AU738274B2 - Cough/cold mixtures comprising non-steroidal anti-inflammatory drugs - Google Patents

Description

'it /ul 1 281&91 Regulation 3.2(2)

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT :.0*0 0 0* 0 :.0 Application Number: Lodged: Invention Title: COUGH/COLD MIXTURES COMPRISING NON-STEROIDAL ANTI- INFLAMMATORY DRUGS The following statement is a full description of this invention, including the best method of performing it known to us ii q COUGH/COLD MIXTURES COMPRISING NON-STEROIDAL ANTI-INFLAMMATORY DRUGS BACKGROUND OF THE INVENTION The present invention relates generally to novel pharmaceutical compositions of matter comprising one or more non-steroidal antiinflammatory drugs (NSAID) in synergistic combination with at least one antihistamine, sympathomimetic drug (nasal decongestant, bronchodilator), cough suppressant and/or expectorant, optionally in combination with suitable pharmaceutically acceptable non-toxic carriers or excipients, and to methods of using said compositions in the treatment, management or mitigation of cough, cold, cold-like and/or flu symptoms and the discomfort, pain, fever and general malaise associated therewith.

Non-narcotic analgesics, most of which are also known as non-steroidal 15 anti-inflammatory drugs (NSAID), are widely administered orally in the treatment of mild to severe pain. Within this class, the compounds vary widely in their chemical structure and in their biological profiles as analgesics, antiinflammatory agents and antipyretic agents. Among the most commonly used members of the non-narcotic analgesic class of drugs are aspirin and 20 acetaminophen. Aspirin and acetaminophen have heretofore been included as the pain reliever and fever-reducing component in conventional cough-cold multi-symptom alleviating compositions.

However, a number of alternative non-narcotic agents offering a variety of advantages over these conventionally employed non-narcotic analgesic antipyretics have now been developed. The principal advantages of these non-steroidal anti-inflammatory drugs include not only the clinically superior analgesic, anti-inflammatory and antipyretic activity of these agents compared to aspirin or acetaminophen, but also a minimisation of the adverse side affects experienced with these conventional agents; more specifically, the gastrointestinal ulcerations experienced with aspirin and the hepatic toxicity prevalent with the chronic use of acetaminophen.

Exemplary prior art cough/cold formulations containing aspirin or acetaminophen include Coricidin®, Coricidin Comtrex®, Dristan®, Daycare®, Cotylenol®, Sinubid® and the like. These formulations generally contain in addition to aspirin or acetaminophen, one or more antihistaminics, decongestants, cough suppressants, antitussives and expectorants.

While aspirin and acetaminophen have been utilised in these previous compositions, it has not been heretofore proposed to use any of the newer non-steroidal anti-inflammatory drugs excluding aspirin, acetaminophen and phenacetin) in the preparation of advantageous cough/cold pharmaceutical compositions, wherein the combination exhibits a synergistic analgesic effect.

SUMMARY OF THE INVENTION It is, therefore, a primary object of the present invention to provide pharmaceutical compositions of matter comprising an analgesically effective S 15 amount of a propionic acid derivative non-steroidal anti-inflammatory drug (NSAID) in synergistic combination with a sympathomimetic decongestant, and, optionally, including pharmaceutically acceptable carriers therefor.

The present invention provides a pharmaceutical composition of matter of use in the treatment of cough, cold, cold-like and/or flu symptoms in a 20 mammalian organism, and adapted for unit dosage oral administration, said composition including a potentiating combination of an analgesically and anti-inflammatory effective amount of at least one propionic acid derivative non-steroidal anti-inflammatory drug (NSAID) selected from ibuprofen and naproxen, or a pharmaceutically acceptable salt thereof and (ii) a sympathomimetically effective amount of pseudoephedrine, or a pharmaceutically acceptable salt thereof. Preferably, the amount of the propionic acid derivative NSAID comprises between 50mg to 600mg in each unit dose. Preferably, the composition further comprises a pharmaceutically acceptable non-toxic carrier. Preferably, the composition is adapted for oral administration in tablet, capsule or liquid form.

