JP2001517626A - Compositions and methods for treating respiratory disorders - Google Patents

Abstract

  (57) [Summary] The present invention relates to compositions and methods that result in improved treatment, management or alleviation of cold, cold-like, allergy, cavity and / or flu symptoms by administering a safe and effective amount of a composition comprising naproxen with cetirizine. .

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] TECHNICAL FIELD THE INVENTION The present invention relates, common cold comprising administering a safe and effective amount of a composition comprising naproxen or related compound with cetirizine or related compounds, flu-like, allergy, cavities and / or flu symptoms Compositions and methods that provide improved treatment, management or relief.

[0002] The prior art common cold is usually not a serious illness, one that fairly prevalent, is uncomfortable, annoy in pain. The term "common cold" applies to mild respiratory illness caused by a variety of different respiratory viruses. Rhinoviruses are a major known cause of common colds, accounting for approximately 30% of adult colds, but several other groups of viruses are also important. Although an immune response can be produced, thereby preventing the infection by some of the respiratory tract viruses, the development of a versatile vaccine that covers all possible exogenous agents is not feasible. Thus, the problem of controlling acute upper respiratory distress presents a complex challenge, and finding a single solution for the long-awaited common cold has become an unrealistic expectation.

[0003] Early symptoms may be minimal with mild malaise, complaints of sore throat and nose. In rhinovirus infection, the symptoms of runny secretions, nasal congestion and sneezing usually begin on the first day of the disease and progress to maximum severity by the second or third day. Sore throat, dryness or itching, hoarseness and cough are associated with nasal symptoms. Other symptoms may include a mild burning sensation in the eyes, loss of smell and taste, pressure or blockage in the sinuses or ears, headaches and mouth damage. Heat is generated, which is unusual. Influenza infections generally include fever, which starts abruptly and lasts for several days and is quite severe; systemic pain and aches and pains; fatigue and collapse; and chest discomfort.

[0004] Currently, for the common cold, only treatment of the symptoms is effective. The cost of treating over-the-counter colds in the United States is estimated at over $ 1.5 billion annually. The direct cost of treatment in outpatient clinics is estimated at almost $ 4 billion. Indirect costs based on salary losses due to binding activities are substantially higher.

[0005] Cough, cold, cold-like, allergy, cavity and / or flu symptoms and discomfort,
Examples of prior art formulations for the treatment of pain, fever and related general malaise include painkillers (aspirin or acetaminophen) and one or more antihistamines, decongestants, cough suppressants, Includes antitussives and expectorants.

The use of non-steroidal anti-inflammatory drugs to remove inflammation and associated pain
Allowed for medical practice. Non-steroids are commonly used to relieve pain and inflammation associated with, for example, bursitis, arthritis, headache, and the like. The most commonly used of the non-narcotic analgesic class of drugs are aspirin, acetaminophen, ibuprofen, ketoprofen, diclofenac and naproxen and their salts (eg lysine, arginine, sodium and potassium) . Aspirin, acetaminophen and ibuprofen are commonly used for cough /
It has been previously included in cold complex symptom relief compositions as a pain relieving and heat reducing ingredient. These commercial products generally contain one or more antihistamines, decongestants, coughs, antitussives and expectorants in addition to aspirin, acetaminophen or ibuprofen.

[0007] The present inventors have determined that selected compositions comprising naproxen and cetirizine are useful for improving cold, cold-like, allergic, cavity and / or flu symptoms, including nasal congestion. Found to provide treatment, management or palliative care.

Accordingly, it is an object of the present invention to provide a method of treating cough, cold, cold-like, allergy, cavity and / or flu symptoms in a mammal in need of such treatment, And administering the composition of the present invention to such an organism.
Symptoms as used herein refer to coryza, nasal congestion, cavity congestion, cavity pain, upper respiratory infections, otitis, cavityitis, and the like.

SUMMARY OF THE INVENTION The present invention provides an improved treatment, management or alleviation of cold, cold-like, allergy, cavity and / or flu symptoms by administering a safe and effective amount of a composition comprising naproxen with cetirizine. Compositions and methods for providing All percentages and ratios used herein are by weight unless otherwise indicated, and measurements were made at 25 ° C unless otherwise indicated.

[0010] Detailed Description of the Invention The present invention, by administering a safe and effective amount of a composition comprising essentially naproxen with cetirizine, cold, cold-like, allergy, improved cavities and / or flu symptoms Compositions and methods for providing treatment, management or relief are provided.

