DESC:The present complete application of provisional application no. 201821006924 is a cognate application of provisional application no. 201821006980.

FIELD OF THE INVENTION
The present invention is directed to stable alcohol free pharmaceutical injectable formulation containing diclofenac and pharmaceutically acceptable carrier or excipients. More particularly, the present invention relates to a stable alcohol free pharmaceutical injectable formulation containing diclofenac or therapeutically equivalent amount of water soluble salt of diclofenac; at least one non-ionic solubilizer or surfactant; optionally, a solubilizer, an anti-crystallizing agent, a chelating agent or any mixture thereof; and at least one pharmaceutically acceptable excipient. The present invention advantageously provides a stable formulation of diclofenac over a long period of time.

BACKGROUND OF THE INVENTION
Diclofenac is a non-steroidal anti-inflammatory drug which is taken or applied to reduce inflammation and also have analgesic, anti-pyretic properties. Diclofenac is also used for the chronic management of various inflammatory diseases such as gout, arthritis, post-operative and post-traumatic inflammation and also for general pain.

Diclofenac is used, most commonly, as the sodium or Potassium salt for relief from pain and inflammation such as Musculoskeletal and joint disorders including rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. Both salts of Diclofenac i.e., Diclofenac Sodium and Diclofenac Potassium and a like salts share almost the same physicochemical properties except their molecular weights. It can be also employed and used as diethylamine salt or diethanolamine or beta-dimethyl amino-ethanol salt.

Diclofenac is an inhibitor of cyclo-oxygenase. It is metabolised in the liver to 4- hydroxydiclofenac and other hydroxylated forms. After glucoronidallon and sulphation, the metabolites are excreted in the urine (65%) and bile (35%).

IUPAC name of diclofenac is 2-[2-(2,6-dichloroanilino)phenyl]acetic acid and molecular formula is C14H11Cl2NO2.

Fig. 1

Diclofenac acts by inhibiting the synthesis of prostaglandins, the principal cause of inflammation and pain. The maximum effectiveness in pain relief can be achieved if the active ingredient immediately reaches the systemic circulation after administration, so consequently the injectable form has always been favoured particularly for the treatment of acute inflammations of the musculo-skeletal system.

There are various commercially available preparations of Diclofenac sodium. Prior art provides various compositions of Diclofenac parenteral preparations.

There have been many efforts for the modification in formulations of Diclofenac. There are number of documents that mention modification in the composition of Diclofenac. Due to limited solubility of Diclofenac Sodium in water, numbers of attempts are being made to solubilize the same and then administer for treatment of mammals for various medical conditions which include but not limited to ankylosing spondylitis, dysmenorrhea, migraine, moderate to severe pain and various types of arthritis.

US 9,211,251 teaches injectable formulations of water-soluble salts of diclofenac, which cause significantly less pain at the site of injection and administered by intradeltoid route, in addition to intragluteal and slow intravenous route.

IN 3704/MUM/2012 relates to a composition comprising Diclofenac and salts thereof. In particular, the invention provides a composition comprising 25 - 200 mg of Diclofenac or salts thereof for the parenteral administration through intramuscular, intravenous route; also for oral, dermal, subcutaneous, cutaneous, nasal, ocular drops, as rectal suppository, vaginal pessaries, intra-articular, and otic delivery. The invention also provides compositions comprising a combination of Diclofenac and other drugs. The invention further provides a method for preparing said composition.

IN1548/MUM/2008 discloses stable aqueous injectable pharmaceutical composition of 75mg of Diclofenac Sodium in 1 ml solution having viscosity of 0.5 to 1.5 mm2/sec; wherein said composition is characterized by comprising a single co-solvent/solubilizer in an amount of 20 to 60% and water as principal solvent

US 2015/0105467 is directed to a pharmaceutical composition containing a unit dose of a diclofenac compound effective to induce analgesia; and a beta-cyclodextrin compound; wherein the dose of the diclofenac compound is less than 10 mg. It also discloses methods of treating a subject in need of analgesia with the pharmaceutical compositions of the invention.

US 7,423,028 relates to Injectable pharmaceutical compositions comprising sodium diclofenac, a cyclodextrin and a polysorbate, suitable for subcutaneous and intramuscular administration.

WO 2005/086763 is directed to stable pharmaceutical compositions containing diclofenac, cyclodextrin, and stabilizers. Specifically, the invention is directed to pharmaceutical compositions in solution for intravanous or intramuscular administration. The present invention advantageously provides pharmaceutical compositions capable of remaining stable over long periods of time.

WO 2006/095363 provides injectable formulations of water-soluble salts of diclofenac in single doses of less than 2 ml, which cause significantly less pain at the site of injection and can be administered by intradeltoid route, in addition to intragluteal and slow intravenous route. More specifically the injectable preparations contain 75 mg to 100 mg of water-soluble salts of diclofenac, in about 1 ml injection solution without significantly raising the viscosity of the injection solution without the use surfactants. The formulations are adjusted to pH 6 to 10 containing up to l00 mg of diclofenac salt in a medium comprising of water, along with one or more co-solvent(s) solubiliser(s), antioxidants, preservatives, buffers, alkali and stabilizers.

There exists an unmet need of stabilized concentrated alcohol free injectable pharmaceutical formulation comprising diclofenac sodium and pharmaceutically acceptable carrier and/or excipients in concentration greater than 50 mg/ml.