In a further aspect of the present invention a method is provided for treating cough, cold, cold-like and/or flu symptoms in a mammalian organism which includes administering a potentiating combination of an analgesically and anti-inflammatory effective amount of at least one propionic acid derivative non-steroidal anti-inflammatory drug (NSAID) selected from ibuprofen and naproxen, or a pharmaceutically acceptable salt thereof and (ii) a sympathomimetically effective amount of pseudoephedrine, or a pharmaceutically acceptable salt thereof.

In a still further aspect of the invention, a method is provided for the preparation of a composition for treating cough, cold, cold-like and/or flu symptoms in a mammalian organism which includes combining a nonsteroidal anti-inflammatory effective amount of at least one propionic acid derivative non-steroidal anti-inflammatory drug (NSAID) selected from ibuprofen and naproxen, or a pharmaceutically acceptable salt thereof and (ii) 15 a sympathomimetically effective amount of pseudoephedrine, or a pharmaceutically acceptable salt thereof, in amounts wherein the combination has a potentiating analgesic effect.

Cold-like symptoms as used herein refers to coryza, nasal congestion, upper respiratory infections, allergic rhinitis, otitis, sinusitis, etc.

O* 20 BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a plot of the observed and expected number of mice protected when administered a combination of naproxen and pseudoephedrine.

Figure 2 is a plot of the observed and expected number of mice protected when administered a combination of ibuprofen and pseudoephedrine.

DETAILED DESCRIPTION OF THE INVENTION More specifically, the applicants herein have found that certain nonsteroidal anti-inflammatory agents are ideally suited for use in cough/cold formulations by reason of their synergistic effect when used in combination with sympathomimetic decongestants, in addition to their enhanced analgesic and anti-inflammatory and antipyretic activity and low incidence of untoward side effects, particularly at the optimum dosages provided for in the present invention, compared to aspirin or acetaminophen.

The superiority of various non-narcotic analgesics belonging to the nonsteroidal anti-inflammatory drug class in comparative studies with aspirin and acetaminophen is well documented in the literature.

Cooper in 1977 found that ibuprofen 400mg had a greater peak effect and longer duration of action that aspirin 650mg. Cooper, Needle, A.E., Kruger, G.O. 1977. "An Analgesic Relative Potency Assay Comparing Aspirin, Ibuprofen and Placebo". J. Oral Surg. 35: 898-903. Cooper in another study in 1982 found 400mg of ibuprofen to be more effective than aspirin 650mg.

Cooper, Engel, Ladov, Precheur, Rosenheck, Rauch, D.

1982. "Analgesic Efficacy of an Ibuprofen-codeine Combination." Pharmacotherapy 2: 162-67. Sunshine et al found ibuprofen to be significantly superior to aspirin in the relief of post-episiotomy pain. Sunshine, 15 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, Campbell, Cooper, Hall, Buckingham, B.

"Suppression of Post Operative Pain by Preoperative Administration of Ibuprofen in Comparison to Placebo, Acetaminophen and Acetaminophen Plus Codeine." J. Clin. Phamacol. (In press).

Naproxen sodium 550mg was compared with 650mg of aspirin and was found to provide earlier and better pain relief than aspirin by Sevelius, H. J.

Clin. Phamacol. 20: 480-485, 1980. "Comparative Analgesic Effects of Naproxen Sodium, Aspirin and Placebo." Flurbiprofen 50 and 100mg was significantly more effective than aspirin 600mg. Flurbiprofen 25mg was slightly less effective than aspirin 600mg.

Sunshine, Olson Laska, E.M. Zighelboim, DeCastro, A., Desarrazin, Pharmaco Ther. 3: 177-181. "Analgesic Effect of Graded Doses of Flurbiprofen in Postepisiotomy Pain." Silberman found suprofen 200mg more effective than aspirin 650mg for pain relief in the treatment of moderate to severe pain resulting from musculoskeletal pain. Silberman, H.M. "Multiple-Dose Comparison of Suprofen, Aspirin and placebo in the Treatment of Musculoskeletal Pain." Pharmacology, 27: S1, 65-73 (1983).

While these reported findings with respect to the outstanding analgesic properties of the non-steroidal anti-inflammatory drugs compared to aspirin or acetaminophen have prompted the widespread acceptance and usage of these newer non-narcotic analgesics, as single entities, for the treatment and management of acute and chronic inflammatory states, notably rheumatoid arthritis and osteoarthritis, the utilisation of these agents in cough/cold compositions has not heretofore been considered.

