the entire composition.

12. The cold and sinus medication of claim 11 wherein said emulsifiersurfactant is selected from the group consisting of non-ionic copolymers, anionic copolymers and mixtures thereof.

13. The cold and sinus medication of claim 12 wherein said emulsifier/surfactant is selected from the group consisting of non-ionic copolymers, anionic copolymers and mixtures thereof.

14. The cold and sinus medication of claim 13 wherein the non-ionic copolymer is selected from the group consisting of poly(oxyethylene)-poly(oxypropylene) block copolymers, polysorbate co-polymers and mixtures thereof.

15. The cold and sinus medication of claim 14 wherein said emulsifier/surfactant is selected from the group consisting of Poloxamer 407.

16. The cold and sinus medication of claim 15 wherein said emulsifier/surfactant comprises from about 0.05% w/v to about 2.0% w/v of the weight of the entire composition.

17. The cold and sinus medication of claim 16 herein wherein said emulifier/surfactant comprises from about 0.05% w/v to about 1.5% w/v of the entire composition.

18. The cold and sinus medication of claim 17 further comprising a second emulsifier/surfactant.

19. The cold and sinus medication of claim 18 wherein said second emulsifier/surfactant is selected from the group consisting of polysorbate copolymers.

20. The cold and sinus medication of claim 19 wherein said polysorbate copolymer is present in an amount of from about 0.02% w/v to about 4.0% w/v by weight of the entire composition.

21. The cold and sinus medication of claim 20 wherein said polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 80 and mixtures thereof.

22. The cold and sinus medication of claim 21 wherein said flavor compounds comprise monoammionium glycyrrhizinate and vanillin extract.

23. The cold and sinus medication of claim 22 wherein said flavor compounds are present in an amount of from about 0.02% to about 0.2% of the total weight of the sinus-cold composition.

24. The cold and sinus medication of claims l, 2 or 21 further comprising preservatives, coloring agents, sweeteners, pH adjusters, additional flavors and mixtu thereof.

25. The cold and sinus medication of claim 24 wherein said preservative is selected from the group consisting of sodium benzoate.

26. The cold and sinus medication of claim 24 wherein said pH adjusters is selected from the group consisting of citric acid, aleic acid, valeric acid, buffers and mixtures thereof.

27. An aqueous, pleasant tasting non-alholic antihistaminic/nasal-decongestant medication comprisin diphenhydramine hydrochloride, pseudoephedrine hydrochloride, glycerin, at least two copolymer surfactants, flavor compounds and water.

28. The antihistaminic/nasal-decongestant medication of claim 27 wherein one co-polymer surfacta is selected from the group consisting of poly(oxyethylene)-poly(oxypropylene) block co-polymers polysorbate co-polymers and mixtures thereof.

29. The antihistaminic/nasal-decongestant medication of claim 28 wherein a second co-polymer surfactant is selected from the group consisting of polysorbate co-polymers.