United States Patent (19) 11 Patent Number: 4,871,733 Sunshine et al. (45) Date of Patent: Oct. 3, 1989

54) COUGH/COLD MIXTURES COMPRISING 51 Int. Cl." ...... A61K 31/19; A61K 31/44; NON-SEDATING ANTHSTAMINE DRUGS A61K 31/55; A61K 31/445; A61K 31/495; A61K 31/.505 75 Inventors: Abraham Sunshine, New York; 52 U.S.C...... 514/212; 514/255; Eugene M. Laska, Larchmont; 514/256; 514/290; 514/315; 514/336; 514/570 Carole E. Siegel, Mamaroneck, all of 58 Field of Search ...... 514/255, 256, 290, 315, N.Y. 514/336, 520, 212 Primary Examiner-Stanley J. Friedman (73) Assignee: Analgesic Associates, Larchmont, Attorney, Agent, or Firm-Burns, Doane, Swecker & N.Y. Mathis 57 ABSTRACT (21) Appl. No.: 230,887 Pharmaceutical compositions and methods of using same comprising a non-steroidal anti-inflammatory 22 Filed: Aug. 11, 1988 drug in combination with a non-sedating antihistamine and optionally one or more other active components Related U.S. Application Data selected from a decongestant, cough suppressant (anti tussive) or expectorant are provided for the relief of 60 Division of Ser. No. 42,120, Apr. 24, 1987, Pat. No. 4,783,465, which is a continuation-in-part of Ser. No. cough, cold, cold-like and/or flu symptoms and the 887,205, Jul. 24, 1986, Pat. No. 4,738,966, which is a discomfort, pain, headache, fever and general malaise division of Ser. No. 752,546, Jul. 8, 1985, Pat. No. associated therewith. 4,619,934, which is a division of Ser. No. 598,502, Apr. 9, 1984, Pat. No. 4,552,899. 29 Claims, No Drawings 4,871,733 1. 2 zation of the adverse side effects experienced with these COUGH/COLD MIXTURES COMPRISING conventional agents; more specifically, the gastrointes NONSEDATING ANTHSTAMINE DRUGS tinal ulcerations experienced with aspirin and the he patic toxicity prevalent with the chronic use of acetami This application is a division of U.S. Ser. No. 042,120, nophen. filed Apr. 24, 1987, now U.S. Pat. No. 4,783,465; which Exemplary prior art cough/cold formulations con is a continuation-in-part of U.S. Ser. No. 887,205, filed taining aspirin or acetaminophen include Coricidin (R), July 24, 1986, now U.S. Pat. No. 4,738,966; which is a Coricidin D (R), Comtrex (R), Dristan (R), Daycare (R), division of U.S. Ser. No. 752,546, filed July 8, 1985, now Cotylenol (E), Sinubid (R) and the like. These formula U.S. Pat. No. 4,619,934; which is a division of U.S. Ser. 10 tions generally contain in addition to aspirin, acetamino No. 598,502, filed Apr. 9, 1984, now U.S. Pat. No. phen or salicylamide, one or more conventional antihis 4,552,899. taminics, decongestants, cough suppressants, antitus sives and expectorants. BACKGROUND OF THE INVENTION While aspirin and acetaminophen have been utilized The present invention relates generally to novel phar 15 in these previous compositions, it has not been hereto maceutical compositions of matter comprising one or fore proposed to use any of the newer non-steroidal more non-steroidal anti-inflammatory drugs (NSAID) anti-inflammatory drugs (i.e., excluding aspirin, acetam in combination with a non-sedating antihistamine and inophen and phenacetin) in the preparation of advanta optionally one or more other active components se geous cough/cold pharmaceutical compositions. lected from a sympathomimetic drug (nasal deconges 20 tant, bronchodilator) cough suppressant and/or expec SUMMARY OF THE INVENTION torant, optionally in combination with suitable pharma It is, therefore, a primary object of the present inven ceutically acceptable non-toxic carriers or excipient, tion to provide pharmaceutical compositions of matter and to methods of using said compositions in the treat comprising an analgesically effective amount of a non ment, management or mitigation of cough, cold, cold 25 steroidal anti-inflammatory drug in combination with a like and/or flu symptoms and the discomfort, pain, non-sedating antihistamine, and optionally one or more headache, fever and general malaise associated there active components selected from a decongestant, cough with. suppressant, expectorant and, further optionally includ Applicants' earlier application, now U.S. Pat. No. ing pharmaceutically acceptable carriers therefor. 4,619,934 was directed to one or more NSAID's in 30 It is a further object of the present invention to pro combination with a conventional antihistamine and vide methods for the symptomatic relief of cough, cold, other optional components. Applicants have now dis cold-like and flu symptoms and the discomfort, pain, covered that the non-sedating antihistamines, which are headache, fever and general malaise associated there pharmacologically and chemically distinct from the with, by the administration of preselected dosages of conventional antihistamines, in combination with one or 35 the pharmaceutical compositions of the present inven more NSAID's offers significant advantages in the tion. Cold-like symptoms as used herein refers to co treatment, management or mitigation of cough, cold, ryza, nasal congestion, upper respiratory infections, cold-like and/or flu symptoms and the discomfort, pain, allergic rhinitis, otitis, sinusitis, etc. fever and general malaise associated therewith. It is Another object of the present invention is to