WO1994007541A1

WO1994007541A1 - Ibuprofen-h2 antagonist combinations

Info

Publication number: WO1994007541A1
Application number: PCT/US1993/008947
Authority: WO
Inventors: Robert T. Sims; William Slivka; Thomas N. Gates; Robert Mcmahon
Original assignee: Merck & Co., Inc.; Mcneil-Ppc, Inc.
Priority date: 1992-09-29
Filing date: 1993-09-21
Publication date: 1994-04-14
Also published as: CA2144155A1; EP0663839A1; MX9306006A; JPH08502254A; AU4931693A; EP0663839A4

Abstract

This invention relates to pharmaceutical compositions for use in the treatment of pain and inflammation and in the relief of indigestion, sour stomach, heartburn and other gastrointestinal disorders in mammals, including 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 relief of indigestion, sour stomach, heartburn, overindulgence and other gastrointestinal disorders of at least one of the H2 antagonists.

Description

TITLE OF THE INVENTION

IBUPROFEN-H2 ANTAGONIST COMBINATIONS

BACKGROUND OF THE INVENTION The non-steroidal anti-inflammatory drugs (NSAID) have been utilized in the treatment of pain/inflammation 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, arthritic pain, gout, menstrual pain, headaches, mild pain following surgery, and pain from soft tissue injuries such as sprains and strains. NSAIDs are within the broader class of non-narcotic analgesics which also includes acetyl salicyclic acid (aspirin) and acetaminophen. NSAIDs, except for acetaminophen, are generally considered to exert their effect by blocking the production of prostaglandins at the site of pain, irritation or injury so that the pain signal does not reach the brain.

Ibuprofen (2-(4-isobutylphenyl)propionic acid) is a well known and commonly employed NSAID. Amino acid salts of racemic ibuprofen including 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 utilizing the single enantiomer (S)-ibuprofen (also known as (-f-)-ibuprofen or dexibuprofen) rather than the racemic mixture of ibuprofen. See U.S. Patent 4,877,620. H2 antagonists are commonly prescribed to treat and prevent ulcers in the walls of the stomach, duodenum or esophagus. H2 antagonists are also used to treat non-ulcerative conditions. Damage to the mucus lining surrounding these tissues enables destructive action of stomach acids which erodes the underlying tissue. Commonly known H2 antagonists for the treatment of ulcers include cimetidine, ranitidine, nizatidine, roxatidine and famotidine.

Combinations of ibuprofen with H2 antagonists have been disclosed. See EPO App. No. 426479A which discloses a pharmaceutical composition for treating the symptoms of overindulgence (headache and acid indigestion) using H2 antagonists including famotidine and an analgesic effective amount of a NSAID including ibuprofen wherein the term is defined to include administration of both the racemic mixture or the pure S enantiomer of ibuprofen. There is a need to employ a compound with faster acting and enhanced analgesic capability such as (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; in combination with an H2 antagonist such as famotidine to treat and prevent the pain and discomfort associated with headaches, indigestion, sour stomach, heartburn or other gastrointestinal disorders. There is a need to employ a combination wherein an advantage is that the (S)-ibuprofen lysine salt is more stable than the free acid of ibuprofen and is extremely soluble in water to give substantially neutral (versus acidic) aqueous solutions. The ibuprofenΛysine salt is therefore more suitable for administration to patients than the free acid because of its enhanced solubility in water (and in plasma) and because of its neutrality. Because of these improved and advantageous physical properties, administration of the combination is more effective in the treatment of pain, inflammation, and overindulgence. In addition, an advantage of the (S)-ibuprofen- (S)-lysine in the combination claimed in the instant invention is that this salt is neutral and not acidic and, therefore, unlike the prior art disclosures of H2 antagonist and ibuprofen, does not both acerbate and treat stomach conditions simultaneously.