The non-steroidal anti-inflammatory drugs (NSAID's) for use in the V pharmaceutical compositions and methods of use of the present invention are 15 propionic acid derivatives.

The specific compounds falling within the foregoing definition of the non-steroidal anti-inflammatory 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 sources for their chemical structures, pharmacological activities, 20 side effects, normal dosage ranges, etc. See, for example, Physician's Desk S Reference, 35th Edition, 1981 and The Merck Index, 9th Edition, Merck and Company, Rahway, New Jersey (1976) and Cutting's Handbook of Pharmacology, 6th Edition, Ed. T. Z. Czacky, Appleton-Century-Crofts, New York, 1979, Chapter 49: 538-550.

Of the propionic acid derivatives for use herein, ibuprofen, naproxen, flurbiprofen, fenoprofen, ketoprofen, suprofen, fenbufen, and fluprofen may be mentioned as particularly preferred compounds.

Of course, it will be appreciated by those skilled in the art, that any of the foregoing compounds may be utilised in the form of their pharmaceutically acceptable salt forms, -COO-Na', -COO-K and the like.

Of the foregoing non-steroidal anti-inflammatory drugs, in the practice of the preferred embodiments of the present invention, ibuprofen and naproxen are most preferred.

With respect to the dosage amount of the non-steroidal antiinflammatory drugs in the compositions of the invention, although the specific dose will vary depending upon the age and weight of the patient, the severity of the symptoms, the incidence of side effects and the like, for humans, typical effective analgesic amounts of presently preferred NSAID's for use in unit dose compositions of the invention are about 50-400mg ibuprofen, most preferably 100-200mg, about 125-500mg naproxen; however, greater or lesser amounts may be employed if desired or necessary. With respect to the compounds set forth hereinabove falling within the propionic acid derivative category, suitable dosage ranges for these compounds will generally fall within the range of 25mg to 600mg in each unit dose.

15 A complete description of the various NSAID's, including acceptable analgesically effective amounts thereof for use in unit dose compositions of the present invention also appears in applicant's United States Patent No. 4,486,436.

The cough/cold pharmaceutical compositions of the present invention comprise, in addition to the non-steroidal anti-inflammatory drugs, a Ssympathomimetically effective amount of pseudoephidrine or a pharmaceutically acceptable salt thereof.

For example, pseudoephidrine may be present according to the following formulation details: Drug Preparation Usual Single Dose (Adult) pseudoephedrine (HCI) Tablet, Capsule 60 120mg.

120mg (sustained action) Applicants have already demonstrated a synergistically enhanced analgesic and anti-inflammatory response in a mammalian organism, as shown in the following Examples: EXAMPLE 1 Studies of the Effects of Compositions containing Propionic Acid NSAIDs and Nasal Decongestants in an Acetic Acid Writhing Assay in Mice Compositions containing the NSAIDs naproxen and ibuprofen and the decongestant pseudoephedrine were studied to determine whether their analgesic effects are additive or synergistic. The effects of two compounds are additive if the response to a dose of the two in combination is the same as the response when one of the two is removed from the combination and replaced by an equipotent portion of the other. If instead, the response to a dose of the two is greater, the mixing together of the compounds is said to potentiate their effects and synergism exists.

METHOD

ep Acetic Acid Writing Assay in Mice 15 A standard protocol of Pharmakon Research International Inc. (Waverly .:Pennsylvania), entitled Acetic Acid Writhing Assay in Mice was used to detect and quantify the analgesic activity of the compositions studied. Pharmakon, conducted tests on male CD-1 mice obtained from the Charles River Breeding Laboratories. They were fasted for 4 hours and weighed between 18 and 20 at the time of testing. All mice were dosed sequentially by oral gavage with solutions of the NSAID and/or the decongestant or the vehicle. A dosing volume of 10ml/kg was used for each solution. All doses were randomly S: allocated to mice and the test was performed so that the observer was blind to the treatment.

The test treatments were administered and 30 minutes later the mice were challenged with acetic acid. The latter was prepared as a 0.5% solution in distilled water as follows: 0.5ml of acetic acid q.s. to 100ml with distilled water. Acetic acid was administered at a dose of 10ml/kg intraperitoneally using a 25 gauge, 5/8" long needle on a 1 ml syringe.