provide well known that the conventional antihistamines may suitable dosage unit forms of one or more NSAID's in cause drowsiness or marked drowsiness. While this may combination with a non-sedating antihistamine and op be an advantage at bedtime, if taken during the day, the tionally one or more active components selected from a label recommends that a patient use caution when driv decongestant, cough suppressant or expectorant ing a motor vehicle or operating machinery. The com adapted for convenient oral administration. bination of a non-sedating antihistamine and an NSAID 45 is therefore particularly advantageous for daytime ad DETAILED DESCRIPTION OF THE ministration. INVENTION Non-narcotic analgesics, most of which are also More specifically, the applicants herein have found known as non-steroidal anti-inflammatory drugs, are that certain non-steroidal anti-inflammatory agents are widely administered orally in the treatment of mild to 50 ideally suited for use in cough/cold formulations by severe pain. Within this class, the compounds vary reason of their enhanced analgesic anti-inflammatory widely in their chemical structure and in their biologi and antipyretic activity and low incidence of untoward cal profiles as analgesics, anti-inflammatory agents and side effects, particularly at the optimum dosages pro antipyretic agents. Among the most commonly used vided for in the present invention, compared to aspirin members of the non-narcotic analgesic class of drugs 55 or acetaminophen. are aspirin and acetaminophen. Aspirin, acetaminophen For example, the antipyretic effectiveness of ibu and salicylamide are among the drugs that have hereto profen in comparison to aspirin and to acetaminophen fore been included as the pain reliever and fever-reduc has been studied. Gaitonde, B. B. et al, "Antipyretic ing component in conventional cough/cold multisymp Activity of Ibuprofen (Brufen)', J. A.S.S. Physicians, tom alleviating compositions. India (1973) 21: 579-584 describes the results of two However, a number of alternative non-narcotic randomized, double-blind, parallel studies comparing agents offering a variety of advantages over these con the antipyretic efficacy of ibuprofen to that of aspirin. ventionally employed non-narcotic analgesic antipyret In the first study, 17 adult patients with fever of 100 F. ics have now been developed. The principal advantages or more (orally) due to upper respiratory tract infec of these non-steroidal anti-inflammatory drugs include tions were given a capsule containing either ibuprofen not only the clinically superior analgesic, anti-inflam 200 mg (7 patients) or aspirin 300 mg (10 patients). In matory and antipyretic activity of these agents com the second study, 11 adult patients with resistant, pared to aspirin and acetaminophen, but also a minimi chronic gonococcal urethritis were inoculated with 4,871,733 3 4. T.A.B. vaccine (containing S. typhosa and paratyphi action than aspirin 650 mg. Cooper, S. A., Needle, A. A-B microorganisms). Once peak temperature was E., Kruger, G. O. 1977. "An Analgesic Relative Po reached as indicated by cessation of rigors, each patient tency Assay Comparing Aspirin, Ibuprofen and Pla received either ibuprofen 400 mg (5 patients) or aspirin cebo.” J. Oral Surg. 35: 898-903. Cooper in another 600 mg (6 patients). study in 1982 found 400 mg of ibuprofen to be more In the patients with upper respiratory tract infections effective than aspirin 650 mg. Cooper, S.A., Engel, J., antipyretic effect from both treatments began approxi Ladov, M., Precheur, H., Rosenheck, A., Rauch, D. mately one hour after dosing. The temperature curves 1982. "Analgesic Efficacy of an Ibuprofen-codeine following both treatments were very similar, with the Combination.” Pharmacotherapy 2: 162-67. Sunshine et maximum decrease in temperature being reached 3 10 al found ibuprofen to be significantly superior to aspirin hours following aspirin 300 mg and 4 hours following in the relief of postepisiotomy pain. Sunshine, A. et al, ibuprofen 200 mg. In the second study, where the fever Clinical Pharmacology and Therapeutics, 24:254-250, was induced by the vaccine, the temperature response 1983. curves were again very similar with the mean maximum Dionne in 1982 found ibuprofen to be more effective fall in temperature occurring at about three hours with 15 than acetaminophen in delaying the onset and intensity both treatments. The temperature did not rise, however, of post-operative dental pain. Dionne, R.A., Campbell, at five and six hours in the ibuprofen 400 mg treated R. A., Cooper, S.A., Hall, D. L., Buckingham, B. "Sup patients. In the group treated with aspirin 600 mg there pression of Post operative Pain by Preoperative Admin was a rise in temperature at five hours and a further rise istration of Ibuprofen in Comparison to Placebo, Acet at six hours although at the six hours observation time 20 aminophen and Acetaminophen Plus Codeine.” J. Clin. there were measurements on only three of the six aspirin Pharmacol. (In press). patients. Naproxen sodium 550 mg was compared with 650 mg Sheth, U. K. et al., “Measurement of Antipyretic Ac of aspirin and was found to provide earlier and better tivity of Ibuprofen and