CA2304005A1 - Compositions and methods for treating respiratory disorders - Google Patents
Compositions and methods for treating respiratory disorders Download PDFInfo
- Publication number
- CA2304005A1 CA2304005A1 CA002304005A CA2304005A CA2304005A1 CA 2304005 A1 CA2304005 A1 CA 2304005A1 CA 002304005 A CA002304005 A CA 002304005A CA 2304005 A CA2304005 A CA 2304005A CA 2304005 A1 CA2304005 A1 CA 2304005A1
- Authority
- CA
- Canada
- Prior art keywords
- pharmaceutical composition
- composition according
- cold
- alpha
- group
- Prior art date
- Legal status (The legal status 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 status listed.)
- Abandoned
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 44
- 238000000034 method Methods 0.000 title abstract description 10
- 208000023504 respiratory system disease Diseases 0.000 title description 3
- 206010022000 influenza Diseases 0.000 claims abstract description 21
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229960001803 cetirizine Drugs 0.000 claims abstract description 15
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229960002009 naproxen Drugs 0.000 claims abstract description 11
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims abstract description 11
- 206010020751 Hypersensitivity Diseases 0.000 claims abstract description 8
- 208000026935 allergic disease Diseases 0.000 claims abstract description 8
- 230000007815 allergy Effects 0.000 claims abstract description 8
- 230000000116 mitigating effect Effects 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 claims description 14
- -1 amino acid salt Chemical class 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
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- 239000003172 expectorant agent Substances 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 6
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- 206010028735 Nasal congestion Diseases 0.000 claims description 4
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- LZFCSDIBLCSFAK-WLHGVMLRSA-N (e)-but-2-enedioic acid;2-[2-(dimethylamino)ethyl]-4-methyl-2,3-dihydropyrido[3,2-f][1,4]oxazepine-5-thione Chemical compound OC(=O)\C=C\C(O)=O.O1C(CCN(C)C)CN(C)C(=S)C2=CC=CN=C21 LZFCSDIBLCSFAK-WLHGVMLRSA-N 0.000 claims description 2
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- 239000004472 Lysine Substances 0.000 claims description 2
- HOKDBMAJZXIPGC-UHFFFAOYSA-N Mequitazine Chemical compound C12=CC=CC=C2SC2=CC=CC=C2N1CC1C(CC2)CCN2C1 HOKDBMAJZXIPGC-UHFFFAOYSA-N 0.000 claims description 2
- ISFHAYSTHMVOJR-UHFFFAOYSA-N Phenindamine Chemical compound C1N(C)CCC(C2=CC=CC=C22)=C1C2C1=CC=CC=C1 ISFHAYSTHMVOJR-UHFFFAOYSA-N 0.000 claims description 2
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- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 claims description 2
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- SOYKEARSMXGVTM-HNNXBMFYSA-N dexchlorpheniramine Chemical compound C1([C@H](CCN(C)C)C=2N=CC=CC=2)=CC=C(Cl)C=C1 SOYKEARSMXGVTM-HNNXBMFYSA-N 0.000 claims description 2
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 229960002698 oxatomide Drugs 0.000 claims description 2
- BAINIUMDFURPJM-UHFFFAOYSA-N oxatomide Chemical compound O=C1NC2=CC=CC=C2N1CCCN(CC1)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 BAINIUMDFURPJM-UHFFFAOYSA-N 0.000 claims description 2
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- 229960003436 pentoxyverine Drugs 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- HTYIXCKSEQQCJO-UHFFFAOYSA-N phenaglycodol Chemical compound CC(C)(O)C(C)(O)C1=CC=C(Cl)C=C1 HTYIXCKSEQQCJO-UHFFFAOYSA-N 0.000 description 1
- 229960001802 phenylephrine Drugs 0.000 description 1
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
- 229960000395 phenylpropanolamine Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 208000020029 respiratory tract infectious disease Diseases 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 206010041232 sneezing Diseases 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000006068 taste-masking agent Substances 0.000 description 1
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 1
- 230000001755 vocal effect Effects 0.000 description 1
Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
Abstract
The present invention relates to compositions and methods for providing improved treatment, management or mitigation of cold, cold-like, allergy, sinus and/or flu symptoms by administering a safe and effective amount of a composition comprising naproxen along with cetirizine.
Description
COMPOSITIONS AND METHODS FOR TREATING RESPIRATORY
DISORDERS
TECHNICAL FIE~,D
The present invention relates to compositions and methods for providing improved treatment, management or mitigation of cold, cold-like, allergy, sinus and/or flu symptoms by administering a safe and effective amount of a composition comprising naproxen or a related compound along with cetirizine or a related compound.
EACKGROUND OF THE INVENTION
The common cold, although not usually a serious illness, is a highly pre-valent, discomforting and annoying affliction. The term "common cold" is applied to minor respiratory illnesses caused by a variety of different respiratory viruses.
While rhinoviruses are the major known cause of common colds, accounting for approximately 30 percent of colds in adults, viruses in several other groups are also important. While immune responses occur, and infection with some respiratory tract viruses therefore could be prevented by a vaccine, development of a polytypic vaccine to cover all possible agents is impractical. Thus, the problem of controlling acute upper respiratory disease presents complex challenges, and the long-desired discovery of a single cure for the common cold is an unrealistic expectation.
Early symptoms may be minimal with only mild malaise, sore throat and nasal complaints. With rhinovirus infection, symptoms of nasal discharge, nasal congestion, and sneezing usually commence on the first day of illness and progress to maximum severity by the second or third day. Along with nasal symptoms may come sore, dry or scratchy throat and hoarseness and cough. Other symptoms may include mild burning of the eyes, loss of smell and taste, a feeling of pressure or fullness in the sinuses or ears, headache, and vocal impairment. Fever can occur, but is uncommon. Influenza infection generally includes fever, often of sudden onset and persisting for several days, and with great severity; generalized aches and pains; fatigue and weakness; and chest discomfort.
At present, only symptomatic treatment is available for the common cold.
The costs of treating colds with over-the-counter medications in the United States is estimated at an annual cost of over 1.5 billion dollars. The direct costs of treatment in outpatient clinics is estimated at almost four billion dollars.
Indirect costs, based on the amount of loss in wages because of restricted activity are sub-stantially higher.
