DESC:FIELD OF THE INVENTION
The present invention relates to stable alcohol free pharmaceutical injectable formulations of diclofenac. More particularly, the invention relates to stable alcohol free pharmaceutical injectable formulations containing diclofenac or therapeutically equivalent amount of water soluble salt of diclofenac; at least one solubilizer; an amino acid; and at least one pharmaceutically acceptable excipient. The present invention advantageously provides a stable formulation of diclofenac over a long period of time. Further, the composition of the present invention compensates toxic effects of diclofenac.

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 alike 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.

In spite of said use of diclofenac, the diclofenac induced liver toxicity has been a major concern in today’s time since most of these are used for the long-term treatment. Hepatocytes death is a characteristic presentation that occurs in case of liver injury, mainly due to the fibrosis and necrosis.
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.

IN 1548/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 which is also safe for use.

The present invention discloses a stabilized concentrated alcohol free injectable pharmaceutical formulation, which addresses such problems existing in the art in an economic and effective way.

OBJECTIVES 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 preparations 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 concentrated 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 alcohol free injectable preparations containing single doses 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 alcohol free injectable preparation of water-soluble salts of diclofenac, with a minimized quantity of co-solvents to avoid any possible side effects.

It is yet another object of the invention to provide alcohol free concentrated injectable preparation of water-soluble salts of diclofenac, which reduces the possible hepatotoxic effects of diclofenac.