The present invention addresses such problems existing in the art in an economic and effective way.

OBJECTIVE OF THE INVENTION
An object of the present invention is to provide novel alcohol free pharmaceutical injectable formulations containing diclofenac and pharmaceutically acceptable carrier or excipients.

Another objective of the present invention is to provide method for preparation of stable alcohol free pharmaceutical compositions of diclofenac and pharmaceutically acceptable carrier or excipients.

A preferred object of the present invention is to provide new synergistic alcohol free pharmaceutical compositions of diclofenac and pharmaceutically acceptable carriers or excipients for pain management.

Another objective of the present invention is to provide alcohol free injectable formulations of water-soluble salts of diclofenac, which cause significantly less pain at the site of injection and can be administered by intradeltoid route, in addition to intragluteal and slow intravenous route.

It is yet another object of the invention to provide injectable preparations containing single dose of less than 2 ml.

It is yet another object of the invention to provide alcohol free injectable preparations containing at least 75 mg of water-soluble salts of diclofenac, in about 1 mL injection solution.

It is yet another abject of the invention to provide a full therapeutic alcohol free dose of 75 mg to 100 mg of water-soluble salts of diclofenac in just one mL, without significantly raising the viscosity of the injection solution.

It is yet another object of the invention to provide an alcohol free injectable preparation of water-soluble salts of diclofenac, with a minimized quantity of co-solvents to avoid any possible side effects.

SUMMARY OF THE INVENTION
In one aspect of the present invention, the present invention discloses a stable alcohol free injectable pharmaceutical composition, comprising: a) diclofenac or therapeutically equivalent amount of water soluble salt of diclofenac; b) at least one non-ionic solubilizer or surfactant; c) optionally, at least one solubilizer; d) optionally, at least one anti-crystalizing agent, one chelating agent or any mixture thereof; and e) at least one pharmaceutically acceptable excipient.In another aspect of the present invention, the present invention discloses a process for the preparation of stable alcohol free injectable pharmaceutical composition, comprising: a) suspending diclofenac or therapeutically equivalent amount of water soluble salt of diclofenac in a solvent system comprising one or more non-ionic solubilizers in sterile water or water for injection, with stirring under constant nitrogen purging to prepare a solution A; b) optionally, adding one or more solubilizer in sterile water and under constant stirring to prepare a solution B; c) adding at least one or more pharmaceutical acceptable excipient, in sterile water and under constant stirring to prepare a solution C; d) optionally, adding at least one or more anti-crystallizing agent, chelating agent or mixture thereof, in sterile water and under constant stirring to prepare a solution D; e) adding solution B, C and D in solution A with adjustment of pH between 8-9 using an acid or alkali; f) diluting the final mixed solution with sterile water or water for injection (WFI) to achieve required concentration.
In one feature of the present invention, the water soluble salt of diclofenac is sodium salt.
In one feature of the present invention, the diclofenac or its water soluble salt is preferably present in an amount of 50 mg/ml to 100 mg/ml, more preferably present in an amount of 75 mg/ml.
In one feature of the present invention, the nonionic solubilizer or surfactant is selected from a group consisting of Macrogol-15-hydroxystearate (Solutol HS 15), 4-Octylphenol polyethoxylate (Triton X 100) and polyethoxylated castor oil (Cremophor EL), preferably Macrogol-15-hydroxystearate; and is present in an amount of 50-150 mg/ml.

In one feature of the present invention, the solubilizer is selected from a group comprising of polysorbate 20, polysorbate 80 and a combination thereof.

In one feature of the present invention, the polysorbate 20 is present in an amount of 10-30 mg/ml and the polysorbate 80 is present in an amount of 30-50 mg/ml.

In one feature of the present invention, the anti-crystalizing agent is selected from a group consisting of Glycerol, Propylene Glycol, Sorbitol, Polyvinyl Pyrrolidone, Hydroxy Propyl Methyl Cellulose, Polyvinyl alcohol and mannitol; and is present in an amount of 40-60 mg/ml.

In one feature of the present invention, the chelating agent is disodium EDTA and is present in an amount of 0.1-1.0 mg/ml.

In one feature of the present invention, the pharmaceutically acceptable excipients are selected from a group comprising of diluents, preservatives, antioxidants, buffering agents, amino acids and any combination thereof.

In one feature of the present invention, the diluent is water.

In one feature of the present invention, the preservative is present in an amount in the range of 0.1-5.0 mg/ml and is selected from a group comprising of sodium metabisulfite, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, sodium benzoate, benzalkonium chloride, chlorobutanol, thiomerosal, monothioglycerol, thioglycerols, acetyl cysteine, sodium bisulphate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbates, ascorbylpalmitate, tocopherol and any combination thereof.

In one feature of the present invention, the antioxidant is present in an amount in the range of 0.1-5.0 mg/ml and is selected from a group comprising of sodium metabisulfite, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, sodium benzoate, benzalkonium chloride, chlorobutanol, thiomerosal, monothioglycerol, thioglycerols, acetyl cysteine, sodium bisulphate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbates, ascorbylpalmitate, tocopherol and any combination thereof.

In one feature of the present invention, the amino acid is L-methionine and is present in an amount in the range of 0.1-5.0 mg/ml.

