CA2144152A1

CA2144152A1 - Ibuprofen-caffine combinations

Info

Publication number: CA2144152A1
Application number: CA002144152A
Authority: CA
Inventors: Robert T. Sims; William Slivka; Robert Mcmahon
Original assignee: Individual
Current assignee: Merck and Co Inc; Kenvue Brands LLC
Priority date: 1992-09-29
Filing date: 1993-09-21
Publication date: 1994-04-14
Also published as: AU5132893A; JPH08501796A; WO1994007471A1; MX9306005A; EP0663819A1; EP0663819A4

Abstract

This invention relates to pharmaceutical compositions for use in the treatment of pain and inflammation in mammals, in-cluding humans, by administering compositions comprising (i) an analgesically and anti-inflammatory effective amount of a salt of (S)-ibuprofen substantially free of (R)-ibuprofen wherein the salt is selected from (S)-ibuprofen-(S)-lysine and (S)-ibuprofen-(R)-lysine; and (ii) an amount effective in the enhancement of pain relief of caffeine.

Description

~ 94/0747l 2 1 4 4 ~ ~ 2 PCI`/US93/08896 TITLE OF THE INVENTION
IBUPROFEN-CAFFEINE COMBINATIONS

BACKGROUND OF THE INVENTION
s The non-steroidal anti-infl~mm~tory drugs (NSAID) have been utilized in the treatment of pain/infl~mm~tion and a number of other symptoms including stiffness that are associated with painful conditions affecting muscles, bones, and joints. NSAIDs have been prescribed to relieve back pain, gout, menstrual pain, headaches, mild pain following ~iu~ ;ly~ and pain from soft tissue injuries such as sprains and strains. NSAIDs are within the broader class of non-narcotic analgesics which also includes acetylsalicyclic acid (aspirin) and ace~alllillophen. NSAIDs, exceptfor acetaminophen, are generally considered to exert their effect by blocking the production of prost~ ndins at the site of pain, irritation or injury so that the pain signal does not reach the brain.
Il~u~rofell (2-(4-isobutylphenyl)propionic acid) is a well known and commonly employed NSAID. Amino acid salts of racemic ibuprofen lncluding the lysine or arginine salt are also known pain relievers. See U.S. Pat. No. 4,279,926. Recently, it has been found that a faster onset of pain relief and an enhanced analgesic response can be obtained by ltili7.in~ the single enantiomer (S)-ibuprofen (also known as (+)-ibuprofen or dexibuprofen) rather than the racemic mixture of ibuprofen. See U.S. Patent 4,877,620.
Caffeine is a well known x~nthine alkaloid and is used in a number of foods and medicines. The X~nthines, including caffeine, are known to stim~ te the central nervous system, induce relaxation of smooth muscle constrictions of the smaller bronchi and other smooth muscles, cause dilation of the small pulmonary arteries, and induce 30 stimlll~tion of cardiac muscle with increased cardiac output and the promotion of mild diuresis. It has been postulated that these actions may be related to the antagonism of adenosine receptors.
Combinations of iluu~rofen with caffeine have been disclosed. See U.S. Pat. No. 4,851,444 which broadly discloses the .

~14~2 combination of (S)-ibuprofen and several additional active ingredients including caffeine; 4,587,249 discloses the combination of ibuprofen and caffeine, See also 4,567,183; 4,558,051; 4,486,436; 4,464,376;
4,656,177; 4,777,174. There is a need to employ a compound with faster acting and enhanced analgesic capability as well as enh~nred solubility such as (S)-ibuprofen-(S)-lysine subst~nti~lly free of (R)-ibuprofen in combination with a ~nthine derivative such as caffeine to more eiFfectively treat and prevent the pain and discomfort associated with he~ ches or other aches and pains. The present invention provides both faster onset and enhanced relief of aches and pains associated with the head and body.