- Exemplary prior art formulations for treatment of cough, cold, cold-like, allergy, sinus and/or flu symptoms and the discomfort, pain, fever and general malaise associated therewith generally contain an analgesic (aspirin or acetaminophen) and one or more antihistaminics, decongestants, cough sup-pressants, antitussives and expectorants.
The use of non-steroidal anti-inflammatory drugs to combat inflammation and attendant pain is accepted medical practice. The non-steroidals are commonly employed to relieve pain and inflammation associated with, for example, bursitis, arthritis, headache and the like. Among the most commonly used drugs of the non-narcotic analgesic class of drugs are aspirin, acetaminophen, ibuprofen, ketoprofen, diclofenac and naproxen and their salts (e.g., lysine, arginine, sodium and potassium). Aspirin, acetaminophen and ibuprofen have heretofore been included as the pain reliever and fever-reducing component in conventional cough/cold multisymptom alleviating compositions. These commercially marketed products generally contain in addition to aspirin, acetaminophen or ibuprofen, one or more antihistaminics, decongestants, cough-suppressants, antitussives and expectorants.
The present inventors have found that selected compositions comprising naproxen along with cetirizine provides improved treatment, management or miti-gation of cold, cold-like, allergy, sinus and/or flu symptoms, including nasal congestion.
It is therefore an object of the present invention to pmvide a method for the treatment of cough, cold, cold-like, allergy, sinus and/or flu symptoms in a mam-malian organism in need of such treatment comprising administering to such organism the compositions of the present invention. Such symptoms as used herein refer to coryza, nasal congestion, sinus congestion, sinus pain, upper respiratory infections, otitis, sinusitis, etc.
Sl;m~iMARY OF THE INVENTION
The present invention relates to compositions and methods for providing improved treatment, management or mitigation of cold, cold-like, allergy, sinus and/or flu symptoms by administering a safe and effective amount of a composition comprising napmxen along with cetirizine.
All percentages and ratios used herein are by weight unless otherwise in-dicated. Additionally, all measurements are made at 25°C unless otherwise specified.
DISORDERS
TECHNICAL FIE~,D
The present invention relates to compositions and methods for providing improved treatment, management or mitigation of cold, cold-like, allergy, sinus and/or flu symptoms by administering a safe and effective amount of a composition comprising naproxen or a related compound along with cetirizine or a related compound.
EACKGROUND OF THE INVENTION
The common cold, although not usually a serious illness, is a highly pre-valent, discomforting and annoying affliction. The term "common cold" is applied to minor respiratory illnesses caused by a variety of different respiratory viruses.
While rhinoviruses are the major known cause of common colds, accounting for approximately 30 percent of colds in adults, viruses in several other groups are also important. While immune responses occur, and infection with some respiratory tract viruses therefore could be prevented by a vaccine, development of a polytypic vaccine to cover all possible agents is impractical. Thus, the problem of controlling acute upper respiratory disease presents complex challenges, and the long-desired discovery of a single cure for the common cold is an unrealistic expectation.
Early symptoms may be minimal with only mild malaise, sore throat and nasal complaints. With rhinovirus infection, symptoms of nasal discharge, nasal congestion, and sneezing usually commence on the first day of illness and progress to maximum severity by the second or third day. Along with nasal symptoms may come sore, dry or scratchy throat and hoarseness and cough. Other symptoms may include mild burning of the eyes, loss of smell and taste, a feeling of pressure or fullness in the sinuses or ears, headache, and vocal impairment. Fever can occur, but is uncommon. Influenza infection generally includes fever, often of sudden onset and persisting for several days, and with great severity; generalized aches and pains; fatigue and weakness; and chest discomfort.
At present, only symptomatic treatment is available for the common cold.
The costs of treating colds with over-the-counter medications in the United States is estimated at an annual cost of over 1.5 billion dollars. The direct costs of treatment in outpatient clinics is estimated at almost four billion dollars.
Indirect costs, based on the amount of loss in wages because of restricted activity are sub-stantially higher.
- Exemplary prior art formulations for treatment of cough, cold, cold-like, allergy, sinus and/or flu symptoms and the discomfort, pain, fever and general malaise associated therewith generally contain an analgesic (aspirin or acetaminophen) and one or more antihistaminics, decongestants, cough sup-pressants, antitussives and expectorants.
The use of non-steroidal anti-inflammatory drugs to combat inflammation and attendant pain is accepted medical practice. The non-steroidals are commonly employed to relieve pain and inflammation associated with, for example, bursitis, arthritis, headache and the like. Among the most commonly used drugs of the non-narcotic analgesic class of drugs are aspirin, acetaminophen, ibuprofen, ketoprofen, diclofenac and naproxen and their salts (e.g., lysine, arginine, sodium and potassium). Aspirin, acetaminophen and ibuprofen have heretofore been included as the pain reliever and fever-reducing component in conventional cough/cold multisymptom alleviating compositions. These commercially marketed products generally contain in addition to aspirin, acetaminophen or ibuprofen, one or more antihistaminics, decongestants, cough-suppressants, antitussives and expectorants.
The present inventors have found that selected compositions comprising naproxen along with cetirizine provides improved treatment, management or miti-gation of cold, cold-like, allergy, sinus and/or flu symptoms, including nasal congestion.
It is therefore an object of the present invention to pmvide a method for the treatment of cough, cold, cold-like, allergy, sinus and/or flu symptoms in a mam-malian organism in need of such treatment comprising administering to such organism the compositions of the present invention. Such symptoms as used herein refer to coryza, nasal congestion, sinus congestion, sinus pain, upper respiratory infections, otitis, sinusitis, etc.
Sl;m~iMARY OF THE INVENTION
The present invention relates to compositions and methods for providing improved treatment, management or mitigation of cold, cold-like, allergy, sinus and/or flu symptoms by administering a safe and effective amount of a composition comprising napmxen along with cetirizine.
All percentages and ratios used herein are by weight unless otherwise in-dicated. Additionally, all measurements are made at 25°C unless otherwise specified.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compositions and methods for providing improved treatment, management or mitigation of cold, cold-like, allergy, sinus and/or flu symptoms by administering a safe and effective amount of a composition consisting essentially of naproxen along with cetirizine. -'ri ' a The present invention relates to the use of 2-[4-(diphenyl-methyl)-1-piperazinyl]-acetic acids and the amides and non-toxic, pharmaceutically acceptable salts thereof, in compositions also containing napmxen.
