JP2002527351A - Composition for preventing and treating cold and flu-like symptoms associated with respiratory tract infection - Google Patents

Abstract

  (57) [Summary] The present invention is a composition for the prevention and treatment of cold and flu-like symptoms associated with sign infection. It also includes methods of using such compositions.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD OF THE INVENTION

[Field of Application] The present invention relates to a composition and a method for preventing and treating cold and flu-like symptoms caused by respiratory tract infection. These compounds and their methods of application are both effective in preventing the onset of cold and flu symptoms, or in significantly relieving those already suffering from such symptoms.

[0002] A number of different viruses and virus strains are known to cause symptoms associated with respiratory tract virus infection. Precisely determining the specific cause of the disease is difficult and impractical, as there are many predisposing factors whose contribution to symptomatic signs is not well understood. These include, but are not limited to, physical fatigue, psychological stress, and overall physical health.

[0003] Despite the viruses and related factors that cause the onset of cold and flu symptoms, many therapeutic agents have been proposed to alleviate the symptoms of common cold.
In recent years, cough / cold products marketed commonly contain one or more of the following actives:
Nasal decongestants such as pseudoephedrine, oxymetazoline, antihistamines such as doxylamine, antitussives such as dextromethorphan, expectorants such as guaifenesin, and antipyretics such as acetaminophen. In an attempt to improve existing cold remedies, experts in the field have suggested some other medications,
Subsequently, a cold trial is being conducted to test its efficacy. Examples of these therapies, interferon-.alpha. ₂ (Douglas et al., Prophylactic Efficacy
of Intranasal Alpha ₂ -Interferon Against Rhinovirus infection in the Fami
ly Setting, The New England Journal of Medicine, 314, pp. 65-70, 1986); bradykinin antagonists (Higgins et al., A Study of the Efficacy of the Brad).
ykinin Antagonist, NPC567, in Rhinovirus Infections in Human Volunteers,
Antiviral Research vol. 14, pp. 339-344, 1990); glucocorticoids (Farr et al., A Randomized Controlled Trial of Glucocorticoid Prophylaxis)
Against Experimental Rhinovirus Infection, The Journal of Infectious Dis
eases vol. 162, pp. 1173-1177, 1990); nedocromil (Barrow et al., The
Effect of Intranasal Nedocromil Sodium on Viral Upper Respiratory Tract
Infections in Human Volunteers, Clinical and Experimental Allergy vol.
20, pp. 45-51, 1990); a combination of interferon-α2, ipratropium and naproxen (Gwaltney, Combined Antiviral and Antimediato).
r Treatment of Rhinovirus Colds, The Journal of Infectious Diseases vol.
166, pp. 776 782, 1992); zinc salts (Potter et al., DIAS Rounds, Zinc Loz).
enges for Treatment of Common Colds, The Annals of Pharmacotherapy vol.
27, pp. 589-592, 1993).

[0004] A number of patents have also been issued disclosing compositions for the prevention and treatment of common colds and methods of using the same. Examples of such patents include: U.S. Patent Nos. 5,240,694; 5,422,097 and 5,492,689; all of which are directed against Gwaltney, a treatment using a combination of anti-viral and anti-inflammatory compounds. U.S. Pat. Nos. RE 33,465 and 5,409,905; both to Eby and discloses treatment using zinc salts; U.S. Pat. No. 5,626,831 to Van Moerkerken; Discloses treatment using an orally administered aminocarboxylic acid compound; U.S. Pat. Nos. 4,619,934 and 4,552,899.
No .; both to Sunshine and disclose the treatment of cough and cold using a composition comprising a non-steroidal anti-inflammatory drug such as NSAIDS together with an anti-histamine effector such as chlorpheniramine. .

[0005] Despite the numerous compositions and prophylactic treatments known in the art, there is a need to provide consistent and effective methods of preventing and treating cold and flu symptoms.

SUMMARY OF THE INVENTION [0006] The present invention is for airway compositions for the prevention and treatment of cold and flu-like symptoms due to respiratory tract infections and methods of using such compositions. These methods involve the administration of an airway composition comprising a compound conforming to the following chemical structure:

[0007]

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[0008] The following are definitions that should be applied to the terms used to describe the invention. "Respiratory tract composition" refers to an airway passage through the nose and mouth.
seges). These compositions include, but are not limited to, vials, pump sprays, compressed sprays, nebulizers, air inhalers, and other packaging and equipment known or to be further developed. "Cold and flu-like symptoms" refer to conditions commonly associated with respiratory tract viral infections. These symptoms include nasal congestion, chest congestion, sneezing, rhinorrhea, fatigue or malaise, cough, fever, chills, body aches, sore throats and headaches, and other known cold and flu-like symptoms However, these are not limited. "Pharmaceutically acceptable vehicle" refers to any solid, liquid, or gas that is combined with a compound in a composition of the present invention to deliver the compound to the respiratory tract of a user. These vehicles are generally considered safe for human use.

