US 20100168238A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0168238 A1 Serrano et al. (43) Pub. Date: Jul. 1, 2010

(54) PHARMACEUTICAL COMPOSITION (86) PCT No.: PCT/FR2008/050263 CONTAINING PHLOROGLUCINOL AND PARACETAMOL § 371 (0X1), (2), (4) Date: Jan. 20, 2010 (75) Inventors: Jean-Jacques Serrano, Montpellier (FR); Claudette Serrano, (30) Foreign Application Priority Data Montpellier (FR) Feb. 19, 2007 (FR) ...... 1753351 Correspondence Address: WOODCOCK WASHBURN LLP Publication Classi?cation CIRA CENTRE, 12TH FLOOR, 2929 ARCH (51) Int. Cl. STREET A61K 31/196 (2006.01) PHILADELPHIA, PA 19104-2891 (US) A61P 1/06 (2006.01) (52) U.S. Cl...... 514/563 (73) Assignee: Promindus (Actions Promotionnelles Dans L’Industrie (57) ABSTRACT Et Le Commerce), Casablance (MA) The invention relates to a pharmaceutical composition for oral or rectal administration, that contains phloroglucinol and (21) Appl. No.: 12/527,592 paracetamol in a pharmaceutically acceptable carrier. The inventors have evidenced a synergy developed by these tWo (22) PCT Filed: Feb. 18, 2008 active ingredients in antispasmodic therapy. US 2010/0168238 A1 Jul. 1,2010

PHARMACEUTICAL COMPOSITION cations or any particular precautions for use, except With CONTAINING PHLOROGLUCINOL AND morphine, Which has a spasmogenic effect. PARACETAMOL [0014] It is used in various forms, more particularly in the form of: [0015] coated tablets, [0001] The subject of the present invention is a pharmaceu [0016] lyophiliZates (Lyocs), tical composition containing an antispasmodic (phlorogluci [0017] effervescent tablets, nol) and an analgesic (paracetamol). Said composition, Which [0018] injectable solutions. is suitable for oral or rectal administration, is particularly [0019] The toxicity of phloroglucinol is very Weak. By Way effective in antispasmodic therapy. of example, it is possible to take up to eight Lyocs (lyo [0002] A spasm is a sudden, intense, very painful involun philiZed systems) per day (Which represents 640 mg) or three tary contraction. It may be of renal origin in the case of injectable vials of 40 mg intravenously per day. nephritic colic, of hepatic origin in the case of hepatic colic, of [0020] Phloroglucinol is also used in children. intestinal origin in the case of intestinal spasms and of spastic [0021] Paracetamol (CAS: 103-90-2; 4-acetylaminophe colitis, or of gynecological origin in the case of dysmenor nol) is itself also very Widely knoWn and used as an active rhea. Irrespective of the origin thereof, the spasm is accom ingredient of medicaments. It is used alone or in combination panied by extremely intense and persistent pain. With another active ingredient such as codeine or vitamin C. [0003] TWo types of antispasmodic exist: To the inventors’ knowledge, it has not been combined With [0004] neurotropic antispasmodics, such as atropine and an antispasmodic. HoWever, a publicationiTHE EURO derivatives thereof, scopolamine, quaternary ammoni PEAN JOURNAL OF HOSPITAL PHARMACY SCIENCE, ums such as tiemonium iodide, butylhyoscine bromide, Vol. 12, No. 5, 2006, pages 9 l -95iexists Which presents the etc., and results of a physicochemical study of stability and compat [0005] musculotropic antispasmodics, such as papaver ibility of paracetamol and phloroglucinol, formulated ine, mebeverine, trimebutine, pinaverium bromide, together, in solutions for intravenous injection. This publica phloroglucinol and derivatives, etc. tion, Which is strictly analytical, mentions only intravenous [0006] The neurotropic antispasmodics are less commonly administration, contains no result of pharmacological tests, used due to adverse effects Which folloW from their antimus and neither describes nor suggests any potentiating synergy carinic pharmacological action. In fact, muscarinic receptors (see beloW). are very Widely distributed in a variety of organs and of [0022] Paracetamol is a compound Which is particularly peripheral and central tissues. Thus, a desired pharmacologi indicated as an analgesic and for its antipyretic properties. It cal action, on intestinal peristalsis for example, is in most is a substance that is perfectly Well-tolerated in adults and in cases accompanied by adverse effects on salivary secretion, children. Of all the antipyretic analgesics, it is the most the heart, the respiratory system, the urogenital system, etc. In Widely used. It has no anti-in?ammatory properties and there addition, said neurotropic antispasmodics are strictly con fore does not develop any gastrotoxicity, even When taken traindicated in the case of glaucoma, prostatic hypertrophy, chronically and at a high dose. It has no or negligible side micturition disorders, pyloric stenosis, etc. effects: at the very most, it has beenpossible to note some rare [0007] On the other hand, musculotropic antispasmodics, cases of hypersensitivity, reversible upon interruption of the Which are much better tolerated, With more limited secondary treatment. actions, are much more commonly