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

Definitions

• 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.
• the common cold although not usually a serious illness, is a highly prevalent, discomforting and annoying affliction.
• the term "common cold” is applied to minor respiratory illnesses caused by a variety of different respiratory viruses. While rhino viruses 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.
• 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 suppressants, antitussives and expectorants.
• analgesic aspirin or acetaminophen
• antihistaminics one or more antihistaminics, decongestants, cough suppressants, antitussives and expectorants.
• 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.
• 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.
• compositions comprising naproxen along with cetirizine provides improved treatment, management or mitigation of cold, cold-like, allergy, sinus and/or flu symptoms, including nasal congestion.
• symptoms refer to coryza, nasal congestion, sinus congestion, sinus pain, upper respiratory infections, otitis, sinusitis, etc.
• 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.
• 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.
• the present invention relates to the use of 2-[4-(diphenyl-methyl)-l- piperazinyl]-acetic acids and the amides and non-toxic, pharmaceutically acceptable salts thereof, in compositions also containing naproxen.
• Cetirizine and related compounds have the general formula:
• 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.
• 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.
• 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.
• 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 according to the present invention are: 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]-acetic acid and its dihydrochloride; potassium 2-[2-[4-[(4-chlorophenyl)phenylmethyl]- 1 -piperazinyl]ethoxy]-acetate; 2-[2-[4-[(4-diphenylmethyl)-l-piperazinyl]ethoxy]-acetic acid and its dihydrochloride; 2-[2-[4-[(4-fluorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]acetic acid and its hydrate.
• cetirizine compounds of formula possess interesting pharmacological properties.
• they are useful as antiallergic, antihistaminic, bronchodilatory 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- ⁇ -methylacetic acid, the aklyl esters thereof wherein the alkyl moiety has 1 to 12 carbon atoms, and the pharmaceutically acceptable addition salts thereof.
• Particularly preferred are: 3,4- dihydro-6-chloro-2-naphthyl- ⁇ -methylacetic acid, the alkyl esters thereof wherein the alkyl moiety has 1 to 12 carbon atoms, and the pharmaceutically acceptable addition salts thereof.
• Naproxen and similar compounds are derivatives of 2-naphthylacetic acid, a compound which can be represented by the formula:
• Naproxen itself is (S)-6-Methoxy-2-methyl-2-napthaleneacetic acid and preferably the sodium salt.
• Naproxen and its related compounds are generally used in amounts of 50 to 660 mg, preferably from about 100 to 330 mg and more preferably from about 150 to about 220 mg.
• 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.
• a decongestant 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.
• 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
• the expectorants include glyceryl guaiacolate, terpin hydrate, ammonium chloride, N-acetylcysteine and bromhexine, ambroxol, their pharmaceutically acceptable salts, and mixtures thereof. All 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.
• ⁇ - agonists such as those disclosed in U.S. Patent 5,478,858, issued December 26, 1995, incorporated herein by reference in its entirety.
• oral dosage forms can be used, including such solid forms as tablets, caplets, capsules, granules, lozenges and bulk powders and liquid forms such as syrups and suspensions.
• Controlled release dosage forms which provide a controlled release of these active(s) are also useful.
• These oral forms comprise a safe and effective 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-coated or multiple compressed, containing suitable binders, lubricants, diluents, 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, emulsions, pseudo emulsions, suspensions, and solutions and/or suspensions reconstituted from non-effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, taste-masking agents, coloring agents, and flavoring agents.
• suitable solvents preservatives, emulsifying agents, suspending agents, diluents, sweeteners, taste-masking agents, coloring agents, and flavoring agents.
• Specific examples of pharmaceutically acceptable 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, incorporated by reference herein. Techniques and compositions for making solid oral dosage forms are described in Marshall, "Solid Oral Dosage Forms," Modern Pharmaceutics. Vol. 1.
• caffeine 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 100 mg.
• 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 mixture available from FMC), guar gum and the like. Such suspending agents are well known to those skilled in the art.
• 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.
• compositions of this invention preferably contain from about 5 to about 25 volume/volume percent and, most preferably, from about 10 to about 25 volume/ volume percent, of the co-solvent.
• 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 like 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.
• the amount of the pharmaceutical composition administered depends 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.
• each individual dosage of the pharmaceutical 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.
• a hard gelatin capsule composition for oral administration is prepared by combining the following ingredients:
• Pseudoephedrine HC1 60 mg. (120 mg. sustained released)
• Triturate active ingredients and q.s. with lactose to selected capsule size Triturate active ingredients and q.s. with lactose to selected capsule size.
• Cetirizine is [2-[4-[(4-Chlorophenyl)phenylmethyl]-l-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.
• a hard compressed caplet composition for oral administration is prepared by combining the following ingredients:
• Opadry clear / Colorcon (containing 5.0 mg. 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.
• a hard compressed tablet composition for oral administration is prepared by combining the following ingredients:
• Microcrystalline cellulose 110 mg Microcrystalline cellulose 110 mg.
• Opadry clear / Colorcon (containing 5.0 mg.
• 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.
• a liquid composition for oral administration is prepared by combining the following ingredients:
• 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 succharin, and actives other than naproxen sodium are added sequentially and dissolved with agitation.
• the high frucose is then added.
• 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.
• 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.

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Citations (6)

• 1998
  • 1998-08-28 KR KR1020007002958A patent/KR20010024187A/ko not_active Application Discontinuation
  • 1998-08-28 CA CA002304005A patent/CA2304005A1/en not_active Abandoned
  • 1998-08-28 BR BR9812660-1A patent/BR9812660A/pt not_active Application Discontinuation
  • 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/hu unknown
  • 1998-08-28 EP EP98938852A patent/EP1014983A1/en not_active Withdrawn
  • 1998-08-28 JP JP2000512542A patent/JP2001517626A/ja not_active Withdrawn
  • 1998-08-28 CN CN98811202A patent/CN1278728A/zh active Pending
  • 1998-09-17 PE PE1998000885A patent/PE118999A1/es not_active Application Discontinuation
  • 1998-09-21 CO CO98054352A patent/CO5011084A1/es unknown
• 2000
  • 2000-03-17 NO NO20001412A patent/NO20001412D0/no unknown

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