CA1327315C

CA1327315C - Cough/cold mixtures comprising non-sedating antihistamine drugs

Info

Publication number: CA1327315C
Application number: CA000564793A
Authority: CA
Inventors: Abraham Sunshine; Eugene M. Laska; Carol E. Siegel
Original assignee: Richardson Vicks Inc
Current assignee: Richardson Vicks Inc
Priority date: 1987-04-24
Filing date: 1988-04-22
Publication date: 1994-03-01
Anticipated expiration: 2011-03-01
Also published as: EP0311677A1; JPH01503539A; DE3854518D1; AU610178B2; US4783465A; DE3854518T2; ZA882884B; EP0311677B1; AU1687388A; WO1988008302A1; ATE128355T1

Abstract

COUGH/COLD MIXTURES COMPRISING
NON-SEDATING ANTIHISTAMINE DRUGS

ABSTRACT OF THE DISCLOSURE
Pharmaceutical compositions and methods of using same comprising a non-steroidal anti-inflam-matory drug in combination with a non-sedating antihistamine and optionally one or more other active components selected from a decongestant, cough suppressant (antitussive) or expectorant are provided for the relief of cough, cold, cold-like and/or flu symptoms and the discomfort, pain, headache, fever and general malaise associated therewith.

Description

,", . ~27315 COUGH/COLD MIX~URE5 COMPRISING
NON-SEDATING ANTIHISTAMINE DRUGS
:.
i~ Background of the Invention The present invention relates generally to novel pharmaceutical compositions of matter compris-ing one or more non-steroidal anti-inflammatory drugs ~NSAID) in combination with a non-sedating antihistamine and optionally one or more other active components selected from a sympathomimetic drug (nasal decongestant, bronchodilator) cough ~uppres~ant and/or expectorant, optionally in combination with suitable pharmaceutically accept-able non-toxic carriers or excipient, and to methods of using ~aid ~ompositions in the treatment, management or mitigation of cough, cold, cold-like and/or flu symptoms and the discomfort, pain, headache, fevex and general malaise associated therewith.
Applicants' earlier application, now U.S.
Patent No. 4,619,934 was directed to one or moxe NSAID'6 in combination with a conventional antihis-tamine and other optional components. Applicants have now discovered that the non-~edating antihi 8 -tamlne~, which are pharmacologically and chemically `~ 25 di~tinct from the conventional antihistamines, in combination with one or more NSAID's offers ~ig-nificant advantage~ in the treatment, management or mitigation of cough, cold, cold-like and/or flu 8ymptom8 and the disco~fort, pain, fever and general malaifie associated therewith~ It i6 well known that the conventional antihi3ta~ines may cause drowsine~s or marked drowsiness. While this may be an ~dvantage at bedt~me, if ta~en auring the day, the label Z~ ~ .

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., ~2~315 ., recommends that a patient use caution when driving a motor vehicle or operating machinery. The comblna-tion of a non-~edating antihistamine and an NSAID is therefore particularly advantageous for daytime administration.
Non-narcotic analgesics, most of which are also known as non-steroidal anti-inflammatory drugs, are widely administered orally in the treatment of mild to severe pain. Within thi~ class, the compounds vary widely in their chemical structure and in their biological profiles as analgesics, anti-inflammatory agents and antipyretic agents.
Among the most commonly used members of the non-narcotic analgesic class of drugs are aspirin and acetaminophen. Aspirin, acetaminophen and salicyla-mide are among the druqs that have heretofore been included as the pain reliever and fever-reducing component in conventional cough/cold multisymptom allevisting compositions.
~owever, a number of alternative non-narcotic agents offering a variety of advantages over these conventionally employed non-narcotic analgesic ~nt~pyretics have now been developed. The principal advantages of these non-steroidal anti-inflammatory drug~ include not only the clinically superior analge~ic, anti-inflammatory and an-tipyretic activity of these agents compared to a~pirin and acet~m~nophen, ~ut al80 a minimization of the adverse side effects experienced w~th the~e ; 30 conventional ~gents~ more specifically, the gastro-intestinal ulcerat~ona experienced with aspirin and ~he hepatic t~xic~ty prevalent with the chron$c use of acetaminophen.

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i: -- 3 '! Exemplary prior art cough/cold formulations ~, containing aspirin or acetaminophen include Corici-di ~, Coricidin ~, Comtre ~, Drista ~, Daycar ~, ' Cotyleno ~, Sinubi ~ and the like. These formula-5 tions generally contain in addition to a~pirin, acetaminophen or ~alicylamide, one or more conven-~ tional antihistaminics, decongestants, cough ,; suppressants, antitussive~ and expectorants.
While aspirin and acetaminophen have been 10 utilized in these previous compositions, it has not been heretofore proposed to use any of the newer '` non-steroidal anti-inflamimatory drugs (i.e., A,~ excluding a~pirin, acetaminophen and phenacetin) in the preparation of advantageous cough/cold phar-15 maceutical compositions.
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Summary of the Invention It is, therefore, a primary object of the present invention to provide pharmaceutical composi-tions of matter comprising an analgesically effec-20 tive amount of a non-steroidal anti-inflammatory 1 drug in combination with a non-sedating antihis-tamine, and optionally one or more active components selected from a decongestant, cough suppxessant, expectorant and, further optionally includ$ng ¦ 25 pharmaceutically acceptable carrier~ therefor.
It i8 a further ob;ect of the present f invention to provide methods for the symptomatic relief of cough, cold, cold-like and flu ~ympto~s j and the di~comfort, pain, headache, fever and 30 general malaise ~ssociated therewith, by the ~dministration of preselected dosages of the , . .-,: .
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13273~