The mice were placed in individual Plexiglas® squares 4" x 4" x deep. After 10 minutes they were observed closely for exhibition of writhing y /r a 10 minute period. For each mouse the total number of writhes that 8 occurred in the 10 minute epoch was recorded. Characteristic patterns of writhing consist of torsion of the abdomen and thorax, drawing the hind legs close to the body and raising the heels of the hind feet off the floor of the Plexiglas® square, marked contraction of the abdominal area and arching of the back so that the caudal ventral surface of the mouse touches the floor of the square.

Statistical Methods The principle measures of analgesia used in the analysis was the number of mice protected. A mouse exhibiting fewer than 50% of the mean number of writhes of the mice in the control group was considered to be protected. (Tabor, RI. Predictive value of analgesic assays in mice and rats.

Adv. Biochem. Psychopharmacol. 9 (1974) 191-211.) 1. Bioassay Analysis-Estimating the ED 5 oS, and the Relative Potency Analgesia was quantified by determining an estimate of the dose- 15 response or tolerance distribution defined as the probability that a sampling unit exhibits a specific analgesic response at dosage d. Of particular importance is the EDo. At this does, a sampling unit exhibits the analgesic response with probability one half. The relative potency of one drug to another, p, is defined to be the ratio of the respective doses that produce 20 equivalent effects. Since the ED 5 0 is a dose that produces a specific analgesic response with probability one half, the relative potency of the NSAID to the decongestant is the ED5o of the NSAID divided by the ED~ of the decongestant.

The dose-response distribution was modeled as the cumulative distribution function of a standard normal random variable, denoted by 4 in the sigmoid model evaluated at u a+p log dose. The method described by Finney DJ (Statistical Methods in Biological Assay, Hafner Publishing Co., New York, 1978; computer program- Bliss 21) was used to estimate the parameters a and p, the ED 0 o's of the NSAID and of the decongestant alone and their relative potency, p. A commonly employed statistical model in which the slope parameters are the same for both drugs was utilised. (Tallarida, RJ, 9 Porreca, F. and Cowan, A. Statistical analysis of drug-drug and site-site interactions with isobolograms. Life Sci., 45 (1989) 947-961.) The assumption of parallelism was tested in each analysis and no statistical evidence of departure from the assumption were found.

2. Determining the Probability that a Mouse is Protected and the Expected Number of Mice Protected If there are N, mice in a test group, the expected number of mice protected is N, times the probability that a mouse is protected. When d is equal to the EDso the expected number of mice protected is NJ2.

The expected number of mice protected for a given dose d may be computed from the estimated NSAID dose-response curve. The Bliss program, based on the number of mice protected, yields the dose-response distribution P(a mouse is protected at dose d) 15 c (a+p logd) (1) where the values of the parameters and are estimated from the data.

3. Determining the Expected Number of Mice Protected for the Combination Under the Assumption of Additivity Denote the ED 50 doses of the NSAID and of the decongestant by dn and 20 dp respectively and the dose of a combination of x mg/kg of the NSAID and y mg/kg of the decongestant by Under the hypothesis of additivity any combination for which x and y satisfy the linear relationship y dp (dp -/dn)x dp px (2) is an EDso dose of the combination. Therefore, for all doses satisfying equation the expected number of protected mice is one half of the number tested.

More generally, under the assumption of additivity, the expected number of protected mice may be computed for any dose y) in a combination as follows. Based on the relative potency, the dose of the NSAID that is equipotent to the dose of the decongestant in the combination is calculated. It is equal to p y. The sum of the equipotent dose of the NSAID and the dose of the NSAID in the combination is the NSAID equivalent dose of the combination. Thus, for a combination with doses y) the NSAID equivalent dose x p y. (3) E the expected number of mice protected under the assumption of additivity of a combination of x mg/kg of the NSAID and y mg/kg of the decongestant is E y) N,W(a+3 log (x p (4) where W is taken from equation 4. Statistical Testing for Synergy Whenever the observed number of mice protected is greater than the expected number of mice protected computed under the assumption of additivity there is evidence of a synergistic effect. The plausibility of the assumption of additivity was quantified by a Chi-Square statistic with degrees of freedom equal to the number of dose ratios compared. (Kelly, C. and Rice, 15 J. Monotone smoothing with application to dose-response curves and the assessment of syngerism, Biometrics 46 (1990) 1071-1085.) Large values of the statistic, corresponding to small p values, are evidence against the additivity assumption, are evidence of synergy. This statistical test was also performed in a separate analysis of the data when the model did not 20 constrain the dose response line of the NSAID and of the decongestant to be S- parallel. Additionally, a likelihood ratio test was performed based on the sigmoid model. The three statistical analyses yielded equivalent results. For brevity, only the Chi-Square statistics are reported below.