DETAILED DESCRIPTION OF THE INVENTION
This invention claims ph~rm~ceutical compositions for use in the treatment of pain and infl~mm~tion. The composition comprises:
(i) an analgesically and anti-infl~mm~tory effective amount of a salt of (S)-i~ u~rofen sul,~ lly free of (R)-il~u~rofen wherein the salt is selected from (S)-il~u~rofen-(S)-lysine and (S)-ibuprofen-(R)-lysine; and (ii) an amount effective in enh~ncement of pain relief of caffeine.
This invention is also directed to a method of treating pain and infl~mm~tion in m~mm~l~, including hllm~n~, in need thereof, comprising ~lmini~tering to such org~ni~m:
(i) an analgesically and anti-iILfl~mm~tory effective amount of a salt of (S)-il~u~rofell subst~nti~lly free of (R)-ilw~rofell wherein the salt is selected from (S)-il,uprofen-(S)-lysine and (S)-i~uprofell-(R)-lysine; and(ii) an amount effective in enhancement of pain relief of caffeine.
This invention is fur~er directed to a method of eliciting an onset hastened and enhanced response for ~e treatment of pain and infl~mm~tion in m~mm~l~, including humans, in need thereof, comprising ~(lmini~tering to such org~nism:

2 ~ 2 ~o 94/0747l PCI/US93/08896 (i) an analgesically and anti-infl~mm~tQry effective amount of a salt of (S)-ibul~lofen subst~nti~lly free of (R)-iluu~lofen wherein the salt is selected from (S)-ibu~lofell-(S)-lysine and (S)-ibuprofen-(R)-lysine; and (ii) an amount effective in enhancement of pain relief of 5 caffeine.
Subst~n~i~lly free of (R)-ibuprofen means that the ratio of (S)-ibuprofen to (R)-ibuprofen is at least 90:10.
Salts of (S)-ibuprofen include ph~rm~ceutically acceptable salts such as aLkali metals (sodium or potassium), ~lk~line earth metals o (calcium), or salts with other metals such as m~gnesium, al~lminl-m, iron, zinc, copper, nickel or cobalt.
Ph~rm~( eutically acceptable salts of (S)-ibuprofen further include the amino acid salts, particularly the basic amino acids such as lysine or arginine. Specifically included within the composition of the instant invention is (S)-ibuprofen-(S)-lysine and (S)-ibuprofen-(R)-lysine.
The term m~mm~ or m~mm~ n or~ni~m includes but is not limited to man, dog, cat, horse and cow.
The term treatment encompasses the complete range of 20 therapeutically positive effects associated with ph~rm~ceutical medication including reduction of, alleviation of and relief from the symptoms or illness which affect the org~ni~m (S)-ibuprofen may be prepared following the procedures disclosed in U.S. Patent 4,877,620. Metal salts of ibuprofen may be obtained by 25 contacting a hydroxide, or carbonate with ibuprofen. Amino acid salts of ibuprofen may be obtained by contacting an amino acid in solution with ibuprofen. U.S. Patent No. 4,994,604 describes a process for the formation and resolution of (S)-il,~rofen-(S)-lysine that employs preferential cryst~lli7~tion to separate a pair of diastereomeric salts, 30 (S)-ibu~rofell-(S)-lysine and (R)-ibuyrofell-(S)-lysine. The basic procedure involves (a) contacting (R),(S)-il,~rofell and (S)-lysine in an aqueous-organic solvent ~l~ixl"re; (b) separating any suspended solid from the mixture; and (c) cooling the clear mixtllre until the mixture is supersaturated with respect to each of the (S)-ibuprofen-(S)-lysine and WO 94/07471 2 ~ S 2 PCr/US93/0883 (R)-ibuprofen-(S)-lysine salts; (d) contacting the supersaturated mixture with a slurry of (S)-ibuprofen-(S)-lysine in an aqueous-organic solvent;
and (e) separating the formed crystalline (S)-ibuprofen-(S)-lysine.
Specifically, the racemic ibuprofen starting material is 5 mixed with an organic solvent that is miscible with water. The (S)-lysine is mixed with water and the ibuprofen and lysine solutions are combined.
The mixture is ~git~ted for a time period sufficient to crystallize all the salts, if any, in excess of the solubility limit. The suspended salts are separated to obtain a clear nnother liquor which is generally saturated with respect to the diastereomeric salts (S)-ibuprofen-(S)-lysine and (R)-ibul)rorell-(S)-lysine. Filtration may be employed to effect the separation. The liquor is then cooled to a temperature at which it is supersaturated with respect to each of the l 5 diastereomeric salts. It is preferred that the liquor be cooled to the point at which m~xi~ "~ supersaturation is obtained with respect to each salt without nucleation of either cryst~ hle species. Typically the temperature of the mother liquor must be lowered by about 5 C to reach ma~imllm supersaturation without precipitation of either salt.
20 However, the degree of cooling will depend on the particular solvent composition. The supersaLulaled liquor is then passed into a vessel col,t~ g a slurry of (S)-ibuprofen-(S)-lysine, hereafter referred to as the (S,S) salt, in the same solvent ~y~Lelll employed above for the mi~lre of racemic ibuprofen and (S)-lysine. In the presence of the (S,S) salt crystals acting as a seed, the supersaturation of the (S,S)-salt in the feed liquor is released by the growth of further crystals of the (S,S)-salt. Conversely, there is little or no change in the (R)-ibuprofen-(S)-lysine supersaturation because ~e growth rate of the (R,S) crystals is essentially zero in the absence of any initial (R,S) salt seed. The (S,S) 30 crystals are then separated by filtration or centrifugation and washed with aqueous-organic solvent to yield (S)-ibuprofen-(S)-lysine of purity approxim~tin~ 98%.
The pharmaceutical compositions of the present invention are useful in the rapid and enhanced treatment of pain and 2 ~