used. Thus, phlorogluci [0023] Paracetamol is neither teratogenic nor mutagenic. nol relaxes the contracted smooth ?ber irrespective of the On the other hand, at very high doses, corresponding to cases type of contraction, Without other systemic effects, or any of very large overdoses (since it is necessary to reach doses of contraindication, even at high dose. 10 g per day), it can trigger severe hepatic toxicity. This type [0008] The folloWing may be speci?ed With reference to of overdose is exceptional since paracetamol is used and is phloroglucinol (CAS: 108-73-6; l,3,5-trihydroxy-benZene). effective Without having to exceed, in the most severe cases, It is very Widely knoWn and used, alone, as an active ingre the dose of4 g per day. dient for medicaments. It is thus a musculotropic antispas [0024] Paracetamol is used in various forms, more particu modic. It is particularly active on the digestive system and the larly in the form of: urogenital system. It relieves the smooth muscle ?ber spasm [0025] tablets, in particular effervescent tablets and oro and as a result soothes the pain. It is particularly indicated for: dispersible tablets, [0009] the symptomatic treatment of pain related to [0026] pediatric oral solutions, functional disorders of the gastrointestinal type and of [0027] effervescent poWders, the bile ducts; [0028] suppositories, [0010] the treatment of acute spasmodic and painful [0029] injectable solutes. manifestations of the urinary tracts: nephritic colic; [0030] In such a context, the inventors propose combining [0011] the symptomatic treatment of painful spasmodic said tWo knoWn active ingredients: gynecological manifestations; [0031] on the one hand, phloroglucinol and [0012] the adjuvant treatment of contractions during [0032] on the other hand, paracetamol. pregnancy in combination With rest. [0033] The choice of paracetamol, among the existing anal [0013] Phloroglucinol is perfectly Well-tolerated, and has gesics, is particularly advantageous. Other analgesics have no or negligible side effects: at the very most, it has been been judiciously set aside, such as: possible to note, very rarely, some skin reactions of allergic [0034] nonsteroidal anti-in?ammatories or derivatives type. It is not teratogenic or mutagenic. Clinically, the very thereof, knoWn for their analgesic properties When they Widespread use of phloroglucinol has revealed no risk of are used at loW doses, but having, even at said loW doses, malformation to date. It is not knoWn to have any contraindi the draWbacks of anti-in?ammatories; US 2010/0168238 A1 Jul. 1,2010

[0035] aspirin (acetylsalicylic acid) Which is not only [0051] In the context of the present invention, effervescent gastrotoxic, but also a platelet antiaggregant; tablets (containing the tWo active ingredients: phloroglucinol [0036] tramadol, Which has a central action and is and paracetamol) are particularly preferred. capable of causing a dependence phenomenon and a [0052] The pharmaceutical compositions of the invention WithdraWal syndrome; contain generally from 50 to 200 mg of phloroglucinol. They [0037] dextropropoxyphene, an opioid analgesic. contain in particular 80, 100 or 160 mg of phloroglucinol. [0038] Said phloroglucinol+paracetamol combination [0053] Similarly, they contain generally from 100 to 1000 develops moreover, entirely surprisingly, in an antispasmodic mg of paracetamol, advantageously from 100 to 500 mg of therapy context, a synergy that potentiates the actions of each paracetamol. According to one preferred variant, said com of said phloroglucinol and paracetamol. To obtain an equiva positions contain less than 500 mg of paracetamol, and in lent effectiveness, in the context of the combination, less of at particular from 100 to less than 500 mg of paracetamol. least one of said active ingredients is used. [0054] Those skilled in the art, in vieW of the potency of the [0039] It is to the inventors’ credit to have demonstrated action desired, are able to optimiZe the absolute and relative said synergy and therefore the great advantage of the combi amounts, of the tWo active ingredients, involved. Given the nation: phloroglucinol+paracetamol. potentiating synergy demonstrated, a smaller amount of [0040] The ?rst subject of the present invention concerns a active ingredients is used for an equivalent (but more rapid) pharmaceutical composition, for oral or rectal administration, effect, or, at an equivalent amount used, a more potent and Which comprises, on the one hand, phloroglucinol and, on the more rapid action is observed. other hand, paracetamol, in a pharmaceutically acceptable excipient. Within said composition, the tWo active ingredients [0055] The pharmaceutical compositions of the invention, recommended in antispasmodic therapy, are most particu are formulated together (a unit form is in question); they are larly recommended in the treatment of spasmodic conditions, formulated together for oral or rectal administration. The