EP0674517A1

EP0674517A1 - Compositions containing caffeine and s(+)-ibuprofen or s(+)-flurbiprofen or s(+)-ketoprofen

Info

Publication number: EP0674517A1
Application number: EP94905364A
Authority: EP
Inventors: Richard Wilfred D'souza; Sekhar Mitra
Original assignee: Procter and Gamble Co
Current assignee: Procter and Gamble Co
Priority date: 1992-12-21
Filing date: 1993-12-10
Publication date: 1995-10-04
Also published as: BR9307697A; WO1994014449A1; AU672279B2; PE56194A1; JPH08504818A; MX9400038A; AU5899394A; CA2149317A1; CN1094615A

Abstract

Compositions and methods for providing improved analgesic and/or anti-inflammatory effect by administering a safe and effective amount of a composition comprising an analgesic agent substantially free of its R(-) antipode selected from the group consisting of S(+)-ibuprofen, S(+) flurbiprofen and S(+) ketoprofen, pharmaceutically-acceptable salts thereof, and mixtures thereof along with an amount of caffeine sufficient to hasten the onset.

Description

Compositions containing caffeine and S(+)-1buprofeπ or S(+)-flurb1profen or S(+)-ketoprofen.

TECHNICA1 FTFLD

5 The present invention relates to compositions and methods for providing improved analgesic and/or antl-Inflammatory effect by administering a safe and effective amount of a composition comprising an analgesic agent substantially free or of Its R(-) antipode selected from the group consisting of S(+)-1buprofen, S(+) flurbiprofen and

10 S(+) ketoprofen, pharmaceutically-acceptable salts thereof, and mixtures thereof along with an amount of caffeine sufficient to hasten the onset.

BACKGROUND OF THE INVENTION Inflammation, or the "inflammatory response", is the result of

15 complex interconnected physiological events, including increased vascular permeability, fluid accumulations, and the migration of a changing population of inflammatory cells into the inflamed area. The clinical manifestations of inflammation include swelling (edema), increased local temperature, erythema, and pain. The inflammatory

20 response can be triggered by any of a number of causative factors, including certain bacteria, radiation, hypersensitivity to chemical agents, arthritis-like conditions, and the like. The inflammatory response is generally believed to be a primary defense mechanism in the body, but, unchecked, can become excessive and can result in

25 functional impairment.

The use of non-steroidal anti-inflammatory, anti-pyretic and analgesic drugs, especially the salicylates, which include aspirin and aspirin derivatives, to combat inflammation and attendant pain 1s accepted medical practice. The non-steroidals are commonly employed

30 to relieve pain and inflammation associated with, for example, bursit- is, arthritis, and the like.

While pain is incapable of precise definition due to its basical¬ ly subjective nature, it can generally be said that the term refers to feelings of distress or suffering caused by stimulation of specialized

35 nerve endings. A great variety of drugs have been developed to reduce pain in man and other animals; some directed to eliminating pain at its source, and others directed to blocking the perception of pain by the brain. Among the latter group of drugs that are designed to blo the sensation of pain, are the analgesics, which generally relie pain without causing unconsciousness. Analgesics can be furth classified into two main categories: opioid analgesics, includi morphine, codeine, levorphanol, and the morphine-like analgesi meperidine, and ethadone; and antipyretic analgesics, such aspirin, ibuprofen, phenacetin, acetaminophen, phenylbutazone, a indomethacin.

Although the precise pharmacological action of these analgesi is uncertain, there are certain effects which readily distinguish t opioid analgesics from the antipyretics. In particular, the antipyr tics are weak analgesics, with much of their effect in the peripher nervous system, so that behavioral changes do not usually occu Generally, these analgesics relieve only pain originating from mus cles, joints, tendons and fasciae, and are ineffective against de visceral pain. However, the opioid analgesics are quite effectiv against all types of pain, with broad-based action in the centra nervous system. Aside from potent analgesia, the opioids, also kno as narcotics, often produce effects on mood and other behaviora changes. Perhaps the most notable side effect of opioid analgesics i the fact that their repeated use is associated with tolerance, as wel as psychic and physical dependence.

