OA16267A - Pharmaceutical compositions comprising paracetamol and process for preparing the same. - Google Patents

Abstract

Disclosed herein are injectable compositions containing high concentration of paracetamol or its pharmaceutically acceptable salts wherein the concentration of paracetamol or its pharmaceutically acceptable salt is >150mg/ml in a judiciously tailored solvent system comprising glycofurol, ethanol, water or a solvent system comprising glycofurol, ethanol, polyethylene glycol, water. The viscosity of the said injectables is <28 cps. Further disclosed is the process for preparing the said injectables. The injectables can be administered by intramuscular route, intravenous route or as intravenous infusion after diluting in one of the routinely used intravenous fluids, infusion solutions of antibacterial, antifungal and amoebicidal drugs and along with anxiolytics (Midazolam injection ) or narcotic analgesics (Fentanyl Citrate injection etc) as they remain stable, clear and transparent atleast for 6 hours after dilution.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING PARACETAMOL

AND PROCESS FOR PREPARING THE SAME

Related Application

The invention disclosed in Indian Patent Application No. 630/MUM/2010, filed on Spetember 9, 20I0, is cognate with the invention disclosed in Indian Patent Application no. 3023/MUMZ2009 filed on June 30, 2010, in a way that they constitute a single invention.

Field of the invention

The présent invention relates to parentéral compositions of paracétamol containing therapeutically effective dose of paracétamol, process for préparation thereof including therapeutic use of the said compositions.

Background ofthe invention

Paracétamol (p-acetylaminophenol) is a common analgésie and antipyretic drug that is used for the relief of fever, headaches, and other minor aches and pains. It is a major ingrédient in numerous cold and flu médications and many analgésies prescriptions. The drug is popularly used as an analgésie and antipyretic, and as a pain reliever in acute pain and chronic pain. Paracétamol injections are used for the management of acute febrile conditions as well as analgésie for management of acute pain including post operative pain.

Pharmaceutical préparations comprising paracétamol to be administered orally are well known. It is however well accepted that concentrated parentéral pharmaceutical compositions containing paracétamol in solution offer several advantages over solid compositions as they provide rapid onset of pharmacologie action, since, unlike the oral compositions, which first hâve to first disintegrate and dissolve in the gastrointestinal tract to enable absorption.

The first one comprises 150 mg/ml paracétamol presented in 2 ml solution. This dosage form provides 300-mg of paracétamol per dose which is much below the minimum therapeutic dose of 500 mg. These hâve high viscosîty of about 24,80 cps eau si n g pain when administered by the intramuscular route. Further this dosage form has the additional disadvantage of delivering sub-therapeutic quantities.

The other parentéral formulation comprises aqueous solutions of paracétamol in a concentration of 10 mg/ml, presented in 50 ml and 100 ml vials providing 500 mg and 1000 mg of paracétamol per vial respectively. These dosage forms are administration only by întravenous infusion and obviously unsuitable for intramuscular route. Such dosage forms are not suitable for use in Out-Patient-Department (OPD) settïngs. Concurrent administration of these dosage forms with other intravenous fluids, e.g. Ciprofloxacin I.V. infusion, is inconvénient. Further, manufacture of these dosage forms need additional infrastructure, larger storage space and bulk transport adding to the end cost of these products.

There is therefore an unmet need to provide high concentration paracétamol containing injectable compositions that can deliver the therapeutic dosage (500 mg) in single dose for intramascular administration without causing pain to the patient. Further there is a need for such high concentration dosage forms that can be adapted for administration with I.V. infusions

PCT/IN2009/000038 relates to aqueous, stable pharmaceutical composition comprises paracétamol for parentéral administration, wherein the concentration of paracétamol in the composition is 10 mg/lml. The dosage form is suitable only for intravenous infusion.

PCT/IB2008/003217 discloses stable aqueous formulations containing lOmg/lml of acetaminophen exclusively to be administered by intravenous infusion as well as processes for their préparation.

PCT/NL2004/000819 relates to a composition with the aqueous state for the administration in perfusion of at least an active principle, especially pharmacological such as paracétamol.

PCT/GR200I/000047 discloses stable solutions of paracétamol for parentéral administration wherein the concentration of paracétamol is 150 mg/lml. These need to be administered in multiple doses to achieve the therapeutic dosage of 500mg and hence are not suitable.

PCT/EP1999/005486 describes a pharmaceutical composition, characterized in that: a) it comprises i) paracétamol, ii) ffom 1 to 4 parts by volume of a low molecular weight alcohol for each part by weight of paracétamol, and iii) from 1 to 5 parts by volume of a polyethylene glycol for each part by weight of paracétamol; b) it is substantially anhydrous; and c) it forms a clear solution for injection with 4-10 parts by volume of water for each part by weight of paracétamol. Tbe solutions disclosed are substantially anhydrous which, as disclosed in the said patent, is understood to mcan a composition containing less than 0. 1% by weight of water. The solutions disclosed are expected to be very viscous. Hence, these solutions are to be diluted with water to provide the injection solution wherein each part by weight of paracétamol has, i) from 1 to 4 parts by volume of a low molecular weight alcohol, ii) from 1 to 5 parts by volume of a polyethylene glycol, and iii) from 4 to 10 parts by volume of water.

Example number 1 of the said patent describes the préparation of the concentrated anhydrous solution which has a paracétamol titer of about 210 mg per ml. Example number 2, describes dilution of this concentrated anhydrous solution to produce injection solutions. As calculated, the titer of paracétamol in the injection solutions is about 85.60 mg per ml of injection solutions.

PCT/1B2008/003925 relates to stable aqueous solution of paracétamol containing about 10 mg/lml, to be administered exclusively by intravenous infusion.

PCT/US2008/083458 relates to compositions containing lOmg/ml of Paracétamol for exclusive , administration by intravenous infusion.

PCT/EP2002/0H498 relates to ready-to-use highly stable paracétamol injectable solutions, prepared by mixing paracétamol, water, propylene glyçol, and a citrate buffer wherein the concentration of paracétamol is up to 40 mg/ml for exclusive administration by intravenous infusion.

PCT/EP2002/002696 relates to aqueous parentéral solutions of paracétamol containing l to 17 grams of paracétamol per liter (i.e. I mg per ml to 17 mg per ml) exclusively to be administered by intravenous infusion.

PCT/EP2000/006871 relates to liquid pharmaceutical compositions comprising at least 10% w/v of paracétamol in anhydrous PEG 200. Viscosity of a 22% (w/v) solution Paracétamol as disclosed in example 1 has viscosity 168.4 cps and therefore is unsuitable for use as injectables.

EP2087909 describes ready to use paracétamol injectable solution containing maximum concentration of paracetamîl of 1 gm/100 ml in distilled water and buffering agent for exclusive administration as intravenous infusion.