pharmaceutically acceptable excipient is suitable for such an such as spastic colitis, hepatic colic, nephritic colic and dys menorrhea. oral or rectal administration. [0041] The pharmaceutical compositions of the invention [0056] According to another of its subjects, the present contain the tWo active ingredients identi?ed above. Advanta invention concerns the preparation of a pharmaceutical com geously, they contain no other active ingredient(s). HoWever, position as described above. Said preparation characteristi the use of at least one other active ingredient in said pharma cally comprises the formulation of phloroglucinol and parac ceutical compositions could not in any Way be excluded. etamol, together, in a pharmaceutically acceptable excipient [0042] The pharmaceutically acceptable excipient is not, suitable for oral or rectal administration. per se, original. It is suitable for the formulation of the tWo [0057] The term “formulation” is familiar to those skilled active ingredients. It is suitable for the desired route of admin in the art. The techniques for formulating the tWo active istration (orally or rectally), for the nature of the desired ingredients in question are not, per se, innovative. They es sen galenic form. tially comprise mixing the tWo active ingredients With the [0043] The pharmaceutical compositions of the invention appropriate excipient, With generally the various elements are available in any of the galenic forms suitable for oral or making up said excipient. rectal administration. Said galenic forms may in particular [0058] According to another of its aspects, the present comprise: tablets, capsules, poWders, granules, lyophiliZates, invention concerns the use ofphloroglucinol and of paraceta oral solutes, syrups, suspensions and suppositories. mol for the preparation of a pharmaceutical composition, [0044] This list is not exhaustive. suitable for oral or rectal administration, for use in treating [0045] The term “tablet” denotes tablets of all types, and in spasmodic conditions. Said pharmaceutical composition particular effervescent tablets, dispersible tablets and orodis advantageously consists of a galenic form, as speci?ed above, persible tablets. Which advantageously contains the phloroglucinol and the [0046] According to the invention, the active ingredients in paracetamol in the amounts indicated above. questioniphloroglucinol and paracetamoliare advanta [0059] The invention Will noW be illustrated hereinafter, in geously formulated, together, in the form of effervescent a manner that is in no Way limiting. tablets. Such effervescent tablets generally generate (aque ous) solutions of Which the pH is betWeen 3 and 7. They EXAMPLES advantageously generate solutions of Which the pH is in the region of or equal to 5. [0060] a) Effervescent tablets of the invention Were pre [0047] The effervescent tablets in question develop the pared by combining, respectively, 80, 100 and 160 mg of effervescence in a manner knoWn per se, in particular by phloroglucinol With 125, 250, 400, 500, 750 and 1000 mg of virtue of the combination in their formulation: paracetamol, in a pharmaceutically acceptable excipient con [0048] of at least one organic acid and/or of at least one taining: salt of an organic acid; and [0049] of at least one strong base and/or of at least one salt of a strong base. citric acid q.s. [0050] Said at least one organic acid is advantageously sodium bicarbonate q.s. chosen from citric acid, tartaric acid, malic acid and acetic docusate sodium q.s. acid; said at least one salt of a strong base is advantageously povidone q.s. sodium saccharin, and q.s. chosen from sodium bicarbonate, sodium carbonate, calcium sodium benzoate q.s. bicarbonate, calcium carbonate, magnesium bicarbonate, magnesium carbonate, potassium bicarbonate and potassium carbonate. [0061] Such tablets generate solutions at a pH of 5. US 2010/0168238 A1 Jul. 1,2010

[0062] The exact composition by mass of an effervescent tablet of this type is indicated below: TABLE

% inhibition Statistics Phloroglucinol 40 mg/kg 7 Phloroglucinol 80 mg Paracetamol 50 mg/kg 37 * Paracetamol 250 mg Combination 65 * ** Sodium bicarbonate 295.2 mg Phloroglucinol 80 mg/kg 21 Citric acid 215 mg Paracetamol 50 mg/kg 39 * Povidone 35 mg Combination 85 * ** Sodium benzoate 15.2 mg Phloroglucinol 100 mg/kg 27 * Docusate sodium 0.2 mg Paracetamol 50 mg/kg 40 * * Sodium saccharin 0.5 mg Combination 95 * ** Phloroglucinol 120 mg/kg 32 * Paracetamol 50 mg/kg 39 * * b) Finally, it is proposed to illustrate the advantage of the Combination 100 *** no contraction present invention by presenting hereinafter comparative * p = 0.05 results of pharmacological tests. ** p = 0.01 [0063] During said tests, the antispasmodic and analgesic *** p = 0.001 activity of phloroglucinol, of paracetamol, and of phloroglu cinol combined With paracetamol Was evaluated using the [0074] The examination of these results shoWs that, What ever the doses used, a potentiating