Ibuprofen, or (+) 2-(p-isobutylphenyl)propionic acid, i well-known as a nonsteroidal anti-inflammatory drug having analgesi and antipyretic activity. Ibuprofen is currently marketed prescription in the United States generically, as well as und tradenames such as Motrin^®, which is available in 400, 600 and 800 tablets for oral administration. Ibuprofen has recently also beco available in this country in non-prescription strength (200 mg) und a variety of tradenames, including Advil^® and Nuprirr*, as well as i generic form. For the treatment of mild to moderate pain, 400 every 4 to 6 hours, not to exceed 3200 mg daily, is generall recommended for Motrin*. The lower dose over-the-counter products a generally recommended for minor aches and pains, to be used orally the 200 to 400 mg level, every 4 to 6 hours, not to exceed 1200 daily unless directed by a physician.

Flurbiprofen, or (+) [l,l'-biphenyl]-4-acetic acid, 2-fluoro-alphamethyl , is also well-known as a nonsteroidal anti- inflammatory drug having analgesic and antipyretic activity. Flurbiprofen is currently marketed by prescription in the United States under the tradena e Ansaid^®, which 1s available in 50 and 100 mg tablets for oral administration.

Ketoprofen, or (+) 2-(3-benzoylphenyl)propionic acid, another well-known nonsteroidal anti-inflammatory drug having analgesic and antipyretic activity is currently marketed by prescription in the United States under the tradename Orudis*, which 1s available in 25, 50 and 75 mg capsules for oral administration. For the treatment of mild to moderate pain, 25-50 mg every 6 to 8 hours, not to exceed 300 g daily, is generally recommended for 0rud1s^#. See Physician 's Desk Reference, 46th edition, 1992, publisher Edward R. Barnhart, Medical Economics Company, Inc., Oradell, N.J. 07649, pp. 2351-54, 2319-20 and 2488-90, the disclosure of which is incorporated herein.

As apparent from their chemical nomenclature, these analgesic agents are racemic mixtures. It 1s only the racemic mixture of these agents which have in fact ever been marketed. There have, however, been some studies of the individual S(+) and R(-) enantiomer of ibuprofen. In the body, some of the R(-) enantiomer is converted to the S(+) enantiomer, which is the pharmacologically active form of ibuprofen.

The use of the racemic mixture of ibuprofen together with caffeine has been disclosed in, for example, in U.S. Patent 4,464,376 to Sunshine et al . issued August, 7, 1984. The use of ibuprofen, as well as other of the newer non-steroidal anti-infl mmatory agents (i.e., excluding aspirin, acetaminophen and phenacetin) in the preparation of cough/cold pharmaceutical compositions containing sympathomimetic amines, has been disclosed in, for example, U.S. Patent 4,552,899 to Sunshine et al . issued November 12, 1985.

The use of the S(+) form of ibuprofen has been disclosed in, for example, U.S. Patent 4,851,444 to Sunshine et al . issued July 25, 1989 and in combination with antihistamines in WO 9,205,783 to Gates et al. published April 16, 1992. Surprisingly, the present inventors have found that selected compositions comprising S(+) ibuprofen in combination with caffeine provides further improved analgesic and/or anti-inflammatory effect. SUMMARY OF THE INVENTION The present invention relates to a method of eliciting a sus¬ tained, enhanced analgesic response in a human or lower animal in need of such treatment, comprising administering to such human or lower animal a safe and effective amount of a composition comprising: a. an analgesically and anti-inflammatory effective amount of an analgesic agent substantially free or of its R(-) antipode selected from the group consisting of S(+) ibuprofen, S(+) flurbiprofen and S(+) ketoprofen, pharmaceutically-acceptable salt thereof, and mixtures thereof; and b. an amount of caffeine sufficient to hasten the onset of and enhance the analgesic response.

All percentages and ratios used herein are by weight unless otherwise indicated.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method of eliciting a sustain¬ ed, enhanced analgesic response in a human or lower animal in need of such treatment, comprising administering to such human or lower animal a safe and effective amount of a composition comprising an analgesically and anti-inflammatory effective amount of an analgesic agent substantially free or of its R(-) antipode selected from the group consisting of S(+) ibuprofen, S(+) flurbiprofen and S(+) ketoprofen, pharmaceutically-acceptable salt thereof, and mixtures thereof, and an amount of caffeine sufficient to hasten the onset of and enhance the analgesic response.