The present invention provides both faster onset and enhanced relief of aches and pains associated with the body, head and stomach to provide broad and concurrent symptomatic relief. The combination with famotidine is especially advantageous since (S)- ibuprofen-lysine does not interfere with the metabolism of famotidine nor does famotidine interfere with the metabolism of alcohol. DETAILED DESCRIPTION OF THE INVENTION

This invention claims pharmaceutical compositions for use in the treatment of pain and inflammation and the treatment of mild stomach and esophagus disorders including the treatment of heartburn. The composition comprises:

(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 relief of gastrointestinal or esophagus disorders of at least one of the H2 antagonists.

This invention is also directed to a method of treating pain and inflammation and concurrently treating indigestion, sour stomach, heartburn, overindulgence and other gastrointestinal disorders in mammals, including humans, in need thereof, comprising administering to such organism:

This invention is further directed to a method of eliciting an onset hastened and enhanced response for the treatment of pain and inflammation and the treatment of gastrointestinal or esophagus disorders in mammals, including humans, in need thereof, comprising administering to such organism:

(ii) an amount effective in relief of gastrointestinal or esophagus disorders of at least one of the H2 antagonists. Substantially free of (R)-ibuprofen means that the ratio of (S)-ibuprofen to (R)-ibuprofen is at least 90:10.

Salts of (S)-ibuprofen include pharmaceutically acceptable salts such as alkali metals (sodium or potassium), alkaline earth metals (calcium), or salts with other metals such as magnesium, aluminum, iron, zinc, copper, nickel or cobalt.

Pharmaceutically 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 mammals or mammalian organism includes but is not limited to man, dog, cat, horse and cow.

The term treatment encompasses the complete range of therapeutically positive effects associated with pharmaceutical medication including reduction of, alleviation of and relief from the symptoms or illness which affect the organism.

(S)-ibuprofen may be prepared following the procedures disclosed in U.S. Patent 4,877,620. Metal salts of ibuprofen may be obtained by 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)-ibuprofen-(S)-lysine that employs preferential crystallization to separate a pair of diastereomeric salts, (S)-ibuρrofen-(S)-lysine and (R)-ibuprofen-(S)-lysine. The basic procedure involves (a) contacting (R),(S)-ibuprofen and (S)-lysine in an aqueous-organic solvent mixture; (b) separating any suspended solid from the mixture; and (c) cooling the clear mixture until the mixture is supersaturated with respect to each of the (S)-ibuprofen-(S)-lysine and (R)-ibuρrofen-(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 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 agitated 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 mother liquor which is generally saturated with respect to the diastereomeric salts (S)- ibuprofen-(S)-lysine and (R)-ibuprofen-(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 diastereomeric salts. It is preferred that the liquor be cooled to the point at which maximum supersaturation is obtained with respect to each salt without nucleation of either crystallizable species. Typically the temperature of the mother liquor must be lowered by about 5°C to reach maximum supersaturation without precipitation of either salt. However, the degree of cooling will depend on the particular solvent composition. The supersaturated liquor is then passed into a vessel containing a slurry of (S)-ibuprofen-(S)-lysine, hereafter referred to as the (S,S) salt, in the same solvent system employed above for the mixture 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 the growth rate of the (R,S) crystals is essentially zero in the absence of any initial (R,S) salt seed. The (S,S) crystals are then separated by filtration or centrifugation and washed with aqueous-organic solvent to yield (S)-ibuprofen-(S)-lysine of purity approximating 98%.

The pharmaceutical compositions of the present invention are useful in the rapid and enhanced treatment of pain and inflammation and in the treatment of various mild gastrointestinal disorders including indigestion, sour stomach, overindulgence and heartburn. In particular, the (S)-ibuprofen-(S)-lysine combined with an H2 antagonist such as famotidine is useful for the treatment of pain, inflammation, and the various gastrointestinal disorders such as indigestion, sour stomach, or heartburn. The utilization of (S)-ibuprofen and in particular (S)- ibuprofen-(S)-lysine in an analgesic/H2 antagonist combination offers significant advantages over the combination of racemic ibuprofen and an H2 antagonist or (S)-ibuprofen and an H2 antagonist.