EP0916347 discloses injection solution of paracétamol and combinations of paracétamol with other substances like hyoscine - n- butyl bromide and codeine phosphate

Indian Patent Application number 1746/MUM/2008 relates to a pharmaceutical formulation of paracétamol that provides easy administration to the patients. The above application claims paracétamol injection containing maximum concentration of paracétamol at 15% w/v using combinations of glycofurol and water. However these solutions do not deliver the required therapeutic dose of 500mg in 2 to 3 ml.

Indian Patent Application number 1532/DEL/2008 relates to administration of paracétamol through intravenous route in which paracétamol is solubilised in water for injection in combination with passive ingrédients like buffers, isotonicity agents, etc. However these also do not provide the required therapeutic dose of 500mg in 2 to 4 ml.

Indian Patent Application No. 1529/DEL/2008 relates to compositions of paracétamol and ofloxacin for administration through intravenous route employîng an aqueous vehicle.

Indian Patent Application No. 1530/DEL/2008 describes compositions of paracétamol and cîprofloxacin in aqueous vehicle to be administered by intravenous route.

Indian Patent Application No.l53l/DEL/2008 describes a composition of paracétamol and diclofenac sodium in aqueous vehicle for intravenous administration.

Indian Patent Application No. 2708/DEL/2006 comprises aqueous solution of therapeutic active substances; preferably paracétamol complexed with hydroxyl propyl beta cyclodextrin (HP- B-CD) encapsulated in physiologically and pharmaceutically acceptable oil containing conventional lipophilie surfactant which in tum being dispersed in aqueous medium containing known hydrophilic surfactant.

Indian Patent Application No. 3782/DELNP/2005 relates to a novel injectable formulation of paracétamol, comprising an aqueous solvent, buffering agent with a pKa between 4.5 and 6.5, isotonie agent and dimer of paracétamol wherein the said dimer is used for the stabilization of the formulation.

Indian Patent Application No. 8070/DELNP/2008 relates to an aqueous paracétamol solution for use by perfusion, comprising at least one substance that can react with phenolates.

Paracétamol is sparingly soluble in water, therefore various solvents like propylene glycol, polyethylene glycol 400, glyceryl formai, glycofurol and éthanol etc hâve been used in the prior art, since paracétamol shows higher solubility in these solvents as compare to water. However there is no prior art disclosing paracétamol injectables with 500mg of paracétamol in a single dose of about 2 or 3 ml.

O

A solîtary prior art namely IN1746/MUM/2008 reported the use of 44% v/v glycofurol in combination with 10% v/v alcohol (name of alcohol not disclosed) in combination with water to solubuilise a maximum of 150 mg/ml of paracétamol. The same prior art reports the use of 48% v/v glycofurol in combination with water to solubilize a maximum of 150 mg/ml paracétamol. The challenge before the pharmaceutical îndustry is to provide injections comprising greater than 150 mg/ml up to about 250 mg/ml paracétamol, so that the therapeutic dose of 500 mg can be delivered as an injection of 2 to 3 mi of the solution. Further despite such high concentrations, the injections hâve to be of viscosity not more than 28 CPS. This has not been achieved to date.

Summary of the invention

The main object of the présent invention is to provide high concentration parentéral compositions of paracétamol delïvering füll therapeutic dose of paracétamol, processes for preparing the same and use thereof.

Another object of the présent invention is to provide high concentration parentéral compositions of paracétamol delivering therapeutic dose of 500 mg paracétamol in 2 to 3 ml.

Another object of the invention is to provide parentéral compositions of paracétamol containing paracétamol from about 166 mg to 250 mg per ml.

Yet another object of the invention is to provide parentéral compositions containing paracétamol from about 166 to 250 mg per ml in a solvent System comprising glycofurol, éthanol and water.

Yet another object of the invention is to provide parentéral compositions containing paracétamol from about 166 to 250 mg per ml in a solvent system comprising glycofurol, éthanol, polyethylene glycol and water.

Another object of the présent invention is to provide a parentéral pharmaceutical formulation of paracétamol or pharmaceutically acceptable sait thereof with viscosity less than 28 CPS, suitable for intramuscular and intravenous administration.

The above and other objects of the présent invention are attained according to following preferred embodiments of the présent invention. However the scope of the invention is not restricted to the particular embodiments discussed herein after.

In one of the embodiments of the présent invention there is provided parentéral pharmaceutical formulations of paracétamol or pharmaceutically acceptable salts thereof, wherein the concentration of the active în a solvent System is >l50mg/mI, the said formulation having viscosity of <28 cps.

In another embodiment of the présent invention, there is provided parentéral pharmaceutical formulations of paracétamol or pharmaceutically acceptable salts thereof, wherein the concentration of the active in a solvent system is >l50mg/mI having viscosity of 7 to 28 cps, preferably 7 to 22 cps.

Further, the process for préparation of parentéral compositions of paracétamol or pharmaceutically acceptable salts thereof having the active concentration in the range of about 166 to 250 mg/ml, comprises:

a. Solubilising the requisite quantities paracétamol or its pharmaceutically acceptable sait thereof in a solvent System under inert atmosphère;

b. optionally adding antioxidant, chelating agent, benzyi alcohol,

c. optionally adjusting pH between 4 to 8;

d. adjusting the volume of the solution to a preset volume;

e. Filtering the solution through 0.22 micron fiiter media;

f. Filling the solution in ampoules/vials under inert atmosphère;

g. optionally, autoclaving the ampoules/vials.

Detailed Description of the invention

The présent invention provides high concentration parentéral compositions of paracétamol or its pharmaceutically acceptable sait thereof comprising full therapeutic dose of paracétamol in a small volume of injection solutions that can be administered by both intramuscular and intravenous routes.

The solubility of paracétamol in various solvents, such as glycofurol, PEG, éthanol, and propylene glycol were determined by us. The solubility of paracétamol in glycofurol, PEG 400, éthanol, propylene glycol and water is about 205 mg/ml, 190 mg/ml, 160 mg/ml, Il3 mg/ml and 14 mg/ml respectively. Further, the viscosity of the paracétamol solution in glycofurol at concentration of 205mg/ml is about 57 CPS which is unacceptable for applications as injectables. As indicated in the earlier sections, the prior art has failed to provide injectables with high concentrations of paracétamol (500mg in 2 or 3 ml solutions) in any solvent Systems. The challenge lies in taiioring the appropriate solvent system to provide injectables containing paracétamol in 166 mg/ml to 250 mg/ml so that the therapeutic dose of paracétamol (500mg) can be delivered in 2 to 3 ml without compromising in viscosity of these injectables.

We hâve surprisingly found that substantially high concentration solutions of paracétamol can be prepared without significantly increasing the viscosity, by a judicious combination of solvents to create solvent Systems of glycofurol, éthanol and water or solvent Systems of glycofurol, éthanol, polyethylene glycol and water. The high concentration of paracétamol achieved în such compositions are significantly higher than those achieved in prior art or in commercially available paracétamol injections.