pharmaceutical compositions of the present inven-tion. Cold-like symptoms as used herein refers to coryza, nasal congestion, upper respiratory infec-t tions, allergic rhinitis, otitis, sinusitis, etc.
,; 5 An additional object of the present invention is to provide methods for the treatment of an allergic reaction in a mammalian organism in need ', of such treatment by administering to such organism ; an allergic symptom relieving effective ~mount of a ' 10 certain non-steroidal anti-inflammatory agent in combination with at least one of the non-sedating antihistamines or pharmaceutically acceptable salt thereof. Typical allergy symptoms involve coryza, rhinitis, and the like.
Another object of the present invention is to provide suitable dosage unit forms of one or more NSAID's in combination with a non-sedating antihis-tamine and optionally one or more active components selected from a decongestant, cough suppressant or expectorant adapted for convenient oral admin~stration.

Descri~ption o the Preferred Embo lments of t e Inventlon More specifically, the Applicants herein have found that certain non-steroidal anti-infldm-matory agent~ are ideally suited for use in cough~cold formulation~ by rea~on of th~ir enhanced analges~c ant~-inflnmmatory and antipyretic activity and low ~ncldence of untoward ~ide effect~, par-ticularly at the optimum dosages provided for in the 13273~

present invention, compared to aspirin oracetaminophen.
For example, the antipyretic effectiveness of ibuprofen in comparison to aspirin and to acetaminophen has been studied. Gaitonde, B.B. et al, ~Antipyretic Activity of Ibuprofen (Brufen) n ~ J.
ASS. Phvsicians, India (1973) 21:579-584 describes the results of two randomized, double-blind, parallel ~tudies comparing the antipyretic efficacy of ibuprofen to that of ~rin. In the first study, 17 adult patients with fever of 100F or more (orally) due to upper respiratory tract infections were given a capsule containing either ibuprofen 200 mg ~7 patients) or aspirin 300 mg (10 patients).
In the second study, 11 adult patients with resis-tant, chronic gonococcal urethritis were inoculated with T.A.B. vaccine (containing S. typhosa and paratyphi A + B microorganisms). Once peak temperature wa reached as indicated by cessation of ; 20 rigors, each patient received either ibuprofen 400 mg (5 patlent~) or a~pirin 600 mg ~6 patients).
In the patients with upper respiratory tract lnfections ~ntipyretic effect from both treatment~ began approximately one hour after dosing. The temperature curves following both treatments were very similar, with the maximum decrease in temperature being reached 3 1/2 hours following ~pir-~n 300 mg and 4 1/2 hours following buprofen 200 mg. In the ~econd study, where the fever was induced by the vaccine, the temperature respon~e curve~ were again very similar with the mean maxlmum fall in temperature ozcurring at nbout three hours w~th bsth treatments. The temper~ture ~f~e m~

, ~327~
, did not rise, however, at five and six hours in the ibuprofen 400 mg treated patient~. In the group treated with aspirin 600 mg there was a ri~e in temperature at five hours and a further rise at 6iX
hours altbough at the six hours observation time there were measurements on only three of the 8iX
aspirin patients.
Sheth, U.~. et al, ~Measurement of An-tipyretic Aetivity of Ibuprofen and Paracetamol in 10 Children~, J. Clin. Pharmacol.~ 20:672-675 (1980) reported on a randomized, open label study in which the antipyretic activity of ibuprofen was compared to that of acetaminophen in 22 children aged two to eight years ~uffering from fever due to upper respiratory tract infection and other causes. Both ibuprofen and acetaminophen at the doses used produced a significant fall in the initial tempera-ture, continuing to 12 hours. The rate of fall and maximum effe~t of the two drugs were similar.
Ibuprofen, however, was more effective than aceta-mlnophen at these doses at six and eight hours after drug administration, indicating a longer duration of effect on ibuprofen.
The superiority of the analgesic properties of varlous of the non-narcotic analgesics belonging to the non-steroidal anti-inflammatory drug class in comparative studies with placebo, aspirin and acet~minophen in patients with various types of pain ~ncluding headache, aches and pains a~sociated with ~old~, dental pain, postpartum pain, musculo~keletal pain, menstrual cramping, ~nd 80 forth, ~ well documented in the literature.