Paracetamol in Children', J. pain relief than aspirin by Sevelius, H., J. Clin. Pharan Clin. Pharmacol., 20: 672-675 (1980) reported on a ran 25 col. 20: 480-485, 1980. "Comparative Analgesic Effects domized, open label study in which the antipyretic of Naproxen Sodium, Aspirin and Placebo.” activity of ibuprofen was compared to that of acetami Flurbiprofen 50 and 100 mg was significantly more nophen in 22 children aged two to eight years suffering effective than aspirin 600 mg. Flurbiprofen 25 mg was from fever due to upper respiratory tract infection and slightly less effective than aspirin 600 mg. Sunshine, A., other causes. Both ibuprofen and acetaminophen at the 30 Olson N. Z., Laska, E. M., Zighelboim, I., DeCastro, doses used produced a significant fall in the initial tem A., Desarrazin, C., Pharmaco Ther. 3: 177-181. “Anal perature, continuing to 12 hours. The rate of fall and gesic Effect of Graded Doses of Flurbiprofen in Post maximum effect of the two drugs were similar. Ibu episiotomy Pain.” profen, however, was more effective than acetamino More recently, ibuprofen 200 mg has become avail phen at these doses at six and eight hours after drug 35 able over-the-counter (OTC) and at 200 to 400 mg is administration, indicating a longer duration of effect on indicated for the temporary relief of minor aches and ibuprofen. pains associated with the common cold, headache, The superiority the analgesic properties of various of toothache, muscular aches, backache, for the minor the non-narcotic analgesics belonging to the non-steroi pain of arthritis, for the pain of menstrual cramps and dal anti-inflammatory drug class in comparative studies 40 for reduction of fever. While these reported findings with placebo, aspirin and acetaminophen in patients with respect to the outstanding analgesic properties of with various types of pain including headache, aches the non-steroidal anti-inflammatory drugs compared to and pains associated with colds, dental pain, postpartum aspirin or acetaminophen have prompted the wide pain, musculoskeletal pain, menstrual cramping, and so spread acceptance and usage of these newer non-nar forth, is well documented in the literature. 45 cotic analgesics, as single entities, for the treatment and A report by Busson, M., "A Double Blind Multicen management of acute and chronic pain as well as inflam tre Comparison of Ibuprofen and Placebo in Colds and natory states, notably rheumatoid arthritis and osteoar Non-specific Headaches', The Boots Company, Ltd. thritis, the utilization of these agents in cough/cold Research Report (1982) presents the results of a double compositions for multi-symptom relief has not hereto blind randomized crossover study of the analgesic effi 50 fore been considered, this despite the fact that ibu cacy of ibuprofen 200 mg or ibuprofen 400 mg com profen's and other NSAID's antipyretic and analgesic pared to placebo in 332 patients with self-diagnosed properties have been well known for more than a de headaches (161 patients) and colds (171 patients). In cade. addition to a composite analysis of the entire popula The non-steroidal anti-inflammatory drugs for use in tion, subgroup analyses were performed on these pa 55 the pharmaceutical compositions and methods of use of tients whose primary compliant was headache and on the present invention may be selected from any of the those patients complaining of colds. The data show that following categories: ibuprofen at both doses produced statistically signifi (1) The propionic acid derivatives; cant improvement both in headache and in aches and (2) The acetic acid derivatives; pains associated with colds compared with placebo, in (3) The fenamic acid derivatives; all composite and subgroup comparisons except the 200 (4) The biphenylcarboxylic acid derivatives; and mg ibuprofen vs. placebo in cold patients in the parallel (5) The oxicans. groups (first treatment only) comparison. Patient pref. Accordingly, the term “NSAID' as used herein is erence in the composite, headache, and cold groups was intended to mean any non-narcotic analgesic non-steroi also significantly in favor of both ibuprofen treatments 65 dal anti-inflammatory compound, including the phar as compared to placebo. maceutically acceptable non-toxic salts thereof, falling Cooper in 1977 found that for pain relief ibuprofen within one of the five structural categories above but 400 mg had a greater peak effect and longer duration of excluding aspirin, acetaminophen and phenacetin. 