Stable injectable ibuprofen formulation

Description

Technical field

[0001] The present invention relates to a composition for injectable formulation and to a pharmaceutical composition comprising it, as defined by the claims. The invention also concern the use of the composition and of the pharmaceutical composition.Introduction

[0002] There are different problems associated to post operative pain and fever that are normally due to respiratory, cardio circulatory, digestive, metabolic, immunological, urological, musculoskeletal and psychological complications.

[0003] Ibuprofen is a well known non-steroidal anti-inflammatory drug with antipyretic and analgesic activities. Poor solubility of Ibuprofen in water always remains an obstacle to develop a stable injectable formulation.

[0004] Different combinations of Ibuprofen with amino acids were developed to solubilize Ibuprofen in water.

[0005] The existing claimed formulations available for Ibuprofen injectable contain combination of Ibuprofen with Arginine with different molar ratios for concentrate and ready to use products.

[0006] Cardolor a leading market product is 100mg / mL Ibuprofen concentrate, a combination of Ibuprofen and Arginine with molar ratio 1:0.92, require 0.9% Sodium Chloride, 5% dextrose or Ringer's lactate solution to make 4mg / mL of Ibuprofen isotonic intravenous solution. Claimed pH is about 7.6 but stability of diluted solution in 0.9% sodium chloride and 5% dextrose is about 24 hours maximum and pH of diluted solution is about 6 at room temperature.

[0007] Other ready to use formulations also contains Ibuprofen and Arginine with different molar ratios use 0.9% sodium chloride as osmotic agent. Trometamol or salts of sodium and potassium are used as buffering agent.

[0008] Patent applications such as ES2422563, CN 103301118, CN 101069681 and CN103284985 propose various formulations for injection based on ibuprofen.

[0009] Extra sodium in bloodstream may increase blood pressure and is not suitable for patients at low sodium intake. Increased amount of sodium in bloodstream may increase the risk of heart and stroke.

[0010] Buffers are used to stabilize the pharmaceutical liquid formulations. All ready to use Ibuprofen formulation are practically stable at pH 7.8 to 9.0 as result increase blood pH. Increased blood pH may increase blood coagulation time. Using such intravenous solutions extreme care is required to avoid perivascular infiltration. Local tissue damage and subsequent sloughing may occur if extra vasation occurs.

[0011] Therefore known compositions with solubilized ibuprofen present several drawbacks. That is why, one aim of present invention is to provide a composition with solubilized ibuprofen and exempt from, or minimizing, the drawbacks of the known compositions.

[0012] Another aim of present invention is to provide an aqueous, sodium free, dextrose free and buffer free stable Ibuprofen Injectable formulation.Summary of Invention

[0013] The composition according to the independent claims provides a composition or a pharmaceutical composition exempt from, or minimizing the drawbacks of the known composition of above mentioned problems. Dependent claims describes optional features.

[0014] The present invention provides a composition with a solubilized ibuprofen thanks to an aqueous solution of ibuprofen and arginine with a molar ratio of ibuprofen:arginine comprised between 1:1.22388 and 1:1.9908 or 1:1.22-1:1.99, in combination with a aqueous solution of a diuretic compound comprising between 4.05% and 4.25 % w / v of the diuretic compound, which is mannitol as defined by the claims.

[0015] Advantageously, the composition according to the present invention comprises a perfect combination ratio of Ibuprofen and Arginine in diuretic solution that eliminates the requirement of any buffer and pH adjustment or other additive and the known drawbacks related thereof.

[0016] The composition according to the invention also provides a stable ibuprofen composition for injectable formulation.

[0017] The present invention is an excellent analgesic treatment, for use in hospitals, for post operative pain and fever. The present invention, due to its rout of administration, can provide the patient an early recovery, as well as reduce the time of hospitalization and cost associated to the patient care.

[0018] The current invention is sodium free, dextrose free and buffer free stable Ibuprofen intravenous injection or infusion. Sodium free, dextrose free and buffer free stable Ibuprofen intravenous injection or infusion increases the scope of application of current invention over existing marketed Ibuprofen injectable products and can help to optimize the safety and clinical efficacy of the patient as well as reduce the risk of disorders that may associated with cardiovascular system, hypertension, diabetic, perivascular infiltration and local tissue damage.

[0019] For usage of present invention in high fever and normal body temperature pH of solution is very near to blood pH. At 37°C pH is 7.47, at 38°C pH is 7.41, at 39°C pH is 7.38. Present invention is stable at real time and accelerated stability conditions as per ICH guidelines.

[0020] In one embodiment, the composition comprises mannitol as osmotic agent making current invention Sodium free and dextrose free, as defined by the claims.

[0021] In one embodiment, the pH for stability Ibuprofen infusion solution is 8.20 at 20°C (measured as per requirement of European Pharmacopeia) 8.04 at 25°C and 7.87 at 30°C.

[0022] In one embodiment, the composition is an aqueous, sodium free, dextrose free and buffer free stable Ibuprofen Injectable formulation with molar concentration of ibuprofen to arginine (1:1.9908 - 1:1.22388) in 4.05% - 4.25% w / v solution of mannitol in WFI with temperature dependent pH as defined by the claims. J

[0023] In one embodiment, arginine is replaced by another nitrous oxide or nitric oxide precursor.

[0024] In one disclosure, which is not claimed, ibuprofen is replaced by another analgesic compound, for instance ibuprofen derivatives, or analgesic compound with similar solubility's properties.

Claims

1. Aqueous injectable composition, characterized in that it consists of: - ibuprofen and arginine in a solution of mannitol in water for injection (WFI), comprising between 4.05% and 4.25% w / v of mannitol, wherein the molar ratio of ibuprofen : arginine is comprised between 1:1.22388 and 1:1.9908 or between 1:1.22 and 1:1.99, wherein the concentration of ibuprofen is between 1 mg / mL and 8 mg / mL, and wherein the injectable composition is free of sodium, dextrose, buffer and pH adjusting additives.

2. Composition according to claim 1, wherein the pH of the composition is comprised between 7.4 and 8.2 at a temperature range between 20°C and 39°C.

3. Aqueous injectable composition according to one of claims 1 and 2, wherein the pH of the composition is 7.47 at 37°C, 7.41 at 38°C and 7.38 at 39°C, measured as per requirement of European Pharmacopeia.

4. Aqueous injectable composition according to claim 1, wherein the composition is a sterile injectable formulation.

5. Pharmaceutical composition comprising the aqueous injectable composition according to any one of claims 1 to 4, wherein the said pharmaceutical composition is prepared aseptically.

6. Pharmaceutical composition according to claim 5 wherein the pharmaceutical composition is stable for 48 months in glass bottle with stopper, for instance a rubber and aluminum cap.

7. Pharmaceutical composition according to claim 5 wherein the pharmaceutical composition is stable for 48 months in plastic bottles, for instance bottle made of LDPE, HDPE, PP or COC.

8. Pharmaceutical composition according to claim 5 wherein the pharmaceutical composition is stable for 48 months in polymer bags.

9. Pharmaceutical composition according to claim 5 wherein said pharmaceutical composition is prepared aseptically.

10. Pharmaceutical composition according to anyone of claims 5-9 wherein said pharmaceutical composition is autoclaveable, for instance at a temperature around 121°C.

11. Pharmaceutical composition according to any one of claims 5-10 for preparing therapeutic doses of ibuprofen, in particular ready for use doses.

12. Composition according to any one of claims 1 to 4 or pharmaceutical composition according to any one of claim 5 to 10 for use in an analgesic treatment of a patient.