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, A report by Bus~on, M., ~A Double Blind x Multicentre Compari~on of Ibuprofen and Placebo inColds and Non-specific Headaches", The Boots Company, Ltd. Research Report (1982) presents the 5 results of a double-blind randomizea crossover study ? of the analgesic efficacy of ibuprofen 200 mg or ibuprofen 400 mg compared to placebo in 332 patients with self-diagnosed headaches (161 patientsl and colds (171 patients). In addition to a composite 10 analysis of the entire population, ~ubgroup analyses were performed on those patients whose primary complaint was headache and on those patients complaining of colds. The data show that ibuprofen at both dose~ produced statistically significant 15 improvement both in headache and in aches and pains associated with colds compared with placebo, in all composite and subgroup comparisons except the 200 mg ~' ibuprofen vs. placebo in cold patients in the parallel groups (fir~t treatment only) comparison.
20 Patient preference in the composite, headache, and ~ cold groups was also ~gnificantly in favor of both ¦ ibuprofen treatment~ as compared to placebo.
Cooper ~n 1977 found that for pain relief ibuprofen 400 mg had a greater peak effect and longer duration of action than aspirin 650 mg.
Cooper, S.A., Needle, A.E., ~ruger, G.O. ~1977), ~An Analgesic Relative Potency Assay Comparing Aspirin, Ibuprofen ~nd Placebo.~, J. Oral Surg., 35:898-903.
Cooper in another study ln 1982 found 400 ~g of ~uprofen to be more effective than aspirin 650 mg.
Cooper, S.A , Bngel, J., ~adov, M., Precheur, ~., Rosenheck, A., Rauch, D. (1982), ~Analgesic Bfficacy of an Ibuprofen-codeine Combination.~, . ~ :
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Pharmacothera~v, 2:162-67. Sunshine et al found -ibuprofen to be significantly superior to aspirin in the relief of post-episiotomy pain. Sunshine, A. et al, Clinical Pharmacology and TheraPeutics, 24:254-250 (1983).
Dionne in 1982 found ibuprofen to be more effective than acetaminophen in delaying the onset and intensity of post-operative dental pain.
Dionne, R.A., Campbell, R.A., Cooper, S.A., Hall, D.L., Buckingham, B., ~Suppression of Post operative Pain by Preoperative Administration of Ibuprofen in Comparison to Placebo, Acetaminophen and Acetamino-phen Plus Codeine.~, J. Clin. Phamacol. (In press).
Naproxen sodium 550 mg was compared with 650 mg of aspirin and was found to provide earlier and better pain relief than aspirin by Sevelius, H., J. Clin. Pharmacol., 20:480-485 (1980), ~Comparative Analgesic Effects of Naproxen Sodium, Aspixin and Placebo.~
Flurbiprofen 50 and 100 ~g was significant-ly more effective than aspirin 600 mg. Flurbiprofen 25 mg wa9 slightly less effective than aspirin 600 mg. Sunshine, A., Olson N.Z., Laska, E.M., Zighel-boim, I., DeCastro, A., Desarrazin, C., Pharmaco Ther., 3:177-181, ~Analgesic Effect of Graded Doses of Flurbiprofen in Postepisiotomy Pain.~
More recently, ibuprofen 200 mg has become ~vailable over-the-counter (OTC) and at 200 to 400 mg in indicated for the temporary relief of m~nor aches and p~ins a~sociated with the common cold, he~dache, toothache, muscular aches, backache, for the m~nor pain of arthritis, for the pain of ~L~273~3 .~

, g menstrual cramp and for reduction of fever. While !~these reported ~indings with respect to the out-standing snalgesic properties of the non-steroidal anti-inflammatory drugs compared to aspirin or .5 acetaminophen have prompted the widespread accept-ance and usage of these newer non-narcotic ~nal-gesics, as single entities, for the treatment and -management of acute and chronic pain as well as inflammatory states, notably rheumatoid arthritis and osteoarthritis, the utilization of these agents in cough~cold compositions for multi-gymptom relief has not heretofore been considered, this despite the fact that ibuprofen's and other NSAID's antipyretic and analgesic properties have been well known for more than a decade.
The non-steroidal anti-inflammatory drugs for use in the pharmaceutical compositions and methods-of-use of the present invention may be selected from any of the following categories:
(1) ~he propionic acid derivatives;
(2~ The acetic a~id derivatives;

(3) The fennmic acid derivatives;
~ 4) The biphenylcarboxylic acid deriva-tives; and ~5) The oxicams.
Accordingly, the term ~NSA~D~ as used herein i8 intended to mean ahy non-narcotic anal-ge~ic non-stero$dal ~nti-inflammatory compound, lncluding the pharmaceutically acceptable non-~oxic ~alts t~ereo~, falllng within one of the five . ~