4,871,733 5 6 The specific compounds falling within the foregoing 4,486,436 and 4,522,826, and the entire disclosures of definition of the non-steroidal anti-inflammatory drugs which are incorporated herein by reference. for use in the present invention are well known to those The non-sedating antihistamines are pharmacologi skilled in the art and reference may be had to various cally and chemically distinct from the conventional literature reference sources for their chemical struc antihistamines. The non-sedating antihistamines repre tures, pharmacological activities, side effects, normal sent a new generation of drugs which specifically block dosage ranges, etc. See, for example, Physician's Desk H1-histamine receptors and do not cause sedation. The Reference, 35th Edition, (1981); The Merck Index, 9th sedative properties of conventional antihistamines are Edition, Merck and Company, Rahway, N.J. (1976); 10 well known and for daytime use especially represent a and Cutting's Handbook of Pharmacology, 6th Edition, significant disadvantage during treatment. The FDA's Ed. T. Z. Czacky, M.D., Appleton-Century-Crofts, Tentative Final Monograph has proposed that the label New York (1979), Chapter 49:538-550. ing for category IOTC antihistamines, in general, carry Of the propionic acid derivatives for use herein, ibu 5 the warning, "May cause drowsiness; alcohol may in profen, naproxen, flurbiprofen, fenoprofen, ketoprofen, crease the drowsiness effect. Avoid alcoholic beverages fenbufen, and fluprofen may be mentioned as particu while taking this product. Use caution while driving a larly preferred compounds. motor vehicle or operating machinery.' The non-sedat Of the acetic acid derivatives, presently preferred 20 ing antihistamines are only peripherally active, that is, members include tolmetin sodium, sulindac and indo they do not penetrate the blood-brain barrier in signifi methacin. cant amounts to cause drowsiness. Thus, unlike the Of the fenamic acid derivatives, particularly pre conventional antihistamines, the labeling for the non ferred compounds include mefenamic acid and me sedating antihistamines do not carry warnings to pa clofenamate sodium. 25 tients to refrain from driving a car or operating machin The particularly preferred biphenylcarboxylic acid ery during therapy or concomitantly using alcohol or derivatives for use in the present invention include di other central nervous system depressants as they do for flunisal and flufenisal. conventional antihistamines. Nor are the non-sedating 30 antihistamines contraindicated in patients who are suf The particularly advantageous oxicans include fering from glaucoma, bronchial asthma, or prostatic piroxicam, Sudoxicam and isoxicam. hypertrophy. Of course, it will be appreciated by those skilled in In vivo studies have shown that the non-seadating the art, that any of the foregoing compounds may be antihistamines preferentially bind to peripheral rather utilized in the form of their pharmaceutically acceptable 35 salt forms, e.g., -COONa, -COOK, and the than central H1-histamine receptors. Since conventional like. antihistamines which produce sedation have greater Of the foregoing non-steroidal anti-inflammatory affinities for central H1-histamine receptors, the lesser drugs, in the practice of the preferred embodiments of penetration of the non-sedating antihistamines into the 40 central nervous system may be responsible for their the present invention, ibuprofen and naproxen are most apparent lack of central nervous system effects. In addi preferred. tion, as a general rule, the non-sedating antihistamines With respect to the dosage amount of the non-steroi possess minimal or no antiserotoninergic, anticholin dal anti-inflammatory drugs in the compositions of the ergic or antiadrenergic activity. Psychomotor and vi invention, although the specific dose will vary depend 45 sual function tests in man have shown that the non ing upon the age and weight of the patient, the severity sedating antihistamines do not impair psychomotor of the symptoms, the incidence of side effects and the performance or adversely affect subjective feelings, in like, for humans, typical effective analgesic amounts of contrast to conventional antihistamines which were presently preferred NSAID's for use in unit dose com 50 active in these tests. The non-sedating antihistamines positions of the invention are about 100-500 mg diflu neither affect the EEG as sedative antihistamines are misal, about 50-600 mg ibuprofen, most preferably known to do, nor interact with other depressant drugs 100-400 mg, about 125-500 mg naproxen, about 25-100 (such as alcohol or benzodiazepines) to produce en mg flurbiprofen, about 50-100 mg fenoprofen, about hanced depressant effects. 10-20 mg piroxicam, about 125-250 mg mefenamic 55 The lack of sedative effects from the non-sedating acid, about 100-400 mg fenbufen or about 25-50 mg antihistamines may be especially useful in children, ketoprofen; however, greater or lesser amounts may be where prescribing of conventional antihistamines is employed if desired or necessary. With respect to the often hindered because of the daytime sedation they compounds set forth hereinabove falling within the 60 produce. propionic acid derivative category, suitable dosage The non-sedating antihistamines include acrivastine, ranges for these compounds will generally fall within AHR-11325, astemizole, azatadine, azelastine, cetiri the range of 25 mg to 600 mg in each unit dose. zine, ebastine, ketotifen, lodoxamide, loratidine, A complete description of the various NSAID's, 65 levocabastine, meguitazine, oxatomide, setastine, tazi including acceptable analgesically effective amount fylline, temelastine, and terfenadine. Representative thereof for use in unit dose compositions of the present chemical structures for many of the non-sedating anti invention also appears in applicants' U.S. Pat. Nos. histamines are presented in Table I.

