OA18374A - Injectable formulations of paracetamol. - Google Patents

Abstract

The present invention relates to low volume intravenous injections of paracetamol or its pharmaceutically acceptable salt and method of preparation thereof. The formulations provide high concentration of paracetamol or its pharmaceutically acceptable salt in a solvent system of the present invention which can be administered not only through intra- muscular & intravenous infusion route but also suitable for slow IV bolus administration after dilution with aqueous fluids to final volume of not more than 20 ml. These injectable formulations remain stable and are also suitable for administration through slow intravenous route with minimized side effects (such as phlebitis, pain etc.)

Description

INJECTABLE FORMULATIONS OF PARACETAMOL

Field of the Invention

The présent invention relates to low volume intravenous injections of paracétamol and method of préparation thereof.

Backarouiid of the Invention

Paracétamol a para-aminophenol dérivative provides analgésie, antipyretic and weak anti-inflammatory activity. It is widely used over-the-countcr analgésie and antipyretic. It is commonly used for the relief of hcadachcs and other minor achcs and pains as well as fever. It is also used in combination with opioid analgésies for the management of severe pain such 10 as post-surgical pain and providing palliative care in advanced cancer patients.

Paracétamol or Acetaminophen is available in a variety of dosage forms such as tablets, capsules, Liquid syrups, suspensions, suppositories etc. that can be administered through different routes of administration. The oral and parentéral routes are the most preferred routes of administration. (Jarde O., Boccard E., Parentéral versus Oral Route 15 Increases Paracétamol Efficacy. Clinical Drug Investigation, Dec 1997, 14(6): 474-481.)

The parentéral route of administration is preferred due to the issue of rapid dégradation and poor absorption of drug following oral administration. Further, the parentéral route of administration is the only route available for effective management of the patient*s clinical conditions when rapid absorption of drug is essential for quicker onset of action and faster 20 relief from the symptoms.

In case of emergency or when patients are unconscious or unable to accept oral médications, the parentéral route is the preferred route. Drug absorption after parentéral delivery is rapid and, blood levels attained are more favourable than those achieved by oral dosage forms. (Aulton Μ. E.: Pharmaceutics, The Science of Dosage Form Design.

Churchill Livingstone, Second édition, 5)

Other advantages of the parentéral formulations of paracétamol are that they can be administered before or during the surgery thereby permitting the initiation of effective analgcsia in the early phase of the postoperative period. (Pasero C., The Rôle of Intravenous Acetaminophen in Acute Pain Management. Pain Management Nursing, Jun 2012, 13(2):

107-124.) These injections avoid first-pass hepatic exposure and metabolism via portai circulation, which reduces the incidence of hepatic injury. These injections rarely cause hepatotoxicity, and has been shown to be safe for use in patients with underlying liver conditions. (Viscusi E. R., IV Acetaminophen Improves Pain Management and Reduces Opioid Rcquirements in Surgical Patients: A Review of the Clinical Data and Case-based Présentations, April 2012, 38(4): 1-8.)

Despite the advantages of the parentéral formulations of paracétamol, very few options of parentéral formulations of paracétamol arc available in the market. The key reasons for their non-availability are the drug’s poor aqueous solubility and instability in présence of water,

Most of the formulations of Paracétamol are available in the form of very dilute aqueous solutions and are suitable for administration exclusively via intravenous infusion route. These large volume formulations are associated with the disadvantages related to volume overload especially in patients with compromised heart and kidney functions. In addition to their long duration of administration, and necessity to maintain a spécifie infusion rate etc the manufacturing cost of these formulations is relatively high..(Swarbrick J., Encyclopcdia of Pharmaccutical Technology, Informa Hcalthcarc USA, Third Edition, 1001-1003.)

W02009098716 and W02009/047634 disclose stable aqueous pharmaceutical compositions comprising paracétamol for parentéral administration, wherein the concentration of Paracétamol in the composition is lOmg/ml and therefore the said compositions are suitable only for administration via Intra-Venous (IV) infusion. W02003033026 discloses ready to use stable injectable formulations wherein the concentration of Paracétamol is upto 40 mg/ml for administration only by IV infusion route.