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13273~5 .
,", -- 10 --tructural categories above but excluding a~pirin, acetaminophen and phenacetin.
., While ~ome of these compounds are primarily .-usea at the present time as anti-inflammatory agents 5 and others are primarily used as analge~ics, in fact all of the contemplated compounds have both ~nal-gesic and anti-inflammatory activity and can be used at appropri~te dosage levels for either purpose in ~.the compositions and methods of the present inven-~10 tion. Th2 compounds in groups (1) through (4 typically contain a carboxylic acid function;
however, those acids are sometimes administered in the form of their pharmaceutically a~ceptable acid addition or alkali metal salts, e.g., sodium salts.
The Epecific compounds falling within the forego~ng definition of the non-steroidal anti-infl2mmatory drugs for use in the present invention are well known to those skilled in the art and : reference may be had to various literature reference ~ources for their chemical structureC~ pharmacologi-cal activities, ~ide effects, normal dosage ranges, ¦ etc. See, for axample, Physician's Desk Reference, 35~h Edition (1981)s The Merck Index, 9th Edition, ¦ Nerck and Company, Rahway, New Jer~ey (1976); and Cutting's Handbook of Pharmacolosy, 6th Ed~tion, Ed.
T.Z. Czacky, M.D., Appleton-Century-Crofts, New York (1979), Chapter 49:538-550.
The propionic acid derivatives for use herein include, but are not li~ited to, lbuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbu~en, ketoprofen, indoprofen, pirprofen, ~arprofen, oxaprozin, pranoprofen, miroprofen, tloxnprofen, suprofen, al~inoprofen, tiaprofenic ~........ ~ .

-` 13273 .,:

acid, fluprofen znd bucloxic acid. Structurally -~ related propionic acid derivatives having similar analgesic and ~nti-inflammatory properties are also intsnded to be encompassed by this group. Presently preferred members of the propionic acid group include lbuprofen, naproxen, flurbiprofen, fenopro-fen, ~etoprofen, and fenbufen.
Thus, ~propionic acid derivatives~ as defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs having a free -CH(CH3)COo~ or -CH2CH2COOH qroup (which optionally can be in the form of a pharmaceutically acceptable ~alt group, e.g., -CH(CH3)C00-Na+ or -C~2CH2COO-Na~), typically attached directly or via a carbonyl function to a ring ~ystem, preferably to an aromatic ring ~ystem.
The acetic acid derivatives for use herein include, but are not limited to, indomethacin, sulindac, tolmetin, zomepirac, diclofenac, fenclofenac, alclofenac, ibufenac, isoxepac, ~urofenac, tiopinac, zidometacin, acemetacin, fentiazac, clidana~ and oxpinac. Structurally related acetic acid derivatives having similar analgesic and anti-inflammatory propertie~ are also intended to be encompassed by this group. Presently preferred members of the acetic acid group include tolmetin sodium, sulindac and indomethacin.
Thus, ~acetic acid derivatives~ as defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs havlng a free -CH2COOH group (which opt~onally c~n be in the form of a phar-maceutically ~cceptable salt group, e.g., -C~2C00-Nal), typlcally attached directly to a ring 132731~

system~ preferably to an aromatic or heteroaromatic ring ~ystem.
~ The fenamic acid derivatives for use herein 'J'~.` include, but are not limited to, mefenamic acid, meclofena~ic acid, flufenamic acid, niflumic acid and tolfenamic a~id. Structurally related fenamic acid derivatives having similar analgesic and anti-inflammatory properties are also intended to be encompassed by this group. Presently preferred members of the fenamic acid group include mefenamic acid and meclofenamate 60dium (meclofenamic acid, sodium salt).
Thus, ~fenamic acid derivative~ as defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs which contain the basic ¦ ~tructure ~' ~hich can be~r a varlety of substituent~ and in which the ree -C00~ group can be $n the form of a pharmaceutically ~cceptable ~alt group, ~.g, -C00-Na+.

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, - 13 -. The biphenylcarboxylic acid derivatives for use herein include, but are not limited to, difluni-sal and flufenisal. Structurally related biphenyl-~ carboxylic acid derivatives having similar analgesic .~ 5 and anti-inflammatory properties are also intended to be enc~mpassed by thi~ group. Preferred members of this group are diflunisal and flufenisal.
~ ~hus, ~biphenylcarboxylic acid derivative"
as defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs which contain the bas1c otructure i:

COOH

which can bear a variety of substituents and in which the free -COOH group can be in the form of a pharmaceutically acceptable salt group, e.g., -C00-Na+.
The oxicams for u~e herein include, but are not li~ited to pirox~cam, ~udoxicam, isoxicam and CP-14,304. Structurally related oxicams having - .

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~, - 14 -~' similar analgesic and anti-inflammatory properties ~, are al~o intended to be encompassed by this group.
A preferred member of this group is piroxicam.
Thus, ~oxicams~ as defined herein are non-i 5 narcotic analgesics/non-steroidal anti-inflammatory i drugs which have the qeneral formula ~1 ~--C~ R

'I 2 1~ where R i8 an aryl or heteroaryl ring 8y8tem.
Of course, it will be appreciated by those ~killed in the art, that any of the foregoing compounds may be utilized in the form of their pharmaceutically acceptable salt forms, e.g., - -COO-Na+, -COO-R+, and the like.
Of the foregoing non-stero1dal anti-lnfl o atory drugs, in the practice of the preferred lS embodiment~ of the present invention, ibuprofen and naproxen are most preferred.