In one feature of the present invention, the composition further comprising acid or base for pH adjustment; wherein the acid is hydrochloric acid and the alkali is sodium hydroxide; and is present in an amount of sufficient quantity so as to adjust the pH of the composition in the range of 6-10, more preferably in the range of 8-9.

DESCRIPTION OF THE INVENTION
The invention is directed to a novel alcohol free pharmaceutical injectable formulation containing diclofenac and pharmaceutically acceptable excipients. The present invention provides formulations of diclofenac with pharmaceutically acceptable carrier or excipients. These formulations unexpectedly provide for significant efficacy and duration of pain relief.

The present invention relates to an alcohol free pharmaceutical composition in the form of a parenteral injection solution comprising the active ingredient diclofenac or its pharmaceutically acceptable salts along with pharmaceutically acceptable excipients selected from Tween 20, Solutol , Tween 80 and sodium metabisulfite either individually or in any combination thereof.

The term “diclofenac” herein refers to diclofenac or a pharmaceutically acceptable salt of diclofenac. A pharmaceutically acceptable salt of diclofenac, can be an alkali metal salt, for example the sodium or the potassium salt, or the salt formed with an amine, e.g., a mono-, di- or tri-C1-C4 alkylamine, for example diethyl- or triethyl-amine, hydroxy-C2 -C4 alkylamine, for example ethanolamine, or hydroxy-C2 -C4 alkyl-C1 -C4 alkylamine, for example dimethylethanolamine, or a quaternary ammonium salt, for example the tetramethylammonium salt or the choline salt of diclofenac (see, e.g., U.S. Pat. No. 5,389,681). Preferably the diclofenac salt is diclofenac sodium.

The “pharmaceutical compositions” for use in accordance with the present invention can be formulated in any conventional manner using one or more pharmaceutically acceptable carriers or excipients. A “pharmaceutically acceptable” carrier or excipient, as used herein, means carrier or excipient as approved by a regulatory agency of the Federal or a state government or listed in the Official Pharmacopoeia or other generally recognized pharmacopoeia for use in mammals, and more particularly in humans.

Pharmaceutical compositions include solid dosage forms, e.g., for perioral, transnasal (powder), or rectal (suppository) administration; and liquid dosage forms, e.g., for parenteral administration (injection), transnasal (spray), or perioral administration. In a specific embodiment, the pharmaceutical compositions of the present invention are liquid compositions formulated for intravenous or intramuscular administration, and particularly intravenous administration.

The term “dosage” is intended to encompass a formulation expressed in terms of mg/kg/day. The dosage is the amount of an ingredient administered in accordance with a particular dosage regimen. A “dose” is an amount of an agent administered to a subject in a unit volume or mass, e.g., an absolute unit dose expressed in mg of the agent. The dose depends on the concentration of the agent in the formulation, e.g., in moles per liter (M), mass per volume (m/v), or mass per mass (m/m). The two terms are closely related, as a particular dosage results from the regimen of administration of a dose or doses of the formulation. The particular meaning in any case will be apparent from context.

“Surfactant” herein refers to a compound that lowers the surface tension between two liquids or between a solid or a liquid and increase the solubility. A surfactant must contain a hydrophilic region and a lipophilic region. Surfactants are of four types: Anionic, Cationic, Non-ionic and Amphoteric surfactants.

The pharmaceutically acceptable carrier liquid is germ and pyrogen-free water in accordance with the specifications of national pharmacopoeias for intravenous or intramuscular administrable solutions.

The pharmaceutically acceptable carriers or excipients or ingredients preferably used in the present invention are FDA approved carriers or excipients or ingredients.

The carrier liquid may comprise non-toxic excipients that are acceptable for injection formulations, for example water-soluble excipients required for establishing isotonic conditions, for example ionic additives, or non-ionic additives. The ionic additives may include but not limited to sodium chloride. The non-ionic additives may include but not limited to sorbitol, mannitol, glucose, lactose, fructose or sucrose. In particular, those additives, for example sodium chloride or mannitol, are present in the amounts prescribed in national pharmacopoeias that are required for establishing isotonic conditions in the injection solutions.

The term “Tween 20” also named as “Polysorbate 20” herein refers to a polysorbate-type nonionic surfactant/emulsifying agent prepared by the ethoxylation of sorbitan. In other words, it is an oily liquid derived from PEG-ylated sorbitan (a derivative of sorbitol) esterified with fatty acids. Tween 20 (Polyoxyethylene sorbitan monolaurate) is used for the preparation of stable oil-in-water emulsions in a number of domestic, scientific, pharmaceutical and biochemical applications due to its good stability and nontoxicity. Further, it is also used as a dough improver, crystallisation retarder, solubiliser, stabiliser, flavour dispersant, wetting agent, fruit or vegetable coating, defoamer for yeast/sugar.

The term “Tween 80” also named as “Polysorbate 80” herein refers to a polysorbate-type nonionic surfactant/emulsifying agent prepared from polyethoxylated sorbitan (chemical compounds derived from the dehydration of sugar alcohol) and oleic acid. Tween 80 is used as an emulsifier or defoamer in foods, vitamins, medicines, and vaccines. It can also act as a surfactant in soaps and cosmetics, as well as a solubilizer which helps to dissolve ingredients for easily blending or mixing with each other.