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 solubilizer; c) an amino acid; and d) at least one pharmaceutically acceptable excipient.
In an embodiment of one aspect of the present invention, the water soluble salt of diclofenac is sodium salt.
In an embodiment of one aspect of the present invention, the diclofenac or its water soluble salt is present in an amount of 50 mg/ml to 100 mg/ml.
In an embodiment of one aspect of the present invention, the diclofenac or its water soluble salt is present in an amount of 75 mg/ml.
In an embodiment of one aspect of the present invention, the solubilizer is selected from a group comprising of cyclodextrin, polysorbate 20 (Tween 20), Cremophor EL, acetic acid, 3-hydroxyethylactamide, polyethylene glycol, Cremophor RH 40, d-alpha-tocopherol polyethylene glycol 1000 succinate, sulfobutylether-beta-cyclodextrin, L-alpha-dimyristoylphosphatidyl- glycerol, hydrogenated soy phosphatidylcholine and any combination thereof.
In an embodiment of one aspect of the present invention, the cyclodextrin is selected from a group comprising of hydroxyethyl, hydroxypropyl, their corresponding mixed ethers, and mixed ethers with methyl or ethyl groups selected from the group consisting of methyl-hydroxyethyl, ethyl-hydroxyethyl and ethyl-hydroxypropyl ethers of a, ß, ?-cyclodextrin.
In an embodiment of one aspect of the present invention, the solubilizer is selected from a group comprising of hydroxypropyl ß-cyclodextrin, polysorbate 20 and a combination thereof.
In an embodiment of one aspect of the present invention, the amount of hydroxypropyl ß-cyclodextrin is in the range of 100-500 mg/ml.
In an embodiment of one aspect of the present invention, the amount of polysorbate 20 is in the range of 0.10-20.0 mg/ml.
In an embodiment of one aspect of the present invention, the amino acid is selected from a group comprising alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, l-methionine, phenylalanine, proline serine, threonine, tryptophan, tyrosine, valine and any combination thereof.
In an embodiment of one aspect of the present invention, the amino acid is present in an amount preferably in the range of 0.1-5.0 mg/ml.
In an embodiment of one aspect of the present invention, the pharmaceutically acceptable excipients are selected from a group comprising of diluents, preservatives, antioxidants, buffering agents and any combination thereof.
In an embodiment of one aspect of the present invention, the diluent is water.
In an embodiment of one aspect of the present invention, the preservative 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 an embodiment of one aspect of the present invention, the preservative is present in an amount in the range of 0.1-5.0 mg/ml.
In an embodiment of one aspect of the present invention, the antioxidant 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 an embodiment of one aspect of the present invention, the antioxidant is present in an amount in the range of 0.1-5.0 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.
In an embodiment of one aspect of the present invention, the buffering agent is present in an amount in the range of 1.0-10.0 mg/ml.
In an embodiment of one aspect of the present invention, the composition further comprising acid or base for pH adjustment.
In an embodiment of one aspect of the present invention, the acid is hydrochloric acid.
In an embodiment of one aspect of the present invention, the alkali is sodium hydroxide.
In an embodiment of one aspect of the present invention, the acid or base is present in an amount of sufficient quantity so as to adjust the pH of the composition in the range of 6-10.
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 solubilizers in sterile water or water for injection, with stirring under constant nitrogen purging to prepare a solution A; b) adding an amino acid(s) in sterile water and stirring under constant nitrogen purging to prepare a solution B; c) adding at least one pharmaceutically acceptable excipient to above prepared solution B; d) adding solution B in solution A with adjustment of pH between 8-9 using an acid or alkali; e) diluting the final mixed solution with sterile water or water for injection (WFI) to achieve required concentration.
In an embodiment of another aspect of the present invention, the water soluble salt of diclofenac is sodium salt.
In an embodiment of another aspect of the present invention, the diclofenac or its water soluble salt is present in an amount of 50 mg/ml to 100 mg/ml or in therapeutically equivalent amounts.
In an embodiment of another aspect of the present invention, the diclofenac or its water soluble salt is present in an amount of 75 mg/ml or in therapeutically equivalent amounts.
In an embodiment of another aspect of the present invention, the solubilizer is selected from a group comprising of cyclodextrin, polysorbate 20 (Tween 20), Cremophor EL, acetic acid, 3-hydroxyethylactamide, polyethylene glycol, Cremophor RH 40, d-alpha-tocopherol polyethylene glycol 1000 succinate, sulfobutylether-beta-cyclodextrin, L-alpha-dimyristoylphosphatidylglycerol, hydrogenated soy phosphatidylcholine and any combination thereof.
In an embodiment of another aspect of the present invention, the cyclodextrin is selected from a group comprising of hydroxyethyl, hydroxypropyl, their corresponding mixed ethers, and mixed ethers with methyl or ethyl groups selected from the group consisting of methyl-hydroxyethyl, ethyl-hydroxyethyl and ethyl-hydroxypropyl ethers of a, ß, ?-cyclodextrin and any combination thereof.
In an embodiment of another aspect of the present invention, the solubilizer is selected from a group comprising of hydroxypropyl ß-cyclodextrin, polysorbate 20 and a combination thereof.
In an embodiment of another aspect of the present invention, the amount of hydroxypropyl ß-cyclodextrin is preferably in the range of 100-500 mg/ml.
In an embodiment of another aspect of the present invention, the amount of polysorbate 20 is preferably in the range of 0.10-20.0 mg/ml.
In an embodiment of another aspect of the present invention, the amino acid is selected from a group comprising alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, l-methionine, phenylalanine, proline serine, threonine, tryptophan, tyrosine and valine.
In an embodiment of another aspect of the present invention, the amino acid is present in an amount preferably in the range of 0.1-5.0 mg/ml.
In an embodiment of another aspect of the present invention, the pharmaceutically acceptable excipients comprising diluents, preservatives, antioxidants, buffering agents and any combination thereof.
In an embodiment of another aspect of the present invention, the diluent is water.
In an embodiment of another aspect of the present invention, the preservative 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.
In an embodiment of another aspect of the present invention, the preservative is present in an amount preferably in the range of 0.1-5.0 mg/ml.
In an embodiment of another aspect of the present invention, the antioxidant 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.
In an embodiment of another aspect of the present invention, the antioxidant is present in an amount preferably in the range of 0.1-5.0 mg/ml.
In an embodiment of another 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.
In an embodiment of another aspect of the present invention, the buffering agent is present in an amount preferably in the range of 1.0-10.0 mg/ml.
In an embodiment of another aspect of the present invention, the pharmaceutically acceptable excipients further comprising acid or base for pH adjustment.
In an embodiment of another aspect of the present invention, the acid is hydrochloric acid.
In an embodiment of another aspect of the present invention, the alkali is sodium hydroxide.
In an embodiment of another aspect of the present invention, the acid or base is present in an amount of sufficient quantity so as to adjust the pH of the composition preferably in the range of 6-10.
In an embodiment of another aspect of the present invention, the step a) is stirred for 1-2 hours at a temperature in the range of 55-65°C.
In an embodiment of another aspect of the present invention, the step b) is stirred for 1-2 hours at a temperature in the range of 55-65°C.