synergy (from 40% to Siegmund test or “Writhing test”. The principle of this test, 50%) of the phloroglucinol+paracetamol combination, on the Which is familiar to those skilled in the art, is brie?y summa painful spasm, is alWays demonstrated. This synergy is riZed hereinafter. The intraperitoneal injection of phenylben already highly statistically signi?cant from the loW doses Zoquinone in mice causes a painful spasm, Which can be onWard (p:0.001), and it alWays increases With the increase reduced With antispasmodic substances (causal medication) in doses. and analgesic substances (symptomatic medication). [0075] It is noted that, for a combination of 120 mg of [0064] The test Was carried out on batches of 10 male mice, phloroglucinol and 50 mg of paracetamol (per kg), there is no of the SWiss strain, having an average Weight of 22 g12. The contraction. The animals are completely protected (saturated spasmodic and painful syndrome caused by the intraperito system). neal injection of 0.25 ml of the phenylbenZoquinone solution [0076] The above numbers most certainly demonstrate the is characterized by hind limb stretching movements and unobvious nature of the invention and also the great advan dorso-abdominal musculature tWisting movements, Which tage thereof. accounted for a period of time of 30 min, starting from 15 min folloWing the administration of the phenylbenZoquinone. 1. A pharmaceutical composition for oral or rectal admin [0065] An antispasmodic and analgesic effect manifests istration, comprising phloroglucinol, paracetamol, and a itself through a reduction in the number of spasmodic attacks, pharmaceutically acceptable excipient. Which is dependent on the dose. For each test, the substance 2. The pharmaceutical composition as claimed in claim 1, being studied is administered by means of an esophageal Wherein the composition is in a form selected from the group tube, 30 min before the phenylbenZoquinone. consisting of tablets, capsules, poWders, granules, lyo [0066] For experimental ease, the following Were used: philiZates, oral solutes, syrups, suspensions and supposito [0067] phloroglucinol Lyoc (lyophiliZate), and ries. 3. The pharmaceutical composition as claimed in claim 1 [0068] effervescent paracetamol (tablet); the tWo sub Wherein the composition is in the form of an effervescent stances being perfectly soluble and miscible. tablet. [0069] To test the products administered in isolation (prior 4. The pharmaceutical composition as claimed in claim 3, art), on the one hand, phloroglucinol lyocs (lyophiliZed sys Wherein tems) Were dissolved in distilled Water, and on the other hand, the effervescent tablet further comprises effervescent paracetamol tablets Were solubiliZed in distilled at least one organic acid and/or at least one salt of an Water (the solution obtained has a pH of 5). organic acid, said organic acid being selected from the [0070] To test the pharmaceutical compositions of the group consisting of citric acid, tartaric acid, malic acid invention, such phloroglucinol lyocs (lyophiliZed systems) and acetic acid, and and such effervescent paracetamol tablets Were dissolved and at least one strong base and/or at least one salt of a strong solubiliZed together. The solution Which contains the tWo base, said at least one salt of a strong base being selected active ingredients itself also has a pH of 5. from the group consisting of sodium bicarbonate, [0071] Given the metabolism in this animal species, the sodium carbonate, calcium bicarbonate, calcium car mouse, Which is more accelerated than in humans, those bonate, magnesium bicarbonate, magnesium carbonate, skilled in the art, specialists in pharmacology, most com potassium bicarbonate and potassium carbonate. monly use doses Which are multiples of the human dose in 5. The pharmaceutical composition as claimed in claim 1, order to be able to readily obj ectiviZe the results. Wherein the phloroglucinol is present at a dose of betWeen 50 [0072] The results are expressed as percentage of inhibition and 200 mg. of the spasm and of the pain relative to control animals Which 6. The pharmaceutical composition as claimed in claim 1, receive only 20 ml/kg of distilled Water. Wherein the paracetamol is present at a dose of betWeen 100 [0073] Said results are recorded in the table beloW, accom and 1000 mg. panied by the statistical calculation. 7. (canceled) US 2010/0168238 A1 Jul. 1,2010

8. (canceled) 12.A method of treating a spasmodic condition comprising 9. (canceled) administering a therapeutically effective amount of a phar maceutical composition according to claim 1 to the patient. 10. The pharmaceutical composition of claim 5, Wherein 13. The method of claim 12, Wherein the spasmodic con the phloroglucinol is present at a dose of 80, 100 or 160 mg. dition is spastic colitis, hepatic colic, nephritic colic, or 11. The pharmaceutical composition of claim 5, Wherein dysmenorrheal. the paracetamol is present at a dose of betWeen 100 and 500 mg.