~0 94/07471 PCI/US93/08896 infl~mm~tion. In particular, the (S)-ibu~rof~;ll-(S)-lysine combined with caffeine is useful for the tre~tment of pain, and infl~mm~tion. The tili7~tion of (S)-ibul~r~fell and in particular (S)-ibupr~fen-(S)-lysine in an analgesic/caffeine combination offers significant advantages over the 5 combination of racemic ibu~rofen and caffeine or (S)-ibuprofen and caffeine.
(S)-ibuprofen and in particular the lysine salt of (S)-ibuprofen provides a faster onset of pain and infl~mm~tion relief and an enhanced degree of relief compared to racemic ibu~rofen. These o benefits contribute to overall enhanced and faster relief of symptoms associated with headaches and other aches and pains when the (S~-ibu~lofell -(S)-lysine is combined with a x~nthine derivative such as caffeine.
The absence or reduction of (R)-il,llprofell also provides 15 significant benefits. The allergic conlrailldications sometimes associated with iluu~rofell ~(lmini~tration are absent or reduced in a (R)-ibuprofen-free or subsl~-lti~lly-free composition. An additional advantage may be that less met~abolic energy will be used to convert the inactive (R)-ibu~rofen to the active (S)-ibuylofell. In addition, a reduced burden 20 may be placed on the urogenital ~y~lelll since ~(lmini~tration of the pure (S)-ibul~rofell elimin~tes the need to excrete the (R)-ibuprofen or its metabolites. The absence of the (R)-enantiomer also reduces or elimin~tes the incorporation of this molecule into fatty tissue. The renal burden and renal toxicities sometimes associated with racemic ibuprofen 25 therapy may be reduced or elimin~ted in a (S)-ibuprofen composition that is subst~nti~lly free of the (R) enantiomer.
Caffeine and x~nthine alkaloids are known in the art and may be used in combination with (S)-il,uprorell (S)-lysine. Caffeine is well tolerated and has minim~l side effects and thus advantageously may 30 be used in the present invention in combination with (S)-ibuprofen (S)-lysine. The composition of (S)-ibuprofen-(S)-lysine with caffeine provides a combination which siml~lt~neously and selectively provides enhanced relief from he~d~ches, pain, and infl~mm~tion. This combination also has an advantage under circulllstances where a WO 94/07471 PCI/US93/088~
2 ~ 2 m~mm~ n org~ni~m requires enhanced pain relief and wakefulness or mental altertness.
The absence of inactive enantiomers, particularly (R)-il,~roren provides for significant size and weight advantages in a combination dosage form, particularly a sustained release dosage form.
Where a sustained release dosage of ibuprofen may have required 800 to 1000 mg, the employment of (S)-ibuprofen-(S)-lysine reduces the weight to 400 to 500 mg, and provides for a more practical size tablet for an ibuprofen/caffeine combination.
o An effective amount of (S)-ibuprofen, or a salt thereof, for use in a unit dose composition of this invention may range from 50-800 mg of (S)-il..l~rofen. The preferred amount of (S)-ibuprofen is about 100 to 400 mg. The amount of a salt such as (S)-ibuprofen-(S)-lysine is determined based on the amount of (S)-ibuprofen contained therein.
Caffeine is advantageously used in the present invention in combination with (S)-il,uprorell-(S)-lysine. The amount of caffeine used in the present invention in h~ n~ may range from 20 to 400 milli~rams (mg). Advantageously, 32 to 65 mg is ~tlmini~tered in combination with 100 to 400 mg of (S)-il~u~rofen (S)-lysine. The combination claimed in the instant invention is advantageously ~lmini~tered orally. However, in patients with hypersecretory conditions, intractable ulcers, or in patients who are unable to take oral medication, the claimed combination may be ~tlministered intravenously in a suitable dosage within the limits described for oral treatment.
The present composition may be ~clmini~tered in the form of tablets, caplets, gelcaps, capsules, elixirs, syrups, or suspensions. For oral ~imini~tration~ the active ingredients may be ~tlmixed with a ph~ ceutically acceptable diluent such as lactose, sucrose, cellulose, dicalcium phosphate, calcium sulfate, rn~nnitol, and, in a liquid 3 composition, ethyl alcohol. Acceptable emulsifying or suspending agents such as PVP, gelatin, natural sugars, corn sweeteners, natural and syn~etic gums such as acacia, sodium ~lgin~te, guar gum, agar, bentonite, carboxyrnethylcellulose sodium, polyethylene glycol and waxes, may also be admixed with the active components. Where ~o 94/07471 2 1 4 ~ I 5 2 PCI/US93/08896 necessary, lubricants such as m~nP.sium stearic acid talc or m~nesium stearate, and disintegrators or superdi~integrators such as starch, sodium starch glycolate or cross-linked PVP may also be included.
Electrolytes such as dicalcium phosphate, sodium benzoate, sodium 5 acetate and sodium chloride may also be used.
The active components may also be form~ ted in sustained release or effervescent formlll~tions. These form~ tions depending upon whether they are sustained release or effervescent may be employed in oral, dermal, rectal or vaginal ~lmini~trations. The o sustained release forml-l~*ons also include layered formlll~*ons which provide for distinct release ratio and thus may be more effective in allowing for short and long term relief.
The following examples illustrate the compositions of the present invention which may be readily prepared and as such are not to 5 be considered as limitin.~ the invention set forth in the claims.