The concentration of paracétamol achieved in the composition of the présent invention range from about 166 mg/ml - 250 mg/ml, thereby providing full therapeutic dose of paracétamol as injectable comprising 500 mg in 2 ml - 3 ml and I gm in 4 ml or 6 ml respectively.

The compositions of the présent invention can be administered by intramuscular route, intravenous route or as intravenous infusion after diluting in one of the routinely used intravenous fluids (Dextrose Inj. 5% w/v, Sodium chloride Inj. 0.9% w/v, Pédiatrie maintenance solution with 5% w/v Dextrose, Sodium chloride Inj. 0.9% w/v & Dextrose 5% w/v, Sodium chloride Inj. 0.45% w/v, Multiple Electrolyte & Dextrose Inj. Type-3, Compound sodium lactate Inj., Dextrose Inj. 10% w/v, Multiple Electrolyte & Dextrose Inj. Type-IV, Multiple Electrolyte & Dextrose Inj. Type-V, Ringer Lactate, etc) as well as after diluting in infusion solutions of antibacterial, antifungal and amoebicidal drugs like ciprofloxacin, ofloxacin, levofloxacin, prazufloxacin, gatifloxaeîn, moxifloxacin, metronidazole, fluconazole, linezolid, etc.

The compositions of the présent invention can also be co-administered as intravenous infusion after diluting the required dose in routinely used intravenous fluids along with anxiolytics (eg.Midazolam injection) or narcotic analgésie (eg. Fentanyl Citrate injection).

The compositions of the présent invention may be presented in ampoules/vials containing from about 2 ml to about 3 ml injection solutions or multi-dose vials containing injection solutions that provide multiple doses of paracétamol to deliver 500 mg paracétamol.

A suitable preservative is optionally incorporated in the compositions.

The compositions of the présent invention are capable of being delivered in single dose ampoules/vials containing 500 mg to 2 gm paracétamol for intravenous use.

Accordingly for intravenous administration, 4 or 8 ml of an injection solution containing 250mg/ml of paracétamol will provide a dose of l gram or 2 grams dose of paracétamol respectively. Likewise, 6 or 12 ml of an injection solution containing about 166 mg/ml of paracétamol disclosed herein, will provide t gram or 2 grams dose of paracétamol respectively.

Further the amount of paracétamol provided by about 166 mg/ml injection solutions is about lgm/6ml, about 1.5 gm/9ml, about 2 gm/12 ml. similarly the amount of paracétamol provided by 250 mg/ml injection solutions are about lgm/4 ml, about L5 mg/6 ml, about 2 gm/8 ml.

Selected pharmaceutical compositions described herein can be injected intramuscularly in the giuteal, deltoid or inner thigh muscles using 22 or 23 gauge needles.

In an embodîment, the parentéral compositions of the présent invention comprise paracétamol or its pharmaceutically acceptable salts in a concentration ranging from about 166 to 250 mg/ml solubilized in glycofurol, éthanol and water.

In another embodîment, the parentéral compositions of the présent invention comprise paracétamol or its pharmaceutically acceptable salts in a concentration ranging from about 166 to 250 mg/ml solubilized in glycofurol, éthanol, polyethylene glycol and water.

Polyethylene glycol is selected from polyethylene glycol 400/600.

In accordance with another embodîment of the présent invention, suitable antioxidant or mixtures thereof is optionally incorporated in the composition.

Suitable antîoxidants are selected from Monothioglycerol, Ascorbic Acid, Sodium Ascorbate, Erythorbic Acid, Potassium Metabisulfite, Sodium Metabi sulfite, Propionic Acid, Sodium Formaldéhyde Sulphoxylate, reduced Glutathione, Thiourea, Cysteine, N-acetlcysteinc, Méthionine, Sodium sulfite, Sodium citrate etc.

In yet another embodîment ofthe présent invention chelating agent or mixture thereof is optionally incorporated in the composition.

Suitable chelating agent herein used comprises Trisodium Edetate, Disodium

Edetate, Sodium Edetate, Edetate Calcium Disodium, Fumaric Acid, Malic Acid etc.

The injectable solutions of présent invention ensure stability of paracétamol during the shelf life.

Further, the injectables produced as per the présent invention are clear transparent solutions and upon dilution with one of the routinely used întravenous fluids the solutions remain clear and transparent for at least up to six hours post dilution thereby making them safe for IV administration

Further, the compositions of the présent invention are compatible with infusion solutions of antibacterial, antifungal and amoebicidal drugs like ciprofloxacin, ofloxacin, levofloxacin, prazufloxacin, gatifloxacin, moxifloxacin, metronidazole, fluconazole, linezolid, etc., and such infusion solutions remain stable, clear and transparent for at least up to six hours post dilution.

Further, the compositions of the présent invention produce clear transparent solutions when diluted in routinely used întravenous fluids, along with anxiolytics (Midazoiam injection ) or narcotic analgésies (Fentanyl Citrate injection etc), and remain stable, clear and transparent for at least up to six hours post dilution.

As mentioned in the section on prior art, commercîally avaîlable paracétamol injections 150 mg/ml exhibit viscosity of about 25 CPS at 25 degree C. The solitary prior art ïn which the solution of paracétamol rangîng from 60 mg/ml ( 6% w/v) to 150 mg/ml (15% w/v) hâve been prepared in glycofùrol: éthanol : water (about 44: 10 : 46 or about 4:1:4) and glycofùrol: water (48 : 52 or about 1:1). The viscosity of the examples disclosed in the prior art has not been mentioned in a patent spécification and hence the same were prepared by us in our laboratory and the viscosity as per examples 1 and 2 were 13, 5 CPS and 14.8 CPS respectively. It is to be noted that the concentrations of the solutions reported in the said prior art is between 60mg/ml to 150 mg/ml.

Surprisingly the compositions of présent invention in which the concentration of paracétamol is from about 166 to 250 mg per ml, i.e. about 16.6% to 25% w/v (which is significantly higher than any injectable reported in prior art and commercially available product) having viscosity in the range of about 7 to 28 CPS at 25 C. It may further be noted that the judiciously selected solvent System in the présent invention enable substantial lowering of viscosity despite significantly higher concentration of paracétamol in the compositions of the présent invention as compared to the viscosities of the low concentration solutions reported in the prior art.

