"STABLE HIGH CONCENTRATION INJECTABLE FORMULATION OF DICLOFENAC"
2. APPLICANT($)
(a) NAME: M/s Akums Drugs & Pharmaceuticals Limited through its Director
a~d Authorized representative Sh. Sanjeev Jain (Inventor).
(b) NATIONALITY: AN INDIAN Company Incorporated under the provisions of
Companies Act, 1956
(c) ADDRESS: 304, Mohan Place, LSC, Block-C, Saraswati Vihar, Delhi-110034
3. PREMBLE TO THE DESCRIPTION:
"The following specification particularly describes the invention and the
manner in which it is to be performed"
4. COMPLETE v
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DESCRIPTION
FIELD OF THE INVENTION
The present invention relates to an innovation of a pharmaceutical formulation. Further, the
present invention discloses a pharmaceutical formulation comprising Diclofenac in an injectable
dosage form. Furthermore, the present invention describes the method to manufacture a stable,
high concentration Diclofenac injection with a novel solvent system.
USE OF THE INVENTION
The use of the invention is to administer a therapeutic dose of Diclofenac through injectable
dosage form. Further, the administration of Diclofenac injection formulated through the process
of invention results in no pain at the si~e of injection and no side effects. Thus, the formulation
of this invention is safe and. effective and increases patient's convenience.
PRIOR ART
Indian Patent Application Number 1382/MUM/2008 discloses a pharmaceutical formulation
containing high concentration of Diclofenac (or its salts) injection that provides ease of
administration to the patient. Diclofenac and its pharmaceutically acceptable salts in higher
concentration (75 mg/ml) injectable dosage form results in unique painless and easy to
administrate dosage form. The formulation contains pharmaceutically acceptable and clinically
safe excipients. The formulation does not cont~In propylene glycol and its derivatives as they
cause irritation at the site of injection. The formulation contains pharmaceutically acceptable
preservatives and buffering agents in water for injection base.
Indian Patent Number 231566 discloses a process for the preparation of a synergistic antispasmodic
composition to be used as injection which comprises distilling Benzyl alcohol as pain
reducer and dissolving it in a solvent propylene glycol, separately dissolving Diclofenac or its
'·
salts, in water, mixing the said pain reducer solution with the Diclofenac or its salts solution to
form a dissolved mixture, mixing pitofenone hydrochoride with said dissolved mixture and
adding thereto Fenpiverinium bromide to form the desired injectable composition wherein
Diclofenac or its salts, pitofenone hydrochloride and Fenpiverinium bromide are present in the'
following proportions : Diclofenac or its salts .. from 1.0 to 10 % w/v. Pitofenone hydrochloride
from 0.05 to 2.0 % w/v. Fenpiverinium bromide .. from 0.001 to 0.2% w/v.
PCT/182004/003918 relates to 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.
US5389681 relates to a pharmaceutical composition in the form of a sterilizable parenteral
solution comprising a diclofenac salt and stabilizers, such as ethyl lactate combined with
glutathione or N-acetylcysteine.
US4711906 discloses 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
staoilizer.
PROBLEMS TO BE SOLVED
Till today there are very few formulations which provide the administration of therapeutically
effective amount of Diclofenac in the body through injection, without causing much pain.
Further, most of the formulation of Diclofenac in market contains Propylene Glycol as a solvent.
• .. ..
Propylene glycol is a known irritant and high concentration of propylene glycol in the injectable
formulation will cause pain and irritation. Thus, the present formulation is directed to a stable
formulation which does not cause any pain at the sight of injection. Further, for dissolving high
quantity of Diclofenac, an optimum solvent system is required. Thus the present invention
provides a unique solvent system through which a less viscous injectable formulation of
Diclofenac can be prepared, that results in improving patient's compliance.
The majority of the Diclofenac injections available in the market can only be injected, with ease,
on intra-gluteal muscles. However, the injection prepared according to the present inventive
process can be injected in both intra-gluteal as well as intra-deltoid muscles.
The prior art mentioned above contains solvent systems which results in a high viscous
formulation. The present invention results in a low viscous formulation.
OBJECT OF THE INVENTION
The object of the present invention is to provide a high concentrated Diclofenac injection.
Another object of the present invention is to provide a formulation which has a very low volume,
yet provides a therapeutic quantity of Diclofenac.
Yet another object of the present invention is to provide a less viscous solution which adds to
patient's compliance.
Another object of the Present invention is to provide a process which is_industrially applicable,
resulting in a stable formulation and can be administered intra-gluteal, intra-deltoid muscles as
well as Intravenous infusion.
Another object of the present invention is to provide a formulation which is stable and does not
precipitate through a range of temperature.
GENERAL STATEMENT OF INVENTION
The present invention is related to a stable, high concentrated Diclofenac injection with low
viscosity. The low viscous high concentrated injection will cause virtually no pain at the site of
injection.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is related to a method of formulating a highly concentrated and low
viscous formulation of Diclofenac injection. The present invention is a low viscous injection
which is easier in administration and also the invention is stable through a range of temperature,
in which the other high concentration diclofenac injections gets precipitated.
The formulations manufactured according to invention passes the freeze thaw test.