(S)-Il)uyrore~l lysine/car~ei~le Tablet (S)-ibuprofen-(S)-lysine 342 mg caffeine 65 mg PVP 15 mg Avicel PH1Ol 40 mg Magnesium Stearate 4 mg (S)-Ibuprofen lysine/ca~reil.e Tablet (S)-ibuprofen-(S)-lysine 342 mg 3 caffeine 20 mg PVP 15 mg Avicel PH1Ol 40 mg Magnesium Stearate 4 mg wo 94/0747~ 5 2 PCI/US93/088 F,XAMPLE 3 (S)~ uL rofen lysine/caffeine Sustained Release (S)-ibuprofen-(S)-lysine 400 mg caffeine 65 mg PVP 30 mg Avicel PHlOl 80 mg Magnesium Stearate 8 mg Methocel ElOMCR 66 mg Methocel KlOOMLV 200 mg (S)-Ibuprofen (S)-lysine/caffeine Sustained Release 15 (S)-ibuprofen-(S)-lysine 400 mg carrei-le 200 mg PVP 30 mg Avicel PHlOl 80 mg Magnesium Stearate 8 mg 20 Methocel ElOMCR 66 mg Me~ocel KlOOMLV 200mg F,XAMPLE 5 (S)-Ibuprofen-(S)-lysine/caffeine Solution 2s (S)-ibuprofen-(S)-lysine 342 mg caffeine 65mg g.s. syrup 5 ml F,XAMPLE 6 (S)-IlJu~lofell-(S)-lysine/caffeine Solution (S)-ibuprofen-(S)-lysine 342 mg caffeine 200 mg g.s. syrup 5 ml