In the preferred embodiment, the compositions of the présent invention having concentration of paracétamol of about 250 mg/m! enable administrating full therapeutic dose of 500 mg paracétamol in 2 ml injection solution of lower viscosity (about 16 CPS) as compared to viscosity of commercially available 150 mg/ml paracétamol injections as well as compositions disclosed in prior art

In another preferred embodiment, the compositions of the présent invention having concentration of paracétamol of about 166.66 mg/ml enable administration of full therapeutic dose of 500 mg paracétamol in 3 ml injection solutions of much lower viscosity (7.45 CPS) as compared to commercially available 150 mg/ml paracétamol injections as well as compositions disclosed in prior art

The pH of the compositions is in the range of about pH 4 to about pH 8, preferably between pH 5 to pH 7 and more preferably between pH 5.5 to pH 7. In accordance with the invention, the pH of the composition is optionally adjusted to the above values using suitable acid/alkali. Optionally, the pH is adjusted by adding buffering agents to obtain pH between pH 4 to pH 8, preferably between pH 5 to pH 7 and more preferably between pH 5.5 to pH 7.

The acid/alkali is selected from hydrochloric acid, sulphuric acid, acetic acid, citric acid, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, etc

A suitable buffer for the compositions comprises a citrate buffer, phosphate buffer and the like.

In one embodiment, the.composition of présent invention contain about 166 to 200 mg per ml in a solvent System comprising glycofùrol 25 to 40 % v/v, éthanol 20 to 37% v/v and water (quantity sufficient)

In another embodiment, the composition of présent invention contain about 200 to 250 mg per ml in a solvent System comprising glycofùrol 25 to 40 % v/v, éthanol 23 to 35% v/v and water (quantity sufficient)

In y et another embodiment, the composition of présent invention contain about 166 to 200 mg per ml in a solvent System comprising glycofùrol 25 to 42 % v/v, éthanol I0 to 35% v/v, polyethylene glycol 3 to 19% v/v and water (quantity sufficient)

In yet another embodiment, the composition of présent invention contain about 200 to 250 mg per ml in a solvent System comprising glycofùrol 30 to 40 % v/v, éthanol 24 to 35% v/v, polyethylene glycol 3 to 6% v/v and water (quantity sufficient)

Optionally 2 to 6% v/v benzyl alcohol is incorporated in the compositions.

Optionally antioxidants and chelating agents are incorporated in the compositions.

Optionally buffer, acid/alkali can be incorporated in the compositions.

The solvent system comprising glycofùrol, éthanol and water for composition containing about 166 mg/ml to 250 mg/ml contains glycofùrol: éthanol: water from about 2.8: 2.0: 5. 1 (example no. 7) to about 1:1:1 (exemple 12 & 19).

This is in sharp contrast to the ratio of glycofùrol and éthanol reported in IN1746/MUM/2008 of 10: 1 or a solvent System containing only glycofùrol and water.

i

Viscosity of compositions of présent invention having concentration of paracétamol ranging from about ]66 mg/ml to 200 mg/ml prepared using solvent system comprising glycofurol, éthanol and water ranges from about 7 to about 16 CPS.

Viscosity of compositions of présent invention having concentration of paracétamol ranging from about 200 mg/ml to 250 mg/ml prepared using solvent system comprising glycofurol, éthanol and water ranges from about 16 to about 28 CPS.

Viscosity of compositions of présent invention having concentration of paracétamol ranging ffom about 166 mg/ml to 200 mg/ml prepared using solvent system comprising glycofurol, éthanol, propylene glycol and water ranges from about 9 to about 14 CPS.

Viscosity of compositions of présent invention having concentration of paracétamol ranging from about 200 mg/ml to 250 mg/ml prepared using solvent system comprising glycofurol, éthanol, propylene glycol and water ranges from about 14 to about 28 CPS.

The process for préparation of parentéral compositions of paracétamol or pharmaceutically acceptable salts thereof having the active concentration in the range of about 166 to 250 mg/ml, comprises:

a. Solubilising the requisite quantifies paracétamol or its pharmaceutically acceptable sait thereof in a solvent system under inert atmosphère;

b. optionally adding antioxidant, chelatîng agent, benzyl alcohol,

c. optionally adjusting pH between 4 to 8;

d. adjusting the volume of the solution to a preset volume;

e. Filterîng the solution through 0.22 micron filter media;

f. Filling the solution in ampoules/vials under inert atmosphère;

g. optionally, autoclaving the ampoules/vials.

Glycofurol is added to-lhe requisite quantity of éthanol and part of water for injection with stirring under inert gas flushing. The requisite quantity of benzyl alcohol and/or polyethylene glycol 400/600 is optionally added to the above solution followed by addition of the requisite quantity of paracétamol till it completely dissolves. Requisite quantity of antioxidant is added to the above solution. Further requisite of suitable chelating agent and buffer is added and water for injection is added to achieve the required volume. If the pH of the solution is not in the desired range, suitable acid/alkali is added to adjust the pH between 4 to 8. A suitable buffer is optionally used to maintain the solution pH 4 and 8. The solution is filtered through 0.2 micron filter and filled into single/multi- dose containers of suitable volumes under inert gas flushing. Optionally the injection solution is sterilized by autoclaving and thereafter filled into single/multi- dose containers of suitable volumes.

In one of the embodiments, the antioxidant when used may be added in the beginning of the process in the solution of glycofural, éthanol and part of injection.

In another embodiment the solvent system of glycofurol, éthanol, polyethylene glycol and part of water for injection is prepared with contînuous stirring, under inert gas flushing and polyethylene glycol is not added at any other stage of the process.

In yet another embodiment the solvent system of glycofurol, éthanol, polyethylene glycol and part of water for injection is prepared wherein the antioxidant is dissolved in the part water of injection.

The addition sequence of the ingrédients is not restricted to the embodiments disclosed above and a person skilled in the art may arrive at various combination of the compositions disclosed herein.

The following non-limitïng examples illustrate in details about the invention. However, they are, not intended to be limiting the scope of présent invention in any way

Examples

The compositions of the présent invention are prepared in accordance of the procedure given above and hence not reproduced to avoid répétition.

Example 1

Table I

Composition of Paracétamol Injection:

S. No.	Ingrédients	Amount
1	Paracétamol	250 mg
2	Glycofurol	0.324 ml
3	PEG 400	0.050 ml
4	Ethanol	0.300 ml
5	Monothioglycerol	7.50 mg
6	IN NaOH solution	q.s. to adjust pH to about 6.5
7	Water for injection	q.s. to 1 ml

The viscosity of injectable solution is 18,59 cps and pH of résultant solution is adjusted to 6.5.

Exatnple 2

Table: 2

Composition of Paracétamol injection:

S. No.	Ingrédients	Amount
1	Paracétamol	250 mg
2	Glycofurol	0.324 ml
3	PEG 400	0.050 ml
4	Ethanol	0.300 ml

5	Monothioglycerol	7.50 mg
6	Disodium Hydrogen phosphate	0.50 mg
7	Citric acid (5% w/v)	q.s. to adjust pH to about 6.2
8.	Water for injection	q.s. to l ml

The viscosity of injectable solution is 23.42 cps and pH of résultant solution is adjusted to 6.25.