The term "S(+)" as applied to the analgesic agents herein is intended to encompass not only the dextrorotatory or S(+) isomer of these agents but also any pharmaceutically acceptable, analgesically effective salt thereof. The expression "substantially free of the R(-) antlpopde" as used in conjunction with the term "S(+)" means that the S(+) enantiomer is sufficiently free of its R(-) antipode to exert the desired onset-hastened and enhanced analgesic effect. Practically speaking, this means that the active ingredient should contain at least 90% by weight of the S(+) enantiomer and 10% or less weight R(-) enantiomer. Preferably, the weight ratio of S(+) enantiomer to R(-) enantiomer is greater than 20:1, more preferabl greater than 97:3. Most preferably the S(+) enantiomer is 99 or more % by weight free of R(-) enantiomer, i.e.., the weight ratio of S to R is approximately equal to or greater than 99:1.

The safe and effective amount of S(+) ibuprofen used in the compositions of the present invention generally ranges from about 50 to about 800 mg, preferably from about 50 to about 400 mg, more preferably from about 50 to about 200 mg and most preferably from about 50 to about 100 mg. The safe and effective amount of S(+) flurbiprofen used in the compositions of the present invention generally ranges from about 12.5 to about 300 mg, preferably from about 12.5 to about 200 mg, more preferably from about 12.5 to about 100 mg and most preferably from about 12.5 to about 50 mg. The safe and effective amount of S(+) ketoprofen used in the compositions of the present invention generally ranges from about 5 to about 100 mg, preferably from about 5 to about 75 mg, more preferably from about 5 to about 50 mg and most preferably from about 5 to about 25 mg.

The amount of caffeine used in the compositions of the present invention generally ranges from about 20 to about 200 mg, preferably from about 32 to about 200 mg, more preferably from about 32 to about 150 mg and most preferably from about 32 to about 100 mg.

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from nonorganic bases include sodium, potassium, lithium, ammonia, calcium, magnesium, ferrous, zinc, manganous, aluminum, ferric, manganic salts and the like. Salts derived from pharmaceutically acceptable organic non- toxic bases include salts of primary, secondary, tertiary and quater¬ nary amines, substituted amines including naturally occurring substi¬ tuted amines, cyclic amines and basic ion exchange resins, such as triethylamine, tripropylamine, 2-dimethylaminoethanol, 2-diethylamino- ethanol, lysine, arginine, histidine, caffeine, procaine, N-ethylpip- eridine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglycamine, theobro ine, purines, piperazine, piperidine, poly- amine resins and the like. Preferably, the pharmaceutical compositions of the presen invention comprise the S(+) enantiomer and caffeine in a ratio of S(+) enantiomerrcaffeine of from about 10:1 to about 1:10, preferably fro about 5:1 to about 1:5 and most preferably from about 2:1 to about 1:5.

Various oral dosage forms can be used, including such solid forms as tablets, gelcaps capsules, granules, lozenges and bulk powders and liquid forms such as syrups and suspensions. These oral forms com¬ prise a safe and effective amount, usually at least about 5% of the active component. Solid oral dosage forms preferably contain from about 5% to about 95%, more preferably from about 10% to about 95%, and most preferably from about 25% to about 95% of the active compo- nent. Liquid oral dosage forms preferably contain from about 1% to about 50% and more preferably from about 1% to about 25% and most preferably from about 3% to about 10% of the active component.

Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated or multiple compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, preservatives and flow-inducing agents.

Liquid oral dosage forms include aqueous and nonaqueous solu¬ tions, emulsions, suspensions, and solutions and/or suspensions reconstituted from non-effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, taste-masking agents, coloring agents, and flavoring agents. Specific examples of pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms, are described in U.S. Patent 3,903,297, Robert, issued Sep- tember 2, 1975, incorporated by reference herein. Techniques and compositions for making solid oral dosage forms are described in Marshall, "Solid Oral Dosage Forms," Modern Pharmaceutics. Vol. 7. (Banker and Rhodes, editors), 359-427 (1979), incorporated by refer¬ ence herein. Techniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin) and pills are described in Remington's Pharmaceutical Sciences (Arthur Osol , editor), 1553-1593 (1980), incorporated herein by reference.