The term “Solutol” also named as “Solutol HS 15” or “Macrogol-15-hydroxystearate” or “Kolliphor HS 15” herein refers to a nonionic solubilizer and emulsifying agent obtained by reacting ethylene oxide/polyethylene glycol with polyglycol mono- and di-esters of 12-hydroxy stearic acid. The main application is as nonionic solubiliser for manufacturing of aqueous parenteral preparations.

“Methionine” is one of nine essential amino acids in humans and naturally available as L-methhionine (L-alpha-amino-gamma-methylmercaptobutyric acid). Methionine is essential for absorption and bio-availability of selenium and zinc. Methionine chelates heavy metals, such as lead and mercury, aiding their excretion. It also acts as a lipotropic agent and prevents excess fat buildup in the liver. This excipient stabilizes proteins by a variety of mechanisms. The term methionine and L-methionine can be used interchangeably in the specification.

“Sodium metabisulfite” is a white crystalline or powder solid with a slight sulfur odor, prepared by evaporating a solution of sodium bisulfite saturated with sulfur dioxide. It is used as a preservative and antioxidant in various food and pharmaceutical preparations.

Preservatives used in the composition may include but not limited to Sodium metabisulfite, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, sodium benzoate, benzalkonium chloride, benzyl alcohol, chlorobutanol, and thiomerosal.

Inhibiting crystallization can be critical to maintain a certain solubilization of a drug within a medium. Because bioavailability of the crystalline form of an active ingredient is typically significantly lower in comparison to the dissolved state. Crystallization can be inhibited both in liquid and in solid formulations. Potential recrystallization in a liquid form can take place at any point in time after formulation, during storage or administration. In order to prevent crystallization, Glycerol as an anti-crystallizing agent has been used.
“Glycerol” also called glycerine or glycerin, is a simple polyol compound. Glycerol is a trihydroxy sugar alcohol that is an intermediate in carbohydrate and lipid metabolism. It is a colorless, odorless, viscous liquid that is sweet-tasting and non-toxic. It is used as a solvent, emollient, pharmaceutical agent, or sweetening agent. The glycerol backbone is found in many lipids which are known as glycerides. It is widely used in the food industry as a sweetener and humectant and in pharmaceutical formulations.

“Chelating agent” is a substance whose molecules can form several bonds to a single metal ion. In other words, a chelating agent is a multidentate ligand. An example of a simple chelating agent is ethylenediamine.

“Edetate Disodium” (Disodium EDTA) is the disodium salt form of edetate, a heavy metal chelating agent with anti-hypercalcemic and anti-arrhythmic properties. Edetate, a heavy metal antagonist, chelates divalent and trivalent metals, forming soluble stable complexes which are readily excreted by the kidneys. In brief, Edetate disodium is a chelating agent that sequesters a variety of polyvalent cations such as calcium. It is used in pharmaceutical manufacturing and as a food additive.

Thus in accordance of this invention, the alcohol free formulations are adjusted to pH 6 to 10 containing up to 100 mg of diclofenac salt in a medium comprising of water, along with one or more co-solvent(s)/solubiliser(s), antioxidants, preservatives, buffers, alkali and stabilizers.

In one aspect, the present invention provides a composition comprising diclofenac or its salts in combination with other pharmaceutically acceptable excipients selected from at least one nonionic solubilizer or surfactant, a solubiliser, sodium metabisulfite or any combination thereof.

In one aspect, the present invention provides a composition comprising diclofenac or its salts in combination with other pharmaceutically acceptable excipients selected from at least one nonionic solubilizer or surfactant, a solubiliser, L-methionine or any combination thereof.

In one aspect, the present invention provides a composition comprising diclofenac sodium in combination with other pharmaceutically acceptable excipients selected from Tween 20, Solutol, Tween-80 and sodium metabisulfite either individually or in any combination thereof.

In one aspect, the present invention provides a composition comprising diclofenac sodium in combination with other pharmaceutically acceptable excipients selected from Tween 20, Solutol, Tween-80 and L-methionine either individually or in any combination thereof.

In another aspect, the present invention provides a composition comprising diclofenac sodium, and Solutol.

In another aspect, the present invention provides a composition comprising diclofenac sodium, and Tween 20.

In another aspect, the present invention provides a composition comprising diclofenac sodium, Tween 20 and Solutol.

In another aspect, the present invention provides a composition comprising diclofenac sodium, Tween 20, Solutol and Tween 80.

In another aspect, the present invention provides a composition comprising diclofenac sodium, Tween 20, Solutol, Tween 80 and sodium metabisulfite.

In another aspect, the present invention provides a composition comprising diclofenac sodium, Tween 20, Solutol, Tween 80 and L-methionine.

In another aspect, the present invention provides a composition comprising diclofenac sodium, Solutol and Tween 80.

In one another aspect, the present invention provides a composition comprising diclofenac sodium and Tween 80.

In one another aspect, the present invention provides a composition comprising diclofenac sodium, Tween 20 and Tween 80.

In an embodiment of one aspect of the present invention, the composition has Tween 20 in the range of 0.1 to 10.0 wt%.

In an embodiment of one aspect of the present invention, the composition has Tween 20 in the range of 0.5 to 5.0 wt%.