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ij~ With re6pect to the dosage amount of the non-~teroidal anti-in1ammatory drugs in the compositions of the invention, although the specific dose will vary depending upon the age and weight of the patient, the ~everity of the symptoms, the incidence of ~ide effects and the li~e, for humans, typical effective analgesic amounts of presently preferred NSAID's for use in unit dose compositions of the invention are about 100 - 500 mg diflunisal, about 50 - 600 mg ibuprofen, most preferably 100 - 400 mg, about 125 - 500 mg naproxen, about 25 - 100 mg flurbiprofen, about 50 - 100 mg fen~pro-fen, about 10 - 20 mg piroxicam, about 125 ~ 250 mg mefenamic acid, about 100 - 400 mg fenbufen or about ;j 15 25 - 50 mg ketoprofen; however, greater or lesser amounts may be em~loyed if desired or necessary.
With respect to the compounds set forth hereinabove fall$ng within the propionic acid derivative category, suitable dosage ranges for these compounds ~¦ 20 will generally fall within the range of 25 mg to 600 mg in each unit dose.
'! ~ In any event, the amounts of NSAID and non-steroidal antl-inflammatory agent to be administered l in a total daily dose ~hould not exceed the general-ly recognized a8 ~afe limits established for the particular NSAID and non-steroidal anti-inflammatory agent when a~m~nistered alone for their respective usual therapeutic ind~cations.

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The non-sedating antihistamines are pharmacologically and chemically distinct from the conventional antihistamines. The non-sedating antihistamines represent a new generation of drugs which specifically block H1-histamine receptors and do not cause sedation. The sedative properties of conventional antihistamines are well known and for daytime use especially represent a significant disadvantage during treatment. The FDA's Tentative Final Monograph has proposed that the labeling for category I OTC antihistamines, in general, carry the warning, "May cause drowsiness; alcohol may increase the drowsiness effect. Avoid alcoholic beverages while taking this product. Use caution while driving a motor vehicle or operating machinery."
The non-sedating antihistamines are only peripheral-ly active, that is, they do not penetrate the blood-brain barrier in significant amounts to cause drowsiness. Thus, unlike the conventional antihis-tamines, the labeling for the non-sedating antihis-tamines do not carry warnings to patients to refrain from driving a car or operating machinery during therapy or concimitantly using alcohol or other central nervous system depressants as they do for convention antihistamines. Nor are the non-sedating antihistamines contraindicated in patients who are suffering from glaucoma, bronchial asthma, or prostatic hypertrophy.
In vivo studies have shown that the non-sedating antihistamines preferentially bind to peripheral rather than central H1-histamine recep-tors. Since conventional antihistamines which produce sedation have greater affinities for central :s ~ i3273~
~, ;~ - 17 -Hl-histamine receptors, the lesser penetration of the non-sedating antihistamines into the central nervous system may be responsible for their apparent lack of central nervous ~ystem effects. In addi-~;1 5 tion, as a general rule, the non-sedating antihis-~;~ tamines possess minimal or no anti~erotoninergic, anticholinergic or antiadrenergic activity.
Psycho~otor and visual function testc in man have shown that the non-~edating antihistamines do not 10 impair psychomotor performance or adversely affect subjective feelings, in contrast to conventional antihistamine~ which were active in these tests.
The non-~edating antihistamines neither affect the EEG as sedative antihistamines are known to do, nor ; 15 interact with other depressant drugs (such as alcohol or benzodiazepines) to produce enhanced ~; depressant effects.
The lack of ~edative effects from the non-sedating antihistamines may be especially useful in 20 chlldren, where prescribing of conventional antihis-~l tamines is often hindered because of the daytime ¦ ~edation they produce.
The non ~edating antihistamines include but L are not limited to acrivastine, AHR-11325, as-~ 25 temizole, azatadine, azelastine, cetirizine, !` ebastine, ketotifen, lodoxam~de, loratidine, levocabastine, mequitazine, oxatomide, ~etastine, tazifylline, temela~tine and terfenadine. Represen-tative chemical structures for many of the non-30 sedating antlhist~mines are presented in Table I.

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The preferred non-sedating antihi ta~ines for use in the practice of the present invention are astemizole and terfenadine. Terfenadine i~ marketed in the United States as Seldane, a registered trademark of Merrill Dow Pharmaceuti~als.
The amount of the non-sedating antihis-tamine useful in the practi~e of the present invention generally ranges from about 1 mg to about 1000 mg depending on the gpecific non-sedating antihistamine selected; however, greater or lesser ~mounts may be employed if desired or necessary.
The recommended dosage of terfenadine, for instance, is 60 mg orally (1 tablet or 10 ml of suspension) once or twice daily. In children aged 6 to 12 years, the dosage i8 30 mg ~5 ml of suspen-sion) to 60 mg twice daily depending on body weight.
In children aged 3 to 5 years, the dosage i8 15 mg twice daily. Some studies suggest doses ranging from 20 mg thrice da~ly to 200 mg thrice daily.
Terfenadine has also been demonstrated to be of value in exercise-induced asthma when given orally ~n a single do~e of 120-mg or 180 mg.
The usual dose of astemizole is ld mg to 25 mq onoe daily. Astemizole has a half-life of several days and thus it may be given as a single tablet daily, which i8 an important advantage in obtaining greater patient compliance~ therefore, lt ~an advantageously be added to one of the longer acting NSAID's. The recom ended dose of mequitazine 30 i8 5 ~g twice ~aily. Temelastine i0 being evaluated in humans at a do~e of 100 mg once or ~wice daily.

