HK1166602B - Compositions of non-steroidal anti-inflammatory drugs decongestants and anti-histamines - Google Patents

Description

Compositions of non-steroidal anti-inflammatory drugs, decongestants and antihistamines

The present application is a divisional application of chinese patent application 200380106488.6 entitled "composition of non-steroidal anti-inflammatory drugs, decongestants and antihistamines" filed on day 12/18/2003.

This application claims priority to U.S. provisional application No. 60/434,342, filed on 12/18/2002, which is hereby incorporated by reference in its entirety.

Technical Field

The present invention relates to an improved dosage form of a medicament for the treatment of rhinitis associated with allergies and colds

Background

Decongestants and antihistamines

Rhinitis is an inflammatory disease of the nasal passages. Symptoms of rhinitis typically include sneezing, runny nose, nasal congestion, and increased nasal secretions. Untreated rhinitis may lead to other conditions, including infection of the sinuses, ears, and lower respiratory tract.

Two types of oral drugs are commonly used to treat rhinitis: decongestants and antihistamines. Decongestants and antihistamines differ in their mechanism of action, therapeutic effect, and side effects. It is common practice to combine these two drugs to produce a more complete relief of rhinitis symptoms, which is not possible with either drug alone.

The decongestants commonly used in the treatment of rhinitis include the sympathomimetic (symptomimemetic) pseudoephedrine and phenylephrine. These agents act to constrict blood vessels in the nasal mucosa and thereby reduce tissue swelling and nasal congestion. Decongestants were found to be better than antihistamines for restoring patency to obstructed nasal airways. Nasal decongestants are excitatory (stimulants). However, decongestants can cause nervousness, restlessness and insomnia, especially when taken at night.

Histamine is a mediator released by cells (mast cells) lining the nasal mucosal walls. On release, histamine is known to bind to local receptors causing sneezing, nasal itching, swelling of the nasal mucosa, and increased nasal secretions. Antihistamines can alleviate these effects, albeit by a different mechanism than decongestants. Antihistamines block histamine binding to histamine receptors in the nasal mucosa. Side effects of antihistamines include mental acuity impairment and sedation.

The combination of decongestants and antihistamines employs two mechanisms and has been shown to provide more complete relief of rhinitis symptoms than treatment with either component alone. Currently, many cold and allergy relief products contain both types of drugs. The combination of the decongestant and the sedating antihistamine in a single dosage unit balances the excitatory and sedating effects of the components. However, some individuals vary in their sensitivity to decongestants or antihistamines. Thus, some individuals experience the combined effects of excitement and/or sedation.

Examples of commercially available formulations containing a decongestant and an antihistamine having sedative effects include:

1.CHLOR-TRIMETON.^TM4-hour Allergy/Decongestant containing 4mg chlorpheniramine (antihistamine with sedative effect) and 60mg pseudoephedrine sulfate (Decongestant with stimulant effect) and recommended to be taken every 4 to 6 hours (1/2 dose for children 6 to less than 12 years of age);

2.CHLOR-TRIMETON.^TM12-hour Allergy/Decongestant containing 8mg chlorpheniramine (antihistamine with sedative effect) and 120mg pseudoephedrine sulfate (Decongestant with stimulant effect) and recommended to be taken every 12 hours (only for adults and children over 12 years old);

3.BROMFED^TMa tablet containing 4mg of bromphenine (antihistamine with sedative effect) and 60mg of pseudoephedrine sulfate (decongestant with stimulant effect) and recommended to be taken every 4 to 6 hours (1/2 at this dose for children 6 to less than 12 years of age);

4.BROMFED.^TMcapsules containing 12mg of brompheniramine (antihistamine with sedative effect) and 120mg of pseudoephedrine sulfate (decongestant with stimulant effect) and recommended to be taken every 12 hours (only for adults and children over 12 years old);

5.BENADRYL^TMan Allergy Decongestant tablet containing 25mg diphenhydramine hydrochloride (an antihistamine having sedative effect) and 60mg pseudoephedrine sulfate (a Decongestant having an excitatory effect) and recommended for adults and children over 12 years of age to take every 4 to 6 hours, not more than 4 tablets within 24 hours; and

6.TAVIST-D.^TMa tablet containing 1.34mg of fumarate salt of clemastine (antihistamine having sedative effect) and 75mg of phenylpropanolamine hydrochloride (decongestant having stimulant effect) and recommended to be taken every 12 hours (only for adults and children over 12 years old).