The injection comprises diclofenac, solvent, preservative and other essential ingredients used
for the formulation of injection.
Prior to the above formulation, surfactants were added to increase the solubility of diclofenac in
the formulation and without surfactant, a single solvent system does not provide a stable
formulation
The inventor was surprised to see that no surfactant is required to formulate the product as the
solvent used was sufficient to keep dissolve the diclofenac in the formulation through a range of
temperature. ··-
The concentration of diclofenac range from 30 mg/ml to 100 mg/ml. The solvent system may be
selected either from dimethyl acetamide or N-Methylpyrrolidone, or transcutol or the
combination of above.
The preferable concentration of diclofenac injection is 37.5 mg/ml and 75mg/ml.
The preservative is preferably Benzyl alcohol.
The other ingredients included are those which may be required for the formulation of an
injection. The other ingredients may include Antioxidants preferably sodium sulphite and a
buffer to maintain the pH.
The present invention may be formulated, but not limited to, in the following manner.
Specificat Quantity Required
S. No. Material Name
ion mg/ml Kg/1000 Lit
1. Diclofenac Sodium IP 75mg 75 kg*
2. Dimethyl Acetamide BP 0.2 ml 200 ltr.
3. Benzyl Alcohol IP 0.04ml 40 ltr.
4. Sodium Sulphite IP 3mg 3 kg
a.s. to pH 8.1 to a.s. to pH
5. 0.5 N HCI IH
9.0 8.1 to 9.0
6. Water for injection .IP as to 1 ml as to 1o oo Lit _-, -·
Method of Manufacture
Preparation of Solvent system
- 5 -·-- - -=z =e .s-~ ~ - •• : I
Take approx 200 Liters of DMA (Dimethyl Acetamide) and add Benzyl Alcohol 40 Liters put
under stirring approx. 20 minutes.
Addition of API
Now add 75 Kg of Diclofenac Sodium J.P. to the above solution under stirring until the entire
drug get dissolved and a clear solution is obtained. Keep it under stirring for about 30 minutes.
Then added 250.0 Liters of W.F.I. and kept it under stirring for about 15 min.
Addition of Antioxidant:
Take 50.0 liters of W.F.I. in a SS vessel and heat upto 50-60"C for 15 min then add 3.0 Kg of
Sodium Sulphite under stirring until the entire Sodium Sulphite get dissolved and cool the
solution 30-35"C before use. Then· transferred Sodium Sulphite solutions to the above API
solution under stirring and stir for 20 min.
Volume make up:
Now make up the v:olume up to 990 Liters with W.F.I. and keep under stirring for another 120
minutes followed by pH adjustment.
pH Adjustment
Add sufficient amount of 0.5 N HCL to adjust the pH (8 - 9) followed through the addition of
re_maining W.F.I. to make up the volume up to 1000 liters. ~tir it for 30 minutes.
·-- ·-.
Filtration
Filter final solution through 0.22JJ filter. Now send the sample to Q.C. for analysis.
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According to another embodiment, the present invention can also be formulated through the
above process with •the following ingredients, that will effectively provides a concentration of
75mg/2mL
5. Quantity
Material Name Specification Label Claim UOM
No. Required
1. Diclofenac Sodium IP 75 mg/2ml Kg 37.5*
2. Dimethyl Acetamide BP - Lit. 200
3. Benzyl Alcohol IP 0.04 ml/2ml Lit. 20
4. Sodium ~ulphite IP - Kg 3
5. 0.5 N HCI IH - Lit. 3
6. Water for Injections IP - Lit. q.s.
Toxicity Study:
The preferable embodiment of the invention has also undergone toxicity study and shows that
the formulation manufactured by using the process and the ingredients disclosed in the ·- invention is-non· toxic and does not give any unknown side effects. ...-
The toxicity study concludes as follows:
There was abnormality and lesion found from histopathological examination of the organs viz.
Heart, Kidneys, Liver, Lung, Stomach.
The drug did not show any significant feature of abscess, heamatological toxicity, behavioral
toxicity, hepatotoxicity and hepatotoxicity in any of the specimen.
SIGNATURE of Mr. Sanjeev Jain (Inventor and Authorized representative of
Applicant)
(Sh. Sanjeev Jain)
Delhi
Dated 31/05/2016

We claim:
1) An aqueous parenteral formulation of high concentration of diclofenac solvent and stabilizer
system, causing no pain at the site of injection and can be administered via iritragluteal muscle,
intradeltoid muscle and in the form intravenous infusion comprising:
a) Diclofenac which is
b) Solubilised in a solvent with
c) Stabilizer which stabilizes the formulation
2) Diclofenac as claimed in claim 1 will be having the concentration from 35 mg to 100 mg/ml.
3) The solvent system as claimed in claim 1 may be selected either from dimethyl acetamide or
N-Methylpyrrolidone, or transcutol or the combination of above.
/
4) The solvent system claimed in claim 1 will be preferably dimethyacetamide.
5) Suitable stabilizer as claimed in claim 1 may be Benzalkonium chloride and Benzyl alcohol,
more preferably Benzyl alcohol,
SIGNATURE of Mr. Sanjeev Jain (Inventor and Authorized representative of
Applicant)