Claims

WHAT IS CLAIMED IS:

1. A pharamaceutical composition for use in the treatment of pain and inflammation and the enhancement of pain relief in mammals, including humans comprising:
(i) an analgesically and anti-inflammatory effective amount of a salt of (S)-ibuprofen substantially free of (R)-ibuprofen wherein the salt is selected from (S)-ibuprofen-(S)-lysine and (S)-ibuprofen-(R)-lysine; and (ii) an amount effective in the enhancement of pain relief of caffeine.

2. The composition of Claim 1 comprising at least 50 mg of (S)-ibuprofen-(S)-lysine.

3. The composition of Claim 1 comprising between 20-400 mg of caffeine.

4. The composition of Claim 1 comprising 100-400 mg of (S)-ibuprofen-(S)-lysine and 32-65 mg of caffeine.

5. A method of treating pain and inflammation and enhancing pain relief in a mammalian organism in need of such treatment, comprising administering to such organism:
(i) an analgesically and anti-inflammatory effective amount of a salt of (S)-ibuprofen substantially free of (R)-ibuprofen wherein the salt is selected from (S)-ibuprofen-(S)-lysine and (S)-ibuprofen-(R)-lysine; and (ii) an amount effective in the enhancement of pain relief of caffeine.

6. A method according to Claim 5 wherein the composition administered to a mammalian organism in need thereof comprises:
(i) an analgesically and anti-inflammatory effective amount of (S)-ibuprofen-(S)-lysine substantially free of (R)-ibuprofen ; and (ii) an amount effective in the enhancement of pain relief of caffeine.

7. A method of eliciting an onset enhanced and hastened response or the treatment of pain and inflammation and the enhancement of pain relief in a mammalian organism in need of such treatment, comprising administering to such organism:
(i) an analgesically and anti-inflammatory effective amount of a salt of (S)-ibuprofen substantially free of (R)-ibuprofen wherein the salt is selected from (S)-ibuprofen-(S)-lysine and (S)-ibuprofen-(R)-lysine; and (ii) an amount effective in the enhancement of pain relief of caffeine.

8. A method according to Claim 7 wherein the composition administered to a mammalian organism in need thereof comprises:
(i) an analgesically and anti-inflammatory effective amount of (S)-ibuprofen-(S)-lysine substantially free of (R)-ibuprofen ; and (ii) an amount effective in the enhancement of pain relief of caffeine.

9. A method of reducing the side effects associated with the administration of a racemic ibuprofen/caffeine combination which comprises the administration of:
(i) an analgesically and anti-inflammatory effective amount of a salt of (S)-ibuprofen substantially free of (R)-ibuprofen wherein the salt is selected from (S)-ibuprofen-(S)-lysine and (S)-ibuprofen-(R)-lysine; and (ii) an amount effective in the enhancement of pain relief of caffeine.

10. A method according to Claim 9 wherein the composition administered to a mammalian organism in need thereof comprises:
(i) an analgesically and anti-inflammatory effective amount of (S)-ibuprofen-(S)-lysine substantially free of (R)-ibuprofen; and (ii) an amount effective in the enhancement of pain relief of caffeine.

11. A method of reducing the size and weight of a pharmaceutically effective amount of an ibuprofen/caffeine combination dosage form which comprises combining (i) an analgesically and anti-inflammatory effective amount of a salt of (S)-ibuprofen substantially free of (R)-ibuprofen wherein the salt is selected from (S)-ibuprofen-(S)-lysine and (S)-ibuprofen-(R)-lysine; and (ii) an amount effective in the enhancement of pain relief of caffeine.

12. A method according to Claim 11 wherein the composition administered to a mammalian organism in need thereof comprises:
(i) an analgesically and anti-inflammatory effective amount of (S)-ibuprofen-(S)-lysine substantially free of (R)-ibuprofen ; and (ii) an amount effective in the enhancement of pain relief of caffeine.