Formulations combining both decongestants and non-sedating antihistamines into a single dosage unit have become commercial products. Although such formulations offer the advantage of no sedative effect, their efficacy does not approach that provided by sedating antihistamines, especially for rhinitis due to colds.

Non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs (NSAIDS) have a low incidence of adverse side effects due to their analgesic, anti-inflammatory and antipyretic activityPreferably, it is suitable for use in cold preparations. Exemplary non-steroidal anti-inflammatory drug-containing Cold preparations include Advil Cold and Sinus^TMMotrin Cold and Flu^TM、Motrin IB Sinus^TMAnd Dristan Sinus^TM200mg of ibuprofen and 30mg of pseudoephedrine, respectively.

U.S. patent No. 5,025,019 teaches pharmaceutical compositions comprising a non-steroidal anti-inflammatory drug in combination with at least one additional active ingredient selected from an antihistamine, decongestant, cough suppressant or expectorant, and methods of using the same.

While these combinations provide effective symptomatic treatment of rhinitis caused by colds and allergies, they do not alleviate the side effects of decongestants and antihistamines in sensitive individuals. There is therefore a need in the art for a treatment for the symptoms of rhinitis that can alleviate the side effects caused by the treatment.

Summary of The Invention

The invention relates to a pharmaceutical composition, which comprises the following components in effective dose: a non-steroidal anti-inflammatory drug (NSAID), a decongestant, and an antihistamine, wherein the effective amount of the decongestant or the antihistamine or both is less than about 75% of the amount present in an approved dose of the decongestant or the antihistamine, or both, relative to the amount of the NSAID corresponding to about 100% of the amount present in a normal strength dosage form of the NSAID.

One embodiment of the invention is a pharmaceutical composition comprising pseudoephedrine hydrochloride in an amount of about 10 to about 60mg per dosage unit, chlorpheniramine maleate in an amount of about 1 to about 4mg per dosage unit, and ibuprofen in an amount of about 200 to about 400mg per dosage unit.

The invention further relates to a method of alleviating symptoms of rhinitis in a mammal. The method comprises administering an antihistamine effective amount of an antihistamine, a decongestant effective amount of a decongestant, and an anti-inflammatory effective amount of a non-steroidal anti-inflammatory drug, wherein the effective amount of the decongestant or the antihistamine, or both, is less than about 75% of the amount present in an approved dose of the decongestant or the antihistamine, or both, relative to the amount of the NSAID corresponding to about 100% of the amount present in a normal strength dosage form of the NSAID. According to the method, the antihistamine, the decongestant and the non-steroidal anti-inflammatory agent are preferably present in a single dosage form. However, they may also be provided in separate dosage forms for administration together, or in separate dosage forms with instructions for how to achieve an effective dosage of the invention.

In addition to the three components described above, antitussives may be delivered in accordance with the present invention.

Detailed Description

It has been found that the addition of a non-steroidal anti-inflammatory drug to a composition comprising an antihistamine and/or a decongestant enhances the efficacy of the antihistamine and decongestant, thereby allowing a reduction in the total dose of either or both drugs. In particular, the amount of antihistamine and/or decongestant can be less than or equal to about 75% of the amount present in a stated dose of the decongestant or antihistamine relative to the amount of the NSAID corresponding to about 100% of the amount present in a normal strength dosage form of the NSAID. This combination of a 100% dose of an NSAID with a reduced dose of an antihistamine or a decongestant or both results in an enhanced effect of the decongestant and/or antihistamine. This novel combination of a non-steroidal anti-inflammatory drug with reduced levels of antihistamines and/or decongestants produces equivalent or greater relief of rhinitis symptoms, including allergies, colds, cold-like symptoms, and influenza symptoms, than conventional products containing higher amounts of antihistamines and decongestants. This finding is particularly advantageous because reducing the amount of antihistamine and decongestant is likely to reduce the undesirable side effects of each of these components, such as the stimulatory effect of the decongestant and drowsiness associated with antihistamines.

The term "rhinitis" as used herein refers to inflammation of the nasal mucosa, which may result from a cold, influenza, or allergy. Rhinitis may be characterized by one or more cold-like symptoms.