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

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 cyclodextrin, Tween 20, methionine, trisoidum citrate 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.

“Pharmaceutically acceptable buffer” is meant a compound which resists a change in pH when H+ or OH- is added. A buffering agent can be a single compound or a combination of compounds. Pharmaceutically acceptable buffer are for e.g. a compound which allows to buffer the solution for parenteral administration to a pH of 6.8 to 8.0.

“Antioxidant” herein refers to a compound, employed to protect the active agent from oxidative degradation particularly under the accelerated conditions of thermal sterilization.

“Preservative” herein refers to a substance that prevents or inhibits the growth of microorganisms in the pharmaceutical preparation.

“Buffering agent” herein refers to a weak acid or base that is used in liquid preparation to prevent change in pH for providing product stability.

“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 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 “Cyclodextrin” herein refers to as oligosaccharides having biological properties similar to their linear counterparts, but differentiate in their physicochemical properties. More particularly, Cyclodextrins (CDs) belong to a family of cyclic oligosaccharides (BETA-cyclodextrin (7cyclo-(1,4)-anhydroglucose units) with a hydrophilic outer surface and a lipophilic central cavity. CD molecules are relatively large with a number of hydrogen donors and acceptors, due to which, they do not permeate lipophilic membranes. Cyclodextrins are able to form water-soluble inclusion complexes with many poorly soluble lipophilic drugs. Due to their property of forming water-soluble inclusion complexes, Cyclodextrins are used to enhance the aqueous solubility of drugs and to improve drug bioavailability and stability. Cyclodextrin complexation helps in formulating poorly soluble drugs as aqueous parenteral solutions, nasal sprays and eye drop solutions. Cyclodextrin oligosaccharides are non-toxic and pharmacologically inactive excipients for being used in both drug and food products.

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.

“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.

“Trisodium Citrate” is a tribasic salt of citric acid. It is produced by complete neutralisation of citric acid with high purity sodium hydroxide or carbonate followed by crystallisation. Trisodium citrate dihydrate is a non-toxic, neutral salt with low reactivity. It is chemically stable if stored at ambient temperatures. Trisodium citrate dihydrate is widely used in foods, beverages and various technical applications mainly as buffering, sequestering or emulsifying agent.

“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.

In one aspect, the present invention provides an alcohol free composition comprising diclofenac or its salts in combination with other pharmaceutically acceptable excipients selected from a cyclodextrin, a polysorbate-type nonionic surfactant, an amino acid, a citrate salt, a preservative, an antioxidant, or any combination thereof. In a preferred aspect, cyclodextrin is Hydroxypropyl Beta Cyclodextrin, polysorbate-type nonionic surfactant is Tween-20, amino acid is methionine, citrate salt is trisodium citrate, and sodium metabisulfite is preservative and antioxidant.

In one aspect, the present invention provides an alcohol free composition comprising diclofenac sodium in combination with other pharmaceutically acceptable excipients selected from cyclodextrin, Tween 20, methionine, trisodium citrate and sodium metabisulfite either individually or in any combination thereof.

In another aspect, the present invention provides an alcohol free composition comprising diclofenac sodium, and cyclodextrin.

In another aspect, the present invention provides an alcohol free composition comprising diclofenac sodium, cyclodextrin and Tween 20.

In another aspect, the present invention provides an alcohol free composition comprising diclofenac sodium, cyclodextrin, Tween 20 and methionine.

In another aspect, the present invention provides an alcohol free composition comprising diclofenac sodium, cyclodextrin, Tween 20, methionine and trisodium citrate.

In another aspect, the present invention provides an alcohol free composition comprising diclofenac sodium, cyclodextrin, Tween 20, methionine, trisodium citrate and sodium metabisulfite.

In one another aspect, the present invention provides an alcohol free composition comprising diclofenac sodium and Tween 20.