4,871,733

TABLE I-continued Non-Sedating Antihistamines Common Name or Generic Name Chemical Structure Chemical Name mequitazine (OI S IO) yl-methyl)-10H-phenothiazine10-(1-azabicyclo(2.2.2)oct-3- N

CH2 N oxatomide 1-(3-(4-(diphenylmethyl)-1- piperazinyl)propyl)-1,3- dihydro-2H-benzimidazol-2-one

tazifylline O 3,7-dihydro-7-(2-hydroxy-3-(4- CH3 I / N (3-(phenylthio)propyl)-1- n NCH2CH(OH)CH2N N(CH2)3S piperazinyl)propyl)-1,3- N dimethyl-1H-purine-2,6-dione als 2) \-/ O N CH3 temelastine O 2-(4-(5-bromo-3-methyl-2- N M methyl-3-pyridinyl)methyl)- CH3 (CH2NH-( / CH2 O CH3 4(1H)-pyrimidinone N N N H

Br terfenadine alpha-(4-(1,1- dimethylethyl)phenyl)-4- ph Hs piperidinebutanol(hydroxydiphenylmethyl)-1- HO-O N-(CH2)3-CH C-CH3 CH3

(8-chloro(6,11-dihydro-11-(1- Cl carboethoxy-4-piperidylidene)- O 5-H-benzo(5,6cyclohepta(1,2-b-pyridine)