Cetirizine The present invention relates to a composition containing naproxen, wherein 2- [4- (diphenyl-
Methyl) -1-piperazinyl] -acetic acid and amides and the use of non-toxic pharmaceutically acceptable salts thereof. Cetirizine and related compounds, together with non-toxic pharmaceutically acceptable salts thereof, have the following general formula:

[0012]

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In the formula, Y is a hydroxyl group or a —NH ₂ group, and X and X ′ independently represent a hydrogen atom, a halogen atom, a linear or branched lower alkoxyl group or a trifluoromethyl group; Is 1 or 2, and n is 1 or 2, preferably 2
It is.

The term “lower alkoxy” as used herein refers to the residue of both straight and branched chain aliphatic alcohols having 1 to 4 carbon atoms, for example, methoxy, ethoxy, propoxy. And so on. Halogen is preferably chlorine or fluorine.

The term “non-toxic pharmaceutically acceptable salt” as used herein, refers to acetic acid,
Additional salts of acids and amides in formulations having pharmaceutically acceptable acids such as citric acid, succinic acid, ascorbic acid, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, as well as metal salts (e.g., , Sodium or potassium salts), ammonium salts, amine salts and amino acid salts.

Preferred compounds according to the invention are: 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetic acid and its dihydrochloride; potassium 2 -[2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetate; 2- [2- [4-[(4-diphenylmethyl) -1-piperazinyl] ethoxy]- Acetic acid and its dihydrochloride; 2- [2- [4-[(4-fluorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid and its hydrate.

[0017] The cetirizine compound of the formulation has the desired pharmaceutical properties. In particular, they are useful as antiallergic agents, antihistamines, tracheodilators and anticonvulsants,
Used at a level of about 5 to about 20 mg.

Preferred compounds are 3,4-dihydro-6-fluoro-2-naphthyl-α-methyl acetic acid, its alkyl esters wherein the alkyl moiety has 1 to 12 carbon atoms, and its pharmaceutically acceptable additional Salt. Particularly preferred are: 3
, 4-Dihydro-6-chloro-2-naphthyl-α-methylacetic acid, its alkyl esters, wherein the alkyl moiety has 1 to 12 carbon atoms, and pharmaceutically acceptable additional salts thereof. These compounds are described in detail in U.S. Patent No. 4,525,358 of June 25, 1985, which is incorporated herein by reference in its entirety.

Naproxen Naproxen and analogous compounds are derivatives of 2-naphthylacetic acid, which can be represented by the following formula:

[0020]

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The Arabic numerals and α symbol indicate the positions used herein in the nomenclature of 2-naphthylacetic acid derivatives. This is a general formula for naproxen and related compounds. These are further described in U.S. Pat. No. 3,896,157, which is hereby incorporated by reference in its entirety. Naproxen itself is (S) -6-methoxy-2-methyl-2
-Naphthaleneacetic acid, preferably the sodium salt.

[0022] Naproxen and its related compounds are generally used in an amount of 50 to 660 mg, preferably about 100 to 330 mg, more preferably about 150 to about 220 mg.

Additional Pharmaceutical Actives The compositions of the present invention can also include at least one other pharmaceutically active agent selected from the following classes: (a) a decongestant, (b) an expectorant, c) additional antihistamines and (d) antitussives. Decongestants useful in the compositions of the present invention include pseudoephedrine, phenylpropanolamine, phenylephrine and ephedrine, pharmaceutically acceptable salts thereof, and mixtures thereof. Antitussives useful in the present invention include dextromethorphan, clofedianol, carbetapentane, caramiphen, noscapine, diphenhydramine, codeine, hydrocodone, hydromorphone, hominoben, pharmaceutically acceptable salts thereof,
And mixtures thereof. Additional antihistamines useful in the present invention include chlorpheniramine, brompheniramine, dexchlorpheniramine, dexbrompheniramine, triprolidine, azatazine, doxylamine, tripelenamine, cyproheptadine, hydroxyzine, carbinoxamine, phenindamine, bromodiphenhydramine, pyrilamine. , And pharmaceutically acceptable salts thereof, with acrylastine, AHR-11325, astemizole, azatazine, azelastine, ebastine, ketotifen, rhodoxamide, loratidine, levocabastine, mequitazine, oxatomide, cetastine, tadifylin and temerastine,
Such pharmaceutically acceptable salts as well as non-sedating antihistamines, including mixtures thereof, and the like. Expectorants useful in the present invention (also known as mucolytics) include glyceryl guaiacolate, terpin hydrate, ammonium chloride, N-
Includes acetylcysteine and bromhexine, ambroxol, pharmaceutically acceptable salts thereof, and mixtures thereof. All of these components and their acceptable dosage ranges are described in the following: S published November 8, 1988.
U.S. Pat. No. 4,783,465 to Unshine et al., U.S. Pat. No. 4,619,934 to Sunshine et al. These are incorporated into the text.