In one another aspect, the present invention provides an alcohol free composition comprising diclofenac sodium, Tween 20 and methionine.

In one another aspect, the present invention provides an alcohol free composition comprising diclofenac sodium, Tween 20, methionine and trisodium citrate.

In one another aspect, the present invention provides an alcohol free composition comprising diclofenac sodium, Tween 20, methionine, trisodium citrate and sodium metabisulfite.

In still another aspect, the present invention provides an alcohol free composition comprising diclofenac sodium and methionine.

In still another aspect, the present invention provides an alcohol free composition comprising diclofenac sodium, methionine and trisodium citrate.

In still another aspect, the present invention provides an alcohol free composition comprising diclofenac sodium, methionine, trisodium citrate and sodium metabisulfite.

In still one another aspect, the present invention provides an alcohol free composition comprising diclofenac sodium and trisodium citrate.

In still one another aspect, the present invention provides an alcohol free composition comprising diclofenac sodium, trisodium citrate and sodium metabisulfite.

In still one another aspect, the present invention provides an alcohol free composition comprising diclofenac sodium and sodium metabisulfite.

In one embodiment of the present invention, the amount of diclofenac sodium in the composition of the present invention is preferably in the range of 50-100 mg/ml, more preferably in the range of 60-90 mg/ml, most preferably 75 mg/ml.

In another embodiment of the present invention, the amount of cyclodextrin in the composition of the present invention is preferably in the range of 100-500 mg/ml, more preferably in the range of 200-400 mg/ml, most preferably in the range of 250-350 mg/ml.

In one another embodiment of the present invention, the amount of Tween 20 in the composition of the present invention is preferably in the range of 0.10-20.0 mg/ml, more preferably in the range of 0.20-15.0 mg/ml, most preferably in the range of 0.50-10.0 mg/ml.

In still another embodiment of the present invention, the amount of L-methionine in the composition of the present invention is 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 still one another embodiment of the present invention, the amount of trisodium citrate in the composition of the present invention is preferably in the range of 1.0-10.0 mg/ml, more preferably in the range of 2.0-9.0 mg/ml, most preferably in the range of 4.0-8.0 mg/ml.

In yet another embodiment of the present invention, the amount of sodium metabisulfite in the composition of the present invention is 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 yet one another embodiment of the present invention, the amount of sodium hydroxide in the composition of the present invention is in amount of sufficient quantity so as to adjust the pH of the composition preferably in the range of 6-10, more preferably the range of 7-9 and most preferably in the range of 8-9.

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.

Cyclodextrins used in the composition may include but not limited to a (alpha)-cyclodextrin: 6-membered sugar ring molecule, ß (beta)-cyclodextrin: 7-membered sugar ring molecule and ? (gamma)-cyclodextrin: 8-membered sugar ring molecule.

Amino acids used in the composition may include but not limited to alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline serine, threonine, tryptophan, tyrosine and valine.

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, chlorobutanol, and thiomerosal.

Buffering agents used in the composition may include but not limited to citric acid, fumaric acid, acetic acid, trisodium citrate, sodium phosphate, potassium phosphate, disodium hydrogenphosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydroxide or phosphoric acid.

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

EXAMPLES
Example 1
Preparation of alcohol free formulation containing Diclofenac sodium:
Preparation of Solution A:
A parenteral preparation containing diclofenac sodium is prepared in an inert gas atmosphere by suspending the hydroxypropyl beta-cyclodextrin and diclofenac sodium in sterile water in a mixture of requisite quantity and mixed for 1 hour at 60°C.
Preparation of Solution B:
Tween 20, L-methionine, Trisodium citrate and Sodium metabisulfite is mixed in appropriate quantity of sterile water and mixed till it gets dissolved.