N COCH2CH3 O

65 States as Seldane, a registered trademark of Merrill The preferred non-sedating antihistamines for use in Dow Pharmaceuticals. the practice of the present invention are astemizole and The amount of the non-sedating antihistamine useful terfenadine. Terfenadine is marketed in the United in the practice of the present invention generally ranges 4,871,733 11 12 from about 1 mg to about 1000 mg depending on the specific non-sedating antihistamine selected; however, TABLE II-continued USUAL greater or lesser amounts may be employed if desired or SINGLE necessary. DRUG DOSE The recommended dosage of terfenadine, for in (FORM-SALT) ACTION PREPARATIONS ADULT stance, is 60 mg orally (1 tablet or 10 ml of suspension) benzonatate CS Capsule 100 mg once or twice daily. In children aged 6 to 12 years, the 100 mg dosage is 30 mg (5 ml of suspension) to 60 mg twice chlophedianol CS Elixir 25 mg (HCl) 25 mg/5 cc daily depending on body weight. In children aged 3 to terpin hydrate E Tablet, Elixir 85-300 mg 5 years, the dosage is 15 mg twice daily. Some studies 10 300 mg suggest doses ranging from 20 mg thrice daily to 200 mg quaifenesin E Tablet, Capsule, 25-200 mg thrice daily. Terfenadine has also been demonstrated to (glyceryl Elixir, 100 mg, quaiacolate 100 mg/5 cc be of value in exercise-induced asthma when given potassium E Tablet, Elixir 150-300 mg orally in a single dose of 120 mg or 180 mg. (Iodide) 100 mg, The usual dose of astemizole is 10 mg to 25 mg once 15 (citrate) 100 mg/5cc daily. Astemizole has a half-life of several days and thus potassium E Elixir 45-300 mg it may be given as a single tablet daily, which is an guaicolsulfonate 80 mg/5 cc important advantage in obtaining greater patient com D = decongestant CS = cough suppressant pliance; therefore, it can advantageously be added to E = expectorant one of the longer acting NSAID's. The recommended 20 dose of meduitazine is 5 mg twice daily. SK&F93944 is In the pharmaceutical compositions and methods of being evaluated in humans at a dose of 100 mg once or the present invention, the foregoing active ingredients twice daily. will typically be administered in admixture with suitable The cough/cold pharmaceutical compositions of the pharmaceutical diluents, excipients or carriers (collec present invention comprise, in addition to the non 25 tively referred to herein as "carrier' materials) suitably steroidal anti-inflammatory drugs, at least one non selected with respect to the intended form of adminis sedating antihistamine as an active ingredient and op tration, i.e., oral tablets, capsules, elixirs, syrups, suspen tionally one or more active ingredients from the follow sions, etc. and consistent with conventional pharmaceu ing pharmacological classes: sympathomimetics (decon tical practices. For instance, for oral administration in gestants), cough suppressants-antitussives and expecto 30 the form of tablets or capsules, the active drug compo rants. Typical therapeutically active components from nents may be combined with any oral nontoxic pharma these categories, along with their usual adult dosage, for ceutically acceptable inert carrier such as lactose, use in the pharmaceutical compositions and methods of starch, sucrose, cellulose, magnesium stearate, dical the invention are set forth in the following Table II. Of 35 cium phosphate, calcium sulfate, mannitol, ethyl alco course, sustained release formulations would contain hol (liquid forms) and the like. Moreover, when desired higher doses than those set forth in Table II. or necessary, suitable binders, lubricants, disintegrating These non-sedating antihistamines could enhance the agents and coloring agents can also be incorporated in analgesic properties of the NSAID's, such as ibuprofen the mixture. Suitable binders include starch, gelatin, and naproxen, as has been observed for conventional natural sugars, corn sweeteners, natural and synthetic antihistamines. Notably, diphenhydramine, a conven gums such as acacia, sodium alginate, carboxymethyl tional antihistamine, in combination with a non-steroi cellulose, polyethylene glycol and waxes. Among the dal anti-inflammatory drug, ibuprofen, has already been lubricants there may be mentioned for use in these dos demonstrated by Applicants to produce a synergisti age forms, boric acid, sodium benzoate, sodium acetate, cally enhanced analgesic response in a mammalian or 45 sodium chloride, etc. Disintegrators include, without ganism. Again compare their U.S. Pat. No. 4,522,826. limitation, starch, methylcellulose, agar, bentonite, guar