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, ,. ' ' , 132731~
,., The cough/cold pharmaceutical compositions ! of the presen~ invention comprise, in addition to the non-steroidal anti-inflammatory drugs, at least one non-sedating antihistamine as an active in-gredient and optionally one or more acti~e in-gredients from the following pharmacological classes: sympathGmimetics (decongestants), cough suppressants-antitus~ive~ and expectorants. Typical therapeutically active components from these categories, along with their usual adult dosage, for use in the pharmaceutic&l compositions and methods of the invention are set forth in the following Table II. Of course, sustained release formulations would contain higher doses than those set forth in Table II.
These non-sedating antihistamines could enhance the analgesic properties of the ~SAID' 8, ~uch as ibuprofen and naproxen, as has been observed for conventional antihistamines. Notably, diphen-hydramine, a conventional antihi~tamine, in combina-tion with a non-steroidal anti-inflammatory drug, ibuprofen, has already been demonstrated by Ap-plicants to produce a synergistically enhanced analgesic response in a mammalian organism. As noted earlier, the non-sedating antihistamines could also be useful for the treatment of an allergic reaction.

s 13~731~
., ~ TABLE II
~ USUA~ SINGLE
DRUG (FORN-SALT) ACTION PREPARATIONS DOSE (ADULT) pseudoephedrine D Tablet, Capsule, 30-120 mg (~ulfate, ~Cl) 30 mg, 60 mg, 120 mg (sustained - - action) phenylpro- D Tablet, Capsule, 5-50 mg panolamine Elixir, 25 mg, 50 mg, 12.5 mg/5cc phenylephrine D Tablet, Capsule, 5-25 mg (bitartrate, tan- Elixir, 5 mg, 10 mg, nate, HBr, HCl 25 mg, 5 mg~5cc caramiphen CS Capsule, Elixir,5-20 mg ~edisylate) 20 mg~ 5 mg/5cc dextromethor- CS Tablet, Capsule,2.5-30 mg phan (HBr) Elixir, 15 mg, 30 mg, 15 mg/5cc codeine CS Tablet, Elixir,10-20 mg ~phosphate, 10 mg, sulfate) 10 mg/5cc benzonatate CS Capsule, 100 mg100 mg chlophedianol CS Elixir, 25 mg ~Cl) 25 mg/5cc terpin hydrate E Tablet, Elixir,85-300 mg 300 mg quaifenesin E Tablet, Capsule,25-200 mg Iglyceryl, El~xir, 100 mg, quaiacolate) 100 mg/5cc potassium E Tablet, Elixir,150-300 mg (Iod~de, citrate) 100 mg, 100 mg/Scc pot~$um E Elixir, 45-300 ng guaicolsulfonate 80 mg/5cc D - decongeEtant CS ~ cough suppressant E ~ expectorant `~ 132731~

In the pharmaceutical compositions and methods of the present invention, the ~oregoing active ingredients will typically be administered in admixture with ~uitable pharmaceutical diluents, excipients or carriers ~collectively referred to herein as ~carrier~ materials) suitably selected with respect to the ~ntended form of adminiRtration, i.e., oral tablets, capsules, elixirs, syrups, suspen~ions, etc. and consi~tent with conventional pharmaceutical practices. For instance, for oral administration in the form of tablets or capsules, the active drug components may be combined with any oral non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, ethyl alcohol (liquid forms) and the like. Moreover, whe~ desired or necessary, suitable binder~, lubricants, disintegrating agents and coloring agents can also be $ncorporated in the mixture. Suitable binder~ include starch, gelatin, natural sugar~, corn sweeteners, natural and ~ynthetic gums ~uch as aca~ia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Among the lubricants there ~ay be mentioned for u~e in these dosage orms, boric ~cid, ~odium benzoate, sodium acetate, sodium chloride, etc.
Disi~tegrators include, without llmitation, starch, methylcellulose, agar, bentonite, guar gum, etc.
Sweetening and flavoring agents and pre~ervat~ves can al~o be included where ~ppropriate.
0~ course, addit~on~lly, the compo~ition~
of the present invention may be formulated in ~u~tained relea~e ~orm to provide the rate 132731~

controlled release of any one or more of the components to optimize the therapeutic effects, i.e., analgesia, antihistaminic, etc. while minimiz-ing undesirable side effects. Suitable dosa~e forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matr~ces impregnated with the active components snd shaped in tablet form '~ or capsules containing such impregnated or encapsulated porous polymeric matrices.
As representative suitable formulations consistent with the objects, features and advantages of the present invention, the following non-limiting examples are provided.

