FIELD OF THE INVENTION

The present invention relates to a stable painless parenteral solution comprising about 75 mg /ml of diclofenac or a pharmaceutically acceptable diclofenac salt and polyethoxylated castor oil, which is suitable for intramuscular and/or intravenous administration.

BACKGROUND OF THE INVENTION

Diclofenac is a leading non-steroidal anti-inflammatory drug (NSAID). The drug has been in clinical use for over two decades as a NSAID with analgesic, anti-inflammatory and anti-pyretic activity. Historically, diclofenac has been associated mainly with chronic management of inflammatory and degenerative forms of rheumatism as well as treatment of painful musculoskeletal conditions, acute attacks of gout, painful post-operative and post-traumatic inflammation and pain following dental surgery. For these conditions the drug has been available in delayed release enteric coated tablets, sustained release tablets, suppositories and intramuscular injections. More recently, diclofenac has become available in rapid acting oral preparations for short term treatment of acute conditions. Since 1995, diclofenac sodium is available in the UK and Scandinavia as an intravenous infusion indicated for moderate to severe post-operative pain, or for the prophylaxis of post-operative pain.

Diclofenac has some limitations for Indictable formulation due to its physicochemical properties, which can be summarized as follows:

a) Poor aqueous solubility of the sodium salt: Diclofenac has a particularly high tendency to crystallize from aqueous and organic solutions. Due to the relatively less solubility of diclofenac in water an aqueous injection solution with a reasonable volume may not be obtained.

b) Susceptibility to oxidation: Diclofenac has tendency to oxidize in solution.

c) Injection Volume: Owing to poor solubility, the commercial product is formulated as 25 mg diclofenac sodium per milliliter. The recommended dosage is 75 mg and therefore the product is given as a 3 milliliter intramuscular injection.

d) Co-solvents have an unfavorable intravenous safety profile and are associated with venous sequelae, high hemolytic, e.g. Propylene glycol is irritant and cause pain and irritation at site of subcutaneous or intramuscular injection. Further, it has also been reported that aqueous solution of 2% Propylene glycol iso-osmotic with serum caused 100% haemolysis of erythrocytes in 45 minutes (Martindale, The extrapharmacopeia, 28th Edition)

EP patent no. 1 574 221 B1 and US Appl. no 20050238674 A1 (Shimoda Biotech (Pty) Ltd.) discloses stable parenteral aqueous solution (75 mg in 2 milliliter injection) comprising diclofenac or a pharmaceutically acceptable diclofenac salt and a cyclodextrin, an antioxidant selected from monothioglycerol, or a combination of ethylene diamine tetra-acetic acid and N-acetyl-cysteine.

U.S. Pat. No. 5,679,660 (Farmarc Nederland BV) discloses a method whereby the aqueous solubility of diclofenac was increased with the aid of a cyclodextrin to the extent that it could be formulated into a parenteral formulation containing 75 mg diclofenac per 3 ml. For intramuscular dosage form a volume of 3 ml will not meet with FDA approval. U.S. Pat. No. 5,679,660 (Farmarc Nederland BV) also discloses refrigeration of product is required in order to satisfy a 24 months shelf life. A refrigerated parenteral product however has the disadvantage of discomfort upon injection due to the low temperature of the injected product coupled with the increased cost of product storage.

Indian patent no: 192711 discloses Diclofenac injection, without propylene glycol, which is prepared by a process wherein benzyl alcohol is used in under nitrogen gassing to eliminate oxidation of diclofenac salt. However, this process is not reproducible, simple and cost effective.

For the reason given, it is not possible according to the prior art to obtain a diclofenac sodium injection that is stable, painless, preserved in conformity with statutory requirement, with low injection volume and with increased solubility (i.e. 75 mg/ml).

Hence still there exists need in the art to make diclofenac injection with increased solubility i.e. 75 mg/ml, which is painless, stable, with a low injection volume (meet with USFDA approval) and which can be administered intramuscularly and/or intravenously and which has low side effects, which also is simple and cost effective.

SUMMARY OF THE INVENTION

The objective of the present invention is to provide a stable painless parenteral solution comprising about 75 mg /ml diclofenac or a pharmaceutically acceptable diclofenac salt, which is suitable for intramuscular and/or intravenous administration.

Another objective of the present invention is to provide a stable painless parenteral solution comprising about 75 mg /ml diclofenac or a pharmaceutically acceptable diclofenac salt, and polyethoxylated castor oil, which is suitable for intramuscular and/or intravenous administration.