Cetirizine and related compounds have the general formula:
x ,o ~- ~N-'E (~zhro"Inr Q-1t- ~
Y
X
wherein Y is hydroxyl group or an --NH2 group, X and X' represents independently a hydrogen atom, a halogen atom, a straight or branched chain lower alkoxy radical or a trifluoromethyl radical, m is 1 or 2, and n is 1 or 2, preferably 2, as well as the non-toxic, pharmaceutically acceptable salts thereof. .
The term "lower alkoxy" as used herein means residues of both straight and branched chain aliphatic alcohols having from 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy and the like. The halogen atom is preferably a chlorine or fluorine atom. .
The expression "non-toxic, pharmaceutically acceptable salts" are used herein means not only the addition salts of the acids and amides of formula with pharmaceutically acceptable acids, such as acetic, citric, succinic, ascorbic, hydrochloric, hydrobromic, sulfuric and phosphoric acid, but also the pharmaceutically acceptable salts of the acids or formula such as the metal salts (for example sodium or potassium salts), the ammonium salts, the amine salts and the aminoacid salts.
The present invention relates to compositions and methods for providing improved treatment, management or mitigation of cold, cold-like, allergy, sinus and/or flu symptoms by administering a safe and effective amount of a composition consisting essentially of naproxen along with cetirizine. -'ri ' a The present invention relates to the use of 2-[4-(diphenyl-methyl)-1-piperazinyl]-acetic acids and the amides and non-toxic, pharmaceutically acceptable salts thereof, in compositions also containing napmxen.
Cetirizine and related compounds have the general formula:
x ,o ~- ~N-'E (~zhro"Inr Q-1t- ~
Y
X
wherein Y is hydroxyl group or an --NH2 group, X and X' represents independently a hydrogen atom, a halogen atom, a straight or branched chain lower alkoxy radical or a trifluoromethyl radical, m is 1 or 2, and n is 1 or 2, preferably 2, as well as the non-toxic, pharmaceutically acceptable salts thereof. .
The term "lower alkoxy" as used herein means residues of both straight and branched chain aliphatic alcohols having from 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy and the like. The halogen atom is preferably a chlorine or fluorine atom. .
The expression "non-toxic, pharmaceutically acceptable salts" are used herein means not only the addition salts of the acids and amides of formula with pharmaceutically acceptable acids, such as acetic, citric, succinic, ascorbic, hydrochloric, hydrobromic, sulfuric and phosphoric acid, but also the pharmaceutically acceptable salts of the acids or formula such as the metal salts (for example sodium or potassium salts), the ammonium salts, the amine salts and the aminoacid salts.
The preferred compounds a~rding to the presets invention are:
2-[2-[4-[(4-chlomphenyl~henylmethyl]-1-Piperarinyl]ethoxy)-acetic acid and its dihydrochloride;
potassium 2-[2-[4-[(4-chlorophenylYlmethyll-1-PiPerazinYllethoxY]-acetates 2-[2-[4-[(4-diphenylmethyl~ 1-pipa~azinYl]etlwxyJ-acetic acid and its dihydrochloride;
2-[2-[4-[(4-fluorophe~rl~h~yl]-1-pipa~yl]ethoxy]ac~ic acid and its hydrate.
The cane compounds of formula possess intere~g pharmacological properties. In particular, they are useful as antiallergic, antihistaminic, bmnchodilatory and antispasmodic agents and are used at a level of from about 5 to about 20 mg.
The preferred compounds are 3,4-dihydro-6-fluoro-2-naphthyl-oc-methylacetic acid, the aklyl esters thereof wherein the alkyl moiety has 1 to 12 carbon atoms, and the pharmac~tically acceptable addition salts thereof. Particularly preferred are:
3,4-dihydro-6-chloro-2-naphthyl-a,-methylacetic acid, the alkyl esters thereof wherein the alkyl moiety has 1 to 12 carbon atoms, and the pharmaceutically acceptabie addition salts thereof.
These compourxis are described in detail is U.S. Patent 4,525,358, June 25, 1985, incorporated herein by reference in its entirety.
Napmxen and similar compounds are derivatives of 2-naphthylacetic acid, a compound which can be represented by the formula:
s ~ 1 ~ Z~ COOH
6 ~ ~ 3 The arabic numerals and the alpha symbols indicate the positions used herein in the nomenclature of 2-naphthylacetic acid da~ivatives. This is a general formula for naproxen and its related compounds.
These are further described in U.S. Patent 3,896,157, incorporated herein by reference in its entirety. Napmxen itself is (S~6-Methoxy-2-methyl-2-napthaleneacetic acid and preferably the sodium salt.
SUBSTITUTE SHEET tRULE 26) WO 99/15173 PC'f/IB98/01339 Naproxen and its related compounds are generally used in amounts of 50 to 660 mg, preferably from about l00 to 330 mg and more preferably from.about t50 to about 220 mg.
Additional Pharmaceutical Actives -The compositions of the present invention can also include at least one other pharmacological active selected from the following class: (a) a decongestant, (b) an expectorant (c) an additional antihistamine and (d) an antitussive. The decongestants useful in the compositions of the present invention include pseudoephedrine, phenylpropanolamine, phenylephrine and ephedrine, their pharmaceutically acceptable salts, and mixtures thereof. The antitussives useful in the present invention include those such as dextromethorphan, chlophedianol, car-betapentane, caramiphen, noscapine, diphenhydramine, codeine, hydrocodone, hydromorphone, fominoben, their pharmaceutically-acceptable salts, and mixtures thereof. The additional antihistamines useful in the present invention include those such as chlorpheniramine, brompheniramine, dexchlorpheniramine, dexbromphreniramine, triprolidine, azatadine, doxylamine, tripelennamine, cypro-heptadine, hydroxyzine, carbinoxamine, phenindamine, bromodiphenhydramine, pyrilamine, their pharmaceutically acceptable salts, as well as the non-sedating antihistamines which include acrivastine, AHR-11325, astemizole, azatadine, azelastine, ebastine, ketotifen, lodoxamide, loratidine, levocabastine, mequitazine, oxatomide, setastine, tazifylline, and temelastine, their pharmaceutically acceptable salts and mixtures thereof. The expectorants (also known as mucolytic agents) useful in the present invention include glyceryl guaiacolate, tenpin hydrate, ammonium chloride, N-acetylcysteine and bromhexine, ambroxol, their pharmaceutically acceptable salts, and mixtures thereof. AlI of these components, as well as their acceptable dosage ranges are described in the following: U.S.