W02001008662 is related to pharmaceutical compositions of Paracétamol comprising atleast 10% w/v of Paracétamol in anhydrous PEG200. Viscosities of these compositions are of the order of 168 Cps and are therefore hâve limited use through parentéral route only upon dilution.

♦

1N1746/MUM/2008 relates to injectable formulations of Paracétamol only upto 15% prepared in a solvent System of Glycofurol & water. These formulations provide only upto 150 mg of drug in 1 ml.

WO00/07588 discloses non-aqueous injectable formulations of Paracétamol using alcohol and polycthylene glycol. These injections are formulated in non-aqueous solvents and are not in the ready-to-usc form. The non-aqueous formulations disclosed in the said reference are not suitable for intramuscular (IM) administration without dilution with aqucous fluid.

In US Patent 6028222, column 3 lines 47 to 53 mentions aqucous formulations of paracétamol injections with the Paracétamol concentrations in the range of 2mg/ml to 50 mg/ml in dilute solutions and 60 mg/ml to 350 mg/ml in concenlrated solulions.However in column 6 of the same reference spécification, the said US patent also states the following:

“Using this solution composed of a solvent mixture constituted by 30% of propyleneglycol, by 40% of polyethylene-glycol 400 and by 30% of water (solution no 20), it is 15 possible to dissolve about 200 mg/ml of paracétamol at 20° C. Choosing a concentration of J60 mg/ml allows one to be sure that no recristallization will occur

Thus by their own admission, the inventors in the said US Patent therefore teach that concentration of 160 mg/ml resuit in injectables in which no rccrystallization occurs. The inventors of US’222 themselves admit and illustrate by way of examples that the 20 formulations containing Paracétamol concentration upto 160 mg/ml remain stable. There is no enabling disclosure or teaching of whether concentrations as high as 350 mg/ml will yield an injectable where no recrystallization occurs. It is not obvious whether concentrations in the range 160 mg/ml to 350 mg/ml would be workable based on the teachings of US’222.

When the formulations disclosed in the spécification of US’222 with high concentration of paracétamol (> 160 mg/ml) were prepared by us and diluted to obtain a dose of 1 gm in not more than 20 ml, (i.e. to provide the concentration of atleast 50 mg/ml), the drug crystallised out of these solutions in 3 to 5 minutes. These formulations are therefore not appropriate for slow IV bolus administration after dilution, as crystals appear within 5 minutes of dilution. The results of our sludies are summarised below:

Table 1: Results of dilution of samples of examples disclosed in colunin 7 of the spécification of US6028222

Exîi tnple No.	Concentrât! on reportée! in US’222 @ 25 °C ûng/ml)	Concent rated solution taken (ml)	WFI added to make volume up to (ml)	Crystallization at 25°C observed within (minutes)	Crystallization at20°C observed within (minutes)
3	230	4.3	20	5	2.5
20	200	5.0	20	3	1
21	210	4.7	20	4	2
22	220	4.5	20	3	1.5
17	200	Crystallisation observée	immediately in the concentrated solution.
19	190	Complété solubilisation was not achieved

Il is clear from the above that these formulations are unsuitable for administration through the injectable route. Our studies unequivocally establish and confirm the admission 5 of lhe inventors of US’222 that the concentrated formulations of the said US patent are indeed unstable due to re-crystallisation of the drug.

W02012001494 discloses high concentration aqueous formulations of paracétamol which dcliver 500mg of the drug in a volume of injection as low as 2 to 3 ml maintaining the viscosity in the range of 7 to 28 CPs when measured by Ostwald viscomcter at 25 °C. 10 These formulations suffer from side effects such as phlebitis rendering them unsuitable for IV bolus route and therefore, without dilution, intra-muscular route is the only route of administration available for thèse formulations. We carried out detailed pre-clinical toxicity studies of the formulations disclosed in W02012001494.