RESULTS OF THE NSAID-DECONGESTANT

STUDIES

Naproxen and Pseudoephedrine 1. Design In part A of the experiment, 12 test treatments were studied each of which was administered to a group of 10 mice. Seventy mice were tested on each of 2 days. The test treatments were 6 doses of naproxen: 1, 5, 10, 100 and 250 mg/kg and 6 doses of pseudoephedrine: 1, 5, 10, 50, 100 and 250 mg/kg. In addition there were two groups of size 10 each that served as

I

7 control groups.

11 The mice were randomised to treatments in blocks so that in every group of 14 mice each of the test treatments was administered once and the control vehicle was administered twice. The results of the experiment were used to calculate the ED 50 of naproxen and of pseudoephedrine and their relative potency.

In part B of the experiment, 7 combination doses of naproxen and pseudoephedrine were studied. Each dose ratio was administered to a group of 10 mice. In addition a control group of 10 mice was studied. The expected number protected was computed for each combination dose ratio by utilising equations and above.

Two contiguous groups of dose ratios of the combination were formed.

One included the four groups for which the dose ratio were less than 1.47.

The other included the three remaining groups. For each of these, the dose ratios were greater than or equal to 1.47, which are by and large the ratios relevant to use of this combination in humans.

2. Results Table 1 displays the results of part A of the experiment. For each of the doses the mean percent reduction in writhes and the number of mice protected are shown. The estimated value of a and 3, the ED 5 0's and the 20 relative potency are also given. The estimated ED 50 for naproxen was 33.55 mg/kg and 79.71 mg/kg for pseudoephedrine with a relative potency of .421.

Table 2 displays the doses of the combination and their dose ratios a studied in part B of the experiment. The observed and expected number of mice protected at each combination dose are shown in Figure 1. It can be seen that combination dose groups 1-4 yielded an observed number of protected mice that is essentially equivalent to the expected number. The Chi- Square value of .79 with 4 d.f. over these four combination dose groups gives no indication of departure from additivity. However, combination dose groups 5-7, with a dose ratio ranging from 1.47 to 6.2, demonstrated a substantial departure from additivity. The observed number was considerably larger than 12 the expected number of mice protected. For these three combination dose groups the Chi-Square value was 11.25 with 3 d.f. corresponding to a p value of less than 0.01.

Ibuprofen and Pseudoephedrine 1. Design The dose-response of pseudoephedrine and of ibuprofen were obtained as part of two experiments. In the first, pseudoephedrine was studied together with naproxen. In the second, ibuprofen was studied together with phenylpropanolamine. The data on pseudoephedrine and on ibuprofen was used to determine the ED, of ibuprofen and of pseudoephedrine, their relative potency and the ED, line of additivity.

The data on pseudoephedrine was collected in the experiment described above. Ibuprofen data was collected in an experiment in which ten test treatments were studied, each of which was administered to a group of 11 mice. The test treatments were 5 doses of ibuprofen: 10, 25, 50, 100 and 200 mg/kg and 5 doses of phenylpropanolamine: 5, 20, 50, 100 and 200 mg/kg. In addition there was one group of size 11 that served as a control group. The mice were randomised to treatments in blocks so that in every group of 7 mice each of the test treatments was administered once and the 20 control vehicle was administered once. The results of these experiments were used to calculate the dose-response curves, the ED, of ibuprofen and of pseudoephedrine and their relative potency.

In a further experiment, one dose of the combination of ibuprofen and pseudoephedrine in the ratio of 7 to 1 was studied. The doses were chosen so that they fell on the ED, line of additivity. The combination was administered to a group of 50 mice. In addition a control group of 20 mice were studied. Since the doses of the combination were chosen to fall on the ED, line of equation the expected number of protected mice is 50/2 13 2. Results Table 3 displays the results from which the dose-response curves for ibuprofen and for pseudoephedrine were determined. For each of the doses the mean percent reduction in writhes and the number of mice protected are shown. The estimated ED 50 for ibuprofen of 127.1 mg/kg and 92.1 mg/kg for pseudoephedrine with a relative potency of 1.38.