Patent 4,783,465 to Sunshine et al., issued November 8, 1988, U.S. Patent 4,619,934 to Sunshine et al., issued October 28, 1986, which are incorporated by reference herein.
Additional agents which are found useful in the present compositions are a-agonists such as those disclosed in U.S. Patent 5,478,858, issued December 26, 1995, incorporated herein by reference in its entirety.
Various oral dosage forms can be used, including such solid forms as tab-lets, caplets, capsules, granules, lozenges and bulk powders and liquid forms such as syrups and suspensions. Controlled release dosage forms which pmvide a controlled release of these actives) are also useful. These oral forms comprise a WO 99/16173 PCT/IB9$/01339 safe and eff~tive amount, usually at least about 5% of the active components.
Solid oral dosage forms preferably contain from about 5% to about 95%, more preferably from about 10% to about 95%, and most preferably from about 25% to about 95% of the active components. Liquid oral dosage forms preferably contain from about 1% to about 50% and more preferably from about 1% to about 25% and most preferably from about 3% to about 10% of the active components.
Tablets can be compressed, triturated, enteric-coated, sugar-coated, film-coati or multiple compressed, containing suitable binders, lubricants, dilu-ents, disintegrating agents, coloring agents, flavoring agents, preservatives and flowinducing agents. Also useful are soft gelatin capsules.
Liquid oral dosage forms include aqueous and nonaqueous solutions, emul-sions, pseudo emulsions, suspensions, and solutions and/or suspensions recons-tituted from non-effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, taste-masking agents, coloring agents, and flavoring agents. Specific examples of pharmaceutically ac-ceptable carriers and excipients that may be used to formulate oral dosage forms, are described in U.S. Patent 3,903,297, Robert, issued September 2, 1975, incorpo-rated by reference herein. Techniques and compositions for making solid oral dosage forms are described in Marshall, "Solid Oral Dosage Forms," Modern ~r-maceutics. Vol. 7.7. (Banker and Rhodes, editors), 359-427 (1979), incorporated by reference herein. Techniques and compositions for making tablets {compressed and molded), capsulcs (hard and soft gelatin) and pills are described in Remin on's Pharmaceutical i ces (Arthur Osol, editor), 1553-1593 (1980), incorporated herein by reference.
An additional agent found useful in the present compositions is caffeine.
Caffeine has been found to lessen the minor sedating effect of the cetirizine.
The level of caffeine use is generally from about 20 mg to about 500 mg, preferably from about 50 mg to about 200 mg, most preferably from about 65 mg to about mg.
In preparing the liquid oral dosage forms, the active component is incor-porated into an aqueous-based orally acceptable pharmaceutical carrier consistent with conventional pharmaceutical practices. An "aqueous-based orally acceptable pharmaceutical carrier" is one wherein the entire or predominant solvent content is water. Typical carriers include simple aqueous solutions, syrups, dispersions and suspensions, and aqueous based emulsions such as the oil-in-water type. The most preferred carrier is a suspension of the pharmaceutical composition in an aqueous vehicle containing a suitable suspending agent. Suitable suspending agents include Avicel RC-591 (a microcrystalline-cellulose/sodium carboxymethyl cellulose mix-ture available from FMC), guar gum and the like. Such suspending agents are well known to those skilled in the art. While the amount of water in the compositions of this invention can vary over quite a wide range depending upon the total weight and volume of the active component and other optional non-active ingredients, the total water content, based on the weight of the final composition, will generally range from about 20 to about 75%, and, preferably, from about 20 to about 40%, by weight/volume.
Although water itself may make up the entire carrier, typical liquid formu-lations preferably contain a co-solvent, for example, propylene glycol, glycerin, sorbitol solution and the like, to assist solubilization and incorporation of water-insoluble ingredients, such as flavoring oils and the like into the composi-tion. In general, therefore, the compositions of this invention preferably contain from about 5 to about 25 volume/volume percent and, most preferably, from about to about 25 volume) volume percent, of the co-solvent.
Other optional ingredients well known to the pharmacist's art may also be included in amounts generally known for these ingredients, for example, natural or artificial sweeteners, flavoring agents, colorants and the Iike to provide a palatable and pleasant looking final product, antioxidants, for example, butylated hydroxy anisole or butylated hydroxy toluene, and preservatives, for example, methyl or propyl paraben or sodium benzoate, to prolong and enhance shelf life. A highly preferred optional component is caffeine.
METHOD OF TREATMENT
The amount of the pharmaceutical composition administered dcpends upon the percent of active ingredients within its formula, which is a function of the amount of cetirizine and naproxen and any optional components such as a de congestant, cough suppressant, expectorant, caffeine and/or additional antihistamine required per dose, stability, release characteristics and other pharmaceutical parameters.
Usually from about 1 mg/kg to about 50 mg/kg per day, preferably from about 2 mg/kg to about 30 mg/kg per day and most preferably from about 3 mg/kg per day to about 20 mg/kg per day of the pharmaceutical composition is adminis-tered as described herein. This amount can be given in a single dose, or, preferably, in multiple (two to six) doses repeatedly or sustained release dosages over the course of treatment. Generally, each individual dosage of the pharma-ceutical compositions of the present invention range from about 1 mg/kg to about 25 mg/kg, preferably from about 2 mg/kg to about 15 mg/kg and most preferably from about 3 mg/kg to about 10 mg/kg. While dosages higher than the foregoing are effective to provide relief from cough, cold-like, flu, flu-like and allergic rhinitis symptoms, care must be taken, as with any drug, in some individuals to prevent adverse side effects.
The following examples illustrate embodiments of the subject invention wherein both essential and optional ingredients are combined.
EX~ LE I
A hard gelatin capsule composition for oral administration is prepared by combining the following ingredients:
In i t Amount Naproxen Sodium 220 - 440 mg:
Pseudoephedrine HCI 60 mg. (120 mg. sustained released) Cetirizine * 5 mg.
Triturate active ingredients and q.s. with lactose to selected capsule size.
* Cetirizine is [2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]-ethoxy]acetic acid.
Administration of one or two the above capsules every four to twelve hours to a human in need of treatment provides improved relief from cough, cold-like, flu, flu-like and allergic rhinitis symptoms.
EXAM~'LE I~
A hard compressed caplet composition for oral administration is prepared by combining the following ingredients:
ount Naproxen Sodium 220 or 440 mg.
