COMPLETE DESCRIPTION
SUMMARY OF THE INVENTION
The present invention relates to an injectable dosage form for the arylalkanoic acid class of NSAIDs. The invention also relates to the formulation of sustained release injectable dosage form for the arylalkanoic acid class of NSAIDs.
BACKGROUND OF THE INVENTION
Parenteral drug formulations have become a very important component in the arsenal of available drug delivery options, particularly for drugs having analgesic effect. Parenteral routes of administration, including subcutaneous, intramuscular and intravenous injection, offer numerous benefits over oral delivery in particular situations, for a wide variety of drugs. For example, parenteral administration of a drug typically results in attainment of a therapeutically effective blood serum concentration of the drug in a shorter time than is achievable by oral administration. This is especially true of intravenous injection, whereby the drug is placed directly in the bloodstream. Parenteral administration can also result in more predictable blood serum concentrations of a drug, because losses in the gastrointestinal tract due to metabolism, binding to food and other causes are eliminated. For similar reasons, parenteral administration often permits dose reduction. Parenteral administration is generally the preferred method of drug delivery in emergency situations, and is also useful in treating subjects who are uncooperative, unconscious, or otherwise unable or unwilling to accept oral medication, and

where a faster relief is required in lesser time, especially in acute and chronic painful condition.
If a parenteral drug formulation is to be prepared, it is preferable from patient convenience and safety standpoints that such a formulation be a ready-to-use formulation, i.e. one that does not require dilution or mixing immediately prior to use (as opposed to a reconstitutable formulation). Ready-to-use and dilutable liquid parenteral formulations can also be advantageous from a manufacturing standpoint by avoiding expensive lyophilization and/or other similar manufacturing steps.
Diclofenac is a phenylacetic acid derivative. It is a potent cyclo-oxygenase inhibitor. Because Diclofenac has very poor gastrointestinal (GI) tolerability, it is not particularly well suited for formulation.
Diclofenac is used for the pain and inflammation management. Diclofenac is indicated in painful inflammatory conditions associated with musculoskeletal system, dysmenorrhoea, during post operative and post traumatic period. It is given in chronic inflammatory conditions like Rheumatoid arthritis and osteoarthritis.
The main problem with the injectable diclofenac was the pain at the site of injection. The reasons of the pain at the site of injection of diclofenac can be-
1) The injection of large volumes and
2) The presence of certain irritant exclpients.
As per the recommendations, the small volumes of the injectables should be given through the deltoid route while for administering the larger volumes, gluteal muscle should be the preferred route.

The reason for this is the large volume accommodation of gluteal muscle as compared to deltoid muscle because of the larger size of the former.
If the amount injected in the deltoid muscle is relatively larger, the solution will damage the fiber of the muscle tissue and this will cause pain and discomfort to the patient.
US patent no 4711906 discloses the aqueous, stable, relatively concentrated solutions of diclofenac, which contain a mixture of propylene glycol and polyethylene glycol in defined quantitative proportions. The solutions preferably contain a local anesthetic such as lidocaine and a reducing agent as stabilizer. The solvent consists of 10-70 weight % of a mixture of (a) propylene glycol and (b) polyethylene glycol.
This high amount of the irritating propylene glycol causes discomfort to the patients. Toxic effects have been reported after IV injection or instillation of drugs dissolved in propylene glycol. Propylene glycol may cause hypotension; bradycardia, and QRS and T abnormalities on the ECG; arrhythmia and cardiac arrest; and serum hyperosmolality and lactic acidosis (Karliner, 1967; Demey et al, 1988). Haemolysis may occur after i.v. administration (Demey et al, 1988).
At present, various diclofenac injections are available in the market containing single dose ampoules (75 mg per 3ml) and multidose vials (750mg per 30 ml).
U.S. Patent No. 5,389,681 discloses a pharmaceutical composition in the form of a sterilisable parenteral solution comprising a diclofenac salt and stabilisers, to a process for the preparation of that solution and to the use of stabilisers in that preparation process. The solubilizer used in the above formulation is 1,2-propylene glycol or polyethylene glycol 300-400.