Repeated dose intravenous toxicity studies were carried out in 48 Swiss Albino Mice 15 and 24 New Zealand White Rabbits for 14 consecutive days. The test solution of the paracétamol injections disclosed in W02012001494 were prepared and administered through intravenous route (tail vein) without any dilution at the dose levels of 5 (Low), 15 (Mid) and 25 (high) pL/20 gm body wt of the Swiss Albino Mice. These formulations causcd severe adverse effects at the site of injection and animais from low and mid dose 20 Paracétamol treated groups were less affected when compared to high dose Paracétamol treated groups. Further, when these formulations were administered through marginal ear veins of New Zealand White Rabbits at the dose level of 500, 1500 and 3000 pL/2 kg body wcight/day, they caused adverse effects at the site of injection. The findings of our studies in mice and rabbit suggest that the formulation of paracétamol disclosed in W02012001494 when administered without any dilution through IV bolus route, are not tolerated even at the 5 lowest dose. They cause severe phlebitis and are not suitable for intravenous bolus administration in humans.

When these formulations are diluted to achieve 1 gm of drug in 20 ml of formulation, précipitation of the drug sets in thcrcby making it unsuitablc for administion through slow IV bolus route.

Some of the paracétamol injections disclosed in the prior art are non-aqueous and therefbre not in ready-to use form. Further a severe limitation of prior art formulations is viscositics > 45 Cps which may cause tissue damage and pain at the site of injections.

The aqueous injectable formulations of Paracétamol available till date are either contain very low concentration of the drug which are administered only via the intravenous 15 infusion route, or they arc formulations containing fairly high concentrations of the drug but suffer from severe limitations such as:

a) Without dilution are capable of being administered only through intra-muscular route

b) On dilution with any of the available large volume of compatible parenterals, are suitable for administration only by the intravenous infusion route.

It is not possible to dilute the concentrated formulations known in the art to a volume of about 20 ml which can enable their administration through slow intravenous bolus route wherein the entire dose of the drug (e.g 1 gm in 20 ml ) is be injected within 5 minutes, preferably in 2 minutes to a patient. This limitation results from the appearance of crystals of the drug within minutes of the dilution of the prior art formulations.

There is an unmet need to provide aqueous injections of Paracétamol or its pharmaccutically acceptable sait which are not only stable and suitable for administration through IM & IV infusion route but arc also suitable for administration through slow intravenous bolus injections route but exhibiting minimal or no effccts. In addition to providing stable high concentration solutions, these ready to use formulations niust hâve viscositics of < 35 Cps, preferably < 25 Cps at room température.

There exists a need to provide stable formulations which, enable administration of the therapeutic dose of 1 gm in a volume not more than 20 ml with viscosities <35 Cps, preferably < 25 Cps at room température, thereby rendcring them suîtable for administration through slow intravenous bolus route upon dilution with aqueous fluids over and above the Intramuscular, Intravenous infusion routes.

Objects of the Invention:

The main object of the présent invention is to provide high concentration injectable formulations of paracétamol or its pharmaceutically acceptable sait which when diluted with aqueous fluids are capable of providing a dose of 1 gm of the drug in not more than 20 ml without any crystallisation of drug for a duration of atleast 5 minutes after dilution.

Il is yet another object of the présent invention to provide high concentration stable aqueous injections of paracétamol or its pharmaceutically acceptable sait which, when diluted with aqueous fluids to deliver 1 gm of drug in not more than 20 ml of the formulation, are suîtable for being administered through slow intravenous bolus route.

Another object of the présent invention is to provide high concentration, stable aqueous injections of paracétamol or its pharmaceutically acceptable sait which can be administered through intra-muscular route in their undiluted form and are also suîtable for slow IV bolus administration with minimised side effects such as phlebitis, pain etc.

