WO1994028872A1 - Medication sans alcool contre les rhumes et pour les sinus - Google Patents

Medication sans alcool contre les rhumes et pour les sinus Download PDF

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Publication number
WO1994028872A1
WO1994028872A1 PCT/US1994/005812 US9405812W WO9428872A1 WO 1994028872 A1 WO1994028872 A1 WO 1994028872A1 US 9405812 W US9405812 W US 9405812W WO 9428872 A1 WO9428872 A1 WO 9428872A1
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WO
WIPO (PCT)
Prior art keywords
cold
medication
sinus
weight
group
Prior art date
Application number
PCT/US1994/005812
Other languages
English (en)
Inventor
Charles Pozzi
Original Assignee
Warner-Lambert Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Warner-Lambert Company filed Critical Warner-Lambert Company
Priority to AU69564/94A priority Critical patent/AU6956494A/en
Publication of WO1994028872A1 publication Critical patent/WO1994028872A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline

Definitions

  • 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.
  • 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.
  • 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 conventional carrier for the active and flavor ingredients in most cold/sinus medications is typically a water:alcohol mixture.
  • 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.
  • 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.
  • 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) .
  • Benadryl® Elixir Parke-Davis, Morris Plains, New Jersey
  • Vicks® 44-D Raichardson- Vicks, Shelton, Connecticut
  • 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.
  • high levels of alcohol are required as a solvent for
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Poloxamer 407 a poloxamer such as Poloxamer 407 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.
  • HLB hydrophilic/ lipophilic balance
  • 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.
  • 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.
  • preservatives 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.
  • 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.
  • 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.
  • flavoring agents 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.
  • 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.
  • sweetenings 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

Une médication améliorée, sans alcool, aqueuse, contre les rhumes et pour les sinus offre la même efficacité que les formulations connues de la technique antérieure, avec un goût et des sensations buccales acceptables. Les ingrédients actifs au goût autrement amer se composant d'un antihistaminique et d'un décongestionnant sont solubilisés et dispersés dans la solution aqueuse à l'aide d'un système d'émulsifiant et de tensioactif qui comprend de petites doses de composants aromatisés qui agissent pour masquer davantage le goût des notes médicinales amères.
PCT/US1994/005812 1993-06-04 1994-05-24 Medication sans alcool contre les rhumes et pour les sinus WO1994028872A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU69564/94A AU6956494A (en) 1993-06-04 1994-05-24 Non-alcoholic cold and sinus medication

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US7261493A 1993-06-04 1993-06-04
US08/072,614 1993-06-04
US12340293A 1993-09-17 1993-09-17
US08/123,402 1993-09-17

Publications (1)

Publication Number Publication Date
WO1994028872A1 true WO1994028872A1 (fr) 1994-12-22

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998031344A1 (fr) * 1997-01-15 1998-07-23 Bayer Corporation Masquage du gout pour formulations desagreables au gout

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1051240A (fr) * 1964-11-06
GB919039A (en) * 1959-12-30 1963-02-20 Biorex Laboratories Ltd Anti-tussive compositions comprising glycyrrhetinic acid and related compounds
GB1042637A (en) * 1964-01-20 1966-09-14 Thomae Gmbh Dr K Pharmaceutical compositions containing dihalogeno-amino-benzylamines
US4269835A (en) * 1979-12-13 1981-05-26 Whittle Barry J Nasal composition for relieving nasal distress
EP0152945A2 (fr) * 1984-02-23 1985-08-28 Müller, Bernd Willy Werner, Prof. Dr. Systèmes pharmaceutiques à composants multiples et procédé de leur préparation
WO1986000813A1 (fr) * 1984-07-27 1986-02-13 Schering Aktiengesellschaft Compositions pharmaceutiques renfermant des gels
WO1986002553A1 (fr) * 1984-10-23 1986-05-09 Nastech Pharmaceutical Company, Inc. Nouveau procede d'administration d'agents anti-nausee et anti-emetiques et nouvelles formes de dosage les contenant
EP0215313A2 (fr) * 1985-09-16 1987-03-25 American Cyanamid Company Emulsions pour l'administration parentérale et/ou orale de médicaments peu solubles dans l'eau, ionisables et hydrophobes
EP0455396A1 (fr) * 1990-05-01 1991-11-06 MDV Technologies, Inc. Compositions de gel aqueux et leur utilisation
WO1992004021A1 (fr) * 1990-09-11 1992-03-19 Richardson Vicks Inc. Procede permettant d'ameliorer l'effet analgesique
US5112604A (en) * 1989-09-01 1992-05-12 Riker Laboratories, Inc. Oral suspension formulation
US5114979A (en) * 1989-10-18 1992-05-19 Schering Corporation Fruity flavored nasal decongestant composition

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB919039A (en) * 1959-12-30 1963-02-20 Biorex Laboratories Ltd Anti-tussive compositions comprising glycyrrhetinic acid and related compounds
GB1042637A (en) * 1964-01-20 1966-09-14 Thomae Gmbh Dr K Pharmaceutical compositions containing dihalogeno-amino-benzylamines
GB1051240A (fr) * 1964-11-06
US4269835A (en) * 1979-12-13 1981-05-26 Whittle Barry J Nasal composition for relieving nasal distress
EP0152945A2 (fr) * 1984-02-23 1985-08-28 Müller, Bernd Willy Werner, Prof. Dr. Systèmes pharmaceutiques à composants multiples et procédé de leur préparation
WO1986000813A1 (fr) * 1984-07-27 1986-02-13 Schering Aktiengesellschaft Compositions pharmaceutiques renfermant des gels
WO1986002553A1 (fr) * 1984-10-23 1986-05-09 Nastech Pharmaceutical Company, Inc. Nouveau procede d'administration d'agents anti-nausee et anti-emetiques et nouvelles formes de dosage les contenant
EP0215313A2 (fr) * 1985-09-16 1987-03-25 American Cyanamid Company Emulsions pour l'administration parentérale et/ou orale de médicaments peu solubles dans l'eau, ionisables et hydrophobes
US5112604A (en) * 1989-09-01 1992-05-12 Riker Laboratories, Inc. Oral suspension formulation
US5114979A (en) * 1989-10-18 1992-05-19 Schering Corporation Fruity flavored nasal decongestant composition
EP0455396A1 (fr) * 1990-05-01 1991-11-06 MDV Technologies, Inc. Compositions de gel aqueux et leur utilisation
WO1992004021A1 (fr) * 1990-09-11 1992-03-19 Richardson Vicks Inc. Procede permettant d'ameliorer l'effet analgesique

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998031344A1 (fr) * 1997-01-15 1998-07-23 Bayer Corporation Masquage du gout pour formulations desagreables au gout
US5837286A (en) * 1997-01-15 1998-11-17 Pandya; Harish B. Taste masking for unplatable formulations

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Publication number Publication date
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