TABLE II gum, etc. Sweetening and flavoring agents and preser USUAL vatives can also be included where appropriate. SINGLE Of course, additionally, the compositions of the pres DRUG DOSE 0 ent invention may be formulated in sustained release (FORM-SALT) ACTION PREPARATIONS ADULT form to provide the rate controlled release of any one or pseudoe- D Tablet, Capsule 30-120 mg more of the components to optimize the therapeutic phedrine 30 mg, 60 mg, (sulfate, HCl) 120 mg (sustained effects, i.e., analgesia, antihistaminic, etc. while mini action) mizing undesirable side effects. Suitable dosage forms phenylpro- D Tablet, Capsule, 5-50 mg 55 for Sustained release include layered tablets containing panolamine Elixir, 25 mg, 50 layers of varying disintegration rates or controlled re Ing, 12.5 mg/5 cc phenylephrine D Tablet, Capsule 5-25 mg lease polymeric matrices impregnated with the active (bitaritrate, Elixir, components and shaped in tablet form or capsules con tannate, HBr, 5 mg, 10 mg, 25 mg, taining such impregnated or encapsulated porous poly HCl) 5 mg/5cc meric matrices. caramiphen CS Capsule, Elixir 5-20 mg (edisylate) 20 mg, As representative suitable formulations consistent 5 mg/5 cc with the objects, features and advantages of the present dextroneth- CS Tablet, Capsule, 2.5-30 mg invention, the following non-limiting examples are pro orphan (HBr) Elixir vided. 15 ng, 30 mg 65 15 mg/5 cc EXAMPLE 1. codeine CS Tablet, Elixir 10-20 mg (phosphate, 10 mg Ibuprofen-200 mg sulfate) 10 mg/5 cc Dextromethorphan hydrobromide-30 mg 4,871,733 13 14 Guaifenesin-100 mg 6. The pharmaceutical composition defined by claim Terfenadine-60 mg 2, comprising from 50 mg to 60 mg of ibuprofen or Triturate active ingredients and q.s. with lactose to pharmaceutically acceptable salt thereof. selected capsule size. 7. The pharmaceutical composition defined by claim 6, comprising at least 100 mg of ibuprofen or pharma EXAMPLE 2. ceutically acceptable salt thereof. In each fluid ounce: 8. The pharmaceutical composition defined by claim Naproxen (sodium)-250 mg 3, comprising from 125 mg to 500 mg of naproxen or Dextromethorphan hydrobromide-30 mg pharmaceutically acceptable salt thereof. Astemizole-10 mg 10 9. The pharmaceutical composition as defined by Orange flavoring and alcohol 10% v/v. claim 1, comprising from 1 mg to 1000 mg of said non sedating antihistamine. EXAMPLE 3 10. The pharmaceutical composition as defined by Ibuprofen-200 mg claim 1, further comprising (iii) a pharmaceutically Terfenadine-60 mg 15 acceptable non-toxic carrier. Triturate active ingredients and q.s. with lactose to 11. The pharmaceutical composition as defined by selected capsule size. claim 1, in oral dosage form. From the foregoing, other typical acceptable phar 12. The pharmaceutical composition as defined by maceutical formulations will be apparent to those claim 11, in oral dosage tablet form. skilled in the art of pharmaceutical formulations. 13. The pharmaceutical composition as defined by While this invention has been described and illus claim 11, in oral dosage capsule form. trated with reference to certain preferred embodiments 14. The pharmaceutical composition as defined by thereof, those skilled in the art will appreciate that vari claim 11, in oral dosage suspension form. ous changes, modifications and substitutions can be 15. The pharmaceutical composition as defined by made therein without departing from the spirit of the 25 claim 1, wherein said non-sedating antihistamine is invention. For example, effective dosages other than AHR-1325. the preferred ranges set forth hereinabove with respect 16. The pharmaceutical composition as defined by to the active ingredients may be applicable as a conse claim 1, wherein said non-sedating antihistamine is quence of variations of the responsiveness of the mam azelastine. mal treated, severity of symptoms, dosage related ad 30 17. The pharmaceutical composition as defined by verse effects, if any, observed and similar consider claim 1, wherein said non-sedating antihistamine is ebas ations. Accordingly, such expected variations or differ tine. ences in the practice of the present invention and the 18. The pharmaceutical composition as defined by results obtained are contemplated in accordance with claim 1, wherein said non-sedating antihistamine is the objects and practices of the present invention. It is 35 lodoxamide. intended, therefore, that the invention be limited only 19. The pharmaceutical composition as defined by by the scope of the claims which follow. claim 1, wherein said non-sedating antihistamine is What is claimed is: levocabastine. 