In an embodiment of one aspect of the present invention, the composition has Tween 20 in the range of 1.5 to 2.0 wt%.

In an embodiment of one aspect of the present invention, the composition has Solutol in the range of 0.5 to 50.0 wt%.

In an embodiment of one aspect of the present invention, the composition has Solutol in the range of 5.0 to 25.0 wt%.

In an embodiment of one aspect of the present invention, the composition has Solutol in the range of 8.0 to 15.0 wt%.

In an embodiment of one aspect of the present invention, the composition has Tween 80 in the range of 3.5 to 6.0 wt%.

In yet another embodiment of one aspect of the present invention, the composition has sodium metabisulfite preferably in the range of 0.1-5.0 mg/ml, more preferably in the range of 0.5-3.0 mg/ml, most preferably in the range of 1.0-2.0 mg/ml.

In still another embodiment of one aspect of the present invention, the composition has L-methionine preferably in the range of 0.1-5.0 mg/ml, more preferably in the range of 0.2-4.0 mg/ml, most preferably in the range of 0.5-2.0 mg/ml.
In an embodiment of one aspect of the present invention, the buffering agent is selected from a group comprising citric acid, fumaric acid, acetic acid, trisodium citrate dihydrate, sodium phosphate, potassium phosphate, disodium hydrogenphosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydroxide or phosphoric acid.

The composition may also comprise Diclofenac in combination with other pharmaceutically active ingredients such as other anti-inflammatory, analgesic, and/or anti-pyretic agents.

Thus in accordance of this invention, the alcohol free formulations are adjusted to pH 6 to 10 containing up to 100 mg of diclofenac salt in a medium comprising of water, along with one or more co-solvent(s)/solubiliser(s), antioxidants, preservatives, buffers, alkali and stabilizers.

Some illustrative non-limiting examples of the present invention are described below.

EXAMPLES

Example 1
Preparation of alcohol free formulation containing Diclofenac sodium:
A parenteral preparation containing diclofenac sodium is prepared in an inert gas atmosphere by suspending the Solutol and diclofenac sodium in water for injection in a mixture of requisite quantity and mixed for 1 hour at 40°C. Solution cooled down at room temperature and pH is adjusted with sodium hydroxide to 8 - 9. The solution is diluted with water for injection to achieve the required concentration of 75 mg in 1 ml. The entire process is carried out under inert gas environment. The resultant solution is sterilized by sterile filtration and filled in ampoules flushed with inert gas prior to sealing.

The said composition/formulation has concentration of ingredients/excipients in following amount:

Serial No. Ingredients/Excipients Amount/Concentration
(in mg/ml)
1 Diclofenac sodium 75.00
2 Solutol 200.00
3 Sodium hydroxide q.s. to adjust pH
4 Water for Injection q.s. to 1 mL

Example 2
Preparation of alcohol free formulation containing Diclofenac sodium:
A parenteral preparation containing diclofenac sodium is prepared using below method.
Solution A: Sodium diclofenac and Solutol are dissolved under stirring in appropriate quantity in water for injection at 40°C, until a transparent colorless solution is obtained in an inert gas atmosphere.
Solution B: Tween 20 is dissolved in appropriate quantity in water for injection.
Solution B prepared as above is added to solution A, under stirring and stirred for 1 hour. Solution cooled down at room temperature and pH is adjusted with sodium hydroxide to 8 - 9. The solution is then brought to a final volume with water for injection and placed under stirring. After filtering through a filter, a transparent colourless solution is obtained with a sodium diclofenac concentration which, by HPLC analysis, was found to be 75.0 mg/ml. This solution, is packed and stored in accordance with the usual procedures adopted for injectable pharmaceutical formulations, remained clear for more than three months without showing crystal formation at room temperature.

The said composition/formulation has concentration of ingredients/excipients in following amount:
Serial No. Ingredients/Excipients Amount/Concentration
(in mg/ml)
1 Diclofenac sodium 75.00
2 Solutol 150.00
3 Polysorbate 20 / Tween 20 35.00
4 Sodium hydroxide q.s. to adjust pH
5 Water for Injection q.s. to 1 mL

Example 3
Preparation of alcohol free formulation containing Diclofenac sodium:
A parenteral preparation containing diclofenac sodium is prepared using below method.
Solution A: Sodium diclofenac and Solutol are dissolved under stirring in appropriate quantity in water for injection at 40°C, until a transparent colorless solution is obtained in an inert gas atmosphere.
Solution B: Tween 20 and Tween 80 are dissolved in appropriate quantity in water for injection.
Solution B prepared as above is added to solution A, under stirring and stirred for 1 hour. Solution cooled down at room temperature and pH is adjusted with sodium hydroxide to 8 - 9. The solution is then brought to a final volume with water for injection and placed under stirring. After filtering through a filter, a transparent colourless solution is obtained with a sodium diclofenac concentration which, by HPLC analysis, was found to be 75.0 mg/ml. This solution, is packed and stored in accordance with the usual procedures adopted for injectable pharmaceutical formulations, remained clear for more than three months without showing crystal formation at room temperature.