EP 1574221 (Al) discloses stable parenteral aqueous solutions comprising either (a) diclofenac or a pharmaceutically acceptable diclofenac salt and a cyclodextrin, or (b) an inclusion complex of diclofenac or a pharmaceutically acceptable diclofenac salt and a cyclodextrin, or a mixture of (a) and (b), which are suitable for intramuscular and intravenous administration. The solutions contain diclofenac or diclofenac salt, cyclodextrin, and an antioxidant selected from monothioglycerol, or a combination of ethylene diamine tetra-acetic acid and N-acetyl-cysteine.
WO 2006095363 (A2) discloses 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 100mg 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.
CN 101244278 (A) discloses an injection formulation of diclofenac sodium for intravenous injection and the preparation method, which is characterized in that the diclofenac sodium is included successfully with the inclusion material of propyl-Beta-cyclodextrin. The injection formulation has the advantages of improving the solubility of diclofenac sodium in the solution and reducing the adverse reaction in intravenous injection. The injection formulation exists in the form of injection, frozen powder, sterile powder and large-capacity infusion. The invention also describes the main technical parameters of adopting propyl-

Beta -cyclodextrin to include the diclofenac sodium, such as inclusion method, the concentration of propyl-Beta-cyclodextrin, solution temperature in inclusion and inclusion time.
CN 101485650 (A) discloses the technical field of medicines, in particular to a diclofenac sodium lidocaine hydrochloride injection and a method for preparing the same. The invention aims to overcome defects in the prior art and provides the diclofenac sodium lidocaine hydrochloride injection with stable quality. Moreover, the invention also provides a method for preparing the diclofenac sodium lidocaine hydrochloride injection, which can avoid the technical difficult problem that the active ingredient, namely diclofenac sodium is separated out during the preparation of the injection.
WO 9603121 (Al) discloses an antiphlogistic, analgesic, antipyretic parenteral preparation comprising diclofenac, its salt, or both, a surfactant, and cosurfactant, and water, and having a pH of 3-10 is provided. Another antiphlogistic, analgesic, antipyretic parenteral preparation comprising diclofenac, its salt, or both, a surfactant, and co-surfactant, an oily component, and water, and having a pH of 3-10 is provided. The parenteral preparation can be injected without pain, can avoid occurrence of side effects such as shock, due to the rapid diclofenac plasma concentration increase, that after administration of currently marketed diclofenac preparations, and can exhibit sustained therapeutic levels of diclofenac in plasma.
The present invention provides a logical solution to the problem encountered in the prior art. The present invention provides a preparation of concentrated solution of diclofenac in a small volume thereby reducing the overall volume of the injection, thus lowering the pain of the patient. Small volumes also help the practitioners to administer the injection in the deltoid muscle.

The present invention also discloses that prior to this invention the large volume multi-dose vials of diclofenac were available (30ml). With this invention, smaller dose multi-dose vials can be prepared (10ml) thus increasing the patient's compliance in handling.
Furthermore, the volume of the single dose vial is also reduced with the present formulation from 3ml (prior art) to l-2ml (present invention.
The problem related to prior art was the presence of impurities in the raw material such as l-(2,6-dichlorophenyl)-l,3-dihydro-2H-indol-2-one, 2-[(2,6- dichlorophenyl) amino] benzaldehyde, [2-[(2,6- dichlorophenyl)amino]phenyl]methanol, 2-[2-[(2-bromo-6-chlorophenyl)amino]phenyl]acetic acid and l,3-dihydro-2H-indol-2-one (as listed in Pharmacopoeia) which can be forwarded in the finished product, through various formulation procedures, if not taken care of. The impurities present in the final formulation are relatively more fatal than the impurities present in the raw material. Furthermore, the impurities in the product can also be forms due to the degradation of the product.
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