Additional agents which have been found to be useful in the compositions of the present invention are α-agonists as disclosed in US Pat. No. 5,478,858 issued Dec. 26, 1995. This will be part of the text with full support.

A variety of oral dosage forms can be used, including solid forms such as tablets, caplets, capsules, granules, lozenges and powder blends, and liquid forms such as syrups and suspensions. Controlled release dosage forms that provide controlled release of these actives are also useful. These oral forms contain a safe and effective amount, usually at least about 5%, of the active ingredient. Solid oral dosage forms are preferably from about 5% to about 9%.
5%, more preferably about 10% to about 95%, and most preferably about 25% to about 9%.
Contains 5% active ingredient. Liquid oral dosage forms are preferably from about 1% to about 50%,
More preferably, it contains from about 1% to about 25%, most preferably from about 3% to about 10%, of the active ingredient.

Tablets can be compressed, ground, enteric-coated, sugar-coated, film-coated or multi-stage compressed, with suitable binders, lubricants, diluents, disintegrants, coloring agents, fragrances, preservatives And a flow aid. Soft gelatin capsules are also useful.

[0027] Liquid oral dosage forms include aqueous and non-aqueous solutions, emulsions, pseudoemulsions, suspensions, solutions and / or suspensions reconstituted from non-boiling granules,
Suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, taste-masking agents (taste-mas
king agent), colorants and fragrances. Specific examples of pharmaceutically acceptable carriers and excipients that can be used to formulate oral dosage forms are described in Robert U.S. Pat.No. 3,903,297, issued Sep. 2, 1975, This will be used as part of the text. Techniques and compositions for preparing solid oral dosage forms are described in Marshall, “Solid Oral
Dosage Forms, “Modern Pharmaceutics, Vol. 7, (editors of Banker and Rhodes), 359-427 (
1979), which is incorporated herein by reference. Techniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin) and pills are described in Remington's Pharmaceutical Sciences, edited by Arthur Osol, 1553-15.
93 (1980), which is incorporated herein by reference.

An additional agent that has been found useful in the present invention is caffeine. Caffeine was found to reduce the weak sedative effect of cetirizine. The level of caffeine used is from about 20 mg to about 500 mg, preferably from about 50 mg to about 200 mg.
mg, most preferably from about 65 mg to about 100 mg.

In preparing liquid oral dosage forms, the active ingredient is incorporated into aqueous-based, orally acceptable pharmaceutical carriers consistent with conventional pharmaceutical practice. An "aqueous-based orally acceptable carrier" is one in which all or the major solvent involved is water. Common carriers include simple aqueous solutions, syrups, dispersions and suspensions, as well as aqueous-based emulsions, such as the oil-in-water form. The most preferred carrier is a suspension of the pharmaceutical composition in an aqueous carrier containing a suitable suspending agent. Suitable suspending agents include Avicel RC-591 (a microcrystalline cellulose / sodium carboxymethyl cellulose mixture available from FMC), guar gum and the like. Such suspending agents are well known to those skilled in the art. Although the amount of water in the compositions of the present invention can vary over a fairly wide range depending on the total weight and volume of the active ingredients and any other inactive ingredients, the total water content may vary. Based on the weight of the product, generally about 2
It ranges from 0 to about 75% w / v, preferably from about 20 to about 40% w / v.

Although water itself can be the entire carrier, common liquid formulations are preferably co-solvents, such as propylene, to aid solubilization and incorporation of the water-insoluble ingredients, such as, for example, seasoning oils. Glycol, glycerin, sorbitol solution and the like. Thus, in general, the compositions of the present invention preferably comprise from about 5 to about 25 vol / vol%
, Most preferably about 10 to about 25% v / v cosolvent.

[0031] Any other ingredients known to pharmacists also include these ingredients, such as natural or artificial sweeteners, flavoring agents, coloring agents, etc. to provide a finished product with a pleasing and pleasing appearance.
It may also contain antioxidants such as butylated hydroxyanisole or butylated hydroxytoluene, and preservatives such as methyl or propylparaben or sodium benzoate to extend and increase shell life, in commonly known amounts. it can. A highly preferred optional ingredient is caffeine.