The said composition/formulation has concentration of ingredients/excipients in following amount:
Serial No. Ingredients/Excipients Amount/Concentration
(in mg/ml)
1 Diclofenac sodium 75.00
2 Solutol 120.00
3 Polysorbate 20 / Tween 20 20.00
4 Polysorbate 80 / Tween 80 35.00
5 Sodium hydroxide q.s. to adjust pH
6 Water for Injection q.s. to 1 mL

Example 4
Preparation of alcohol free formulation containing Diclofenac sodium:
A parenteral preparation containing diclofenac sodium is prepared using below method.
Solution A: Sodium diclofenac and Solutol are dissolved under stirring in appropriate quantity in water for injection at 40°C, until a transparent colorless solution is obtained in an inert gas atmosphere.
Solution B: Tween 20 and Tween 80 are dissolved in appropriate quantity of water for injection.
Solution C: L-methionine is dissolved in appropriate quantity in water for injection.
Solution B and Solution C prepared as above is added to solution A, under stirring and stirred for 1 hour. Solution cooled down at room temperature and pH is adjusted with sodium hydroxide to 8 - 9. The solution is then brought to a final volume with water for injection and placed under stirring. After filtering through a filter, a transparent colourless solution is obtained with a sodium diclofenac concentration which, by HPLC analysis, was found to be 75.0 mg/ml. This solution, is packed and stored in accordance with the usual procedures adopted for injectable pharmaceutical formulations, remained clear for more than three months without showing crystal formation at room temperature.

The said composition/formulation has concentration of ingredients/excipients in following amount:
Serial No. Ingredients/Excipients Amount/Concentration
(in mg/ml)
1 Diclofenac sodium 75.00
2 Solutol 120.00
3 Polysorbate 20 / Tween 20 20.00
4 Polysorbate 80 / Tween 80 35.00
5 L-methionine 1.20
6 Sodium hydroxide q.s. to adjust pH
7 Water for Injection q.s. to 1 mL

Example 5
Preparation of alcohol free formulation containing Diclofenac sodium:
A parenteral preparation containing diclofenac sodium is prepared using below method.
Solution A: Sodium diclofenac and Solutol are dissolved under stirring in appropriate quantity in water for injection at 40°C, until a transparent colorless solution is obtained in an inert gas atmosphere.
Solution B: Tween 20 and Tween 80 are dissolved in appropriate quantity of water for injection.
Solution C: Sodium metabisulfite is dissolved in appropriate quantity in water for injection.
Solution B and Solution C prepared as above is added to solution A, under stirring and stirred for 1 hour. Solution cooled down at room temperature and pH is adjusted with sodium hydroxide to 8 - 9. The solution is then brought to a final volume with water for injection and placed under stirring. After filtering through a filter, a transparent colourless solution is obtained with a sodium diclofenac concentration which, by HPLC analysis, was found to be 75.0 mg/ml. This solution, is packed and stored in accordance with the usual procedures adopted for injectable pharmaceutical formulations, remained clear for more than three months without showing crystal formation at room temperature.

The said composition/formulation has concentration of ingredients/excipients in following amount:
Serial No. Ingredients/Excipients Amount/Concentration
(in mg/ml)
1 Diclofenac sodium 75.00
2 Solutol 120.00
3 Polysorbate 20 / Tween 20 20.00
4 Polysorbate 80 / Tween 80 35.00
5 Sodium metabisulfite 1.50
6 Sodium hydroxide q.s. to adjust pH
7 Water for Injection q.s. to 1 mL

Example 6
Preparation of alcohol free formulation containing Diclofenac sodium:
A parenteral preparation containing diclofenac sodium is prepared using below method.
Solution A: Sodium diclofenac and Solutol are dissolved under stirring in appropriate quantity in water for injection at 40°C, until a transparent colorless solution is obtained in an inert gas atmosphere.
Solution B: Tween 20 and Tween 80 are dissolved in appropriate quantity of water for injection.
Solution C: Sodium metabisulfite is dissolved in water for injection.
Solution B and Solution C prepared as above is added to solution A, under stirring and stirred for 1 hour. Solution cooled down at room temperature and pH is adjusted with sodium hydroxide to 8 - 9. The solution is then brought to a final volume with water for injection and placed under stirring. After filtering through a filter, a transparent colourless solution is obtained with a sodium diclofenac concentration which, by HPLC analysis, was found to be 75.0 mg/ml. This solution, is packed and stored in accordance with the usual procedures adopted for injectable pharmaceutical formulations, remained clear for more than three months without showing crystal formation at room temperature.

The said composition/formulation has concentration of ingredients/excipients in following amount:
Serial No. Ingredients/Excipients Amount/Concentration
(in mg/ml)
1 Diclofenac sodium 75.00
2 Solutol HS 15 100.00
3 Polysorbate 20 / Tween 20 18.00
4 Polysorbate 80 / Tween 80 40.00
5 Sodium metabisulfite 1.00
6 Sodium hydroxide q.s. to adjust pH 8-9
7 Glycerol 0
8 Disodium EDTA 0
9 Water for Injection q.s. to 1 mL

Example 7
Preparation of alcohol free formulation containing Diclofenac sodium:
A parenteral preparation containing diclofenac sodium is prepared using below method.
Solution A: Sodium diclofenac and Solutol are dissolved under stirring in appropriate quantity in water for injection at 40°C, until a transparent colorless solution is obtained in an inert gas atmosphere.
Solution B: Tween 20 and Tween 80 are dissolved in appropriate quantity of water for injection.
Solution C: Sodium metabisulfite is dissolved in appropriate quantity in water for injection.
Solution D: Glycerol is dissolved in appropriate quantity of water for injection.
Solution B and Solution C prepared as above is added to solution A, under stirring and stirred for 1 hour. Then, added Solution D to said solution. Solution cooled down at room temperature and pH is adjusted with sodium hydroxide to 8 - 9. The solution is then brought to a final volume with water for injection and placed under stirring. After filtering through a filter, a transparent colourless solution is obtained with a sodium diclofenac concentration which, by HPLC analysis, was found to be 75.0 mg/ml. This solution, is packed and stored in accordance with the usual procedures adopted for injectable pharmaceutical formulations, remained clear for more than three months without showing crystal formation at room temperature.