Cetirizine 5 mg.
Pregelatinized starch 20.0 mg.
Corn starch 80.0 mg.
Croscarmellose sodium 10.0 mg.
Silicone dioxide, colloidal1.5 mg.
Stearic acid, TP fine powder2.0 mg Sodium lauryl sulfate 0.5 mg Opadry clear / Colorcon 5.0 mg.
(containing Hydroxypropylmethyl cellulose) Administration of two caplets every twelve hours to a human in need of treatment provides improved relief from cough, cold-like, flu-like and allergic rhinitis symptoms.
EXAMPLE III
A hard compressed tablet composition for oral administration is prepal~d by combining the following ingredients:
i n of t Naproxen sodium 220 or 440 mg.
Cetirizine 5 mg.
Microcrystalline cellulose 110 mg.
Povidone 10 mg Talc 12 mg Magnesium stearate 2 mg Opadry clear / Colorcon (containing 5.0 mg.
Hydroxypropylmethyl cellulose) Administration of one of the above tablets every twelve hours to a human in need of treatment provides 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:
In edi~'ent % WN
Naproxen sodium 2.200 Cetirizine 0.050 High Fructose corn syrup55%) 55.000 ( Polyethylene Glycol 10.000 Propylene Glycol 10.000 Alcohol (95%) 8.500 Sodium citrate dihydrate0.470 Citric Acid 0.180 Saccharin socium 0.700 Flavor 0.015 Color 0.005 Water, Purified QS QS to 100%
The purified water (approximately 10% of the final batch volume) is poured into a batch container equipped with a lightnin' mixer. The sodium citrate, citric acid, asodium saccharin, and actives other than naproxen sodium are added sequen-tially and dissolved with agitation. The high frucose is then added. In a separate container the colorants are added to purified water (approximately 0.5% of the-final batch volume). This colorant solution is then added to the first batch container. In a separate container the naproxen sodium is added to the alcohol while stirring.
The propylene glycol, polyethylene glycol, and flavors are added to this alcohol premix and the resulting mixture is stirred until homogeneous and then added to the first container. The remaining purified water is added to the resulting mixture and stirred.
Administration of 10 ml to 20 ml (2 to 4 teaspoonsful) every twelve hours to a human in need of treatment provides improved relief from cough, cold-like, flu, flu-like and allergic rhinitis symptoms.
Administration of 20 ml (4 teaspoonsful) every eight to twelve hours to a human in need of treatment provides improved relief from cough, cold-like, flu, flu-like and allergic rhinitis symptoms.
2-[2-[4-[(4-chlomphenyl~henylmethyl]-1-Piperarinyl]ethoxy)-acetic acid and its dihydrochloride;
potassium 2-[2-[4-[(4-chlorophenylYlmethyll-1-PiPerazinYllethoxY]-acetates 2-[2-[4-[(4-diphenylmethyl~ 1-pipa~azinYl]etlwxyJ-acetic acid and its dihydrochloride;
2-[2-[4-[(4-fluorophe~rl~h~yl]-1-pipa~yl]ethoxy]ac~ic acid and its hydrate.
The cane compounds of formula possess intere~g pharmacological properties. In particular, they are useful as antiallergic, antihistaminic, bmnchodilatory and antispasmodic agents and are used at a level of from about 5 to about 20 mg.
The preferred compounds are 3,4-dihydro-6-fluoro-2-naphthyl-oc-methylacetic acid, the aklyl esters thereof wherein the alkyl moiety has 1 to 12 carbon atoms, and the pharmac~tically acceptable addition salts thereof. Particularly preferred are:
3,4-dihydro-6-chloro-2-naphthyl-a,-methylacetic acid, the alkyl esters thereof wherein the alkyl moiety has 1 to 12 carbon atoms, and the pharmaceutically acceptabie addition salts thereof.
These compourxis are described in detail is U.S. Patent 4,525,358, June 25, 1985, incorporated herein by reference in its entirety.
Napmxen and similar compounds are derivatives of 2-naphthylacetic acid, a compound which can be represented by the formula:
s ~ 1 ~ Z~ COOH
6 ~ ~ 3 The arabic numerals and the alpha symbols indicate the positions used herein in the nomenclature of 2-naphthylacetic acid da~ivatives. This is a general formula for naproxen and its related compounds.
These are further described in U.S. Patent 3,896,157, incorporated herein by reference in its entirety. Napmxen itself is (S~6-Methoxy-2-methyl-2-napthaleneacetic acid and preferably the sodium salt.
SUBSTITUTE SHEET tRULE 26) WO 99/15173 PC'f/IB98/01339 Naproxen and its related compounds are generally used in amounts of 50 to 660 mg, preferably from about l00 to 330 mg and more preferably from.about t50 to about 220 mg.
Additional Pharmaceutical Actives -The compositions of the present invention can also include at least one other pharmacological active selected from the following class: (a) a decongestant, (b) an expectorant (c) an additional antihistamine and (d) an antitussive. The decongestants useful in the compositions of the present invention include pseudoephedrine, phenylpropanolamine, phenylephrine and ephedrine, their pharmaceutically acceptable salts, and mixtures thereof. The antitussives useful in the present invention include those such as dextromethorphan, chlophedianol, car-betapentane, caramiphen, noscapine, diphenhydramine, codeine, hydrocodone, hydromorphone, fominoben, their pharmaceutically-acceptable salts, and mixtures thereof. The additional antihistamines useful in the present invention include those such as chlorpheniramine, brompheniramine, dexchlorpheniramine, dexbromphreniramine, triprolidine, azatadine, doxylamine, tripelennamine, cypro-heptadine, hydroxyzine, carbinoxamine, phenindamine, bromodiphenhydramine, pyrilamine, their pharmaceutically acceptable salts, as well as the non-sedating antihistamines which include acrivastine, AHR-11325, astemizole, azatadine, azelastine, ebastine, ketotifen, lodoxamide, loratidine, levocabastine, mequitazine, oxatomide, setastine, tazifylline, and temelastine, their pharmaceutically acceptable salts and mixtures thereof. The expectorants (also known as mucolytic agents) useful in the present invention include glyceryl guaiacolate, tenpin hydrate, ammonium chloride, N-acetylcysteine and bromhexine, ambroxol, their pharmaceutically acceptable salts, and mixtures thereof. AlI of these components, as well as their acceptable dosage ranges are described in the following: U.S.