The amount of the therapeutic methods administered pharmaceutical composition is dependent on the percentage of active ingredient in the formulation, which is the dose, stability, release characteristics and required per other pharmaceutical parameters The effect of the amount of cetirizine and naproxen and any optional ingredients, such as decongestants, coughs, expectorants, caffeine and / or additional antihistamines.

Usually, about 1 mg / kg to about 50 mg / kg per day, preferably about 2 mg / kg to about 30 mg / kg per day, most preferably about 3 mg / kg per day.
From kg to about 20 mg / kg of the pharmaceutical composition is administered as described herein. This amount may be given in a single dose or, preferably, in multiple (2 to 6) repeated doses or a continuous release dose over a series of treatments.
Generally, each individual administration of a pharmaceutical composition of this invention will range from about 1 mg / kg to about 2 mg / kg.
It ranges from 5 mg / kg, preferably from about 2 mg / kg to about 15 mg / kg, most preferably from about 3 mg / kg to about 10 mg / kg. Higher doses are effective in reducing cough, cold-like, influenza, influenza-like and allergic rhinitis symptoms, but when used with either drug, some patients have a negative Patient care must be taken to prevent side effects.

The following examples illustrate embodiments of the present invention, wherein essential and optional components are combined.

EXAMPLE I A hard gelatin capsule composition for oral administration is prepared by combining the following ingredients: Ingredient Amount Naproxen Sodium 220-440mg Pseudoephedrine HCl 60.00mg (120mg, sustained release) Cetirizine ^* 5mg Grind active ingredient and qs to lactose to selected capsule size. *: Cetirizine is [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] -ethoxy] acetic acid.

Administering one or two of the above capsules every 4 to 12 hours to a person in need of treatment may result in improved alleviation of cough, cold-like, flu, flu-like and allergic rhinitis symptoms Bring.

EXAMPLE II A rigid compressed caplet composition for oral administration is prepared by combining the following ingredients. Ingredient amount Naproxen sodium 220 or 440 mg Cetirizine 5 mg Pregelatinized starch 20.00 mg Corn starch 80.00 mg Croscarmellose sodium 10.00 mg Silicon dioxide, colloidal 1.50 mg TP stearic acid fine powder 2.00 mg Sodium lauryl sulfate 0.50 mg Opadry clear / colorolcon ( Opadry clear / Colorcon) (containing hydroxypropyl methylcellulose) 5.0mg

Administration of the two above-mentioned caplets every 12 hours to a person in need of treatment results in improved relief of cough, cold-like, flu-like and allergic rhinitis symptoms.

EXAMPLE III A hard compressed tablet composition for oral administration is prepared by combining the following ingredients. Ingredient Amount naproxen sodium 220 or 440mg cetirizine 5mg Microcrystalline cellulose 110mg Povidone 10mg Talc 12mg Magnesium stearate 2mg Opadry Clear / Kororukon (hydroxypropylmethylcellulose containing) 5.0 mg

Administration of one such tablet every 12 hours to a person in need of treatment results in improved relief from cough, cold-like, flu, flu-like and allergic rhinitis symptoms.

Example IV A liquid composition for oral administration is prepared by combining the following ingredients. Ingredient % W / V Naproxen sodium 2.200 Cetirizine 0.050 High fructose corn syrup (55%) 55.000 Polyethylene glycol 400 10.000 Propylene glycol 10.000 Alcohol (95%) 8.500 Sodium citrate dihydrate 0.470 Citric acid 0.180 Saccharin sodium 0.700 Flavor 0.015 Colorant 0.005 Sufficient To 100% purified water

Pour purified water (about 10% of the final batch volume) into a batch vessel equipped with a lightnin mixer. With sodium citrate, citric acid, asodium saccharin,
Continue to add actives other than naproxen sodium and dissolve with stirring.
High fructose is then added. In a separate container, add the colorant to purified water (about 0.5% of final batch volume). This coloring solution is then added to the first batch container. In a separate container, add naproxen sodium to the alcohol with stirring. Propylene glycol, polyethylene glycol and perfume are added to the alcohol premix, the resulting mixture is stirred until homogenized, and then added to the first vessel. The remaining purified water is added to the resulting mixture and stirred.

For those in need of treatment 10 to 20 ml (2 to 4 teaspoons)
(Cup) every 12 hours results in improved relief from cough, cold-like, flu, flu-like and allergic rhinitis symptoms.