(S)-ibuprofen and in particular the (S)-lysine salt of (S)- ibuprofen provides a faster onset of pain and inflammation relief and an enhanced degree of relief compared to racemic ibuprofen. These benefits contribute to overall enhanced and faster relief of symptoms associated with headaches and other aches and pains that often accompany gastrointestinal disorders and overindulgence when the (S)- ibuprofen-(S)-lysine is combined with an H2 antagonist such as famotidine.

The absence or reduction of (R)-ibuprofen also provides significant benefits. The allergic contraindications sometimes associated with ibuprofen administration are absent or reduced in a (R)-ibuprofen- free or substantially-free composition. An additional advantage may be that less metabolic energy will be used to convert the inactive (R)- ibuprofen to the active (S)-ibuprofen. In addition, a reduced burden may be placed on the urogenital system since administration of the pure (S)-ibuprofen eliminates the need to excrete the (R)-ibuprofen or its metabolites. The absence of the (R)-enantiomer also reduces or eliminates the incorporation of this molecule into fatty tissue. The renal burden and renal toxicities sometimes associated with racemic ibuprofen therapy may be reduced or eliminated in a (S)-ibuprofen composition that is substantially free of the (R) enantiomer.

H2 antagonists are well known in the treatment of ulcers and other gastrointestinal disorders and may be used in combination with (S)-ibuprofen-(S)-lysine. H2 antagonists used for ulcer therapy fall into four major structural classes: imidazole derivatives; substituted furans; aminoalkylphenoxy derivatives and guanidinothiazole compounds. Famotidine (N'-(aminosulfonyl)-3-[[[2-[(diamino- methylene)amino]-4-thiazolyl]methyl]thio] propanimidamide), a member of the latter class, is a competitive inhibitor of histamine H2- receptors and its primary pharmacological activity is the inhibition of gastric acid secretion. Famotidine suppresses both the acid concentration and the volume of gastric acid secretion. Famotidine is well tolerated and has minimal side effects and thus advantageously may be used in the present invention in combination with (S)-ibuprofen-(S)- lysine. Famotidine is also the most potent and selective H2 antagonist. The combination of famotidine and (S)-ibuprofen-(S)-lysine provides a combination which simultaneously and selectively provides relief from headaches, pain, inflammation, and discomfort and injury to the stomach, esophagus, or duodenum from excess production of gastric acid. Furthermore, famotidine may not interact with alcohol so that it may be administered prior to or during ingestion of meals or beverages which contain alcohol. The combination of (S)-ibuprofen-(S)-lysine with famotidine provides rapid and enhanced relief of pain while also providing long acting relief from and treatment of gastrointestinal disorders associated with gastric acid secretion.

The absence of inactive enantiomers, particularly (R)- ibuprofen 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/H2 antagonist combination. In particular, the combination of famotidine which is a highly potent H2 antagonist with (S)-ibuprofen-(S)-lysine reduces the size and weight of all pharmaceutical delivery forms or combination formulations and therefore improves patient compliance or tolerance. The tablet or capsule form of this combination is more readily swallowable by patients in need of treatment thereof.

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)-ibuprofen equivalents. 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. The H2 antagonist employed herein may be selected from any of the commercially available or known H2 antagonists such as cimetidine, ranitidine, roxatidine, nizatidine or famotidine. Famotidine is advantageously used in the present invention in combination with (S)- ibuprofen-(S)-lysine. The amount of famotidine used in the present invention in humans may range from 2.5 mg/day to 40 mg/day. Advantageously, 2.5 to 20 mgs/day is administered in combination with 100 to 400 mg of (S)-ibuprofen-(S)-lysine. The combination claimed in the instant invention is advantageously administered orally. However, in patients with hypersecretory conditions, intractable ulcers, or in patients who are unable to take oral medication, the claimed combination may be administered intravenously in a suitable dosage within the limits described for oral treatment.

