IBUPROFEN-DIURETIC COMBINATIONS

Abstract: This invention relates to a pharmaceutical composition for use in the relief of pain, cramps, bloating and tension experienced during menstruation or premenstruation in a female in need of such relief comprising administering to such female: (i) an analgesically and anti-inflammatory effective amount of (S)-ibuprofen, or a salt thereof, substantially free of (R)-ibuprofen; and (ii) a diuretically effective amount of a diuretic; and (iii) optionally a tension relieving effective amount of pyrilamine maleate.

Description: TITLE OF TEE INVENTION IBUPROFEN-DIURETIC COMBINATIONS BACKGROUND OF THE INVENTION The non-steroidal anti-inflammatory drugs (NSAID) have been utilized in the treatment of pain/ inflammation and have been disclosed as useful in the treatment, management and mitigation of cold symptoms and the pain associated therewith. Ibuprofen (2-(4-isobutylphenyl)propionic acid) is a well known and commonly employed NSAID. Recently, it has been found that a faster onset of pain relief and an enhanced analgesic response can be obtained by the utilization of the single enantiomer S(+)-ibuprofen in comparison to racemic ibuprofen, (see for example U.S. Patent 4,877,620). Diuretics, such as the thiazides, are useful in the relief of water retention. In optional combination with a tension reliever such as pyrilamine maleate, diuretics may offer relief of a variety of symptoms often appearing in the menstrual cycle such as cramps, bloating, tension, and irritability. Combinations of ibuprofen with a diuretic such as pamabro have been disclosed in U.S. Patent 4,888.343. However, despite the fact that the menstrual pain sufferer is in need of quick and enhanced relief, there has been no consideration given to the employment of (S)-ibuprofen, or a salt thereof, in combination with a diuretic and optionally with a tension reliever for the treatment of menstrual symptoms. DETAILED DESCRIPTION OF THE INVENTION This invention relates to a pharmaceutical composition for use in the relief of pain, cramps, bloating and tension experienced during menstruation or premenstruation in a female in need of such relief comprising administering to such female: (i) an analgesically and anti-inflammatory effective amount of (S)-ibupro en, or a salt thereof, substantially free of (R)-ib * uprofen; and (ii) a diuretically effective amount of a diuretic; and (iii) optionally a tension relieving effective amount of pyrilamine maleate. This invention is also directed to a method of relieving pain, cramps, bloating and tension, experienced during menstruation or premenstruation in a female in need of such relief comprising administering to such female: (i) an analgesically and anti-inflammatory effective amount of (S)-ibuprofen, or a salt thereof, substantially free of (R)-ibupro en: (ii) a diuretically effective amount of a diuretic; and (iii) optionally a tension relieving effective amount of pyrilamine maleate. This invention is also directed to a method of eliciting an onset hastened and enhanced response for the relief of pain, cramps, bloating and tension experienced during menstruation or premenstruation in a female in need of such relief, comprising administering to such female: (i) an analgesically and anti-inflammatory effective amount of (S)-ibuprofen, or a salt thereof, substantially free of (R)-ibuprofen; (ii) a diuretically effective amount of a diuretic; and (iii) optionally a tension relieving effective amount of pyrilamine maleate. Substantially free of (R)-ibuprofen should be taken to mean that the ration of (S)-ibuprofen to (R -ibuprofen is at least 90:10. Salts of (S)-ibuprofen include salts with alkali metals, such as sodium or potassium, salts with alkaline earth metals, such as calcium, or salts with other metals such as magnesium, aluminum, iron, zinc, copper, nickel or cobalt. Salts of (S)-ibuprofen further include the amino acid salts, particularly the basic amino acids such as lysine and arginine. Specifically included within the above composition is (S)-ibuprofen- (S)-lysine. (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. The utilization of (S)-ibuprofen in an analgesic-antiinflammatory/diuretic combination offers significant advantages over the combination of racemic ibuprofen with a diuretic which has already been shown to have advantages over acetaminophen combinations (see for example U.S. Patent 4,888,343). (S)-ib-uprofen provides a faster onset of pain-antiinflammatory relief and an enhanced degree of relief compared to racemic ibuprofen. These benefits are increased in an (S)-ibuprofen/diuretic combination as the inhibition of prostaglandin synthetase and the water volume minimization may synergistically cooperate. This has not heretofore been observed because the art has not proposed the combination of the (S)-ibuprofen enantiomer, absent (R)-ibuprofen, with a diuretic. The presence of the (R)-ibuprofen may blur the synergistic effect. The subject using the (S)-ibuprofen/diuretic combination will no longer need to divert metabolic energy to the inversion of the (R)-enantiomer or the removal of this enantiomer. The absence of inversion reduces or eliminates the formation and incorporation into fatty tissue of hybrid-ibuprofen containing triglycerides. Although fluid retention is recognized or a possible side effect of ibuprofen usage the prior art has not heretofore considered the employment of an (S)-ibuprofen/diuretic combination. The absence of the (R)-ibuprofen in these combinations is particularly advantageous as a lesser metabolic burden is placed on the urogenital system for the excretion of the (R)-enantiomer or its metabolites. The renal burden and renal toxicities sometimes associated with ibuprofen therapy are reduced or absent in a substantially (R)-ibuprofen free composition. The absence of (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 reduces the weight to 400 to 500 mg, and provides for a more practical size tablet for an ibuprofen/diuretic combination. An effective amount of (S)-ibuprofen, or a pharmaceutically acceptable salt thereof, for use in a unit dose composition of this invention may range from 50 to 800 mg (S)-ibuprofen. 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 diuretic employed herein may be selected from the benzothiadiazides or acetazolamide and its analogs, or ethacrynic acid, or furose ide or bumetanide or a potassium-sparing diuretic such as amiloride or triamterene, or a xanthine or a combination diuretic such as pamabrom. Preferred diuretics include: Acetazolamide, dichlorophenamide, methazolamide, chlorothiazide, hydrochlorothiazide, benzthiazide, indapamide, trichlormethazide, methylclothiazide, polythiazide, ethacrynic acid, torasemide, furosemide, bumetamide, panabrom, amiloride, or triamterene. A particularly preferred diuretic is hydrochlorothiazide. The amount of diuretic useful in the practice of the present invention may-vary from about 2 mg to 50 mg depending on the specific diurectic. The present compositions may be administered in the form of tablets, capsules, elixirs, syrups or a suspension. For oral administration the active components may be admixed with a pharmaceutically acceptable carrier such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol and in a liquid composition, ethyl alcohol. Acceptable binders such as PVP starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes, may also be admixed with the active components. Where necessary lubricants such as boric acid, sodium benzoate, sodium acetate, sodium chloride and disintegrators such as starch, methylcellulose, agar, bentonite and guar gum and super disintegrators such as docusate sodium, sodium starch glycollate or cross-linked PVP may also be included. The active components may also be formulated in sustained release formulations. These formulations may be employed in oral, dermal, rectal or vaginal administration. Such sustained release forms also include layered formulations which provide for distinct release ratio and thus may be more beneficial in allowing for short and long term relief. The following examples illustrate the compositions of the present invention and as such are not to be considered as limiting the invention set forth in the claims appended hereto. EXAMPLE 1 (S)-ibuprofen. Diuretic Tablet (S)-ibuprofen-(S)-lysine 342 mg Hydrochlorothiazide 15 mg PVP 15 mg Avicel PH101 40 mg Magnesium stearate 4 mg EXAMPLE 2 (S)-ibuprofen-(S)-Lysine, Pyrilamine Maleate. Diuretic Table (S)-ibuprofen-(S)-lysine 342 mg Hydrochlorothiazide 15 mg Pyrilamine Maleate 8 mg PVP 15 mg Avicel PH101 40 mg Magnesium stearate 4 mg EXAMPLE 3 (S)-ibuprofen-(S)-lvsine, Diuretic Sustained Release (S)-ibuprofen 400 mg Hydrochlorothiazide 30 mg PVP 30 mg Avicel PH101 80 mg Magnesium stearate 8 mg Methocel E10MCR 66 mg Methocel K100MLV 200 mg