Another objective of the present invention is to provide a process of preparing a stable painless parenteral solution comprising about 75 mg /ml diclofenac or a pharmaceutically acceptable diclofenac salt, and polyethoxylated castor oil, which is suitable for intramuscular and/or intravenous administration.

DETAILED DESCRIPTION OF THE INVENTION

In an effort to overcome problems associated with prior art diclofenac injection present inventors have found that diclofenac injection comprising about 75 mg/ml can be developed by using polyethoxylated castor oil as solubilizing and stabilizing agent. The present invention overcomes all the problems existing with prior art formulations of diclofenac Injection. The present invention provides a stable painless parenteral solution comprising 75 mg /ml of diclofenac or a pharmaceutically acceptable diclofenac salt, and polyethoxylated castor oil, which is suitable for intramuscular and/or intravenous administration, which has high concentration of diclofenac in 1 ml injectable vehicle, which is painless, and stable over the longer periods of time. The present invention provides diclofenac injection, which has low viscosity, which reduces pain on administration.

The term "parenteral" herein encompasses injection of a composition by means other than through the gastrointestinal tract such as into or through the skin of a subject, and includes intramuscular administration and intravenous administration. Any known device useful for parenteral injection of drugs can be used to effect such administration.

The phrase "a stable painless parenteral solution" as used herein refers to a composition that does not cause pain, irritation while administration via intramuscular or intravenous route. Further composition a) retains its chemical purity within desired limits and b) does not exhibit any undesired changes in physical characteristics; during storage of the composition on the shelf until it is consumed by the patient. Particularly, the composition does not show turbidity, crystallization, precipitation, colour change or any other physical change making it unacceptable for parenteral administration. Preferably the composition of the present invention is a clear solution.

The parenteral solution of the present invention will have polyethoxylated castor oils include those manufactured by Rhone-Poulenc (Cranbury, N.J.) under the Alkamuls® brand and those manufactured by BASF (Parsippany, N.J.) under the Cremophor® brand. It is preferred to use the polyethoxylated castor oils classified as PEG-15 to PEG-50 castor oils, and more preferred to use PEG-30 to PEG-35 castor oils. It is most preferred to use those polyethoxylated castor oils known as Cremophor® EL and Alkamuls® EL-620; preferably Cremophor® ELP.

In addition to the polyethoxylated castor oils, parenteral solution of the present invention optionally comprises buffers, antioxidants, pH adjusting agents and the like and mixtures thereof.

Examples of buffers that may be used in the composition of the present invention, includes, but are not limited to phosphate, borate, citrate, acetate, carbonate, borate-polyol complexes and the like and mixtures thereof.

Examples of antioxidants that may be used in the composition of present invention, include, but are not limited to, ascorbic acid, malic acid, citric acid, sodium citrate, burtylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, sodium ascorbate, sodium metabisulfite and the like and mixtures thereof.

Examples of the alkaline agents that may be used as pH adjusting agents, include, but are not limited to, sodium hydroxide (NaOH), potassium hydroxide (KOH), tromethamine, monoethanolamine, sodium bicarbonate (NaHCO3) and other organic bases.

Examples of the acidic agents that may be used as pH adjusting agents include, but are not limited to, hydrochloric acid, citric acid, tartaric acid, lactic acid and other organic acids and the like and mixtures thereof.

The pH of the solution may be measured by any conventionally known techniques for example, digital pH meter.

According to one embodiment, the suitable container used to dispense the composition of the present invention, include, but are not limited to ampoules, vials, prefilled syringes and the like.

Sterilization methods that may be used in the present invention, include, but are not limited to, filtration sterilization, autoclaving, aseptically preparing and dispensing in the sterile containers or combination of one or more said methods.

The various embodiments of the present invention can be assembled in several different ways.

In one embodiment the present invention provides a stable painless parenteral solution comprising 75 mg /ml of diclofenac or a pharmaceutically acceptable diclofenac salt, and polyethoxylated castor oil, which is suitable for intramuscular and/or intravenous administration.

In yet another embodiment the present invention provides a stable painless parenteral solution comprising about 75 mg/ml of diclofenac or a pharmaceutically acceptable diclofenac salt, and polyethoxylated castor oil from about 10 % w/v to about 20 % w/v, and pharmaceutically acceptable excipients which is suitable for intramuscular and/or intravenous administration.