Table 4 displays the doses of the combination and the dose ratio studied in the second stage of experiment. The ibuprofen equivalent combination dose is 127.1 mg/kg, the EDso of ibuprofen. The observed and expected number of mice protected at the ibuprofen equivalent combination dose is shown in Figure 2. It can be seen that the observed number of protected mice was 40 which is substantially larger than the expected number of 25 This yielded a Chi-Square value of 18 with 1 d.f.

corresponding to a p .001 which indicates a highly statistically significant 15 departure from additivity.

CONCLUSION

The combination of propionic acid NSAIDs and sympathomimetic nasal decongestants at dose ratios from about 1 to 1 to about 8 to 1 produce synergistic analgesic effects in acetic acid writhing tests in mice. As the acetic 20 acid writhing test is a model commonly adopted to predict analgesic effects in humans, these results also are an indication of the synergistic analgesic effects of these combinations in humans.

s 14 TABLE 1 Bioassay to Obtain ED50s and Relative Potency naproxen pseudoephedrine dose total number of reduction n of mice total number reduction n of mice mg/kg writhes in group in number of protected" of writhes in in number of protected" writhes group writhes 1 288 0 1 241 16 0 249 13 2 258 10 0 205 29 3 164 43 4 153 47 4 161 44 4 100 126 56 7 171 40 4 250 63 78 9 54 79 7 control 574* Number of mice in control group 20; mean 28.7 writhes per mouse Number of mice per treatment group 10 except in pseudoephedrine 250mg/kg where Nt 9.

Estimates of Parameters Bioassay Parameter Bliss M a naproxen -1.569 P naproxen 1.029 mg/kg naproxen 33.55 a pseudoephedrine -1.957 P pseudoephedrine 1.029 mg/kg pseudoephedrine 79.71 Relative Potency 0.421 A Bioassay based on sigmoid model. The measure of analgesic efficacy was based on number of mice protected.

TABLE 2 Analysis of Combination Data combo combination dose combo naproxen number of mice protected dose dose equivalent number naproxen pep ratio dose* observed expected* 1 5.0 50.1 0.10 26.10 5 4.55 2A 13.5 46.2 0.35 32.95 5 4.97 3A 20.4 38.5 0.53 36.61 5 5.16 4 27.2 30.8 0.88 40.17 4 5.32 34.0 23.1 1.47 43.73 10 5.47 6/ 40.9 15.4 2.65 47.38 8 5.61 7/ 47.8 7.7 6.20 51.14 7 5.74 S pep pseudoephedrine nap equivalent dose control dose of naproxen .421 X Combo dose of pep.

Expected number of mice protected computed per equation 4.

mean number of writhes per mouse in control group 33.8 Departure from additivity model for combos 1-4: Chi-Square 4 d.f. .79.

Departure from additivity model for combos 5-7: Chi-Square 3 d.f. 11.25, p .01.

TABLE 3 Bloassay to Obtain ED50s and Relative Potency ibuprofen pseudoephedrine dose total number of reduction n of mice total number reduction n of mice mg/kg writhes in group in number of protected* of writhes in in number of protected* writhes group writhes 1 241 16 0 258 10 0 277 24.1 2 164 43 4 200 45.2 6 305 16.4 2 161 44 4 100 284 22.2 4 171 40 4 200 155 57.5 6 250 54 79 7 control 365* Number of mice in control group for PEP 20; mean 28.7 writhes per mouse.

Number of mice in control group for ibuprofen 11; mean 33.2 writhes per mouse.

Number of mice per treatment group 11 for ibuprofen and 10 for PEP except in PEP 250mg/kg where Nt 9.

Estimates of Parameters Bioassay Parameter Bliss

M

a ibuprofen -1.83 3 ibuprofen 0.872 mg/kg ibuprofen 127.1 a pseudoephedrine -1.712 p pseudoephedrine 0.872 mg/kg pseudoephedrine 92.1 Relative Potency 1.38 Bioassay based on sigmoid model. The measure of analgesic efficacy was based on number of mice protected.