In preparing the liquid oral dosage forms, the active component is incorporated into an aqueous-based orally acceptable pharmaceutical carrier consistent with conventional pharmaceutical practices. An "aqueous-based orally acceptable pharmaceutical carrier" is one wherein the entire or predominant solvent content 1s water. Typical carriers include simple aqueous solutions, syrups, dispersions and suspensions, and aqueous based emulsions such as the oil-in-water type. The most preferred carrier is a suspension of the pharma¬ ceutical composition in an aqueous vehicle containing a suitable suspending agent. Suitable suspending agents include Avicel RC-591 (a microcrystalline cellulose/sodium carboxyβethyl cellulose mixture available from FMC), guar gum and the like. Such suspending agents are well known to those skilled in the art. While the amount of water in the compositions of this invention can vary over quite a wide range depending upon the total weight and volume of the active component and other optional non-active ingredients, the total water content, based on the weight of the final composition, will generally range from 2 about 20 to about 75%, and, preferably, from about 20 to about 40%, by weight/volume. Although water itself may make up the entire carrier, typical liquid formulations preferably contain a co-solvent, for example, propylene glycol, glycerin, sorbitol solution and the like, to assist solubilization and incorporation of water-insoluble ingredients, such as flavoring oils and the like into the composition. In general, therefore, the compositions of this invention preferably contain from about 5 to about 25 volume/volume percent and, most preferably, from about 10 to about 20 volume/ volume percent, of the co-solvent.

The compositions of this invention may optionally contain one or more other known therapeutic agents, particularly those commonly utilized in cough/cold preparations, such as, for example, a cough suppressant such as dextromethorphan, chlophedianol, carbetapentane, caramiphen, noscapine, diphenhydramine, codeine, hydrocodone, hydromorphone, fominoben, their pharmaceutically-acceptable salts; an expectorant or mucolytic such as glyceryl guaiacolate, terpin, ammonium chloride, N-acetylcysteine and bromhexine, ambroxol, their pharmaceutically acceptable salts; and an antihista ine such as chlorpheniramine bromphenira ine, dexchlorpheniramine, dexbrompheniramine, triprolidine, doxylamine, tripelennaraine, cyproheptadine, carbinoxamine, bromodiphenhydramine, phenindamine, pyrilamine, azatadine, their pharmaceutically acceptable salts, as well as the non-sedating antihistamines which include acrivastine, AHR-11325, phenindamine, astemizole, azelastine, cetirizine, ebastine, ketotifen, lodoxamide, loratidine, levocabastine, mequitazine, oxatomide, setastine, tazifylline, temelastine, and terfenadine, their pharmaceutically acceptable salts: all of these components, as well as their acceptable dosage ranges are described in the following: U.S. Patent 4,783,465 to Sunshine et al . , issued November 8, 1988, U.S. Patent 4,619,934 to Sunshine et al., issued October 28, 1986, which are incorporated by reference herein. Also useful are broncho- dilators such as theophylline and albuterol as well as other analgesic agents such as acetaminophen and aspirin. A highly preferred optional component is caffeine, which is preferably present at a level of from about 10% to about 50%.

Other optional ingredients well known to the pharmacist's art may also be included in amounts generally known for these ingredients, for example, natural or artificial sweeteners, flavoring agents, colorants and the like to provide a palatable and pleasant looking final prod¬ uct, antioxidants, for example, butylated hydroxy anisole or butylated hydroxy toluene, and preservatives, for example, methyl or propyl paraben or sodium benzoate, to prolong and enhance shelf life.

METHOD OF TREATMENT The amount of the pharmaceutical composition administered depends upon the percent of active ingredients within its formula, which is a function of the amount of the ibuprofen and caffeine and any optional components such as a decongestant, expectorant and/or antihistamine required per dose, stability, release characteristics and other pharmaceutical parameters.