DETAILED DESCRIPTION OF THE INVENTION The present invention is for a respiratory tract composition for preventing or treating cold and flu-like symptoms associated with respiratory tract infections and methods of using the composition. The method results from the administration of a composition to the respiratory tract comprising a compound conforming to the following chemical structure:

[0010]

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Wherein R is hydrogen (—H); hydroxyl group (OH); an ester group having the structure —OCOR ″, where R ″ is a C1 to C18 branched and straight chain alkyl group, unsubstituted aryl Group, chlorine (-Cl), fluorine (-F), aryl group substituted with bromine (-Br), hydroxyl group (-OH), carboxyl group (-COOH), -OR
Consisting of groups having "" and -COOR "", wherein R "" is selected from the group consisting of branched and straight chain alkyl groups having from 1 to about 4 carbon atoms. X is selected from the group consisting of oxygen (-O) and nitrogen (-N); and R 'is hydrogen (-H); dihydrogen atom (- H ₂ );
And R ".

[0012] These compounds can also be in a base- or salt-free form. Examples of such salts include, but are not limited to, maleic acid, hydrogen chloride, hydrogen bromide, EDTA, tartaric acid, and mixtures thereof.

Compounds suitable for use in the present invention include those wherein R is selected from the group consisting of —OH, —OCOR ″ and —H, X is —O, and R ′ is -H and R "
And those having the above structure selected from the group consisting of Where R is -O
Most preferred are H, X is -O and R 'is -H. Such a suitable compound is 3-carboxy-2-hydroxy-N, N, N-trimethyl-1
-Propanaminium hydroxide, an inner salt, Merck Index, 10th edition, 1
See 983, p257. Such compounds are also known in the art as L-carnitine or levocarnitine. L-carnitine is available from Lonza, Ltd. Basel, Switzerla
Commercially available from nd.

The use of L-carnitine is known in the art for the acute treatment of patients with secondary carnitine deficiency, primary systemic carnitine deficiency and congenital metabolic disorders caused by dietary supplementation of renal patients. Physicians Desk Reference, pp2623-2624 and pp27
See 67-2768, 1997. L-carnitine is also known for use in dietary supplements, special dietary foods and meal replacements, sports supplements, and commercial products sold as general nutritional supplements. It is usually found as a single ingredient in multi-component products in solid or liquid form (tablets, capsules, tonics, beverages) to make it orally digestible.

[0015] The inner salt of 3-carboxy-2-hydroxy-N, N, N-trimethyl-1-propanaminium hydroxide or L-carnitine may be structurally modified to give an ester. Synthetic reactions to produce such esters are routinely performed by those skilled in the chemical arts. Examples of reagents and synthetic techniques useful for making such esters are found in many references, including
Fieser, Reagents for Organic Synthesis, p. 1309, 1967; Furuta, Gao, Yama
moto, Organic Synthesis, pp. 72, 86, 1993; and Bremer, Biochemical Prepa
ration, Vol. 12, p. 69, 1968. These L-carnitine inner salt esters are alpha, beta, gamma and delta tocopherol; 1,2-dimethyl-3-hydroxypyrid-4-one; (S) (−) 6-hydroxy-2,5, 7,
From the group consisting of 8-tetramethylchroman-2-carboxylic acid or a mixture of (S) (-) and (R) (+) 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid It has a carboxyl group esterified by the selected compound. Other L-carnitine esters useful in the present invention include ascorbic acid, (S) (-) 6-
Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid or (S) (-
) And (R) (+) 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, including those having the hydroxyl group of the above compounds esterified. 6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid is available from Aldrich Chemical Company as "Trolox". Subsequent types of these esters can be further esterified at the carboxyl group with R ". The absolute configuration and enantiomeric design of these compounds is well established by established terminology," S and R "and" + and-". Is defined using each of the following. See Dean, Handbook of Organic Chemistry. Pp. 1-48, 1-51, 1987.

The levels of the above compounds will vary with the composition. For example, when the composition form is a liquid, the level of compound may be from about 0.01% to about 50% of the composition, preferably about 0.1%.
It ranges from about 05% to about 20%, most preferably from about 0.1% to about 5%. When the composition form is a powder, the level of compound in the composition can range from about 0.01% to about 100%, preferably from about 0.1% to about 99%, and most preferably from about 20% to about 100% of the composition. It is in the range of 90%.