Patent 4,783,465 to Sunshine et al., issued November 8, 1988, U.S. Patent 4,619,934 to Sunshine et al., issued October 28, 1986, which are incorporated by reference herein.
Additional agents which are found useful in the present compositions are a-agonists such as those disclosed in U.S. Patent 5,478,858, issued December 26, 1995, incorporated herein by reference in its entirety.
Various oral dosage forms can be used, including such solid forms as tab-lets, caplets, capsules, granules, lozenges and bulk powders and liquid forms such as syrups and suspensions. Controlled release dosage forms which pmvide a controlled release of these actives) are also useful. These oral forms comprise a WO 99/16173 PCT/IB9$/01339 safe and eff~tive amount, usually at least about 5% of the active components.
Solid oral dosage forms preferably contain from about 5% to about 95%, more preferably from about 10% to about 95%, and most preferably from about 25% to about 95% of the active components. Liquid oral dosage forms preferably contain from about 1% to about 50% and more preferably from about 1% to about 25% and most preferably from about 3% to about 10% of the active components.
Tablets can be compressed, triturated, enteric-coated, sugar-coated, film-coati or multiple compressed, containing suitable binders, lubricants, dilu-ents, disintegrating agents, coloring agents, flavoring agents, preservatives and flowinducing agents. Also useful are soft gelatin capsules.
Liquid oral dosage forms include aqueous and nonaqueous solutions, emul-sions, pseudo emulsions, suspensions, and solutions and/or suspensions recons-tituted from non-effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, taste-masking agents, coloring agents, and flavoring agents. Specific examples of pharmaceutically ac-ceptable carriers and excipients that may be used to formulate oral dosage forms, are described in U.S. Patent 3,903,297, Robert, issued September 2, 1975, incorpo-rated by reference herein. Techniques and compositions for making solid oral dosage forms are described in Marshall, "Solid Oral Dosage Forms," Modern ~r-maceutics. Vol. 7.7. (Banker and Rhodes, editors), 359-427 (1979), incorporated by reference herein. Techniques and compositions for making tablets {compressed and molded), capsulcs (hard and soft gelatin) and pills are described in Remin on's Pharmaceutical i ces (Arthur Osol, editor), 1553-1593 (1980), incorporated herein by reference.
An additional agent found useful in the present compositions is caffeine.
Caffeine has been found to lessen the minor sedating effect of the cetirizine.
The level of caffeine use is generally from about 20 mg to about 500 mg, preferably from about 50 mg to about 200 mg, most preferably from about 65 mg to about mg.
In preparing the liquid oral dosage forms, the active component is incor-porated into an aqueous-based orally acceptable pharmaceutical carrier consistent with conventional pharmaceutical practices. An "aqueous-based orally acceptable pharmaceutical carrier" is one wherein the entire or predominant solvent content is water. Typical carriers include simple aqueous solutions, syrups, dispersions and suspensions, and aqueous based emulsions such as the oil-in-water type. The most preferred carrier is a suspension of the pharmaceutical composition in an aqueous vehicle containing a suitable suspending agent. Suitable suspending agents include Avicel RC-591 (a microcrystalline-cellulose/sodium carboxymethyl cellulose mix-ture available from FMC), guar gum and the like. Such suspending agents are well known to those skilled in the art. While the amount of water in the compositions of this invention can vary over quite a wide range depending upon the total weight and volume of the active component and other optional non-active ingredients, the total water content, based on the weight of the final composition, will generally range from about 20 to about 75%, and, preferably, from about 20 to about 40%, by weight/volume.
Although water itself may make up the entire carrier, typical liquid formu-lations preferably contain a co-solvent, for example, propylene glycol, glycerin, sorbitol solution and the like, to assist solubilization and incorporation of water-insoluble ingredients, such as flavoring oils and the like into the composi-tion. In general, therefore, the compositions of this invention preferably contain from about 5 to about 25 volume/volume percent and, most preferably, from about to about 25 volume) volume percent, of the co-solvent.
Other optional ingredients well known to the pharmacist's art may also be included in amounts generally known for these ingredients, for example, natural or artificial sweeteners, flavoring agents, colorants and the Iike to provide a palatable and pleasant looking final product, antioxidants, for example, butylated hydroxy anisole or butylated hydroxy toluene, and preservatives, for example, methyl or propyl paraben or sodium benzoate, to prolong and enhance shelf life. A highly preferred optional component is caffeine.
METHOD OF TREATMENT
The amount of the pharmaceutical composition administered dcpends upon the percent of active ingredients within its formula, which is a function of the amount of cetirizine and naproxen and any optional components such as a de congestant, cough suppressant, expectorant, caffeine and/or additional antihistamine required per dose, stability, release characteristics and other pharmaceutical parameters.
Usually from about 1 mg/kg to about 50 mg/kg per day, preferably from about 2 mg/kg to about 30 mg/kg per day and most preferably from about 3 mg/kg per day to about 20 mg/kg per day of the pharmaceutical composition is adminis-tered as described herein. This amount can be given in a single dose, or, preferably, in multiple (two to six) doses repeatedly or sustained release dosages over the course of treatment. Generally, each individual dosage of the pharma-ceutical compositions of the present invention range from about 1 mg/kg to about 25 mg/kg, preferably from about 2 mg/kg to about 15 mg/kg and most preferably from about 3 mg/kg to about 10 mg/kg. While dosages higher than the foregoing are effective to provide relief from cough, cold-like, flu, flu-like and allergic rhinitis symptoms, care must be taken, as with any drug, in some individuals to prevent adverse side effects.
The following examples illustrate embodiments of the subject invention wherein both essential and optional ingredients are combined.
EX~ LE I
A hard gelatin capsule composition for oral administration is prepared by combining the following ingredients:
In i t Amount Naproxen Sodium 220 - 440 mg:
Pseudoephedrine HCI 60 mg. (120 mg. sustained released) Cetirizine * 5 mg.
Triturate active ingredients and q.s. with lactose to selected capsule size.
* Cetirizine is [2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]-ethoxy]acetic acid.
Administration of one or two the above capsules every four to twelve hours to a human in need of treatment provides improved relief from cough, cold-like, flu, flu-like and allergic rhinitis symptoms.
EXAM~'LE I~
A hard compressed caplet composition for oral administration is prepared by combining the following ingredients:
ount Naproxen Sodium 220 or 440 mg.