Cold-like symptoms as used herein refer to catarrh (corryzea), nasal congestion, upper respiratory tract infections, allergic rhinitis, otitis, sinusitis, and the like. Runny nose and nasal congestion may also be cold symptoms.

The term "effective amount" or "therapeutically effective amount" of an active agent provided herein is defined as an amount of the agent that is at least sufficient to provide the desired therapeutic effect. As described above, the present invention is based on the discovery that: the effective dose of the decongestant and/or antihistamine can be reduced if administered with a conventional dose of the NSAID. The precise amount required will vary from subject to subject, depending on age, general condition of the subject, the severity of the condition being treated, and the particular active agent being administered, among other factors.

The term "normal approved dose" of an active agent as provided herein is defined as the amount of the agent that has been approved by the U.S. food and drug administration for administration in humans in a specific dosage form to be safe and effective. A stated dose is therefore the dose found in a pharmaceutical product, i.e. the amount of active agent per unit dosage form. In the present invention, reference to a ratio of prescribed doses refers to a dose prescribed for the same patient population (e.g., adult to adult or pediatric to pediatric) and a dose prescribed for the same dosage form (e.g., elixir, tablet, capsule, caplet (capsule), controlled release, etc.).

In the practice of the present invention, one of ordinary skill in the art may take any prescribed dosage form of Over The Counter (OTC) or prescribed decongestant and/or antihistamine, reduce it by, for example, 25% to 50% or more, and co-administer it with a prescribed amount (dose) of an NSAID to achieve effective relief of rhinitis with reduced side effects. In one embodiment, the present invention contemplates the use of less than or equal to about 75% and greater than 1% of the amount present in an approved dose of one or more of the decongestant, antitussive or antihistamine, wherein the amount is relative to the amount of the NSAID corresponding to about 100% of the amount present in a normal strength dosage form of the NSAID. Another range is from about 10% to about 65%. Yet another range is from about 30% to about 55%. A range of about 35% to about 50% is also possible.

Since the present invention contemplates compositions comprising a total of three components (i.e., a decongestant, an antihistamine and an NSAID), wherein either the decongestant or the antihistamine, or both, are present in lower amounts relative to conventional OTC decongestant and/or antihistamine products on the market, one can readily achieve the present invention by reducing the dose of conventional antihistamine and/or decongestant products on the market when the antihistamine and/or decongestant is administered with a product containing a standard dose of an NSAID. Such a decrement can be achieved by: dividing an adult dose in half, for example, administering half the amount of an elixir or dividing a tablet in half, or using a reduced dosage form such as a decongestant and/or antihistamine product formulated for children, in combination with an adult formulation of an NSAID at a prescribed dose.

Antihistaminic agents

The term "antihistamine", when used in conjunction with the treatment of nasal symptoms associated with allergy or cold, generally refers to histamine H₁A receptor antagonist. A number of chemicals are known to have histamine H₁Receptor antagonist activity. Many useful compounds can be classified as ethanolamines, ethylene diamines, alkylamines, phenothiazines or piperidines. Representative of H₁Receptor antagonists include, but are not limited to: astemizole, azatadine, azelastine, acrivastine, bromofinasterine, chlorpheniramine, clemastine, neoantiemetic, carpesine, cyproheptadine, oxypyr, descarboethoxyloratadine (also known as SCH-34117), desloratadine, doxylamine, dimetridazine, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, mizolastine, mequitazine, miterin, nobiletin, meclizine, promethazine, norbenazol, pimozol, tepyramine, promethazine, terfenadine, tripelennamine, temetastine, trimeprazine, and triprolidine. Other Compounds can be assayed for H by known methods₁Activity of the receptor, includingThe contraction response of isolated guinea pig ileum to histamine was blocked anisotropically.

In the above-mentioned histamine H₁Among the receptor antagonists, chlorpheniramine is specifically exemplified herein. A typical adult dose of chlorpheniramine is 4mg orally every 4-6 hours, up to a maximum of 24mg per day, as needed. A typical pediatric dose of chlorpheniramine is 2mg orally every 4-6 hours, up to a maximum of 12mg per day. The preferred salt is chlorpheniramine maleate. Conventional adult dosages may then be reduced to 3mg orally every 4-6 hours, or further reduced to 2mg, up to a maximum of 12-18mg per day, as required, according to the present invention. Similarly, in one embodiment of the invention, the pediatric dose is 1.5mg, or 1mg, orally every 4-6 hours, up to a maximum of 6-9mg per day. In a further embodiment, the invention allows for combining pediatric doses of chlorpheniramine with adult doses of an NSAID, such as ibuprofen.