The present composition may be administered in the form of tablets, caplets, gelcaps, capsules, elixirs, syrups, or suspensions. For oral administration, the active ingredients may be admixed with a pharmaceutically acceptable diluent such as lactose, sucrose, cellulose, dicalcium phosphate, calcium sulfate, mannitol, and, in a liquid composition, ethyl alcohol. Acceptable emulsifying or suspending agents such as PVP, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, guar gum, agar, bentonite, carboxymethylcellulose sodium, polyethylene glycol and waxes, may also be admixed with the active components. Where necessary, lubricants such as magnesium stearic acid talc or magnesium stearate, and disintegrators or superdisintegrators such as starch, sodium starch glycolate or cross-linked PVP may also be included. Electrolytes such as dicalcium phosphate, sodium benzoate, sodium acetate and sodium chloride may also be used.

The active components may also be formulated in sustained release or effervescent formulations. These formulations depending upon whether they are sustained release or effervescent may be employed in oral, dermal, rectal or vaginal administrations. The sustained release formulations also include layered formulations 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 be considered as limiting the invention set forth in the claims.

EXAMPLE 9

CSVIbuprofen-CSVlvsine/famotidine Solution

(S)-ibuprofen-(S)-lysine 342 mg famotidine 20 mg g.s. syrup 5 ml

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical composition for use in the treatment of pain and inflammation and the treatment of gastrointestinal disorders such as indigestion, sour stomach, overindulgence and heartbum in a mammals, including humans comprising:

(ii) an amount effective in the relief of gastrointestinal disorders and in inhibition of gastric acid secretion of an H2 receptor antagonist.

2. The composition of Claim 1 wherein the ibuprofen is present as (S)-ibuprofen-(S)-lysine.

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

4. The composition of Claim 1 wherein the H2 antagonist is selected from: cimetidine, ranitidine, roxatidine, nizatidine or famotidine or a pharmaceutically acceptable salt thereof.

5. The composition of claim 4 wherein the H2 antagonist is famotidine.

6. The composition of claim 5 comprising between 5 mg to 40 mgs of famotidine.

7. A method of treating pain and inflammation and treating gastrointestinal disorders such as indigestion, sour stomach, overindulgence and heartburn 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 treatment of gastrointestinal disorders or associated symptoms of at least one of the H2 antagonists.

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;

(ii) an amount effective in the inhibition of gastric acid secretion of famotidine.

9. A method of eliciting an onset enhanced and hastened response for the treatment and prevention of pain and inflammation and the treatment of gastrointestinal disorders such as indigestion, sour stomach, symptoms associated with overindulgence and heartburn in a mammalian organism in need of such treatment, comprising administering to such organism:

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; (ii) an amount effective in the inhibition of gastric acid secretion of famotidine.

11. A method of reducing the side effects associated with the administration of an ibuprofen/H2 antagonist 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 at least one of the H2 antagonists.

12. A method according to Claim 11 wherein the composition administered to a mammalian organism in need thereof comprises:

13. A method of reducing the size and weight of a pharmaceutically effective amount of an ibuprofen/H2 antagonist 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 at least one of the H2 antagonists.

14. A method according to Claim 13 wherein the composition administered to a mammalian organism in need thereof comprises:

(i) an analgesically and anti-inflammatory effective amount of (S)-ibuρrofen-(S)-lysine;

15. A method of treating gastrointestinal disorders, overindulgence and pain before or during ingestion of a meal accompanied by alcoholic beverages, comprising: administration of a combination 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)-ibuρrofen-(R)-lysine and (ii) famotidine wherein the famotidine does not interact with ethanol from the ingestion of the alcoholic beverage.

16. A method according to Claim 15 wherein the composition administered to a mammalian organism in need thereof comprises:

17. A method of providing rapid relief of pain and inflammation with (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 providing long lasting relief of gastrointestinal disorders associated with the secretion of gastric acid with a pharmaceutically effective amount of famotidine.

18. A method according to Claim 17 wherein the composition administered to a mammalian organism in need thereof comprises: