FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
AND
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. TITLE OF THE INVENTION
"Stable formulation dosage of paracetamol"
2. APPLICANT(S)
(a) NAME: J.B. CHEMICALS AND PHARMACEUTICALS LTD.
(b) NATIONALITY: An Indian Corporation
(c) ADDRESS: Neelam Centre, B- Wing, 4th floor, Hind Cycle Road, Worli, Mumbai 400 030,
Maharastra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be
performed.

Technical Field of the Invention
The present invention in general relates to a stable pharmaceutical dosage form for intravenous administration having analgesic activity. More particularly, the present invention relates to a stable pharmaceutical dosage form for intravenous administration of analgesic and antipyretic drug ingredient Paracetamol.
Background of the Invention
Paracetamol is chemically N-(4-hydroxyphenyl) acteamide and is considered to be main metabolite of phenacetin and acetanidile having analgesic and antipyretic properties. The mechanism of analgesic action of paracetamol has not been fully determined and may act predominately by inhibiting prostaglandin synthesis in the central nervous system and to a lesser extent through a peripheral action by blocking pain impulse generation. In recommended therapeutic dosage, it is usually well tolerated. However, acute overdose may cause fatal hepatic damage.
It is also known that Paracetamol is very slightly soluble in water. This characteristic represents a major obstacle to its administration by injection. Moreover, presence of water, Paracetamol undergoes degradations which also give rise to pink- to brown-colored derivatives. The most common types of degradation are hydrolysis to p-aminophenol and/or oxidation by, for example, oxygen dissolved in water. This second reaction appears to be responsible for the formulation of the said derivatives. Also, the stability of Paracetamol aqueous formulations is dependent on variables such as removal of dissolved oxygen from carrier, optional further presence of antioxidant in the formulation and adjustment to suitable pH. Hence an injectable aqueous formulation of Paracetamol wherein the stability of the formulation is achieved is highly desirable.
Several studies have confirmed the effectiveness and safety of Paracetamol's intravenous administration. Paracetamol is well absorbed when intramuscularly administered and its blood level is similar to that obtained after its oral administration. The absorption rate is slower of that obtained when Paracetamol is orally administered, resulting in desirable blood levels for more prolonged time. There is also another advantage of injectable Paracetamol since the 20% loss of the drug that is observed after oral administration doesn't exist. Therefore, Paracetamol parenteral solutions are indepensable for use in modern therapeutics for a greater and quicker therapeutic effect.
The preparation of parenteral formulations of paracetamol has been known in the art. US Patent No. 6992218 teaches a method for preparing aqueous formulations with easily oxidizable active principles, notable phenols. The method comprises deoxygenation of the solution by bubbling it with at least one inert gas until the oxygen content is below 2ppm. Also, in the art a buffer system has been suggested for the parenteral formulations of Paracetamol to maintain the pH to the required value (US Patent No. 6028222).
EP1752139A1 and EP1372628A2 describe liquid formulations of paracetamol for infusion, without using a buffer system. However, the formulations comprise antioxidants selected from a group of ascorbic acid, N-acetyl-L-cysteine and thiol group-containing stabilizer compounds.
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Whilst Paracetamol is soluble in many organic solvents, however solutions of paracetamol with such solvents are unfit for therapeutic use, because of the produced toxicity when parenterally administered (intramuscularly or intravenously) and because of the present invention technical problems, i.e., chemical instability leading to the precipitates, low fluidity etc. There is thus still a great need for a paracetamol pharmaceutical formulation which, besides containing therapeutic levels of paracetamol, can be injected easily and does not give rise to chemical instability.
Summary of the Invention
The objective of the present invention is to provide stable pharmaceutical dosage form for intravenous administration of therapeutically effective amount of paracetamol.
Further it is an objective of the present invention to provide pharmaceutical dosage forms of paracetamol, having analgesic activity, which are formulated to avoid chemical instability.
Detailed Description of the Invention
The present invention relates an aqueous, parenteral dosage form of paracetamol which comprises a therapeutically effective dose of paracetamol.
In an embodiment, stable pharmaceutical dosage forms as disclosed in the invention are formulated as parenteral formulations, in particular infusible formulations, in a solvent.
In another embodiment of the present invention, the preferable solvent is water and propylene glycol. In another embodiment, stable pharmaceutical dosage forms as disclosed in the context of the present invention may optionally include pharmaceutically acceptable excipients.
In yet another embodiment, the present invention provides stable pharmaceutical dosage form, having analgesic activity comprising a therapeutically effective dose of paracetamol with solvents and other pharmaceutically acceptable excipients.
Paracetamol is used in the present invention in therapeutically effectively dose. In an embodiment, paracetamol is preferably used in amount of 10mg/ml.
Propylene glycol is used in the present invention as a solvent for paracetamol solubility. In an embodiment, propylene glycol is preferably used in amount of 8mg/ml.
The presence of citrate buffer, associated with propylene glycol, is used to obtain high stability of the present invention. By citrate buffer is meant any chemical system allowing the co-existence in equilibrium of citric acid and one or more salts thereof. An example of said systems is a buffer based on citric acid monohydrate and
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disodium hydrogen phosphate dihydrate. Disodium hydrogen phosphate dihydrate and critic acid monohydrate is preferably used in amount of 0.50mg/ml and 0.47mg/ml.
Antioxidant is used in the present invention to protect paracetamol from oxidative degradation. The antioxidant used in the invention but is not limited to sodium metabisulphite. In an embodiment, sodium metabisulphite is preferably used in amount of 0.50mg/ml.
As an alternative or in addition to the use of antioxidants, the antioxidant effect may be achieved by displacing oxygen from the solution. This may be achieved by purging the solution with a water insoluble inert gas. Inert gases which are known to a person skilled in the art may be employed, this include but not limited to nitrogen.
In an embodiment, the pharmaceutical solution is purged with nitrogen to displace the oxygen from the solution. In another embodiment, the oxygen content in the solution is found to be not more than 3ppm.
Isotonic agent is used in the present invention to impart same osmotic pressure as the body fluid to the formulations. Isotonicity of the preparation is achieved by adding an appropriate quantity of isotonic agent. Isotonic agent used in the invention but is not limited to sodium chloride. In an embodiment sodium chloride is preferably used in amount of 2mg/ml.
The pharmaceutical dosage form of the present invention can be prepared according to techniques that are well known in pharmaceutical chemistry, comprising mixing, dissolution, sterilization and the like.
The following examples are included to illustrate certain aspects of the invention in greater detail but are not intended to limit the scope of the invention. Various examples as well as alternate embodiments will be evident to a person skilled in the art upon reference to the description and are presumed to be within the scope of the invention.
Example 1
Pharmaceutical formulation of paracetamol

Sr. No. Ingredients Quantity per mi

in mg
1. Paracetamol BP 10.00
2. Propylene Glycol BP 8.00
3. Citric Acid Monohydrate BP 0.47
4. Sodium Metabisulphite BP 0.50
5. Disodium Hydrogen Phosphate Dihydrate BP 0.89
6. Sodium Chloride BP 2.00
7. Water for Injections BP q.s. to 1 ml
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Nitrogen (in-house)

q.s.

Manufacturing procedure:
Required amounts of paracetamol, propylene glycol, sodium metabisulphite, citric acid monohydrate and disodium hydrogen phosphate dihydrate are dissolved in water for injection, with stirring under inert atmosphere, until each of the ingredients dissolved completely. After a clear solution is obtained, the volume is made up with water for injection and sodium chloride is added. After Alteration through a sterile 0.22|am pore size filter, the solution is purged with inert gas such as nitrogen and subsequently filled in holding vessel (Cap 600L) and layer with filtered Nitrogen. The vials are sealed with rubber closure and aluminum seals and sterilized at 121 °C-151b/sq inches pressure for 15 minutes.

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Claims
We claim -
1. A stable pharmaceutical formulation having analgesic activity consisting essentially of 1) a therapeutically effective dose of paracetamol, 2) propylene glycol, 3) citrate acid monohydrate, 4) disodium phosphate dihydrate, 5) sodium metabisulphite, 6) sodium chloride and 7) water for injection.
2. The pharmaceutical formulation of claim 1, wherein the formulation is provided as aqueous solution.
3. The pharmaceutical formulation of claim 1, wherein the therapeutically effective dose of paracetamol is preferably 10mg/ml.
4. The pharmaceutical formulation of claim 1, wherein the formulation is provided for intravenous administration.