Cetirizine 5 mg.
Pregelatinized starch 20.0 mg.
Corn starch 80.0 mg.
Croscarmellose sodium 10.0 mg.
Silicone dioxide, colloidal1.5 mg.
Stearic acid, TP fine powder2.0 mg Sodium lauryl sulfate 0.5 mg Opadry clear / Colorcon 5.0 mg.
(containing Hydroxypropylmethyl cellulose) Administration of two caplets every twelve hours to a human in need of treatment provides improved relief from cough, cold-like, flu-like and allergic rhinitis symptoms.
EXAMPLE III
A hard compressed tablet composition for oral administration is prepal~d by combining the following ingredients:
i n of t Naproxen sodium 220 or 440 mg.
Cetirizine 5 mg.
Microcrystalline cellulose 110 mg.
Povidone 10 mg Talc 12 mg Magnesium stearate 2 mg Opadry clear / Colorcon (containing 5.0 mg.
Hydroxypropylmethyl cellulose) Administration of one of the above tablets every twelve hours to a human in need of treatment provides 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:
In edi~'ent % WN
Naproxen sodium 2.200 Cetirizine 0.050 High Fructose corn syrup55%) 55.000 ( Polyethylene Glycol 10.000 Propylene Glycol 10.000 Alcohol (95%) 8.500 Sodium citrate dihydrate0.470 Citric Acid 0.180 Saccharin socium 0.700 Flavor 0.015 Color 0.005 Water, Purified QS QS to 100%
The purified water (approximately 10% of the final batch volume) is poured into a batch container equipped with a lightnin' mixer. The sodium citrate, citric acid, asodium saccharin, and actives other than naproxen sodium are added sequen-tially and dissolved with agitation. The high frucose is then added. In a separate container the colorants are added to purified water (approximately 0.5% of the-final batch volume). This colorant solution is then added to the first batch container. In a separate container the naproxen sodium is added to the alcohol while stirring.
The propylene glycol, polyethylene glycol, and flavors are added to this alcohol premix and the resulting mixture is stirred until homogeneous and then added to the first container. The remaining purified water is added to the resulting mixture and stirred.
Administration of 10 ml to 20 ml (2 to 4 teaspoonsful) every twelve hours to a human in need of treatment provides improved relief from cough, cold-like, flu, flu-like and allergic rhinitis symptoms.
Administration of 20 ml (4 teaspoonsful) every eight to twelve hours to a human in need of treatment provides improved relief from cough, cold-like, flu, flu-like and allergic rhinitis symptoms.
Claims (10)
1. A pharmaceutical composition for providing improved treatment, management or mitigation of cold, cold-like, allergy, sinus or flu-symptoms by administering a safe and effective amount of a composition comprising:
(a) an analgesic which is naproxen or a related compound or a pharmaceutically acceptable salt thereof; and (b) cetirizine or a related compound.
(a) an analgesic which is naproxen or a related compound or a pharmaceutically acceptable salt thereof; and (b) cetirizine or a related compound.
2. A pharmaceutical composition according to Claim 1 wherein said cetirizine or related compound is selected from the group consisting of selected from the group consisting of methyl 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-.alpha.,.alpha.-dimethylbenzeneacetate, 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid, 1-[p-(2-hydroxymethyl-2-propyl)-phenyl]-4-[4(.alpha.-hydroxy-.alpha.-phenylbenzyl)-1-piperidinyl]butanol, and mixtures thereof.
3. A pharmaceutical composition according to Claim 2 which contains an additional analgesic agent selected from the group cosisting of ibuprofen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofen and diclofenac.
4. A pharmaceutical composition according to Claim 3 wherein said naproxen or related compound or additional analgesic agent is the amino acid salt and is selected from the group consisting of triethylamine, tripropylamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, ornithine, arginine, histidine, caffeine, procaine, N-ethylpiperidine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglycamine, theobromine, purine, piperazine and piperidine and mixtures thereof.
5. A pharmaceutical composition according to Claim 3 additionally comprising a pharmaceutical active selected from the group consisting of decongestants, expectorants, additional antihistamines, antitussives and mixtures thereof.
6. A pharmaceutical composition according to Claim 5 wherein said additional antihistamine is selected from the group consisting of chlorpheniramine, brompheniramine, dexchlorpheniramine, dexbromphreniramine, triprolidine, doxylamine, tripelennamine, cyproheptadine, carbinoxamine, bromodiphen-hydramine, pyrilamine, acrivastine, AHR-11325, phenindamine, astemizole, azatadine, azelastine, ebastine, ketotifen, lodoxamide, loratidine, levocabastine, mequitazine, oxatomide, setastine, tazifylline, temelastine, and mixtures thereof or pharmaceutically acceptable salts thereof.
7. A pharmaceutical composition according to Claim 5 which comprises the S(+) enantiomer of naproxen or related compound or the additional analgesic agent.
8. A pharmaceutical composition according to Claim 7 wherein said S(+) enantiomer of the additional agent is selected from the group consisting of S(+)-ketoprofen lysinate, S(+)-ibuprofen lysinate and mixtures thereof.
9. A pharmaceutical composition according to Claim 1 which in additionally comprises an .alpha.-agonist compound, caffeine, and mixtures thereof.
10. The use of a an analgesic and antihistamine for the manufacture of a medicament for the treatment of sinus pressure, sinus pain, sinus drainage, nasal congestion, cough, cold, cold-like or flu symptoms in a mammalian organism in need of such treatment, said treatment comprising administering to such organism the composition of Claim 1.