Decongestants

Decongestants useful in the pharmaceutical compositions and methods of use of the present invention include, but are not limited to, pseudoephedrine, phenylephrine (phenylephrine), phenylpropanolamine. One skilled in the art will recognize many other suitable decongestants and their prescribed dosages.

An exemplary decongestant is pseudoephedrine. A typical adult dose of pseudoephedrine is 60mg every 4-6 hours, up to a maximum of 240mg per day. A typical pediatric dose of pseudoephedrine is 15mg every 6 hours for children aged 2-5 up to a maximum of 60mg per day, and 30mg every 6 hours for children aged 6-12 up to a maximum of 120mg per day. Thus, in particular embodiments of practicing the invention, the adult dose can be reduced to 45 or 30mg every 4-6 hours, up to 120 to 180mg per day, and the pediatric dose can be reduced to about 11 or 7.5mg every 6 hours, up to 30-45mg per day. As is apparent from the above, the present invention contemplates the use of a double pediatric dose of a decongestant with a conventional adult dose of an NSAID for an adult.

NSAIDs

Non-steroidal anti-inflammatory drugs (NSAID's) for use in the pharmaceutical compositions and methods of use of the invention may be selected from any one of the following classes:

(1) a propionic acid derivative;

(2) an acetic acid derivative;

(3) fenamic acid (fenamic acid) derivatives;

(4) a diphenyl carboxylic acid derivative;

(5) oxicams (oxicams), and

(6) cox-2 inhibitors.

Thus, the term "NSAID" as used herein is intended to refer to any non-steroidal anti-inflammatory compound that falls within one of the six structural classes above, including pharmaceutically acceptable non-toxic salts thereof.

The specific compounds defined above that fall within the nsaids useful in the present invention are compounds well known to those skilled in the art, and references can be found in various literature sources for their chemical structure, pharmacological activity, side effects, conventional dosage ranges, and the like. See, for example, Physician's Desk Reference and The Merek Index.

Among the propionic acid derivatives used in the present invention, ibuprofen, naxproxen, flurbiprofen, fenoprofen, ketoprofen, suprofen, fenbufen, and fluprofen may be mentioned as exemplary compounds. Among acetic acid derivatives, exemplary compounds include sodium toluoylpyridinium acetate (tolmetin sodium), zomepinic acid, sulindac, and indomethacin. Among fenamic acid derivatives, exemplary compounds include mefenamic acid and the sodium salt of mefenamic acid in combination with a base (meclofenamidoside). Exemplary biphenyl carboxylic acid derivatives useful in the present invention include diflunisal and fluoroacetylsalicylic acid. Exemplary oxicams include piroxicam, sudoxicam and isoxicam. Exemplary Cox-2 inhibitors include celecoxib, rofecoxib, meloxicam, and nimesulide. Of the aforementioned non-steroidal anti-inflammatory drugs, ibuprofen is exemplified in the practice of the exemplary embodiments of the present invention.

Regarding the dosage of the NSAID in the compositions of the present invention, although the specific dosage will vary with the age and weight of the patient, the severity of symptoms, the occurrence of side effects, etc., typical effective analgesic amounts of NSAID's for humans are about 100-500mg diflunisal, about 25-100mg sodium zoxamate, about 50-400mg ibuprofen, more preferably 100-200mg ibuprofen, about 125-500mg naproxen, about 25-100mg flurbiprofen, about 50-199mg fenoprofen, about 10-20mg piroxicam, about 125-250mg mefanoic acid, about 100-400mg fenbufen, or about 25-50mg ketoprofen; however, larger or smaller amounts may be used as desired or necessary.

Antitussive agent

Antitussives act on the brain to suppress the cough reflex. Such cough suppressants are useful for relieving persistent dry cough. The most commonly used drugs are methamphetamine (an NMDA receptor antagonist), codeine, and pholcodine (an opioid). However, those skilled in the art will appreciate that there are many other known and commonly used antitussives that may be used. Optionally the invention relates to the use of an antitussive. The antitussives may be used in an amount of less than or equal to 75% of the prescribed dose.

