PHARMACEUTICAL PAIN RELIEF COMPOSITION

Abstract

The present invention thus relates to an anhydrous pharmaceutical composition comprising an anti-inflammatory principle chosen from the derivatives of aryl-propionic acid, an antispasmodic in the triphenol family and an effervescent excipient.

Claims

1. Anhydrous pharmaceutical composition comprising an anti-inflammatory principle chosen from the derivatives of aryl-propionic acid, an antispasmodic of a triphenol and a buffered effervescent excipient.

2. Composition according to claim 1, wherein the anti-inflammatory chosen from derivatives of aryl-propionic acid is chosen from the group consisting of ketoprofen, dexketoprofen, naproxen, ibuprofen and flurbiprofen.

3. Composition according to claim 1, wherein that the antispasmodic of a triphenol family is 1,3,5-benzenetriol.

4. Composition according to claim 1, wherein the buffered effervescent excipient comprises an association of at least one organic acid and/or at least one organic acid salt with at least one strong base and/or at least one salt of a strong base.

5. Composition according to claim 1, wherein the effervescent excipient comprises an association of citric acid+sodium bicarbonate.

6. Composition according to claim 1, which is in a form of effervescent tablets, effervescent granules or effervescent powders.

7. A method of orally treating spasmodic disorders chosen from spasmodic colitis, hepatic colic, renal colic and dysmenorrhea which comprises orally administering to a patient in need thereof the composition according to claim 1.

8. The method according to claim 7, wherein said dysmenorrhea is secondary dysmenorrheas associated with an endometriosis.

9. The method according to claim 7, wherein said spasmodic disorder is renal colic crisis.

10. Method for manufacturing a composition according to claim 1, comprising the following steps: a) preparing an effervescent mixture comprising an association of at least one organic acid and/or at least one organic acid salt with at least one strong base and/or at least one salt of a base, b) adding an aqueous or hydroethanolic solvent, c) granulating, d) drying to form a dry effervescent mixture, e) preparing a preliminary mixture containing an anti-inflammatory principle chosen from derivatives of aryl-propionic acid and an antispasmodic active principle of a triphenol, f) adding the dry effervescent mixture obtained at d), g) homogenizing and obtaining of an effervescent composition.

11. Composition according to claim 2, wherein the antispasmodic of a triphenol is 1,3,5-benzenetriol.

12. Composition according to claim 2, wherein the buffered effervescent excipient comprises an association of at least one organic acid and/or at least one organic acid salt with at least one strong base and/or at least one salt of a strong base.

13. Composition according to claim 3, wherein the buffered effervescent excipient comprises an association of at least one organic acid and/or at least one organic acid salt with at least one strong base and/or at least one salt of a strong base.

14. Composition according to claim 2, wherein the effervescent excipient comprises an association of citric acid+sodium bicarbonate.

15. Composition according to claim 3, wherein the effervescent excipient comprises an association of citric acid+sodium bicarbonate.

16. Composition according to claim 4, wherein the effervescent excipient comprises an association of citric acid+sodium bicarbonate.

17. Composition according to claim 5, wherein the effervescent excipient comprises an association of citric acid+sodium bicarbonate.

18. Composition according to claim 2, which is in the form of effervescent tablets, effervescent granules or effervescent powders.

19. Composition according to claim 3, which is in the form of effervescent tablets, effervescent granules or effervescent powders.

20. Composition according to claim 4, which is in the form of effervescent tablets, effervescent granules or effervescent powders.

Description

EXAMPLES

Effervescent Tablet

[0118] Quantities for a tablet:

[0119] Anhydrous citric acid: approximately 830 mg

[0120] Anhydrous sodium bicarbonate: approximately 2250 mg

[0121] Taste correctors: approximately 50 mg

[0122] Lubricants: approximately 70 mg

[0123] Surfactant: approximately 0.75 mg

[0124] Wet-granulation method: the ingredients of the effervescent excipient are incorporated successively in a mixer. The premixing takes place in 3 minutes. Wettings carried out by spraying or aspiration of the solvent under partial vacuum, consisting of a hydroethanolic mixture (25% water and 75% ethanol). The quantity of granulation solvent is 0.9% with respect to the weight of the powder.