[0017] Depending on the desired form and delivery device used, the compositions of the present invention may include a pharmaceutically acceptable vehicle. Pharmaceutically acceptable vehicles for the liquid form compositions of the present invention include aqueous buffered solutions or dispersions; aqueous buffered solutions or dispersions containing co-solvents such as ethanol, propylene glycol, water-miscible solvents. Liquid aerosol propellants, as well as mixtures thereof. Preferably, these vehicles have an osmotic pressure approximately equal to that of human plasma and a normal nasal secretion for use in internasal products, or a pulmonary environment for use in inhaled products. With similar pH. The vehicle may also contain a buffer for pH stability, and a preservative to prevent the inoculation of microorganisms into the administration device inserted into the nose. Volatile oils, sensates, and flavoring agents may also be included to provide the desired in-use odor and composition taste. The vehicle may also include a surfactant to assist in spreading the composition throughout the respiratory tract. Gums, thickeners, thickeners, mucoadhesive polymers and mixtures thereof may be included from the nasal cavity to the oropharynx to slow the normal physiological clearance of the solution. When the composition of the present invention is in liquid form, the vehicle will comprise about 50% to 99.99% of the therapeutic composition, preferably about 80% to about 99.95%, and most preferably about 95% to about 99.9%. Used at the level.

When the composition of the present invention is in solid form, the vehicle may be applied in powder form without the use of a particular vehicle. However, vehicles are often added to aid processing of the composition to provide acceptable fluidity and particle size for inhalation applications. Other particulate or powdered pharmaceutically acceptable filler materials may be used in the compositions of the present invention to enhance flow, stability, handleability, hygroscopicity; advantageous flavor, taste and / or feel. It may be combined with an object. In the present invention, the solid vehicle comprises from 0% to about 99.99%, preferably from about 1% to about 99.9% of the composition.
%, Most preferably from about 10% to about 80%.

EXAMPLES The following are non-limiting examples of compositions of the present invention. All ingredients are by weight in 100 g of composition. Example 1 Nasal Spray Solution 1.00 g without L-carnitine base 0.70 g nonionic detergent ¹ 0.11 g dibasic sodium phosphate 0.38 g monobasic potassium phosphate 0.04 g benz Alconium chloride 0.26 g chlorhexidine gluconate 0.01 g disodium EDTA Flavoring agent ² camphor and eucalyptol ³ Up to 100 g with purified water 1 Available as Nylcomed, Inc. as Tyloxapol. 2 Flavoring agents are used at a level to provide a pleasant taste. 3 Added at a level to provide a pleasant aroma during use.

Add all ingredients to the cold water and stir while maintaining the cold water temperature until dissolved. The solution is adjusted to a pH of 5.5 to 6.5. Adjust the volume with water and filter through a cellulose acetate membrane filter. The composition is filled into a manually operated nasal spray. Spray about 5 to 500 microliters of the solution into each nostril. Repeat 3 times daily.

Example 2: Nasal drop 0.115 g of methylcellulose gum 0.350 g of sodium chloride 0.540 g of monobasic potassium phosphate 0.310 g of dibasic potassium phosphate 0.145 g of poloxamer block Polymer ¹ 1.170 g of propylene glycol 0.568 g of L-carnitine hydrochloride 0.025 g of benzalkonium chloride Flavoring agent ² camphor and eucalyptol ³ Up to 100 g with purified water 1 Available as Pluronic 127 from BASF Corporation. 2 Flavoring agents are used at a level to provide a pleasant taste. 3 Added at a level to provide a pleasant aroma during use.

Add all ingredients except methylcellulose to the cold water and stir until dissolved until the cold water temperature is maintained. The solution is adjusted to pH 6.5 to 7.0, adjusted with water and filtered through a cellulose acetate membrane filter. Add methylcellulose to the cold solution and stir under refrigeration until hydrated. Fill the drop vial with this solution and cap. Tilt the head up and drop one drop of this solution into each nostril. Hold the head in this position for a while to allow the solution to diffuse into the nasal turbinates. Repeat 3 times daily.

Example 3: Inter-nostril powder 5.0 g acetyl L-carnitine 5.0 g dextrose powder 1.0 g ethanol Flavor ¹ camphor and eucalyptol ³ lactose powder up to 100 g 1 Flavor provides a pleasant taste Use in appropriate amount. 2 Added at an appropriate level to provide a pleasant odor during use.

Mix acetyl L-carnitine and dextrate in a V mixer. The mixture is milled in a fluid energy mill at a dry air pressure of 100 pounds per square inch. The milled material is mixed by geometric addition with lactose in a V-mixer. Dissolve camphor, eucalyptol and flavoring agent in ethanol and spray coat the powder with this liquid in a V-mixer. The ethanol after mixing is evaporated by pan drying. This powder is filled into a dry powder metering pump. Such pumps include the Prohaler DPI from Valois Corporation. 10 milligrams of this powder is applied to each nostril while inhaling. Repeat 3 times daily.