Detailed Description of the Invention:

The présent invention provides stable high concentration aqueous injections of paracétamol or ils pharmaceutically acceptable salts, which when diluted with aqueous fluids to not more than 20 ml, romain stable and are suîtable for administration through slow intravenous route.

An injectable formulation of the présent invention comprises 250 mg/ml paracétamol or its pharmaceutically acceptable sait, a solvent System comprising Glycofurol and/or another solvent, Lower chain alcohol, a stabiliser, and water.

The other solvent is selected front Surfactants, Cyclodextrins, Dimethylacetainide dérivatives, Transcutol, N-Methyl Pyrollidone, or polyhydric alcohol(s) such as Propylene Glycol, Glycérine, Sorbitol and Poly ethylene glycols may be used.

The other solvent is preferably selected from N-methyl pyrollidone, 5 Dimethylacetamide, Transcutol, Cyclodextrins, or mixtures thereof.

The amount of glycofurol in the formulations ranges from 0 to 40 % w/v, preferably 0 to 35 % w/v of the formulation. The amount lower chain alcohol ranges from 0 to 30 % w/v, preferably 0 to 25 % w/v of the formulation. The amount of the other solvent in the formulations ranges from 0 to 55 % v/v of the formulation.

The stabiliser is selected from grades of polymeric compounds such as Plasdone for example Plasdone C 17, Plasdone C 30 and their like or any combination thereof. The stabiliser is 0 % w/v to 5 % w/v, preferably 2 % w/v to 4 % w/v of the formulation.

In one embodiment the injectable containing 250 mg paracétamol or its pharmaceutically acceptable sait in 1 ml. In another embodiment, the dose of 500 mg of 15 drug can be delivered in a volume of 2 ml. In another embodiment, the dose of 1 gm can be delivered in a volume of 4 ml. These embodiments are suitable for administration through the Intramuscular route.

In one of the embodiments, these formulations when diluted using low volume of aqueous fluids, can deliver the therapeutic dose of 1 gm of Paracétamol or its 20 pharmaceutically acceptable sait in 20 ml of the formulation without any recrystallization for alleast upto 5 minutes after dilution, In another embodiment, such formulations do not exhibit recrystallization in atleast 8 to 20 minutes after dilution.

The aqueous fluids for dilution are selected from water for injection or any other medicated/ non-medicated aqueous fluids suitable for slow IV bolus administration. These 25 formulations also provide the option of dilution with large volume of aqueous fluids in order to deliver the drug through intravenous infusion route.

Thèse formulations rcsult in complète solubilisation of Paracétamol or its pharmaceutically acceptable sait. The formulations containing 1 gm of drug when diluted vvitli aqueous fluids upto 20 ml, do not exhibit and recrystallization atleast upto 5 minutes after dilution, more preferably upto a period of atleast 8 minutes after dilution

Injectable formulations comprising 250 mg/ml of paracétamol or its pharmaceutically acceptable sait, the solvent system of the présent invention with a 5 stabiliser in a spccified range provides injectable formulations which on dilution with aqueous fluids upto 20 ml of formulation, are suitable for slow IV bolus route of administration with significantly minimised side effects such as phlebitis.

The formulations of the présent invention arc stable throughout the shelf life of the formulations. In the présent invention, water is used in a quantity sufficient to make up the 10 final volume of the formulation. Water to make up the final volume in these formulations is less than or equal lo50 % w/v, preferably less than or equal to 45 % w/v of the formulations.

The said formulations of the présent invention can further be diluted with the help of water for injection or conventional aqueous IV fluids such as normal saline, dextrose solution or any other parentéral carriers known in the art such that a dose of 1 gm of 15 Paracétamol or ils pharmaceutically acceptable sait is delivered in 20 ml volume of the final formulation.