[0125] The granulation is carried out at atmospheric pressure for 5 minutes.

[0126] Drying is obtained by reducing the atmospheric pressure to 70 millibar; at this pressure, the boiling point of the solvent is reached. Drying is continued by raising the temperature to a residual moisture content of the powder of less than 0.5%.

[0127] The premix containing the active principles is prepared by intimate mixing in quantities corresponding to a ratio of 200 mg of ibuprofen to 80 mg of phloroglucinol.

[0128] The two mixtures are homogenised and then compressed by means of a press in a ratio such as to obtain 200 mg of ibuprofen and 80 mg of phloroglucinol in a tablet with a mass of approximately 3.5 g.

Results of Stability Studies

[0129] Ibuprofen-Phloroglucinol 200 mg/80 mg Effervescent Tablets

TABLE-US-00001 Results Results Compliance at at 9 Determinations limits release months Organoleptic Effervescent Compliant Compliant characteristics tablets, white to yellowish- white in colour Test Disaggregation <5 min 150 to 200 to 200 210 pH determination 5.50 to 6.50 6.06 6.11 Substances related to ibuprofen 4- 0.20% ND ND isobutylacetophenone other impurity 0.20% ND ND Sum of impurities 0.70% ND ND Substances related to phloroglucinol Phloroglucide 0.20% ND 0.04% other impurity 0.20% ND ND Sum of impurities 1.0% ND 0.04% Dosages Ibuprofen per tablet 0.200 g 0.197 g 0.198 g (0.190 g to 0.210 g) Phloroglucinol per 80 mg 79.21 mg 79.54 mg tablet (76 mg to 84 mg) ND: not detected.

Investigation of Impurities in the Active Principles

[0130] The active principles ibuprofen and phloroglucinol dihydrate are listed in the 9th edition of the European Pharmacopoeia.

[0131] The exclusion, identification and qualification thresholds for impurities in the two active principles are in accordance with ICH Q3 A.

[0132] Below is a summary table.

TABLE-US-00002 Reporting Identification Qualification Active Mono- Dose threshold threshold threshold principle graph max ICHQ3 A Ph. Eur ICH Q3 A Ph. Eur ICH Q3 A Ph. Eur Ibuprofen Ph. Eur 2 g/d 0.05% 0.03% 0.1% 0.05% 0.15% 0.15% 9.0 Phloroglucinol Ph. Eur 2 g/d 0.05% 0.05% 0.1% 0.1% 0.15% 0.15% dihydrate 9.0
Investigation of Impurities in the Finished Product (Ibuprofen+Phloroglucinol 200 mg/80 mg Effervescent Tablets)

[0133] The thresholds for exclusion, identification and qualification of impurities in the finished product correspond to ICH Q3 B requirements. Below are summary tables.

[0134] The thresholds for exclusion, identification and qualification of impurities in the finished product correspond to ICH Q3 B requirements. Below are summary tables.

TABLE-US-00003 Reporting threshold Analysis of the Finished Maximum daily finished product dose ICH Q3 B product Ibuprofen >1 g/d 0.05% 0.05% Phloroglucinol 1 g/d 0.10% 0.10%

TABLE-US-00004 Identification threshold Analysis of the Finished Maximum daily finished product dose ICH Q3 B product Ibuprofen >10 mg-2 g 0.20% 0.20% Phloroglucinol >10 mg-2 g 0.20% 0.20%
These results show that the forms according to the invention preserve the deleterious interactions of the active principles with each other in that no impurities are formed even over 9 months.

TABLE-US-00005 Qualification threshold Analysis of Finished Maximum daily the finished product dose ICH Q3 B product Ibuprofen >100 mg-2 g 0.20% 0.20% Phloroglucinol >100 mg-2 g 0.20% 0.20%

Pharmacological Effect

[0135] The analgesic and/or antispasmodic effect is assessed by a test in which a painful spasm is induced by the intraperitoneal injection of acetic acid in a mouse.