[0025] Example 4: inhalants 0.60g of acetyl L- carnitine 0.40g of sorbitan trioleate propellant 114-oleate 49.50g ¹ 49.51g of propellant ^{2 1 Freeon 114 EIDuPont 2 Freeon 12} EIDuPont

Acetyl L-carnitine is micronized in a fluid energy mill at a pressure of 100 pounds per square inch. Dissolve sorbitan trioleate in the mixed propellant. Acetyl L-carnitine is dispersed in the sorbitan trioleate / propellant liquid. The dispersion is filled into the cans of a compression metered dose inhaler using conventional filling techniques. While inhaling, 100 to 200 microliters are dispensed into the mouth from the metered dose inhaler.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE , KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZW (71) Applicant ONE PROCTER & GANBL E PLAZA, CINCINNATI, OHIO, UNITED STATES OF AMERICA (72) Inventor Mizoguchi, Harco Fairfield, Obergar, Drive, Ohio, USA 5740 (72) Inventor Singer, Robert Ernest Jr., Ohio, USA, Fairfield, Kingsmont, Court 3 (72) Inventor Smith, Ronald Lee United States of America, Yard Lee, Pennsylvania Culver City, drive 1190 F-term (reference) 4C076 AA24 AA29 AA49 AA93 BB03 BB25 DD19 DD23 DD26 DD34 DD38 DD46 DD48 DD49 DD51 DD61 EE23 EE31 EE48 EE49 4C206 AA01 FA41 FA42 MA05 NA14 ZA59 ZB11 ZC54

Claims (10)

[Claims] 1. A tracheal composition for the prophylaxis and treatment of colds and flu-like symptoms due to respiratory tract infections, said composition comprising a compound having the following structure: Wherein R is hydrogen (—H); hydroxyl group (OH); an ester group having the structure —OCOR ″ (where R ″ is a C1 to C18 branched and straight chain alkyl group, an unsubstituted aryl group, chlorine) (-Cl), an aryl group substituted with fluorine (-F), bromine (-Br), a hydroxyl group (-OH), a carboxyl group (-COOH), a structure -OR '''
And -COOR "", wherein R "" is selected from the group consisting of branched and straight chain alkyl groups having 1 to 4 carbon atoms.
; X is selected from the group consisting of oxygen (-O) and nitrogen (-N); and, R 'is hydrogen (-H); from the group consisting of and R "; 2 hydrogen atoms (-H ₂₎ X is selected from the group consisting of oxygen (—O) and nitrogen (—N); and R ′ is selected from hydrogen (—H); dihydrogen (—H ₂ ); and R ″ Selected from the group consisting of: 2. The composition of claim 1, wherein said compound is a compound of the formula
The composition comprises from 0.01% to 100%. 3. The composition according to claim 2, wherein the compound is such that R is —O.
H, -COR "and -H, wherein X is -O and R 'is selected from the group consisting of -H and R". object. 4. The composition according to claim 3, wherein said compound is such that R is --O.
H. wherein X is -O; and R 'is -H. 5. The composition of claim 4, wherein said compound is 3-carboxy-2-hydroxy-N, N, N-trimethyl-1-propanaminium hydroxide inner salt. object. 6. A liquid composition according to claim 5, comprising from 0.01% to 50% of said compound. 7. The composition according to claim 6, wherein the composition is 50% to 99.99%.
The composition further comprising a pharmaceutically acceptable vehicle. 8. A method for producing a composition comprising a compound conforming to the following structure: Wherein R is hydrogen (—H); hydroxyl group (OH); an ester group having the structure —OCOR ″ (where R ″ is a C1 to C18 branched and straight chain alkyl group, an unsubstituted aryl group, chlorine) (-Cl), an aryl group substituted with fluorine (-F), bromine (-Br), a hydroxyl group (-OH), a carboxyl group (-COOH), a structure -OR '''
And -COOR "", wherein R "" is selected from the group consisting of branched and straight chain alkyl groups having 1 to 4 carbon atoms.
; X is selected from the group consisting of oxygen (-O) and nitrogen (-N); and, R 'is hydrogen (-H); from the group consisting of and R "; 2 hydrogen atoms (-H ₂₎ It is selected; X is selected from oxygen or -O and the group consisting of nitrogen, or -N; and, R 'is hydrogen; is selected from the group consisting of and R "; 2 hydrogen atoms (-H ₂₎ The method wherein the composition is used for the prevention and treatment of cold and flu-like symptoms due to respiratory tract infection. 9. The method of claim 8, wherein the composition is administered to the respiratory tract, wherein the compound of the composition is selected from the group where R consists of -OH, -OCOR "and -H. Selected, wherein X is -O and R 'corresponds to a structure wherein R' is selected from the group consisting of -H and R ". 10. The method of claim 9, wherein the compound matches a structure where R is -OH, X is -O, and R 'is -H.