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US93403397A | 1997-09-19 | 1997-09-19 | |
US08/934,033 | 1997-09-19 | ||
PCT/IB1998/001339 WO1999015173A1 (en) | 1997-09-19 | 1998-08-28 | Compositions and methods for treating respiratory disorders |
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CA2304005A1 true CA2304005A1 (en) | 1999-04-01 |
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CA002304005A Abandoned CA2304005A1 (en) | 1997-09-19 | 1998-08-28 | Compositions and methods for treating respiratory disorders |
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EP (1) | EP1014983A1 (en) |
JP (1) | JP2001517626A (en) |
KR (1) | KR20010024187A (en) |
CN (1) | CN1278728A (en) |
AU (1) | AU8744398A (en) |
BR (1) | BR9812660A (en) |
CA (1) | CA2304005A1 (en) |
CO (1) | CO5011084A1 (en) |
HU (1) | HUP0004813A2 (en) |
NO (1) | NO20001412D0 (en) |
PE (1) | PE118999A1 (en) |
WO (1) | WO1999015173A1 (en) |
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CA2419653A1 (en) * | 2000-09-08 | 2002-03-14 | Warner-Lambert Company | Prevention of acute sinusitis and sinus attack |
MXPA03011705A (en) * | 2001-06-20 | 2004-03-19 | Schering Corp | Antihistamines for the treatment of nasal congestion and nasal obstruction. |
US6863901B2 (en) | 2001-11-30 | 2005-03-08 | Collegium Pharmaceutical, Inc. | Pharmaceutical composition for compressed annular tablet with molded triturate tablet for both intraoral and oral administration |
US6827946B2 (en) | 2001-12-05 | 2004-12-07 | Collegium Pharmaceutical, Inc. | Compositions containing both sedative and non-sedative antihistamines |
US7166641B2 (en) * | 2002-10-02 | 2007-01-23 | Yung Shin Pharmaceutical Industrial Co., Ltd. | Pharmaceutically acceptable salts containing local anesthetic and anti-inflammatory activities and methods for preparing the same |
TWI313598B (en) | 2002-12-18 | 2009-08-21 | Wyeth Corp | Compositions of non-steroidal anti-inflammatory drugs, decongestants and anti-histamines |
US20050192355A1 (en) * | 2004-02-17 | 2005-09-01 | Wyeth | Compositions of non-steroidal anti-inflammatory drugs and decongestants or anti-histamines |
CN101073563B (en) * | 2007-02-07 | 2010-10-06 | 西安利君制药有限责任公司 | Chiral composition containing dextrothyroxine buprofenli and levomethadyl cysteliqin and its double slow-releasing tablet |
GB0719518D0 (en) * | 2007-10-05 | 2007-11-14 | Therapeutics Ltd E | Therapy |
US8252330B2 (en) | 2009-01-05 | 2012-08-28 | Mcneil-Ppc, Inc. | Tablet containing coated particles of cetirizine, pseudoephedrine, and/or naproxen |
CA2748783A1 (en) | 2009-01-05 | 2010-07-08 | Mcneil-Ppc, Inc. | Three layer tablet containing cetirizine, pseudoephedrine, and naproxen |
WO2010078543A1 (en) * | 2009-01-05 | 2010-07-08 | Mcneil-Ppc, Inc. | Tablet containing cetirizine pseudoephedrine, and naproxen containing a barrier layer |
GB0905954D0 (en) * | 2009-04-06 | 2009-05-20 | E Therapeutics Plc | Treatment of exacerbations of asthma |
CN103446587A (en) * | 2011-12-28 | 2013-12-18 | 汪明 | Application of mastocyte inhibitor in preparation of medicine for resisting influenza virus infection |
CN103251590B (en) * | 2013-05-13 | 2014-12-17 | 中国科学院武汉病毒研究所 | Application of doxylamine succinate in preparing drug for treating or preventing influenza virus |
US10420756B2 (en) * | 2015-03-26 | 2019-09-24 | Sen-Jam Pharmaceutical Llc. | Methods and compositions to inhibit symptoms associated with veisalgia |
CN109464670B (en) * | 2017-09-08 | 2022-08-02 | 中国科学院微生物研究所 | Key amino acid site for regulating and controlling nucleoprotein nuclear production of influenza A virus and influenza B virus and application of key amino acid site as anti-influenza virus drug target |
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US4783465A (en) * | 1984-04-09 | 1988-11-08 | Analgesic Associates | Cough/cold mixtures comprising non-sedating antihistamine drugs |
US4871733A (en) * | 1984-04-09 | 1989-10-03 | Analgesic Associates | Cough/cold mixtures comprising non-sedating antihistamine drugs |
US5260073A (en) * | 1990-05-21 | 1993-11-09 | Norwich Eaton Pharmaceuticals, Inc. | Use of phenylpropanolamine as a mucus secretogogue in the upper airways |
CA2170488A1 (en) * | 1993-09-07 | 1995-03-16 | Sekhar Mitra | Compositions containing an amino acid salt of propionic acid non-steroidal anti-inflammatory agent and at least one of a decongestant, an expectorant, an antihistamine and an antitussive |
EP0841947A1 (en) * | 1995-07-28 | 1998-05-20 | The Procter & Gamble Company | Compositions containing analgesics and antihistamines and methods for treating respiratory disorders |
US5648358A (en) * | 1996-03-05 | 1997-07-15 | Mitra; Sekhar | Compositions and methods for treating respiratory disorders |
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1998
- 1998-08-28 EP EP98938852A patent/EP1014983A1/en not_active Withdrawn
- 1998-08-28 JP JP2000512542A patent/JP2001517626A/en not_active Withdrawn
- 1998-08-28 BR BR9812660-1A patent/BR9812660A/en not_active Application Discontinuation
- 1998-08-28 KR KR1020007002958A patent/KR20010024187A/en not_active Application Discontinuation
- 1998-08-28 CA CA002304005A patent/CA2304005A1/en not_active Abandoned
- 1998-08-28 CN CN98811202A patent/CN1278728A/en active Pending
- 1998-08-28 AU AU87443/98A patent/AU8744398A/en not_active Abandoned
- 1998-08-28 WO PCT/IB1998/001339 patent/WO1999015173A1/en not_active Application Discontinuation
- 1998-08-28 HU HU0004813A patent/HUP0004813A2/en unknown
- 1998-09-17 PE PE1998000885A patent/PE118999A1/en not_active Application Discontinuation
- 1998-09-21 CO CO98054352A patent/CO5011084A1/en unknown
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2000
- 2000-03-17 NO NO20001412A patent/NO20001412D0/en unknown
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WO1999015173A1 (en) | 1999-04-01 |
KR20010024187A (en) | 2001-03-26 |
JP2001517626A (en) | 2001-10-09 |
AU8744398A (en) | 1999-04-12 |
CN1278728A (en) | 2001-01-03 |
PE118999A1 (en) | 2000-02-03 |
CO5011084A1 (en) | 2001-02-28 |
BR9812660A (en) | 2000-08-22 |
HUP0004813A2 (en) | 2001-08-28 |
EP1014983A1 (en) | 2000-07-05 |
NO20001412D0 (en) | 2000-03-17 |
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