Usually from about 1 mg/kg to about 50 mg/kg per day, preferably from about 2 mg/kg to about 30 mg/kg per day and most preferably from about 3 mg/kg per day to about 20 mg/kg per day of the pharmaceutical composition is administered as described herein. This amount can be given in a single dose, or, preferably, in multiple (two to six) doses repeatedly or sustained release dosages over the course of treatment. Generally, each individual dosage of the pharmaceutical compositions of the present invention range from about 1 mg/kg to about 25 mg/kg, preferably from about 2 mg/kg to about 15 mg/kg and most preferably from about 3 mg/kg to about 10 mg/kg. Typical unit dosage forms for oral administration generally comprise from about 50 mg to about 2000 mg, preferably from about 100 mg to about 600 mg and most preferably from about 100 mg to about 400 mg of the ibuprofen and from about 25 mg to about 200 mg, preferably from about 50 mg to about 200 mg and most preferably from about 50 mg to about 100 mg of caffeine. While dosages higher than the foregoing are effective to provide analgesic relief, care must be taken, as with any drug, in some individuals to prevent adverse side effects.

The following examples Illustrate embodiments . of the subject invention wherein both essential and optional ingredients are com¬ bined. EXAMPLE I

A hard gelatin capsule composition for oral administration is prepared by combining the following ingredients:

Ingredient Amount

S(+) Ibuprofen 100 mg Caffeine 100 mg

Triturate active ingredients and q.s. with lactose to selected capsule size.

Administration of 1 or 2 of the above capsules to a human in need of treatment provides improved analgesic and/or anti-inflammatory effect.

EXAMPLE II A hard gelatin capsule composition for oral administration is prepared by combining the following Ingredients:

Ingredient Amount S(+) Flurbiprofen 50 mg

Astemizole 5 mg

Caffeine 50 mg

Glyceryl guaiacolate 100 mg

Triturate active ingredients and q.s. with lactose to selected capsule size.

Administration of 1 or 2 of the above capsules to a human in need of treatment provides improved analgesic and/or anti-inflammatory effect. EXAMPLE III A liquid composition for oral administration is prepared by combining the following ingredients:

Ingredient %_V( Y S(+) Ibuprofen 1.00

Caffeine 1.00

Alcohol (95%) 25.000

Propylene Glycol 25.000

Sodium Citrate 2.000 Citric Acid 0.250

Liquid Sugar (Simple Syrup) 25.00

Glycerin 7.000

Colorants 0.008

Flavor 0.500 Water, Purified QS 100.000

The purified water (approximately 10% of the final batch volume) is poured into a batch container equipped with a lightnin' mixer. The sodium citrate, citric acid and Caffeine are added sequentially and dissolved with agitation. The glycerin and liquid sugar are then colorants added. In a separate container the colorants are added to purified water (approximately 0.5% of the final batch volume). This colorant solution is then added to the first batch container. In a seperate container the ibuprofen is added to the alcohol while stir¬ ring. The propylene glycol and flavors are added to this alcohol premix and the resulting mixture is stirred until homogeneous and then added to the first container. The remaining purified water is added to the resulting mixture and stirred.

Administration of 10 ml to 20 ml (2 to 4 teaspoonsful) to a human in need of treatment provides improved analgesic and/or anti-inflammatory effect. EXAMPLE IV A liquid composition for oral administration is prepared by combining the following ingredients:

Inoredient %_H Y S(+) Ibuprofen 1.00

Caffeine 1.00

Chlorpheniramine Maleate 0.02

Pseudoephedrine HC1 0.30

Alcohol (95%) 25.00 Propylene Glycol 25.00

Sodium Citrate 2.00

Citric Acid 0.25

Liquid Sugar (Simple Syrup) 25.00 Glycerin 7.00 Colorants 0.008

Flavor 0.50

Water, Purified QS 100.00

The purified water (approximately 10% of the final batch volume) is poured into a batch container equipped with a lightnin' mixer. The sodium citrate, citric acid, pseudoephedrine HCL and chlorpheniramine maleate are added sequentially and dissolved with agitation. The glycerin and liquid sugar are then added. In a seperate container the colorants are added to purified water (approximately 0.5% of the final batch volume). This colorant solution is then added to the first batch container. In a separate container the ibuprofen is added to the alcohol while stirring. The propylene glycol and flavors are added to this alcohol premix and the resulting mixture is stirred until homogeneous and then added to the first container. The remaining purified water is added to the resulting mixture and stirred.