Pharmaceutical composition

The compositions of the present invention are formulated in a single dosage form, which may be solid (e.g., tablets, capsules, sachets, lozenges, etc.), liquid (e.g., solution or suspension), or an inhalation aerosol or patch. Solid compounds are typically administered orally, while liquids may be administered orally or by injection. Other dosage forms such as suppositories may also be used.

Exemplary compositions of the present invention relate to solid dosage forms such as bulk powders, tablets, caplets, pills, capsules, sachets, granules, and any other dosage form suitable for oral administration. For the purposes of this specification and the appended claims, the term "tablet" also refers to a tablet, caplet or any other solid dosage form suitable for oral administration.

A binder is an agent that imparts cohesive properties to a powdered substance. The binder imparts cohesiveness to the tablet formulation, ensures that the tablet remains intact after compression, and improves its free-flowing properties by making into granules of the desired hardness and size. Suitable binder materials include, but are not limited to, starches (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, lactose, and sorbitol), polyethylene glycols, waxes, natural and synthetic gums, such as acacia, tragacanth, sodium alginate, cellulose, and Veegum, and synthetic polymers such as polymethacrylates and polyvinylpyrrolidone.

Lubricants have many roles in the tablet manufacturing process. They prevent the tablet material from sticking to the surfaces of the die and punch, reduce interparticle friction, facilitate ejection of the tablet from the die cavity, and can improve the flow rate of tablet granulation. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, talc, sodium lauryl sulfate, sodium stearyl fumarate, polyethylene glycol, or mixtures thereof. Typically, the lubricant is present in an amount of about 0.25% to about 5% by weight of the final composition, more particularly about 0.5 to about 1.5% by weight of the final composition.

A disintegrant is a substance or mixture of substances added to a tablet to facilitate its breaking or disintegration after administration. Substances that act as disintegrants are chemically classified as starches, clays, celluloses, aligns, gums and cross-linked polymers. Examples of suitable disintegrants include, but are not limited to, croscaralmelose sodium, sodium starch glycolate, starch, magnesium aluminum silicate, colloidal silicon dioxide, methylcellulose, agar, bentonite, alginic acid, guar gum, citrus pulp (citrus pulp), carboxymethylcellulose, microcrystalline cellulose, or mixtures thereof. Typically, the disintegrant is present in an amount of about 0.5% to about 25% by weight of the final composition, more particularly in an amount of about 1% to 15% by weight of the final composition.

Glidants are substances that improve the flow characteristics of a powder mixture. Examples of glidants include, but are not limited to, colloidal silicon dioxide, talc, or mixtures thereof. Typically, the glidant is present in an amount of about 0.1% to about 10% by weight of the final composition, more particularly in an amount of about 0.1% to 5% by weight of the final composition.

The adsorbent may be, for example, colloidal silicon dioxide, microcrystalline cellulose, calcium silicate, or mixtures thereof. Typically, the adsorbent is present in an amount of about 0.05% to about 42% by weight of the final composition, more particularly about 0.05% to about 37% by weight of the final composition.

Other components conventionally used in pharmaceutical preparations such as diluents, stabilizers and anti-adherents may be included in the formulation of the present invention, if necessary. Optional ingredients include coloring agents and flavoring agents well known in the art.

The pharmaceutical compositions of the present invention may be formulated so that the active ingredient is released in a sustained release manner. Various formulations are contemplated for the dosage form of these components, including elixirs, suspensions, tablets, caplets, capsules and the like.

The invention is further described by the following examples, which are not intended to limit the scope of the claimed invention in any way.

Detailed Description

Example 1

The dosage form of the pharmaceutical composition of the present invention is prepared from the following active ingredients in the following dosage amounts.

TABLE 1

NSAID	Decongestants	Antihistaminic agents
			Ibuprofen 200mg	Pseudoephedrine 30mg	Chlorphenamine 2mg
Ibuprofen 400mg	Pseudoephedrine 60mg	Chlorphenamine 4mg
			Ibuprofen 200mg	Pseudoephedrine 30mg	Bromphenine 2mg
Ibuprofen 200mg	Pseudoephedrine 30mg	Diphenhydramine hydrochloride 12.5mg
			Ibuprofen 200mg	Phenylpropanolamine hydrochloride 37.5mg	0.67mg of clemastine fumarate

Example 2

A study was conducted to evaluate and compare the analgesic/decongestant/antihistamine efficacy of caplet compositions containing effective amounts of ibuprofen, pseudoephedrine hydrochloride, and chlorpheniramine maleate, in combination with pseudoephedrine and chlorpheniramine in a tablet. The study was multicenter, outpatient, multiple-dose, placebo-controlled, double-blind, double-dummy, parallel group, randomized.