Solution B is slowly added to Solution A with proper mixing and pH is adjusted with sodium hydroxide to 8-9. The solution is diluted with sterile water to achieve the required concentration of 75 mg in 1 ml. The entire process is carried out under inert gas environment. The ingredients may be mixed in any order. 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 Cyclodextrin 330.00
3 Polysorbate 20 / Tween 20 0.5
4 L-methionine 1.0
5 Trisodium citrate 6.0
6 Sodium metabisulfite 1.0
7 Sodium hydroxide q.s. to adjust pH
8 Water for injection q.s. to 1 mL

Example 2Preparation of alcohol free formulation containing Diclofenac sodium:
Preparation of Solution A:
A parenteral preparation containing diclofenac sodium is prepared in an inert gas atmosphere by suspending the hydroxypropyl beta-cyclodextrin and diclofenac sodium in sterile water in a mixture of requisite quantity and mixed for 1 hour at 60°C.
Preparation of Solution B:
Tween 20, L-methionine, Trisodium citrate and Sodium metabisulfite is mixed in appropriate quantity of sterile water and mixed till it gets dissolved.

Solution B is slowly added to Solution A with proper mixing and pH is adjusted with sodium hydroxide to 8-9. The solution is diluted with sterile water to achieve the required concentration of 75 mg in 1 ml. The entire process is carried out under inert gas environment. The ingredients may be mixed in any order. 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 Cyclodextrin 300.00
3 Polysorbate 20 / Tween 20 0.75
4 L-methionine 0.85
5 Trisodium citrate 6.50
6 Sodium metabisulfite 1.20
7 Sodium hydroxide q.s. to adjust pH

Example 3
Preparation of alcohol free formulation containing Diclofenac sodium:
A parenteral preparation containing diclofenac sodium is prepared using other method.
Solution A: Tween 20 is dissolved in deionised water.
Solution B: ß-cyclodextrin is dissolved under stirring, in deionised water at 60°C, until a transparent colourless solution is obtained. Diclofenac sodium and Solution A prepared as above are added to solution B, under stirring and stirred for 1 hour. The pH of the solution is adjusted to 8-9. The solution is then brought to a final volume with deionised water and placed under stirring in inert gas environment. After filtering through a filter, a transparent colourless solution is obtained with a diclofenac sodium concentration which, by HPLC analysis, was found to be 75.00 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 Cyclodextrin 320.00
3 Tween 20 0.60
4 Sodium hydroxide q.s. for pH adjustment

Example 4
Preparation of alcohol free formulation containing Diclofenac sodium:
A parenteral preparation containing diclofenac sodium is prepared using other method.
Solution A: ß-cyclodextrin and Tween 20 is dissolved in deionised water at 60°C.
Diclofenac Sodium in said quantity is added to the Solution A at 60°C and stirred for 2 hours. pH of the solution is adjusted to 8-9. The solution is then brought to a final volume with deionised water and added L-methionine with 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 75.00 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 Cyclodextrin 330.00
3 Tween 20 0.80
4 L-methionine 1.20
5. Sodium Hydroxide q.s to adjust pH

Example 5
Preparation of alcohol free formulation containing Diclofenac sodium:
A parenteral preparation containing diclofenac sodium is prepared using other method.
Solution A: ß-cyclodextrin is dissolved in deionised water at 60 ± 2 °C. Diclofenac sodium is said quantity is added to solution at 60 ± 2 °C and stirred for 2 hours with inert gas purging.
Solution B: Tween 20, L-methionine and trisodium citrate in described quantity is dissolved under stirring, in deionised water.
Solution B is then transferred to Solution A slowly under stirring, stirred for 1 hour. pH is adjusted to 8-9. The solution is then brought to a final with deionized water. After filtering through a filter, a transparent colourless solution is obtained with a Diclofenac sodium concentration which, by HPLC analysis, was found to be 75.00 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 Cyclodextrin 310.00
3 Tween 20 1.20
4 L-methionine 1.80
5 Trisodium citrate 5.50
6. Sodium Hydroxide q.s. to pH adjustment