~XAMPLE 1 Ibuprofen - 200 mg Dextromethorphan hydrobromide - 30 mg Guaifenesin - 100 mg Terfenadine - 60 mg Triturate active ingredients and g. 8 . with lactose to selected capsule size.
:

In each fluid ounce:

Naproxen (sodium) - 250 mg Dextrom~thorphan hydrobromide - 30 mg Astemizole - 10 mg Orange flavoring ~nd alcohol 10~ v/v.

:`
~ ~L32731~
.

:~ - 31 -E8aMPLE 3 Ibuprofen - 200 mg Terfenadine - 60 mg Triturate active ingredients and q. 8. with lactose to selected capsule ~ize.

From the foregoing, other typical accept-able pharmaceutical formulations will be apparent to those skilled in the art of pharmaceutical formulations.
While this invention has been described and S illustrated with reference to certain preferred ~; embodiments thereof, those skilled in the art wîll appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit of the invention. For example, effective dosages other than the preferred range~
et forth hereinabove with respe~t to the active ingredient~ may be applicable a~ a consequence oP
variations of the responsiveness of the mammal treated, ~everity of Eymptoms, dosage related adverse effects, if any, observed and simiiar considerations. Accordingly, such expected varia-tions or differences in the practice of the present invention and the results obtained are contemplated ln accordance with the ob~ects and practices of the present invention~ It i~ intended, therefore, that the invention be limited only by the ~cope of the claims which follow.

Claims

1. A pharmaceutical composition of matter for use in the treatment of cough, cold, cold-like and/or flu symptoms and the discomfort, pain, fever and general malaise associated therewith, in a mammalian organism, and adapted for unit dosage oral administration, said composition comprising (i) an analgesically and anti-inflammatory effective amount of at least one non-steroidal anti-inflammatory drug comprising a propionic acid derivative, an acetic acid derivative, a fenamic acid derivative, a biphenylcarboxylic acid derivative, an oxicam or pharmaceutically acceptable salt thereof, in combinatory immixture with (ii) an antihistaminical-ly effective amount of at least one of the non-sedating antihistamines.

2. The pharmaceutical composition as defined by claim 1, said non-sedating antihistamine comprising acrivastine, AHR-11325, astemizole, azatadine, azelastine, cetirizine, ebastine, ketotifen, lodoxamide, loratidine, levocabastine, mequitazine, oxatomide, setastine, taxifylline, temelastine, terfenadine or pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition as defined by claim 1, said non-steroidal anti-inflam-matory drug comprising a propionic acid derivative.

4. The pharmaceutical composition defined by claim 3, said propionic acid derivative compris-ing ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid or pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition defined by claim 4, said non-steroidal anti-inflammatory drug comprising ibuprofen or pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition defined by claim 4, said non-steroidal anti-inflammatory drug comprising naproxen or pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition defined by claim 1, comprising at least 25 mg of said non-steroidal anti-inflammatory drug.

8. The pharmaceutical composition defined by claim 7, comprising from 25 mg to 600 mg of said non-steroidal anti-inflammatory drug.

9. The pharmaceutical composition defined by claim 5, comprising from 50 mg to 600 mg of ibuprofen or pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition defined by claim 9, comprising at least 100 mg of ibuprofen or pharmaceutically acceptable salt thereof.

11. The pharmaceutical composition defined by claim 6, comprising from 125 mg to 500 mg of naproxen or pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition defined by claim 1, said non-steroidal anti-inflammatory drug comprising an acetic acid derivative.

13. The pharmaceutical composition defined by claim 12, said acetic acid derivative comprising indomethacin, sulindac, tolmetin, diclofenac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac or pharmaceutically acceptable salt thereof.

14. The pharmaceutical composition as defined by claim 13, comprising from 20 mg to 400 mg of said acetic acid derivative.

15. The pharmaceutical composition as defined by claim 1, said non-steroidal anti-inflam-matory drug comprising a fenamic acid derivative.

16. The pharmaceutical composition as defined by claim 15, said fenamic acid derivative comprising mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid or pharmaceutically acceptable salt thereof.

17. The pharmaceutical composition as defined by claim 16, comprising from 250 mg to 500 mg of said fenamic acid derivative.

18. The pharmaceutical composition as defined by claim 1, said non-steroidal anti-inflam-matory drug comprising a biphenylcarboxylic acid derivative .

19. The pharmaceutical composition as defined by claim 18, said biphenylcarboxylic acid derivative comprising diflunisal, flufenisal or pharmaceutically acceptable salt thereof.

20. The pharmaceutical composition as defined by claim 21, comprising from 250 mg to 500 mg of said biphenylcarboxylic acid derivative.

21. The pharmaceutical composition as defined by claim 1, said non-steroidal anti-inflam-matory drug comprising an oxicam.