In yet another embodiment the present invention provides a stable painless parenteral solution comprising about 75 mg/ml of diclofenac or a pharmaceutically acceptable diclofenac salt, and polyethoxylated castor oil wherein the solution has pH from about 7 to about 9.5.

In yet another embodiment the present invention provides a stable painless parenteral solution comprising about 75 mg/ml of diclofenac or a pharmaceutically acceptable diclofenac salt, and polyethoxylated castor oil wherein viscosity of the solution is from about 1 cps to about 4 cps, preferably from about 1 cps to about 2 cps.

In yet another embodiment the present invention provides a stable painless parenteral solution comprising about 75 mg/ml of diclofenac or a pharmaceutically acceptable diclofenac salt, and polyethoxylated castor oil wherein polyethoxylated castor oil is used as solubility enhancing agent.

In yet another embodiment the present invention provides a stable painless parenteral solution comprising about 75 mg/ml of diclofenac or a pharmaceutically acceptable diclofenac salt, and polyethoxylated castor oil wherein polyethoxylated castor oil is used as stability enhancing agent.

In yet another embodiment present invention provides a stable painless parenteral solution comprising about 75 mg/ml of diclofenac or a pharmaceutically acceptable diclofenac salt and polyethoxylated castor oil wherein parenteral solution can be stored without refrigeration.

In yet another embodiment present invention provides a stable painless parenteral solution comprising:

a) 75 mg of diclofenac or a pharmaceutically acceptable salt of diclofenac,
b) polyethoxylated castor oil,
c) ethyl alcohol,
d) EDTA,
e) Sodium Metabisulphite.

In yet another embodiment present invention provides a process for preparing stable painless parenteral solution comprising diclofenac or a pharmaceutically acceptable diclofenac salt which process steps are consisting essentially of:

a) mixing EDTA and water
b) adding 75 mg of Diclofenac Sodium and adjusting pH
c) adding ethyl alcohol, polyethoxylated castor oil, Sodium Metabisulphite with stirring to get clear solution of 1 ml.

While the above description contains many specificities, these should not be construed as limitation in re scope of the invention, but rather as an exemplification of the preferred embodiments thereof. Many other variations are possible. Accordingly, the scope of the invention should be determined not by the embodiments illustrated, but by the appended claims and their legal equivalents.

Example 1

Table No. 1

The formulation was prepared by below process and using formula of table No. 1.

Manufacturing Process:

a) 50% of Water for injection (WFI) in a glass beaker was taken.

b) EDTA was added and dissolved in taken WFI

c) Added and dispersed Diclofenac sodium, pH adjusted to 9.5 with 1N NaOH.

d) Added Alcohol and Cremophor ELP in the above solution of step c. Stirred to get clear solution

e) Checked the pH and adjusted to 9.5 with 1N NaOH

f) Made up the volume to 100% with Water for injection and filtered.

The final formulation was filled in glass ampoule and stored at different stability conditions and results obtained are presented in table No. 2

Table No. 2

claims:

1. A stable painless parenteral solution comprising about 75 mg /ml of diclofenac or a pharmaceutically acceptable diclofenac salt, and polyethoxylated castor oil which is suitable for intramuscular and/or intravenous administration.

2. A stable painless parenteral solution according to claim 1 wherein the solution has viscosity from about 1 cps to about 4 cps.

3. A stable painless parenteral solution according to claim 1 wherein polyethoxylated castor oil is present from about 10 % w/v to about 20 % w/v of the composition.

4. A stable painless parenteral solution according to claim 1 wherein the solution has pH from 7 to 9.5.

5. A stable painless intramuscular injection comprising:

a) 75 mg/ml of diclofenac or a pharmaceutically acceptable salt of diclofenac,

b) polyethoxylated castor oil,

c) ethyl alcohol,

d) EDTA,

e) Sodium Metabisulphite.

6. A stable painless intramuscular injection according to claim 5 wherein the solution has viscosity from about 1 cps to about 4 cps.

7. A stable painless intramuscular injection according to claim 5 wherein polyethoxylated castor oil is present from about 10 % w/v to about 20 % w/v of the composition.

8. A stable painless intramuscular injection according to claim 5 wherein the solution has pH from 7 to 9.5.

9. A process for preparing stable painless parenteral solution comprising diclofenac or a pharmaceutically acceptable diclofenac salt which process steps are consisting essentially of:

a) mixing EDTA and water

b) adding 75 mg of Diclofenac Sodium and adjusting pH

c) adding ethyl alcohol, polyethoxylated castor oil, Sodium Metabisulphite with stirring to get clear solution of 1 ml.