17 TABLE 4 Analysis of Combination Data^ combination dose combo ibuprofen number of mice protected dose equivalent ibuprofen pep ratio dose* observed** expected*** 106.1 15.2 7.0:1 127.10 40 0 0 0.

0 o *o* '.0 000.0 0 S pep pseudoephedrine ibuprofen equivalent dose is the mean number of writhes per mouse in control group 28.1 mean number of writhes per mouse in combination group 6.94 expected number of mice protected is .5 times 50 25 mice departure from additivity model: Chi-Square 1 d.f. 18 p .001 18 In the pharmaceutical compositions and methods of the present invention, the foregoing active ingredients will be combined with the nonsteroidal anti-inflammatory drug(s) and will typically be administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of administration, oral tablets, capsules, elixirs, syrups, etc. and consistent 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, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated in the mixture. Suitable binders include S 15 starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Among the lubricants there may be mentioned for use in these ooo.oi dosage forms, sodium chloride, etc. Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, guar gum, etc. Sweetening and flavouring agents and preservatives can also be included where appropriate.

S: ~Of course, additionally, the compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components to optimise the therapeutic effects, i.e., analgesia, antihistaminic, etc. while minimising undesirable side effects.

Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.

While the invention has been described and illustrated with reference to certain preferred embodiments thereof, those skilled in the art will appreciate m 19 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 ranges set forth hereinabove with respect to the active ingredients may be applicable as a consequence of variations of the responsiveness of the mammal treated, severity of symptoms, dosage related adverse effects, if any, observed and similar considerations. Accordingly, such expected variations or differences in the practice of the present invention and the results obtained are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore that the invention be limited only by the scope of the claims which follow.

S..

Claims (9)

1. A pharmaceutical composition for use in the treatment of cough, cold, cold-like and/or flu symptoms in a mammalian organism, and adapted for unit dosage oral administration, said composition including a synergistic pain relieving combination of: an analgesically and anti-inflammatorily effective amount of at least one propionic acid derivative non-steroidal anti-inflammatory drug (NSAID) selected from the group consisting of ibuprofen, naproxen and pharmaceutically acceptable salts thereof; (ii) a sympathomimetically effective amount of pseudoephedrine, or S, a pharmaceutically acceptable salt thereof; wherein the ratio of the amount of to (ii) present in the composition is from 1 to 1 to 7 to 1.

2. A pharmaceutical composition according to claim 1 wherein each unit dose contains between 50mg to 600mg of said propionic acid derivative. S *SS

3. A pharmaceutical composition according to either of claims 1 or 2 further including a pharmaceutically acceptable non-toxic carrier.

4. A pharmaceutical composition according to claim 3 adapted for oral administration in tablet, capsule or liquid form.

A method for the treatment of cough, cold, cold-like and/or flu symptoms in a mammalian organism which includes administering to a patient in need of such treatment a pharmaceutical composition according to any one of claims 1 to 4.

6. A method for the preparation of a composition for treating cold, cold-like and/or flu symptoms in a mammalian organism including combining: an analgesically and anti-inflammatorily effective amount of at least one propionic acid derivative non-steroidal anti-inflammatory drug (NSAID) selected from ibuprofen and naproxen, or a pharmaceutically acceptable salt thereof; and (ii) a sympathomimetically effective amount of pseudoephedrine, or a pharmaceutically acceptable salt thereof wherein the ratio of the amount of to (ii) is from 1/1 to 7/1 such that the combination has a synergistic effect.

7. A method according to claim 6 wherein the propionic acid derivative NSAID is present in an amount of from 50mg to 600mg per unit dose. o

8. A method according to either of claims 6 or 7 wherein the composition is adapted for oral administration in tablet, capsule or liquid form. S

9. A pharmaceutical composition for use in the treatment of cough, cold, cold-like and/or flu symptoms in a mammalian organism and adapted for unit dosage oral administration, said composition being substantially as hereinbefore described with reference to Example 1. DATED this 4 th day of July 2001 ABRAHAM SUNSHINE, EUGENE M. LASKA and CAROLE E. SIEGEL WATERMARK PATENT TRADEMARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA P7011AU03 IAS/RBP/RES