[0136] Three compositions are tested by intragastric administration: solution reconstituted (pH 5) by dissolution in water of an effervescent tablet according to the invention (200 mg ibuprofen+160 mg phloroglucinol), solution reconstituted (pH 6) by dissolution in water of an effervescent tablet according to the invention but comprising only ibuprofen (200 mg), solution reconstituted (pH 5) by dissolution in water of a tablet according to the invention but comprising only phloroglucinol (160 mg).

[0137] The dose administered to the mice is 5 times the human dose, that is to say therefore 100 mg/kg with regard to ibuprofen and 80 mg/kg with regard to phloroglucinol.

[0138] The inhibiting action of the compositions on pain is assessed on a painful spasm caused in the mouse by the intraperitoneal (IP) injection of a dilute 1% acetic acid solution.

[0139] A reference batch of mice receives the distilled water by intragastric method at 20 ml/kg.

[0140] One batch of mice receives, by the same method, the composition comprising ibuprofen alone.

[0141] One batch of mice receives, by the same method, the composition comprising the phloroglucinol alone.

[0142] One batch of mice receives, by the same method, the composition comprising the association of ibuprofen+phloroglucinol.

[0143] An injection of 0.2 ml of an acetic acid solution (1% in water) was carried out in the peritoneum of each mouse.

[0144] Spasmodic pain syndrome is characterised by twisting movements of the dorso-abdominal musculature.

[0145] After the injection of the acetic acid solution and a latency time of 5 minutes, the number of twistings for the following 15 minutes is counted.

[0146] The analgesic activity is expressed as a percentage of inhibition of the spasmodic pain crisis for each group treated by the therapeutic compositions in comparison with reference animals treated with distilled water.

TABLE-US-00006 Phloroglucinol + Phloroglucinol ibuprofen alone Ibuprofen alone association 35%* 44%* 89%*** *statistically significant p = 0.05 ***statistically significant p = 0.001

[0147] It is found that, in all cases, the antispasmodic action is manifested.

[0148] However, it is much greater and highly significant for the association. Furthermore, the action of the association (89%) is greater than the sum of the percentages obtained (79%) with the solutions containing a single active principle, which demonstrates a potentialising antispasmodic synergy of this association in this buffered effervescent form. This is because preliminary results obtained with non-effervescent and non-buffered aqueous solutions obtained by simple dissolution of the active principles in water illustrate a lesser analgesic effect as products alone than the association as well as a synergic effect this is equally less (than the one obtained because of the buffered effervescent form according to the invention).

[0149] These results are detailed below wherein the products according to the invention (buffered effervescent form) are compared with a formulation of a non-effervescent and non-buffered aqueous solution obtained by simple dissolution of the active principles (ibuprofen and phloroglucinol) at the same dosage, in pure water.

[0150] The batches of animals treated according to the following protocols are implemented:

[0151] A control batch of mice receives distilled water intragastrically at a rate of 20 ml/kg.

[0152] A batch of mice receives by the same route the composition comprising 100 mg/kg of ibuprofen+80 mg/kg of phloroglucinol from an effervescent tablet according to the invention (according to example above) dissolved in distilled water.

[0153] A batch of mice receives by the same route the composition comprising 100 mg/kg of ibuprofen+80 mg/kg of phloroglucinol from the suspension of the two active principles in 3% gum water (considering the low solubility of the active principles).

[0154] Pharmacological activity was evaluated in the same way as above.

[0155] The results are summarized in the table below.

TABLE-US-00007 Ibuprofen + phloroglucinol Ibuprofen + phloroglucinol effervescent buffered non-effervescent non- combination buffered combination 93%* 59%* *statistically significant p = 0.001

[0156] Examination of the results shows that regardless of the administration of the product, the pharmacological activity manifests itself and it is nevertheless considerably greater and synergistic in nature since in the case of an effervescent buffered formulation according to the invention the effect is 60% higher compared with the non-buffered and non-effervescent form.