Administration of 10 ml to 20 ml(2 to 4 Teaspoonsful) to a human in need of treatment provides improved analgesic and/or anti-Inflammatory effect. EXAMPLE V A liquid composition for oral administration is prepared by combining the following ingredients:

Ingredient % W/V S(+) Ibuprofen 1.00

Caffeine 1.00

Pseudoephedrine HC1 0.30

Chlorpheniramine Maleate 0.02

Dextromethorphan HBr 0.15 Alcohol (95%) 25.00

Propylene Glycol 25.00

Sodium Citrate 2.00

Citric Acid 0.25

Liquid Sugar (Simple Syrup) 25.00 Glycerin 7.00

Colorants 0.008

Flavor 0.50

Water, Purified QS 100.00

The purified water (approximately 10% of the final batch volume) is poured into a batch container equipped with a lightnin' mixer. The sodium citrate, citric acid, pseudoephedrine HC1 and chlorpheniramine maleate are added sequentially and dissolved with agitation. The glycerin and liquid sugar are then added. In a seperate container the colorants are added to purified water (approximately 0.5% of the final batch volume). This colorant solution is then added to the first batch container. In a separate container the ibuprofen and dextro¬ methorphan HBr are added sequentially to the alcohol while stirring.

The propylene glycol and flavors are added to this alcohol premix and the resulting mixture is stirred until homogeneous and then added to the first container. The remaining purified water is added to the resulting mixture and stirred.

Administration of 10 ml to 20 ml (2 to 4 teaspoonsful) to a human in need of treatment provides improved analgesic and/or anti-inflammatory effect.

Claims

HΔT IS CLAIMED IS:

1. A pharmaceutical composition adapted to elicit an onset-hastened and enhanced analgesic response in a mammalian organism in need of such treatment and adapted for unit dosage administration, said composition comprising: a. an analgesically and anti-inflammatory effective amount of an analgesic agent substantially free or of its R(-) antipode selected from the group consisting of S(+) ibuprofen, S(+) flurbiprofen and S(+) ketoprofen, pharmaceutically-acceptable salt thereof, and mixtures thereof, and b. an amount of caffeine sufficient to hasten the onset of and enhance the analgesic response.

2. A pharmaceutical composition according to Claim 1 comprising from SO to 800 mg, preferably 50 to 400 mg and most preferably 50 to 200 mg S(+>- ibuprofen.

3. A pharmaceutical composition according to Claim 1 comprising from 12.5 to 300 mg, preferably from 12.5 to 100 mg and most preferably from 12.5 to 50 mg S(+)-flurbiprofen.

4. A pharmaceutical composition according to Claim 1 comprising from 5 to 75 mg, preferably from 5 to 50 mg and most preferably from 5 to 25 mg S(+)- ketoprofen.

5. A pharmaceutical composition according to any of the preceding Claims wherein said composition further comprises at least one other active component selected from the group consisting of an antihistamine, cough suppressant and expectorant and mixtures thereof.

6. A composition according to Claim 5 wherein said antihistamine is selected from the group consisting of chlorpheniramine, brompheniramine, dexchlorpheniramine, dexbromphreniramine, triprolidine, doxylamine, tripelennamine, cyproheptadine, carbinoxamine, bromodiphenhydramine, phenindamine, pyrilamine, azatadine, acrivastine, AHR- 11325, phenindamine, astemizole, azatadine, azelastine, cetirizine, ebastine, ketotifen, lodoxamide, loratidine, levocabastine, mequitazine, oxatomide, setastine, tazifylline, temelastine, and terfenadine, mixtures thereof or pharmaceutically acceptable salts thereof.

7. A method for eliciting an onset-hastened and enhanced analgesic response in a mammalian organism in need of such treatment by administering the phamaceutical composition of any of the preceding Claims.