Patient selection the study was attended by 1070 appropriately selected patients, at least 12 years of age, including males and females. Study participants required: (1) at least two years of history of seasonal allergic rhinitis (including one or more of runny nose, itchy/watery/red eyes, nasal congestion, sneezing, itchy nose/throat/palate, allergy-related headaches and facial pain/pressure/discomfort) and (2) at least moderate headaches, and/or facial pain/pressure/discomfort, which worsen during the allergic season and which are responsive to over-the-counter (OTC) analgesics (based on self-reporting). Eligible subjects are required to undergo a 3-30 day trial period to determine that patients have sufficiently severe allergic symptoms, during which they are assessed for severity reflecting their following symptoms in the morning (upon waking) and in the evening (prior to bedtime): nasal congestion, sneezing, runny nose, itchy nose/throat/palate; eyes itchy/with exudates/red and headache/facial pain/pressure/discomfort. The severity of each symptom was assessed using a 4-point classification scale, where 0-asymptomatic (no symptoms present), 1-mild (symptoms are most slightly perceived and easily tolerated), 2-moderate (symptoms present and annoying but tolerable) and 3-severe (symptoms are poorly tolerated; may interfere with daily activities/sleep). They were also asked whether the pain was headache or facial pain/pressure/discomfort and they were also asked for pain grading: 0-asymptomatic (no symptoms present), 1-mild (symptoms are most mildly recognized, symptoms are easily tolerated), 2-moderate (symptoms present and annoying, but tolerable) and 3-severe (symptoms are poorly tolerated; may interfere with daily activities/sleep). The patient is given a first dose of a medication study (day 1) when the patient experiences at least moderate intensity of allergy-associated pain, and the patient's reflex allergy symptoms total score for the previous six morning and evening assessments of symptom severity is at least 48. Patients were also evaluated for allergy-related pain and asked if they were in pain.

Of the 1070 subjects enrolled in the study and safety analysis, 1044 were eligible for treatment analysis, and of the 1044 patients, 256 received treatment 1; 265 patients received treatment 2; 266 received treatment 3; 257 received treatment 4. See below for a description of treatment. An additional 1032 patients were enrolled in the improved treatment analysis plan.

The composition is administered. The patients studied were randomly divided into four treatment groups. Treatment 1 consisted of one placebo tablet plus 2 ibuprofen/pseudoephedrine/chlorpheniramine (200/30/2 mg in each caplet, respectively) caplets for a total dose of 400/60/4mg ibuprofen/pseudoephedrine/chlorpheniramine every 6 hours. Treatment 2 consisted of one placebo tablet, one placebo caplet plus one ibuprofen/pseudoephedrine/chlorpheniramine (200/30/2 mg per caplet, respectively) caplet every 6 hours. Treatment 3 consisted of one pseudoephedrine/chlorpheniramine tablet (30/2 mg each) plus 2 placebo caplets every 6 hours. Treatment 4 consisted of 1 placebo tablet and two placebo caplets every 6 hours.

Time of administration and monitoring of symptoms. Patients are given one dose about every 6 hours 3 times a day (morning, noon and evening) to up to a total of 19-21 doses over 7 days. Two and three hours after the first dose, patients were evaluated for the severity of their allergy-associated pain using a 4-point scale (4 point scale), where 0 is asymptomatic (no symptoms present), 1 is mild (symptoms are most slightly perceived, symptoms are readily tolerated), 2 is moderate (symptoms present and annoying, but tolerable) and 3 is severe (symptoms are poorly tolerated; may interfere with daily activities/sleep). Before each subsequent administration the patient indicates whether they are experiencing any allergy-related headache and/or facial pain/pressure/discomfort (yes or no answer required). Patients self-rated the severity of the following allergic symptoms in the evening on day 1 (before bedtime) and in the morning (upon waking) and in the evening on days 2-7: nasal congestion, sneezing, runny nose, itchy nose/throat/palate; itchy/watery/red eyes and allergy-related headaches and/or facial pain/pressure/discomfort. The severity of each symptom was assessed using a 4-point classification scale, where 0-asymptomatic (no symptoms present), 1-mild (symptoms are most slightly perceived and easily tolerated), 2-moderate (symptoms present and annoying but tolerable) and 3-severe (symptoms are poorly tolerated; may interfere with daily activities/sleep). On the evening of day 7, after the allergy symptom assessment was complete, subjects provided an overall assessment of the drug treatment study, ranking the treatment of allergy symptoms on a scale of 0 (poor) to 4 (excellent). In addition, patients also evaluated any adverse experiences they experienced during the 7 day drug treatment study. The patient evaluated the poor experience with mild, moderate or severe. Examples of adverse experiences include, but are not limited to, somnolence, dry mouth, dizziness, and insomnia.