22. The pharmaceutical composition as defined by claim 21, said oxicam comprising piroxi-cam, sudoxicam, isoxicam or pharmaceutically acceptable salt thereof.

23. The pharmaceutical composition as defined by claim 22, comprising from 10 mg to 20 mg of said oxicam.

24. The pharmaceutical composition as defined by claim 1, comprising from 1 mg to 1000 mg of said non-sedating antihistamine.

25. The pharmaceutical composition as defined by claim 1, wherein said non-sedating antihistamine is terfenadine or pharmaceutically acceptable salt thereof.

26. The pharmaceutical composition as defined by claim 25, comprising 30 mg to 120 mg of terfenadine.

27. The pharmaceutical composition as defined by claim 1, wherein said non-sedating antihistamine is astemizole or pharmaceutically acceptable salt thereof.

28. The pharmaceutical composition as defined by claim 27, comprising 10 mg to 25 mg astemizole.

29. The pharmaceutical composition as defined by claim 10, comprising at least 100 mg of ibuprofen and 30 mg to 120 mg of terfenadine.

30. The pharmaceutical composition as defined by claim 1, further comprising (iii) a pharmaceutically acceptable non-toxic carrier.

31. The pharmaceutical composition as defined by claim 1, in oral dosage form.

32. The pharmaceutical composition as defined by claim 31, in oral dosage tablet form.

33. The pharmaceutical composition as defined by claim 31, in oral dosage capsule form.

34. The pharmaceutical composition as defined by claim 31, in oral dosage suspension form.

35. A pharmaceutical composition of matter for use in the treatment of an allergic reaction in a mammalian organism in need of such treatment, comprising an allergic symptom relieving effective amount of (i) at least one non-steroidal anti-inflammatory drug comprising a propionic acid derivative, an acetic acid derivative, a fenamic acid derivative, a biphenylcarboxylic acid derivative, an oxicam or pharmaceutically acceptable salt thereof, in combinatory immixture with (ii) at least one of the non-sedating antihistamines.

36. Use of a symptom relieving anti-histaminically, analgesically and anti-inflammatory effective amount of a composition comprising (i) at least one non-steroidal anti-inflammatory drug comprising a propionic acid derivative, an acetic acid derivative, a fenamic acid derivative, a biphenulcarboxylic acid derivative, an oxicam or pharmaceutically acceptable salt thereof, in combinatory immixture with (ii) at least one non-sedating antihistamine or pharmaceutically acceptable salt thereof, for the treatment of cough, cold, cold-like and/or flu symptoms and the discomfort pain, fever and general malaise in a mammalian organism in need of such treatment.

37. Use of the pharmaceutical composition as defined by claim 1, for the treatment of cough, cold, cold-like and/or flu symptoms and the discomfort, pain, fever and general malaise associated therewith, in a mammalian organism in need of such treatment.

38. Use of the pharmaceutical composition as defined by claim 4, for the treatment of cough, cold, cold-like and/or flu symptoms and the discomfort, pain, fever and general malaise associated therewith, in a mammalian organism in need of such treatment.

39. Use of an allergic symptom relieving effective amount of a composition comprising (i) a non-steroidal anti-inflammatory drug comprising a proprionic acid derivative, an acetic acid deriva-tive, a fenamic acid derivative, a biphenylcarboxylic acid derivative, an oxicam or pharmaceutically acceptable salt thereof, in combinatory mixture with (ii) at least one of the non-sedating antihistamines, for the treatment of an allergic reaction in a mammalian organism in need of such treatment.

40. A pharmaceutical composition-of-matter for use in the treatment of cough, cold, cold-like and/or flu symptoms and the discomfort, pain, fever and general malaise associated therewith, in a mammalian organism, and adapted for unit dosage oral administration, said composition comprising (i) an analgesically and anti-inflammatory effective amount of at least one non-steroidal anti-inflammatory drug comprising a propionic acid derivative, an acetic acid derivative, a fenamic acid derivative, a biphenylcarboxylic acid derivative, an oxicam or pharmaceutically acceptable salt thereof, in combinatory immixture with (ii) an antihistaminical-ly effective amount of at least one of the non-sedating antihistamines, acrivastine, AHR-11325, astemizole, azatadine, azelastine, cetirizine, ebastine, ketotifen, lodoxamide, loratidine, levocabastine, mequitazine, oxatomide, setastine, tazifylline, temelastine, terfenadine or phar-maceutically acceptable salt thereof and (iii) one or more active components selected from a deconges-tant, cough suppressant and expectorant.

41. The pharmaceutical composition as defined by claim 40, wherein said active component is a decongestant.

42. The pharmaceutical composition as defined by claim 41, wherein said decongestant is pseudoephedrine, phenylpropanolamine or phenylephrine.

43. The pharmaceutical composition as defined by claim 42, wherein said decongestant is pseudoephedrine.

44. The pharmaceutical composition as defined by claim 40, wherein said active component is a cough suppressant.

45. The pharmaceutical composition as defined by claim 40, wherein said active component is an expectorant.