Example 3

Table 3

Composition of Paracétamol injection:

S. No.	Ingrédients	Amount
I	Paracétamol	200 mg
2	Glycofurol	0.312 ml
3	PEG 400	0.040 ml
4	Ethanol	0.240 ml
5	Monothioglycerol	7.50 mg
6	1 N NaOH solution	q.s. to adjust pH to about 6.2
Ί	Water for injection	q.s. to 1 ml

The viscosity of injectable solution is 14.44 cps and pH of résultant solution is adjusted to 6.20.

Example 4

Table 4

Composition of Paracétamol injection:

S. No.	Ingrédients	Amount
1	Paracétamol	220 mg
2	Glycofurol	0.316 ml
3	PEG 400	0.044 ml
4	Ethanol	0.264 ml
5	Monothioglycerol	7.50 mg
6	1 N NaOH solution	q.s. to adjust pH to about 6.2
7	Water for injection	q.s. to 1 ml

The viscosity of injectable solution is 18.76 cps and pH of résultant solution is adjusted to 6.29.

Example 5

Table 5

Composition of Paracétamol Injection:

S. No.	Ingrédients	Amount
1	Paracétamol	166.66 mg
2	Glycofurol	0.280 ml
3	PEG 400	0.033 ml
4	Ethanol	0.200 ml
5	Sodium metabisulphite	1.5 mg
6	Benzyl alcohol	0.02 ml

7	1 N NaOH solution	q.s, to adjust pH to about 6
8	Water for injection	q.s. to 1 ml

The viscosity of injectable solution is 9.02 cps and pH of résultant solution is

5.82.

Example 6

Table 6

Composition of Paracétamol injection:

S. No.	Ingrédients	Amount
1	Paracétamol	166.66 mg
2	Glycofurol	0.280 ml
3	PEG 400	0.033 ml
4	Ethanol	0.200 ml
5	Sodium metabisulphite	1.00 mg
6	Benzyl alcohol	0.04 ml
7	1 N NaOH solution	q.s. to adjust pH to about 6.3
8	Water for injection	q.s. to 1 ml

The viscosity of injectable solution is 10.03 cps and pH of résultant solution is adjusted to 6.31.

Example 7

Table 7

Composition of Paracétamol injection:

S. No.

Ingrédients

Amount

1	Paracétamol	166.66 mg
2	Glycofurol	0.279 ml
3	Ethanol	0.200 ml
4	Sodium metabisulphite	1 mg
5	Benzyl alcohol	0.02 ml
6	Water for injection	q.s. to 1 ml

The viscosity of injectable solution is 7.45 cps and pH of résultant solution is

5.25.

Example 8

Composition of Paracétamol Injection:

Table 8

S. No.	Ingrédients	Amount
1	Paracétamol	200 mg
2	Glycofurol	0.312 ml
3	PEG 400	0.040 ml
4	Ethanol	0.240 ml
5	Monothioglycerol	7.50 mg
6	Disodium edetate	0.50 mg
7	Water for injection	q.s. to 1 ml

The viscosity of injectable solution is 12.55 cps and pH of résultant solution is adjusted to 6.20.

Example 9

Composition of Paracétamol Injection:

Table 9

S. No.	Ingrédients	Amount
1	Paracétamol	200 mg
2	Glycofurol	0.300 ml
3	Ethanol	0.240 ml
4	Monothioglycerol	7.50 mg
5	Water for injection	q.s. to 1 ml

The viscosity of injectable solution is 13.40 cps and pH of résultant solution is

5.20.

Example 10

Composition of Paracétamol Injection:

Table 10

S. No.	Ingrédients	Amount
1	Paracétamol	200 mg
2	Glycofurol	0.320 ml
3	Ethanol	0.230 ml
4	Sodium metabisulphite	1.0 mg
5	Water for injection	q.s. to 1 ml

The viscosity of injectable solution is 13.90 cps and pH of résultant solution îs

5.40

Example 11

Composition of Paracétamol Injection:

Table l ]

S. No.	Ingrédients	Amount
1	Paracétamol	250 mg
2	Glycofurol	0.360 ml
3	PEG 400	0.060 ml
4	Ethanol	0.300 mi
5	Monothioglycerol	7.50 mg
6	Water for injection	q.s. to 1 ml

The viscosity of injectable solution is 26,11 cps and pH of résultant solution is adjusted to 6.67.

Ëxample 12

Composition of Paracétamol Injection:

Table 12

S. No.	Ingrédients	Amount
I	Paracétamol	166.66 mg
2	Glycofurol	0.32 ml
3	Ethanol	0.37 ml
4	Ascorbic acid	4,0 mg
5	Water for injection	q.s. to 1 ml

The viscosity of injectable solution is 10.79 cps and pH of résultant solution is

5.79.

Example 13

Composition of Paracétamol Injection:

Table 13

S. No.	Ingrédients	Amount
1	Paracétamol	250 mg
2	Glycofurol	0.316 ml
3	PEG 400	0.050 ml
4	Ethanol	0.300 ml
5	Ascorbic acid	4.0 mg
6	Water for injection	q.s. to 1 ml

The viscosity of injectable solution is 16.02 cps and pH of résultant solution is

6.54.

Example 14

Composition of Paracétamol Injection:

Table 14

S. No.	Ingrédients	Amount
1	Paracétamol	166.66 mg
2	Glycofurol	0.420 ml
3	PEG 400	0.034 ml
4	Ethanol	0,201 ml
5	Monothioglycerol	7.5 mg
6	Benzyl alcohol	0.020 ml
7	Water for injection	q.s. to 1 ml

The viscosity of injectable solution is 20.62 cps and pH of résultant solution is

6.30.

Example 15

Composition of Paracétamol injection:

Table 15

S. No.	Ingrédients	Amount
1	Paracétamol	166.6 mg
2	Glycofurol	0.251 ml
3	PEG 400	0.188 ml
4	Ethanol	0.201 ml
5	Benzyl alcohol	0.02 ml
6	Monoth îoglycerol	7.5 mg
Ί	Water for injection	q.s. to 1 ml

The viscosîty of injectable solution is 21.55 cps and pH of résultant solution is

6,56

Example 16

Composition of Paracétamol Injection:

Table 16

S. No.	Ingrédients	Amount
1	Paracétamol	166.66 mg
2	Glycofurol	0.403 ml
3	Ethanol	0.10 ml
4	Monothioglycerol	7.5 mg
5	Benzyl alcohol	0.02 ml
6	PEG 400	0.034 ml
Ί	Water for injection	q.s. to 1 ml

The viscosîty of injectable solution is 14.34 cps and pH of résultant solution is

5.84.

Example 17

Composition of Paracétamol Injection:

Table 17

S. No.	Ingrédients	Amount
1	Paracétamol	166.66 mg
2	Glycofùrol	0.422 ml
3	Ethanol	0.201 ml
4	Monothioglycerol	7.5 mg
5	Benzyl alcohol	0.10 ml
6	PEG 400	0.034 ml
7	Water for injection	q.s. to 1 ml

The viscosity of injectable solution is 19.12 cps and pH of résultant solution is

6.86.

Example 18

Composition of Paracétamol Injection:

Table 18

S. No.	Ingrédients	Amount
1	Paracétamol	250 mg
2	Glycofùrol	0.35 ml
3	Ethanol	0.30 mi
4	Monothioglycerol	7.5 mg
5	Benzyl alcohol	0.02 ml
6	PEG 400	0.05 ml
7	Water for injection	q.s. to 1 ml

The viscosity of injectable solution is 20.92 cps and pH of résultant solution is

6.79.

Example 19

Composition of Paracétamol Injection:

Table 19

S. No.	Ingrédients	Amount
1	Paracétamol	250 mg
2	Glycofürol	0. 38 ml
3	Ethanol	0. 30 ml
4	Sodium metabisuiphite	2 mg
5	Water for injection	q.s. to 1 ml

The viscosity of injectable solution is 18.70 cps and pH of résultant solution is

5.07

Example 20

Composition of Paracétamol Injection:

Table 20

S. No.	Ingrédients	Amount
1	Paracétamol	250 mg
2	Glycofürol	0. 375 ml
3	Ethanol	0. 30 ml
4	Sodium Metabisuiphite	2.0 mg
5	Water for injection	q.s. to 1 ml

The viscosity of injectable solution is 18.80 cps and pH of résultant solution is

6.13.

Example 21

The composition of Example -1 as disclosed herein above, was subjected to dilution in routînely used intravenous fluids and infusion solutions of antibacterial, antifungal and amoebicidal drugs as listed in table 21 hereunder. The intravenous 5 fluids containing the diluted composition were assessed to détermine their suitability for intravenous infusions.

The following parameters of each of the intravenous fluids were assessed were analyzed, prior to dilution and thereafter at sixty minutes interval, the last analysis being done on completion of six hour:

(î) Clarity of intravenous fluids (see results in table 22) (ii) pH of the intravenous fluids (see results in table 23) (iii) Absorbance of the intravenous fluids (see results in table 24)

Further each of the intravenous fluids in which 4 ml of composition (1 gram paracétamol) was diluted, was assessed for analyzed for content of paracétamol, immedîately thereafter at sixty minutes interval up to six hours (see results in table 25)

Table 21

List of routînely used intravenous fluids and infusion solutions of antibacterial, antifungal and amoebicidal drugs, in which composition as per example I was diluted, Each of the intravenous fluids were assigned an alphabetic code number for each of documentation.

Sr. No	Code No.	Brand naine	Solution in whicb Dilution of Paracétamol Injection lgin/4ml was prepared	Batch No	Mfg Date	Exp Date
1	A	TROGYL 100ML	METRON1DAZOLE INJ IP 0.5%W/V	12700190	May-2010	Apr-2015
2	B	SYSCAN 100ML	FLUCONAZOLE INJ US? 2MG/ML	F4610004-A	Apr-2010	Mar-2012
3	C	MOXIF IV 100ML	MOXIFLOXACIN INJ. 4MG/ML	F6759001-A	Feb-2009	Jan-2011

4	D	O-WIN IV 100ML	OFLOXACIN INJ 2MG/ML	9LA34	Jan-2009	Feb-2011
5	E	GATIQUIN 200 ML	GATIFLOXACIN INF. IP 2MG/ML	ZC9146	Aug-2009	Jul-2011
6	F	DEXTROSE INJ 250ML	DEXTROSE INJ IP 5%W/V	907 005	Jul-2009	Jun-2012
Ί	G	SODIUM CHLORIDE 25OML	SODIUM CHLORIDE INJ 0.9%W/V	801093	Jan-2008	Dec-2010
8	H	DENILYTE T 250ML	PEDIATRIC MAINTANCE SOLUTION WITH 5% DEXTROSE (MULTIPLE ELECTROLYTE & DEXTROSE INJ TYPE-1 IP)	906048	Jun-2009	May- 2012
9	I	NS	SODIUM CHLORIDE INJ 0.9%W/V	3060057!	May-2010	Feb-2015
10	J	DNS	SODIUM CHLORIDE INJ 0.9%W/V & DEXTROSE 5%	31701197	Jun-2010	May- 2013
11	K	NIRLYTE-P	MULTIPLE ELECTROLYTE & DEXTROSE INJ TYPE-I IP	302622699	May-2010	Apr-2013
12	L	Sodium Chloride Injection 500 Ml	SODIUM CHLORIDE INJ 0.45%W7V IP	1007 987	Jul-2010	Jun-2013
13	M	5D	DEXTROSE INJ IP 5% W/V	A18592	Sep-2008	Aug-2013
14	N	B. BRAUN	MULTIPLE ELECTROLYTE & DEXTROSE INJ TYPE-3 IP	AJ8617	Oct-2008	Sep-2013
15	0	RL	COMPOUND SODIUM LACFATE INJ IP	AL7791	Dec-2007	Nov-2012
16	P	10D	DEXTROSE INJ IP 10% W/V	811 069	Nov-2008	Oct-2011
17	Q	CIPLOX	CIPROFLOXACIN INJ IP 2MG/ML	XR9017	Jul-2009	Jun-2012
18	R	DENILYTE ‘G’ 500 ML	MULTIPLE ELECTROLYTES & DEXTROSE INJ TYPE-IV IP	1003 340	Mar-2010	Feb-2013
19	S	DENILYTE	MULTIPLE ELECTROLYTES &	909 015	Oct-2010	Aug-2012

		Έ’ 500 ML	DEXTROSE INJ TYPE-V IP
20	T	Compound Sodium Lactate Inj IP 250 ml	COMPOUND SODIUM LACTATE INJ IP	902 010	Feb-2009	Jan-2012

Table 22

Clarity of Intravenous fluids before and after dilution

S. No	Solution Identifier	Clarity of Solution
Before Dilution (Initial)	After Ihr Dilution	After 2hr Dilution	After 3hr Dilution	After 4hrs Dilution	After 5 Hrs Dilution	After 6 Hrs Dilution
I	A	Clear	Clear	Clear	Clear	Clear	Clear	Clear
2	B	Clear	Clear	Clear	Clear	Clear	Clear	Clear
3	C	Clear	Clear	Clear	Clear	Clear	Clear	Clear
4	D	Clear	Clear	Clear	Clear	Clear	Clear	Clear
5	E	Clear	Clear	Clear	Clear	Clear	Clear	Clear
6	F	Clear	Clear	Clear	Clear	Clear	Clear	Clear
7	G	Clear	Clear	Clear	Clear	Clear	Clear	Clear
8	H	Clear	Clear	Clear	Clear	Clear	Clear	Clear
9	I	Clear	Clear	Clear	Clear	Clear	Clear	Clear
10	J	Clear	Clear	Clear	Clear	Clear	Clear	Clear
11	K	Clear	Clear	Clear	Clear	Clear	Clear	Clear
12	L	Clear	Clear	Clear	Clear	Clear	Clear	Clear
13	M	Clear	Clear	Clear	Clear	Clear	Clear	Clear
14	N	Clear	Clear	Clear	Clear	Clear	Clear	Clear
15	O	Clear	Clear	Clear	Clear	Clear	Clear	Clear
16	P	Clear	Clear	Clear	Clear	Clear	Clear	Clear
17	Q	Clear	Clear	Clear	Clear	Clear	Clear	Clear
18	R	Clear	Clear	Clear	Clear	Clear	Clear	Clear
19	S	Clear	Clear	Clear	Clear	Clear	Clear	Clear
20	T	Clear	Clear	Clear	Clear	Clear	Clear	Clear

Table 23 pH of Intravenous fluids before and after dilution

S. No	Solution Identifier	Observed pH
Before Dilution (Initial)	After lhr Dilution	After 2hr Dilution	After 3hr Dilution	After 4hrs Dilution	After 5 Hrs Dilution	After 6 Hrs Dilution
l	A (pH limit 4.5 to 7.0)	5.52	5.44	5.42	5.39	5.38	5.36	5.42
2	B (pH limit 4.0 to 8.0)	5.62	5.42	5.43	5.29	5.30	5.32	527
3	C	4.83	4.89	4.91	4.94	4.95	4.96	4.92
4	D (pH limit 3.8 to 5.8)	5.27	5.32	5.33	5.42	5.44	5.48	5.40
5	E (pH limit 3.5 to 5.5)	4.92	4.96	4.95	4.94	4.95	4.92	4.91
6	F (pH limit 3.5 to 6.5)	4.36	4.32	4.33	4.41	4.42	4.43	4.42
7	G (pH limît 4.5 to 7.5)	6.52	6.47	6.50	6.48	6.47	6.45	6.45
8	H pH limit 3.5 to 6.5	5.51	5.52	5.55	5.49	5.48	5.42	5.47
9	I pH limit 4.5b to 7.5	5.49	5.49	5.51	5.65	5.66	5,61	5.61
10	J pH Iimit3.5 to 6.5	4.26	4.36	4.33	4.34	4.32	4.38	4.32
il	K pH limit3.0 to 7.0	5.59	5.58	5.55	5.62	5.6	5.65	5.63
12	L pH limit4.5 to 7.5	5.93	5.87	5.92	5.79	5.72	5.78	5.75
13	M pH Iimit3.5 to 6.5	4.26	4.52	4.53	4.54	4.55	4.59	4.55
14	N pH limit 3.0 to 7.0	5.43	5.48	5.49	5.45	5.46	5.51	5.46
15	O pH limit 4.0 to 6.5	5.41	5.39	5.36	5.35	5.34	5.31	5.34
16	P pH limit 3.5 to 6.5	3.91	3.99	3.96	4.02	3.99	3.98	4.05
17	Q pH limit 3.5 to 4.6	4.01	4.02	4.03	4.02	4.03	4,06	4.03
18	R pH limit 3.5 to 7.0	3.67	3.64	3.63	3.59	3.58	3.59	3.56
19	S pH limît 3.5 to 7.0	5.51	5.52	5.52	5.49	5.50	5.52	5.47
20	T pH limit 4.0 to 6.5	5.94	5.91	5.90	5.87	5.84	5.86	5.83

Table 24

Absorbance of Intravenous fluids before and after dilution

Sr. No	Solution identifier	Absorbance:
Before Dilution (Initial)	After Ihr Dilution	After 2hr Dilution	After 3hr Dilution	After 4hrs Dilution	After 5 Hrs Dilution	After 6 Hrs Dilution
1	A	0.023	0.074	0.075	0.074	0.073	0.073	0.072
2	B	0.002	0.002	0.006	0.002	0.001	0.001	0.002
3	C	2.601	2.356	2.353	2.310	2.329	2.329	2304
4	D	0.136	0.112	0.113	0.107	0.107	0.108	0.112
5	E	0.046	0.040	0.040	0.041	0.039	0.040	0.045
6	F	0.002	0.008	0.009	0.008	0.007	0.004	0.006
7	G	0.002	0.008	0.005	0.006	0.007	0.005	0.006
8	H	0.014	0.001	0.004	0.006	0.005	0.005	0.006
9	I	0.008	0.005	0.006	0.003	0.008	0.005	0.003
10	J	0.001	0.003	0.003	0.004	0.003	0.002	0.003
11	K	0.009	0.001	0.003	0.003	0.004	0.003	0.002
12	L	0.00	0.00	0.00	0.001	0.001	0.002	0.001
13	M	0.002	0.000	0.002	0.001	0.003	0.003	0.005
14	N	0.008	0.009	0.006	0.005	0.004	0.006	0.005
15	O	0.004	0.006	0.001	0.001	0.002	0.001	0.004
16	P	0.012	0.009	0.015	0.014	0.013	0.009	0.010
17	Q	0.008	0.010	0.016	0.011	0.014	0.016	0.012
18	R	0.006	0.003	0.002	0.005	0.004	0.002	0.002
19	S	0.026	0.027	0.027	0.028	0.031	0.026	0.027
20	T	0.001	0.003	0.006	0.004	0.005	0.003	0.006

Table 25

Assay of paracétamol

Sr. No.	Solution identifier	Assay:
After 1 hrs	After 2 hrs	After 3 hrs	After 4 hrs	After 5 hrs	After 6 hrs
1	A	99.8	99.47	99.32	101.33	99.51	98.57
2	B	100.7	100.89	101.91	101.88	101.58	99.41
3	C	99.8	99.12	100.41	98.94	99.95	100.39
4	D	100.65	100.53	99.72	99.99	99.82	100.47
5	E	98.81	100.95	99.16	99.39	99.5	97.71
6	F	96.19	97.88	96.76	95.31	95.28	96.39
7	G	101.5	101.4	101.01	101.09	101.32	101.08
8	H	99.39	98.55	99.03	98.84	99.03	98.27
9	I	98.96	98.37	99.28	98.67	98.26	98.22
10	J	99.54	98.68	99.96	98.86	98.44	100.06
11	K	97.73	97.41	98.27	99.95	98.27	98.78
12	L	99.37	98.31	99.43	99.78	99.84	98.54
13	M	98.36	98.03	98.01	97.79	98.11	97.99
14	N	98.89	99.67	99.79	99.57	99.71	99.51
15	0	98.90	99.71	98.36	98.98	99.14	99.04
16	P	98.56	98.43	98.45	99.03	98.40	98.06
17	Q	101.51	101.4	101.88	101.99	100.73	101.56
18	R	102.36	102.3	102.72	101.4	101.62	100.94
19	S	99.58	99.33	99.19	98.6	99.14	99.41
20	T	101.31	100.52	100.62	100.71	100.7	100.76

Conclusion

On examining the above tables, one can conclude that:

a) There is no significant change in the clarity, pH and absorbance values of the intravenous fluids, when 4 mi of the composition as per example 1 is diluted in the intravenous fluids.

b) Assay of paracétamol does not show any significant decrease even after six hours of dilution of the compositions in intravenous fluid.

