SUMMARY OF THE INVENTION
The present invention relates to an injectable dosage form for Diclofenac. The
invention also relates to the formulation of sustained release injectable dosage
form for the arylalkanoic acid class of NSAIDs.
BACKGROUND OF THE INVENTION
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-
-The injection of large volumes and
-The presence of certain irritant excipients.
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 471 1906 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 all 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.
Further, the formulation existing in the market are of 1 ml or of above volume.
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.
OBJECTIVES' OF THE INVENTION
The main objective of this invention is to provide the injectable formulation of
NSAlDs of arylalkanoic acid class in a low volume that will cause less pain to
the patient when administered. Thus the present invention can also be
administered through the deltoid, besides gluteal route and intravenous route.
Yet another objective of this invention is to provide the therapeutically effective
dose of diclofenac in a very small volume without increasing the viscosity of the
solution.
Yet another objective of the invention is to provide injectable formulation having
no irritating excipients so as to avoid patient's inconvenience.
Another objective of the invention is to provide a sustained release dosage
formulation for the better patient's compliance.
Another objective of the invention is to provide a smaller volume multi-dose as
well as single dose vial for easy handling.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the formulation of the parenteral preparation
containing the NSAlDs of arylalkanoic acid class containing pharmaceutically
accepted salts of the active ingredients, suitable solvent for dissolving the active
ingredients, the preservative for preserving the solution, the other excipients
such as chelating agents and antioxidants.
Furthermore, this invention also discloses the method for preparation of the
depot formation of the parenteral formulation containing the NSAlDs of
arylalkanoic acid class containing pharmaceutically accepted salts of the active
ingredients, suitable solvent for dissolving the active ingredients, the
preservative for preserving the solution, the other excipients such as chelating
agents and antioxidants and the agents used for depot formation.
The NSAlD of pharmaceutically accepted salts of arylalkanoic acid class may
be the pharmaceutically accepted salt of Diclofenac and Aceclofenac, more
preferably diclofenac. The suitable solvent used in the present invention is Poly
Ethylene Glycol.
The suitable preservative may be Benzalkonium chloride and Benzyl alcohol,
more preferably Benzyl alcohol.
The other excipients may be chelating agents like Disodium EDTA and
antioxidants like sodium sulphite anhydrous.
The agent that provides a depot formation or the sustained release formulation
can be selected from the group consisting of peanut oil, cotton seed oil, sesame
oil, castor oil, olive oil, corn oil, and iodinated poppy seed oil fatty acid ethyl
esters, more preferably castor oil.
The volume of the present invention is from 0.5 ml-0.99 ml preferably 0.75 ml.
Diclofenac present in the said formulation is 75 mg-100 mg, whereas the
solvent used is 10-15% of polyethylene glycol 300, preferably 12% of
Polyethylene glycol 300. The preservative used is 8-12% Benzyl alcohol,
preferably 10% of Benzyl alcohol.
SIGNATURE of Mr. Sanjeev Jain (Inventor and Authorized representative of
Applicant) w (Sh. Sanjeev Jain) Delhi Dated 19/03/2013

CLAIMS
We Claim:
1) An low volume parenteral formulation of high concentration of arylalkanoic
acids comprising:
a) arylalkanoic acid component
b) a solvent
c) Stabilizer, chelating agent and antioxidant and
d) optionally depot forming agents.
2) The arylalkanoic acids as claimed in 1 may be Diclofenac or aceclofenac,
preferably diclofenac, in their pharmaceutically acceptable salts, wherein the
range of diclofenac is from 75 mgl0.5ml to 75mg/0.99ml, preferably 75
mgl0.75ml.
3) Solvent as claimed in claim 1 is 10-15% of polyethylene glycol 300,
preferably 12% of Polyethylene glycol 300.
4) Suitable stabilizer as claimed in claim 1 may be Benzalkonium chloride and
Benzyl alcohol, more preferably Benzyl alcohol, wherein the .range of benzyl
alcohol may be 8% to 12% vlv, more preferably 10% vlv.
5) Chelating agent as claimed in claim 1 may be Disodium EDTA.
6) Antioxidant as claimed in claim 1 may be sodium bisulphite anhydrous.
7) Agent that provides a depot formation, as claimed in claim 1 can be selected
from the group consisting of peanut oil, cotton seed oil, sesame oil, castor oil,
olive oil, corn oil, and iodinated poppy seed oil fatty acid ethyl esters, more
preferably castor oil.
SIGNATURE of Mr. Sanjeev Jain (Inventor and Authorized representative of
Applicant)