And (4) evaluating the standard. The first efficacy parameter was the change from baseline over 7 days, reflecting the overall average of all symptom scores. The second efficacy parameter includes the following main variables: (1) time-weighted sum of pain intensity difference scores at two and three hours after the first dose in the study; (2) change from baseline in the total mean of all antihistamine symptom scores reflected (sneezing, itchy/watery/red eyes, itchy nose/throat/palate) minus the total mean of all symptom scores reflected; (3) the incidence of allergy-related pain prior to dosing (except for baseline measurements); (4) change from baseline in the mean of all reflected symptom scores on each treatment day; (5) comprehensive evaluation of the drug treatment study.

And (5) carrying out statistical analysis. Using version 6.12All analyses were completed. Onset of symptom relief was defined as the first time point at which the subject decreased by ≧ 15% from baseline in all symptom scores. If the subject did not experience a decrease from baseline ≧ 15% throughout the study, the time to onset of censoring (censored) is designated for some of 7 daysA score. Statistically significant treatment differences are indicated if the probability of a random event between treatment groups is 0.05 or less. A statistical trend (trend) is indicated if the probability of a random event between treatment groups is 0.05 < p.ltoreq.0.15 or the observed difference between treatment groups is at least 10%. Other suitable statistical measures may also be employed where appropriate and within the skill of the art to ensure that the study is valid.

All variables based on changes from baseline were analyzed with the ANOVA model, including the effect of treatment, corresponding baseline and center point. In addition, treatment-by-baseline (treatment-by-baseline) and treatment-by-center (treatment-by-center) interaction effects were also evaluated. The incidence of allergy-related pain (not including baseline) prior to dosing was analyzed in a repeated measures logistic model. The model is fitted with an estimation equation generalized in a commutative correlation structure. Treatment efficacy and severity of baseline pain were included in the model. The comprehensive evaluation of the study medication scores was analyzed by the Cochran-Mantel-Haenszel test, against the center point, with a modified ridit score. Furthermore, the interaction of the treatment calculated by the central point was calculated by computer using pseudo-homogeneity test (pseudo-homogeneeitytest). Estimating the distribution of onset times of symptom relief using a Kaplan-Meier estimation algorithm; median time values and their 95% confidence limits are derived by Simon and Lee methods.

For each parameter analyzed by the ANOVA model, 955 confidence intervals for treatment differences were derived based on the least mean square difference and the corresponding standard error. The 95% confidence interval for each pair-wise treatment difference in the incidence of allergy-related pain and the time of onset of symptom relief was based on the log odds ratio and the log risk ratio, and their respective standard error (based on the Wald's test). The confidence interval for treatment differences in the overall evaluation of the drug treatment study was based on the Goodman-Kruskal Gamma statistic and its standard error.

Efficacy results. A total of 1044 patients were enrolled and conducted at least one medication study. A total of 957 patients completed the study. A total of 1044 patients were included in the analysis of all efficacy variables, except for the time-weighted sum of pain intensity differences, where 1032 patients were evaluated.

In the analysis of efficacy variables, the interaction effect of treatment by baseline and treatment by site (treatment-by-site) was found to be generally not significant for the variables (p > 0.1). The baseline averages of the individual's symptoms reflected were nasal congestion 2.3, sneezing 1.7, runny nose 2.0, itchy nose/throat/palate 2.0, itchy/watery/red eyes 2.0 and headache/facial pain/pressure/discomfort 2.3, respectively. The mean reflected (reflexive) symptom score and mean all reflected antihistamine scores on the baseline were 12.21 and 5.71, respectively. Allergy-associated pain was assessed when patients were given a first dose of the drug treatment study, with 49% of subjects being moderate and 51% of subjects being severe among 1032 patients assessed by the time-weighted sum of pain intensity differences. Almost all subjects (99.6%) experienced allergy-related pain when receiving the first dose of the drug treatment study. The treatment groups can be compared in terms of the above baseline variables and symptoms reflected by the baseline individual.