Administering 20 ml (4 teaspoons) every 8 hours to those in need of treatment will result in improved relief from cough, cold-like, flu, flu-like and allergic rhinitis symptoms Bring.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) A61K 31: 445) A61K 31: 445) (81) Designated countries 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, G , GE, GH, GM, HU, ID, IL, 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 & GANBLE PLAZA, CINCINNATI, OHIO, UNITED STATES OF AMERICA F-term (reference) 4C086 AA01 BC21 BC50 CB07 MA02 MA03 MA04 MA05 MA09 MA10 NA05 ZA34 ZA13 Z33 ZA23 ZA23 ZB23 ZA23 ZA23 ZB23 ZA23 ZA23 ZA23 ZA23 ZA23 ZA23 ZA23 ZA23 ZA23 ZA23 ZA23 ZA23 ZA23 ZA23 ZA23 ZA23 ZA23 ZA23 ZA23 ZA23 ZA23 ZA23 ZA23 ZA13 ZA23 ZA23 ZA23 ZA23 ZA23 Z33A23 FA03 FA38 FA51 HA32 KA01 MA02 MA03 MA04 MA05 MA37 MA55 MA57 MA72 NA05 ZA34 ZA59 ZB11 ZB13 ZB33 ZC13 ZC75

Claims (10)

[Claims] 1. An improved treatment, management or alleviation of cold, cold-like, allergy, cavity or flu symptoms comprising: (a) an analgesic which is naproxen or a related compound or a pharmaceutically acceptable salt thereof; b) A pharmaceutical composition resulting from administering a safe and effective amount of a composition comprising cetirizine or a related compound. 2. The method of claim 1, wherein the cetirizine or a related compound is methyl 4- [1-hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α,
α-dimethylbenzene acetate, 4- [1-hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -α, α-dimethylbenzeneacetic acid, 1- [p- (2-hydroxymethyl-2- Propyl) -phenyl] -4- [4 (α-
The pharmaceutical composition according to claim 1, which is selected from the group consisting of hydroxy-α-phenylbenzyl) -1-piperidinyl] butanol and mixtures thereof. 3. Ibuprofen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indoprofen, pirprofen, carprofen, oxaprozin, planoprofen, miloprofen, tioxaprofen, suprofen, aluminoprof The pharmaceutical composition according to claim 2, comprising an additional sedative selected from the group consisting of fen, thiaprofen and diclofenac. 4. The naproxen or related compound or additional sedative is an amino acid salt, triethylamine, tripropylamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, ornithine, arginine,
Histidine, caffeine, procaine, N-ethylpiperidine, hydrabamine,
4. The pharmaceutical composition according to claim 3, which is selected from the group consisting of choline, betaine, ethylenediamine, glucosamine, methylglycamine, theobromine, purine, piperazine and piperidine, and mixtures thereof. 5. The pharmaceutical composition according to claim 3, further comprising a pharmaceutically active substance selected from the group consisting of a decongestant, expectorant, additional antihistamine, antitussive and a mixture thereof. 6. The method according to claim 1, wherein the additional antihistamine is chlorpheniramine, brompheniramine, dexchlorpheniramine, dexbrompheniramine, triprolidine, doxylamine, tripelenamine, cypropeptazine, carbinoxamine, bromodiphenhydramine, pyrilamine, acrivastine, AHR-1132.
5, selected from the group consisting of phenindamine, astemizole, azatazine, azelastine, ebastine, ketotifen, radoxamide, loratidine, levocabastine, mequitazine, oxatomide, cetastine, tadifylline, temerastin and mixtures thereof, or pharmaceutically acceptable salts thereof. Claim 5
A pharmaceutical composition according to claim 1. 7. The pharmaceutical composition according to claim 5, comprising the S (+) isomer of naproxen or a related compound or an additional sedative. 8. The S (+) isomer of the additional agent is selected from the group consisting of S (+)-ketoprofen lysinate, S (+)-ibuprofen lysinate and mixtures thereof. A pharmaceutical composition according to claim 1. 9. The pharmaceutical composition according to claim 1, further comprising an α-agonist compound, caffeine and a mixture thereof. 10. A sedative and an antihistamine for the manufacture of a medicament for the treatment of cavity pressure, cavity pain, cavity drainage, nasal congestion, cough, cold, cold-like or flu symptoms in mammals in need of such treatment. The use of claim 1, wherein the treatment comprises administering the composition of claim 1 to such an organism.