Example 6
Preparation of alcohol free formulation containing Diclofenac sodium:
A parenteral preparation containing diclofenac sodium is prepared using other method.
Solution A: ß-cyclodextrin and Diclofenac sodium are dissolved in deionised water at 65°C and stirred for 3 hours.
Solution B: Tween 20, L-methionine, Trisodium citrate and Sodium metabisulfite in said quantity are dissolved under stirring in deionised water, until a transparent colourless solution is obtained.
Solution B is added to Solution A under stirring and with continuous inert gas purging. pH of the mixed solution is adjusted to 8-9. The solution is then brought to a final volume with deionised water. After filtering through a filter, a transparent colourless solution is obtained with a sodium diclofenac concentration which, by HPLC analysis, was found to be 75.00 mg/ml. This solution, is packed and stored in accordance with the usual procedures adopted for injectable pharmaceutical formulations, remained clear for more than 3 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 Cyclodextrin 250.00
3 Tween 20 10.00
4 L-methionine 1.50
5 Trisodium citrate 7.20
6 Sodium metabisulfite 1.80
7 Sodium hydroxide q.s. to pH adjustment

,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 solubilizer;
c) an amino acid; and
d) 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 present in an amount of 50 mg/ml to 100 mg/ml.
4. The composition as claimed in any of the preceding claims, wherein the diclofenac or its water soluble salt is present in an amount of 75 mg/ml.
5. The composition as claimed in any of the preceding claims, wherein the solubilizer is selected from a group comprising of cyclodextrin, polysorbate 20 (Tween 20), Cremophor EL, acetic acid, 3-hydroxyethylactamide, polyethylene glycol, Cremophor RH 40, d-alpha-tocopherol polyethylene glycol 1000 succinate, sulfobutylether-beta-cyclodextrin, L-alpha-dimyristoylphosphatidylglycerol, hydrogenated soy phosphatidylcholine and any combination thereof.
6. The composition as claimed in any of the preceding claims, wherein the cyclodextrin is selected from a group comprising of hydroxyethyl, hydroxypropyl, their corresponding mixed ethers, and mixed ethers with methyl or ethyl groups selected from the group consisting of methyl-hydroxyethyl, ethyl-hydroxyethyl and ethyl-hydroxypropyl ethers of a, ß, ?-cyclodextrin.
7. The composition as claimed in any of the preceding claims, wherein the solubilizer is selected from a group comprising of hydroxypropyl ß-cyclodextrin, polysorbate 20 and a combination thereof.
8. The composition as claimed in any of the preceding claims, wherein the amount of hydroxypropyl ß-cyclodextrin is in the range of 100-500 mg/ml.
9. The composition as claimed in any of the preceding claims, wherein the amount of polysorbate 20 is in the range of 0.10-20.0 mg/ml.
10. The composition as claimed in any of the preceding claims, wherein the amino acid is selected from a group comprising alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, l-methionine, phenylalanine, proline serine, threonine, tryptophan, tyrosine, valine and any combination thereof.
11. The composition as claimed in any of the preceding claims, wherein the amino acid is present in an amount preferably in the range of 0.1-5.0 mg/ml.
12. 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 and any combination thereof.
13. The composition as claimed in any of the preceding claims, wherein the diluent is water.
14. The composition as claimed in any of the preceding claims, wherein the preservative 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.
15. 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.
16. The composition as claimed in any of the preceding claims, wherein the antioxidant 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.
17. 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.
18. The composition as claimed in any of the preceding claims, wherein 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.
19. The composition as claimed in any of the preceding claims, wherein the buffering agent is present in an amount in the range of 1.0-10.0 mg/ml.
20. The composition as claimed in any of the preceding claims, wherein the composition further comprising acid or base for pH adjustment.
21. The composition as claimed in any of the preceding claims, wherein the acid is hydrochloric acid.
22. The composition as claimed in any of the preceding claims, wherein the alkali is sodium hydroxide.
23. The composition as claimed in any of the preceding claims, wherein the acid or base is present in an amount of sufficient quantity so as to adjust the pH of the composition in the range of 6-10.
24. 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 solubilizers in sterile water or water for injection, with stirring under constant nitrogen purging to prepare a solution A;
b) adding an amino acid(s) in sterile water and stirring under constant nitrogen purging to prepare a solution B;
c) adding at least one pharmaceutically acceptable excipient to above prepared solution B;
d) adding solution B in solution A with adjustment of pH between 8-9 using an acid or alkali;
e) diluting the final mixed solution with sterile water or water for injection (WFI) to achieve required concentration.
25. The process as claimed in claim 24, wherein the step a) and step b) is carried out with stirring for 1-2 hours at a temperature in the range of 55-65°C.