1. A pharmaceutical composition of matter for use in 20. The pharmaceutical composition as defined by the treatment of cough, cold, cold-like and/or flu symp claim 1, wherein said non-sedating antihistamine is toms and the discomfort, pain, fever and general malaise mecquitazine. associated therewith, in a mammalian organism, and 21. The pharmaceutical composition as defined by adapted for unit dosage oral administration, said com claim 1, wherein said non-sedating antihistamine is ox position comprising (i) and analgesically and anti-in atomide. flammatory effective amount of at least one of the pro 22. The pharmaceutical composition as defined by pionic acid NSAIDs, ibuprofen, naproxen, benoxa claim 1, wherein said non-sedating antihistamine is profen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, setastine. indoprofen, pirprofen, carprofen, oxaprozin, prano 23. The pharmaceutical composition is defined by profen, miroprofen, tioxaprofen, alminoprofen, tiapro claim 1, wherein said non-sedating antihistamine is tazi fenic acid, fluprofen and bucloxic acid or pharmaceuti 50 fylline. cally acceptable salt thereof, in combinatory immixture 24. A method for the treatment of cough, cold, cold with (ii) an antihistaminically effective amount of at like and/or flu symptoms and the discomfort, pain, least one of the non-sedating antihistamines, AHR fever and general malaise associated therewith, in a 11325, azelastine, ebastine, lodoxamide, levocabastine, mammalian organism in need of such treatment com mequitazine, oxatomide, setastine, tazifylline, or phar 55 prising administering to such organism a symptom re maceutically acceptable salt thereof. lieving antihistaminically, analgesically and anti-inflam 2. The pharmaceutical composition defined by claim matory effective amount of a composition comprising 1, said non-steroidal anti-inflammatory drug comprising (i) at least one of the propionic acid NSAIDs, ibu ibuprofen or pharmaceutically acceptable salt thereof. profen, naproxen, benoxaprofen, flurbiprofen, feno 3. The pharmaceutical composition defined by claim profen, fenbufen, ketoprofen, indoprofen, pirprofen, 1, said non-steroidal anti-inflammatory drug comprising carprofen, oxaprozin, pranoprofen, miroprofen, tioxa naproxen or pharmaceutically acceptable salt thereof. profen, alminoprofen, tiaprofenic acid, fluprofen and 4. The pharmaceutical composition defined by claim bucloxic acid or pharmaceutically acceptable salt 1, comprising at least 25 mg of said non-steroidal anti-in thereof, in combinatory immixture with (ii) at least one flammatory drug. 65 non-sedating antihistamine AHR-11325, azelastine, 5. The pharmaceutical composition defined by claim ebastine, lodoxamide, levocabastine, mequitazine, ox 4, comprising from 25 mg to 600 mg of said non-steroi atomide, setastine, tazifylline, or pharmaceutically ac dal anti-inflammatory drug. ceptable salt thereof. 4,871,733 15 16 25. A method for the treatment of cough, cold, cold comprising (i) at least one of the propionic acid like and/or flu symptoms and the discomfort, pain, NSAIDs, ibuprofen, naproxen, benoxaprofen, flurbi fever and general malaise associated therewith, in a profen, fenoprofen, fenbufen, ketoprofen, indoprofen, mammalian organism in need of such treatment com pirprofen, carprofen, oxaprozin, pranoprofen, micro prising administering to such organism the pharmaceu 5 profen, tioxaprofen, alminoprofen, tiaprofenic acid, tical composition as defined by claim 1. fluprofen and bucloxic acid or pharmaceutically accept 26. A method for the treatment of cough, cold, cold able salt thereof, in combinatory immixture with (ii) at like and/or flu symptoms and the discomfort, pain, least one of the non-sedating antihistamines, AHR fever and general malaise associated therewith, in a 11325, azelastine, ebastine, iodoxamide, levocabastine, mammalian organism in need of such treatment com O mequitazine, oxatomide, setastine, tazifylline, or phar prising administering to such organism the pharmaceu maceutically acceptable salt thereof. tical composition as defined by claim 2. 28. The method as defined by claim 27, said allergic 27. A method for the treatment of an allergic reaction reaction comprising coryza or rhinitis. in a mammalian organism in need of such treatment, 29. The method as defined by claim 27, wherein said comprising administering to such organism an allergic 15 propionic acid NSAID is ibuprofen. symptom relieving effective amount of a composition is is

20

25

30

35

45

50

55

65