The results of the first efficacy parameter and the primary second parameter highlighted that treatment 1 and treatment 2 (lower doses) produced significantly better results than treatment 3 (no ibuprofen) and treatment 4 (all placebo).

The time-weighted sum of the difference in pain intensity between treatment 1 and treatment 2 in the patients over 3 hours was 2.8. Treatment 3 and treatment 4 groups scored 2.1 and 2.0, respectively. The mean change from baseline in the overall mean of all symptom scores reflected by treatments 1-4 was 5.6, 5.4, 4.6, and 3.8, respectively. The mean change from baseline in the overall mean of all reflected antihistamine symptom scores for each treatment group was 2.9, 2.8, 2.4, and 1.9, respectively.

Thus, patients in treatment 2 had 33% improvement over the time-weighted sum of pain intensity differences over 3 hours in treatment 3 (without ibuprofen) and the mean change from baseline in the total mean of all symptom scores reflected was 17% improvement over treatment 3. The mean change from baseline in the overall mean of all reflected antihistamine symptom scores for patients in treatment 2 group was also 47% improved over treatment 4 group. Although patients in treatment 1 group showed numerically better composite scores (composite scores) for all allergic symptoms and histamine-mediated symptoms, no statistical predisposition could be determined. In addition, the time-weighted sum of the pain intensity differences in treatment 1 and treatment 2 groups had nearly identical scores.

These results indicate that chlorpheniramine at a 2mg dose is effective as an antihistamine because it is more effective than placebo in alleviating histamine-mediated symptoms. Also patients in treatment 1 group were identified as having increased somnolence compared to patients in treatment 2 group.

Conclusion the results of the study indicate that ibuprofen/pseudoephedrine/chlorpheniramine have significant analgesic/decongestant/antihistamine efficacy at a given dose in treating the symptoms tested versus the decongestant and antihistamine alone. It has surprisingly been found that ibuprofen contributes to the overall combination of pain relief associated with allergy but also reduces the severity of other seasonal allergic rhinitis symptoms. This is evidenced by the overall greater effect of treatment 2 (with ibuprofen) compared to treatment 3 (without ibuprofen). It was also surprisingly found that both sets of doses of ibuprofen/pseudoephedrine/chlorpheniramine (400/60/4 and 200/30/2mg total, respectively) were equally effective in alleviating the symptoms of histamine-mediated seasonal allergic rhinitis. In addition, no significant dose response was found between treatment 1 and treatment 2 groups.

All treatments were tolerated and the incidence of adverse experiences was consistent with similar drug treatments reported with the same doses of pseudoephedrine and chlorpheniramine. The recommended dose of ibuprofen/pseudoephedrine/chlorpheniramine is 1 caplet every four to six hours-no more than 6 caplets in 24 hours-since both doses of I/P/C are equally effective while the dose of 2 caplets I/P/C shows an increased incidence of somnolence, dry mouth and weakness relative to the 1 caplet dose. This dosing will allow this product to be taken before bedtime and/or at night (in addition to daytime dosing) and is consistent with the prescribed OTC daily dose of ibuprofen (1200mg), yet lower than the daily doses of pseudoephedrine (240mg) and chlorpheniramine (24mg) in the monograph.

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The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such variations are intended to fall within the scope of the appended claims.

All patents, applications, articles, publications, and test methods mentioned above are incorporated herein by reference.

Claims (4)

1. A pharmaceutical composition in unit dosage forms, each of said unit dosage forms comprising 30mg pseudoephedrine, 2.0mg chlorpheniramine and 200mg ibuprofen.

2. The pharmaceutical composition of claim 1 in the form of a tablet, lozenge, dispersion, elixir, capsule or patch.

3. The pharmaceutical composition of claim 2 in the form of a suspension or solution.

4. The pharmaceutical composition of claim 1, further comprising at least one excipient selected from the group consisting of lubricants, disintegrants, glidants, adsorbents, and mixtures thereof.