The said composition/formulation has concentration of ingredients/excipients in following amount:

Serial No. Ingredients/Excipients Amount/Concentration
(in mg/ml)
1 Diclofenac sodium 75.00
2 Solutol HS 15 100.00
3 Polysorbate 20 / Tween 20 0
4 Polysorbate 80 / Tween 80 0
5 Sodium metabisulfite 0
6 Sodium hydroxide q.s. to adjust pH 8-9
7 Glycerol 50.00
8 Disodium EDTA 0
9 Water for Injection q.s. to 1 mL

Example 8
Preparation of alcohol free formulation containing Diclofenac sodium:
A parenteral preparation containing diclofenac sodium is prepared using below method.
Solution A: Sodium diclofenac and Solutol are dissolved under stirring in appropriate quantity in water for injection at 40°C, until a transparent colorless solution is obtained in an inert gas atmosphere.
Solution B: Tween 20 and Tween 80 are dissolved in appropriate quantity of water for injection.
Solution C: Sodium metabifulite is dissolved in appropriate quantity in water for injection.
Solution D: Glycerol and disodium EDTA is dissolved in appropriate quantity of water for injection.
Solution B and Solution C prepared as above is added to solution A, under stirring and stirred for 1 hour. Then, added Solution D to said solution. Solution cooled down at room temperature and pH is adjusted with sodium hydroxide to 8 - 9. The solution is then brought to a final volume with water for injection and placed under stirring. After filtering through a filter, a transparent colourless solution is obtained with a sodium diclofenac concentration which, by HPLC analysis, was found to be 75.0 mg/ml. This solution, is packed and stored in accordance with the usual procedures adopted for injectable pharmaceutical formulations, remained clear for more than three months without showing crystal formation at room temperature.

The said composition/formulation has concentration of ingredients/excipients in following amount:

Serial No. Ingredients/Excipients Amount/Concentration
(in mg/ml)
1 Diclofenac sodium 75.00
2 Solutol HS 15 100.00
3 Polysorbate 20 / Tween 20 0
4 Polysorbate 80 / Tween 80 0
5 Sodium metabisulfite 0
6 Sodium hydroxide q.s. to adjust pH 8-9
7 Glycerol 50.00
8 Disodium EDTA 0.1
9 Water for Injection q.s. to 1 mL
,CLAIMS:We Claim:
1. A stable alcohol free injectable pharmaceutical composition, comprising:
a) diclofenac or therapeutically equivalent amount of water soluble salt of diclofenac;
b) at least one non-ionic solubilizer or surfactant;
c) optionally, at least one solubilizer;
d) optionally, at least one anti-crystalizing agent, one chelating agent or any mixture thereof; and
e) at least one pharmaceutically acceptable excipient.
2. The composition as claimed in claim 1, wherein the water soluble salt of diclofenac is sodium salt.
3. The composition as claimed in any of the preceding claims, wherein the diclofenac or its water soluble salt is preferably present in an amount of 50 mg/ml to 100 mg/ml, more preferably present in an amount of 75 mg/ml.
4. The composition as claimed in any of the preceding claims, wherein the nonionic solubilizer or surfactant is selected from a group consisting of Macrogol-15-hydroxystearate (Solutol HS 15), 4-Octylphenol polyethoxylate (Triton X 100) and polyethoxylated castor oil (Cremophor EL), preferably Macrogol-15-hydroxystearate; and is present in an amount of 50-150 mg/ml.
5. The composition as claimed in any of the preceding claims, wherein the solubilizer is selected from a group comprising of polysorbate 20, polysorbate 80 and a combination thereof.
6. The composition as claimed in any of the preceding claims, wherein the polysorbate 20 is present in an amount of 10-30 mg/ml and the polysorbate 80 is present in an amount of 30-50 mg/ml.
7. The composition as claimed in any of the preceding claims, wherein the anti-crystalizing agent is selected from a group consisting of Glycerol, Propylene Glycol, Sorbitol, Polyvinyl Pyrrolidone, Hydroxy Propyl Methyl Cellulose, Polyvinyl alcohol and mannitol; and is present in an amount of 40-60 mg/ml.
8. The composition as claimed in any of the preceding claims, wherein the chelating agent is disodium EDTA and is present in an amount of 0.1-1.0 mg/ml.
9. The composition as claimed in any of the preceding claims, wherein the pharmaceutically acceptable excipients are selected from a group comprising of diluents, preservatives, antioxidants, buffering agents, amino acids and any combination thereof.
10. The composition as claimed in any of the preceding claims, wherein the diluent is water.
11. The composition as claimed in any of the preceding claims, wherein the preservative is present in an amount in the range of 0.1-5.0 mg/ml and is selected from a group comprising of sodium metabisulfite, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, sodium benzoate, benzalkonium chloride, chlorobutanol, thiomerosal, monothioglycerol, thioglycerols, acetyl cysteine, sodium bisulphate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbates, ascorbylpalmitate, tocopherol and any combination thereof.
12. The composition as claimed in any of the preceding claims, wherein the antioxidant is present in an amount in the range of 0.1-5.0 mg/ml and is selected from a group comprising of sodium metabisulfite, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, sodium benzoate, benzalkonium chloride, chlorobutanol, thiomerosal, monothioglycerol, thioglycerols, acetyl cysteine, sodium bisulphate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbates, ascorbylpalmitate, tocopherol and any combination thereof.
13. The composition as claimed in any of the preceding claims, wherein the amino acid is L-methionine and is present in an amount in the range of 0.1-5.0 mg/ml.
14. The composition as claimed in any of the preceding claims, wherein the composition further comprising acid or base for pH adjustment; wherein the acid is hydrochloric acid and the alkali is sodium hydroxide; and is present in an amount of sufficient quantity so as to adjust the pH of the composition in the range of 6-10, more preferably in the range of 8-9.
15. A process for the preparation of stable alcohol free injectable pharmaceutical composition, comprising:
a) suspending diclofenac or therapeutically equivalent amount of water soluble salt of diclofenac in a solvent system comprising one or more non-ionic solubilizers in sterile water or water for injection, with stirring under constant nitrogen purging to prepare a solution A;
b) optionally, adding one or more solubilizer in sterile water and under constant stirring to prepare a solution B;
c) adding at least one or more pharmaceutical acceptable excipient, in sterile water and under constant stirring to prepare a solution C;
d) optionally, adding at least one or more anti-crystallizing agent, chelating agent or mixture thereof, in sterile water and under constant stirring to prepare a solution D;
e) adding solution B, C and D in solution A with adjustment of pH between 8-9 using an acid or alkali;
f) diluting the final mixed solution with sterile water or water for injection (WFI) to achieve required concentration.
16. The process as claimed in any of the preceding claims, wherein the water soluble salt of diclofenac is sodium salt.
17. The process as claimed in any of the preceding claims, wherein the diclofenac or its water soluble salt is preferably present in an amount of 50 mg/ml to 100 mg/ml, more preferably present in an amount of 75 mg/ml.
18. The process as claimed in any of the preceding claims, wherein the nonionic solubilizer or surfactant is selected from a group consisting of Macrogol-15-hydroxystearate (Solutol HS 15), Triton X 100 and Cremophor EL, preferably Macrogol-15-hydroxystearate; and is present in an amount of 50-150 mg/ml.
19. The process as claimed any of the preceding claims, wherein the solubilizer is selected from a group comprising of polysorbate 20, polysorbate 80 and a combination thereof.
20. The process as claimed in any of the preceding claims, wherein the polysorbate 20 is present in an amount of 10-30 mg/ml and the polysorbate 80 is present in an amount of 30-50 mg/ml.
21. The process as claimed in any of the preceding claims, wherein the anti-crystalizing agent is selected from a group consisting of Glycerol, Propylene Glycol, Sorbitol, Polyvinyl Pyrrolidone, Hydroxy Propyl Methyl Cellulose, Polyvinyl alcohol and mannitol; and is present in an amount of 40-60 mg/ml.
22. The process as claimed in any of the preceding claims, wherein the chelating agent is disodium EDTA and is present in an amount of 0.1-1.0 mg/ml.
23. The process as claimed in any of the preceding claims, wherein the pharmaceutically acceptable excipients comprising diluents, preservatives, antioxidants, buffering agents, amino acid and any combination thereof.
24. The process as claimed in any of the preceding claims, wherein the diluent is water.
25. The process as claimed in any of the preceding claims, wherein the preservative is present in an amount in the range of 0.1-5.0 mg/ml and is selected from a group comprising sodium metabisulfite, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, sodium benzoate, benzalkonium chloride, chlorobutanol, thiomerosal, monothioglycerol, thioglycerols, acetyl cysteine, sodium bisulphate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbates, ascorbylpalmitate and tocopherol.
26. The process as claimed in any of the preceding claims, wherein the antioxidant is present in an amount in the range of 0.1-5.0 mg/ml and is selected from a group comprising sodium metabisulfite, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, sodium benzoate, benzalkonium chloride, chlorobutanol, thiomerosal, monothioglycerol, thioglycerols, acetyl cysteine, sodium bisulphate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbates, ascorbylpalmitate and tocopherol.
27. The process as claimed in any of the preceding claims, wherein the amino acid is present in an amount in the range of 0.1-5.0 mg/ml and is L-methionine.
28. The process as claimed in any of the preceding claims, wherein the composition further comprising acid or base for pH adjustment; wherein the acid is hydrochloric acid and the alkali is sodium hydroxide; and is present in an amount of sufficient quantity so as to adjust the pH of the composition in the range of 6-10, more preferably in the range of 8-9.
29. The process as claimed in claim 14, wherein the steps a) to e) is stirred for 30 minutes to 3 hours at a temperature in the range of 40-65°C.