Claims: WHAT IS CLAIMED IS: 1. A pharmaceutical composition for use in the relief of pain, cramps, bloating and tension in a female and adapted for unit dosage oval administration said composition comprising: (i) an analgesically and anti-inflammatory effective amount of (S)-ibuprofen or a pharmaceutically acceptable salt thereof, substantially free of (R)-ibuprofen; and (ii) a therapeutically effective amount of a diuretic; and (iii) optionally a therapeutically effective amount of pyrilamine maleate. 2. A composition of Claim 1 wherein the (S)-ibuprofen is present as the salt (S)-ibuprofen- (S)-lysine. 3. A composition of Claim 1 comprising at least 50 mg of (S)-ibuprofen. 4. A composition of Claim 1 wherein the diuretic is selected from the group consisting of: Acetazolamide, dichlorophenamide, methazolamide, chlorothiazide, hydrochlorothiazide, benzthiazide, indapamide, trichlormethazide, methylclothiazide, polythiazide, ethacrynic acid, torasemide, furosemide. bumetamide, panabrom, amiloride, or triamterene. 5. A composition of Claim 4 wherein the diuretic is hydrochlorothiazide. 6. A method of relieving pain, cramps, bloating and tension, experienced during menstruation or premenstruation in a female in need of such relief comprising administering to such female: (i) an analgesically and anti-inflammatory effective amount of (S)-ibuprofen, or a salt thereof, substantially free of (R)-ibuprofen; and (ii) a diuretically effective amount of a diuretic; and ( ' iii)optionally a tension relieving effective amount of pyrilamine maleate. 7. A method of eliciting an onset hastened and enhanced response for the relief of pain, cramps, bloating and tension experienced during menstruation or premenstruation in a female in need of such relief-, comprising administering to such female: (i) an analgesically and anti-inflammatory effective amount of (S)-ibuprofen, or a salt thereof, substantially free of (R)-ibuprofen; and (ii) a diuretically effective amount of a diuretic: and (iii)optionally a tension relieving effective amount of pyrilamine maleate. 8. A method of reducing the side effects associated with the administration of an ibuprofen/ diuretic combination which comprises the administration of (S)-ibuprofen, or a salt thereof, substantially free of (R)-ibuprofen, and a diuretic. 9. A method of reducing the size and weight of an ibuprofen/diuretic combination dosage form, which comprises combining (S)-ibuprofen, or a salt thereof, substantially free of (R)-ibuprofen, and a diuretic.

Inventors: SIMS ROBERT T, SLIVKA WILLIAM, SIMS, ROBERT, T., SLIVKA, WILLIAM
Applicants: MCNEIL PPC INC, MERCK & CO INC, MCNEIL-PPC, INC., MERCK & CO., INC.
Application year: 1991
Main classification: A61K31
IPC codes: A61K31, A61P7