Claims (21)

1. High concentration parentéral compositions of paracétamol or its pharmaceutically acceptable salts delivering full therapeutic dose of 500 mg paracétamol in 2- 3 ml in a solvent System wherein the concentration of paracétamol or its pharmaceutically acceptable salts is >]50mg/ml and viscosity <28 cps

2. High concentration parentéral compositions of paracétamol or its pharmaceutically acceptable salts as claimed in claim l wherein the concentration of paracétamol is 166 mg to 250 mg/ ml.

3. Htgh concentration parentéral compositions of paracétamol or its pharmaceutically acceptable salts as claimed in any of the claims l, 2 wherein the solvent system comprises glycofurol, éthanol and water.

4. High concentration parentéral compositions of paracétamol or its pharmaceutically acceptable salts as claimed in any of the claims 1, 2 wherein the solvent system comprises glycofurol, éthanol polyethylene glycol and water.

5. High concentration parentéral compositions of paracétamol or its pharmaceutically acceptable salts as claimed in Claims 1-4 wherein the viscosity is 16- 28 cps, preferably 7-22 cps.

6. High concentration parentéral compositions of paracétamol or its pharmaceutically acceptable salts as claimed in claims 1-3 and 5 wherein the composition contains the active in terms of paracétamol from 166 to 200 mg in a solvent system comprising glycofurol 25 to 40 % v/v, éthanol 20 to 37% v/v and volume of water to make the total volume of the composition up to 2-3 ml.

7. High concentration parentéral compositions of paracétamol or its pharmaceutically acceptable salts as claimed in claims 1-3, and 5 wherein the composition contains the active in terms of paracétamol from 200 to 250 mg per ml in a solvent System comprising glycofurol 25 to 40 % v/v, éthanol 23 to 35% v/v and volume of water to make the total volume of the composition up to 2-3 ml.

8. High concentration parentéral compositions of paracétamol or its pharmaceutically acceptable salts as claimed in claims l-2 and 4-5 wherein the composition contains the active in terms of paracétamol from 166 to 200 mg per ml in a solvent System comprising glycofurol 25 to 42 % v/v, éthanol 10 to 35% v/v, polyethylene glycol 3 to 19% v/v and volume of water to make the total volume of the composition up to 2-3 ml.

9. High concentration parentéral compositions of paracétamol or its pharmaceutically acceptable salts as claimed in claims l-2 and 4-5 wherein the composition contains the active in terms of paracétamol from 200 to 250 mg per ml in a solvent System comprising glycofurol 30 to 40 % v/v, éthanol 24 to 35% v/v, polyethylene glycol 3 to 6% v/v and volume of water to make the total volume of the composition up to 2-3 ml.

10. High concentration parentéral compositions of paracétamol or its pharmaceutically acceptable salts as claimed in claims 1-2, 4-5, 8-9, wherein the polyethylene glycol is polyethylene glycol 400/600.

11. High concentration parentéral compositions of paracétamol or its pharmaceutically acceptable salts as claimed in claim 6 wherein the viscosity of the composition is 7 to about 16 CPS.

12. High concentration parentéral compositions of paracétamol or its pharmaceutically acceptable salts as claimed in claim 7 wherein the viscosity of the composition is 16 to 28 CPS.

13. High concentration parentéral compositions of paracétamol or its pharmaceutically acceptable salts as claimed in claim 8 wherein the viscosity of the composition is 9 to 14 CPS.

14. High concentration parentéral compositions of paracétamol or its pharmaceutically acceptable salts as claimed in claîm 9 wherein the viscosity of the composition is 14 to about 28 CPS.

15. High concentration parentéral compositions of paracétamol or its pharmaceutically acceptable salts as claîmed in claims 1-14 wherein the compositions optionally contain antioxidants, chelating or/and buffering agents.

16. High concentration parentéral compositions of paracétamol or its pharmaceutically acceptable salts as claimed în claims 1-15 wherein the compositions optionally contain 2 to 6% v/v benzyl alcohol.

17. A process for préparation of parentéral compositions of paracétamol or pharmaceutically acceptable salts thereof having the active concentration în the range of about 166 to 250 mg/m], comprises;

b. solubilising the requisite quantities paracétamol or its pharmaceutically acceptable sait thereof in a solvent system under inert atmosphère;

b. optionally adding antioxidant, chelating agent, benzyl alcohol,

c. optionally adjusting pH between 4 to 8;

d. adjusting the volume of the solution to a preset volume;

e. Filtering the solution through 0.22 micron filter media;

f. Filling the solution in ampoules/vials under inert atmosphère;

g. optionally, autoclaving the ampoules/vials;

wherein the solvent system is either glycofurol, éthanol and water or wherein the solvent system Îs glycofurol, éthanol, polyethylene glycol and water.

18. A process for préparation of parentéral compositions of paracétamol or pharmaceutically acceptable salts thereof having the active concentration in the range of about 166 to 250 mg/ml as claimed in claim 17 wherein pH of the solution in step “c” is adjusted between 4 to 8 using hydrochloric acid, sulphuric acid, acetic. acid, citric acid, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate

19. A process for préparation of parentéral compositions of paracétamol or pharmaceutically acceptable salts thereof having the active concentration in the range of about 166 to 250 mg/ml as claimed in claim 17 wherein pH of the solution in step “c” is adjusted between 4 to 8 using citrate buflfer, phosphate buffer and their like.

20. High concentration parentéral compositions of paracétamol or its pharmaceutically acceptable salts as claimed in daims 1-16 wherein the compositions after diluting in conventional intravenous fluids, infusion solutions of antibacterial, antifungal and amoebicidai drugs and along with anxiolytîcs (Midazolam injection ) or narcotic analgésies (Fentanyl Citrate injection etc) remain stable, clear and transparent at least for 6 hours after dilution.

21. High concentration parentéral compositions of paracétamol or its pharmaceutically acceptable salts as claimed in daims 1-16 wherein the compositions are capable of being administered by intramuscular route, intravenous route or as intravenous infusion.