In another embodiment of the présent formulations, suitable auxiliary ingrédients such as antioxidant(s), pH modifier(s), buffer(s), chelating agent(s), or mixtures thereof may be used. The antioxidant(s) of the formulation can bc selected from Monothioglyccrol, 20 sodium metabisulphite, or their like. The pH modifier(s) the formulation can be selected from Sodium Hydroxide, hydrochloric acid, or their like. The buffer(s) of the formulation can be selected from Dibasic sodium phosphate, monobasic sodium phosphate, or their like.

The said auxiliary ingrédients are used in the pharmaceutically acceptable proportions known in the art.

The viscosity of the présent formulations in their undiluted form is in the range of 5 to 35 CPS when measured by Ostwald viscometer at 25°C. The viscosity of the preferred embodiments of the présent formulations in their undiluted form ranges from 8 to 32 CPs at 25°C. This feature of the formulations of the présent invention not only provides tire advantage of less or no pain and no tissue damage at the site of injection when administered in undilutcd form intra-muscularly but also leads to less or no pain when administered upon dilution upto 20ml via slow IV bolus route over a period of 2 to 5 minutes.

The applicant conducted pre-clinical (animal) toxicity studies to establish the above mentioned advantagcous features of the formulation of the présent invention. Thé said studies and results thereof are summarised as under.

Sub-acute toxicity study of Undiluted Paracétamol injection (1000 mg/4 ml) in rats and mice:

The study was aimed to assess toxicity of paracétamol injection 1000 mg/4 ml (250 mg/ml) in rats and mice after repeated administration for 28 days. The animais were selected, conditioned, and exposed administered the test compound through Intra venous undiluted bolus injection al three dosage levels (15, 25, 35 mg/kg) and observed for 28 days.

Ail animais were observed for abnormal clinical signs and behavioral changes; morbidity and mortality; changes in body weight and food consumption throughout the study period. At the end of study (i.e. 28 days), the animais were also evaluated for hcmatological and biochcmical estimations and histopathology of different organs for détermination of toxicity.

The results showed that there were no mortalities observed among the animais treated due to test compound. There was no signîficant treatment effect on food intake, body weight gain and clinical signs, behavioural activity etc. Further, there were no signîficant changes found in haematological and biochemical parameters of mice and rats treated with ail three dose levels of paracétamol as compared (o control vehicle group.

The resuit concluded that surprisingly no toxicity was observed in rats and mice when undiluted Paracétamol formulation (1000 mg/4 ml) was injected by intravenous bolus route of administration. This is in contrast with the results of the study conducted for the formulations in W02012001494 which were not toleratcd through IV bolus route even at low dose.

Repeated dose toxicity study of Paracétamol injection (1000 mg/4 ml) in rabbits

The objcclive of this study was to assess the local and systemic toxicity in rabbits froml4 days repeatcd administration of Paracétamol Injection (1000 mg/4 ml), prepared as per the présent invention with a spécial emphasis on identifying target organs toxicitics.

In this study, animais were randomly assigncd to four treatment groups. Each group comprised of two female rabbits. Two groups (01 & 02) were given vehicle (Placebo) for Paracétamol Injection (1000 mg/4 ml) diluted upto 20 ml with water for injection. Other two groups (03 & 04) were given Paracétamol Injection (1000 mg/4 ml) diluted upto 20 ml with water for injection. 01 & 03 groups were treated with their respective treatments as once a day dose at volume of 2.52 ml/ 2 Kg Rabbil. 02 & 04 groups were treated with their respective treatments in divided doses administered four limes a day (0.63 ml/2 Kg each time). The diluted injections were administered as slow intravenous infusion at 65 mg/kg dose level within 2 to 5 minutes.

Ail the animais were observed once a day for signs of toxicity throughout the experimental period and twice daily for mortality and morbidity. Body weights were recorded on Day 1, 8, and 14. Feed consumption was calculated on weekly basis. At the end of experiment (Day 14), ail surviving animais were sacrifïced and gross pathology data was recorded.

At the end of study (i.e. 14 days), the animais were evaluated for gross pathology and histopathology of different organs including site of injection for détermination of toxicity. The resuit showed no local or systemic toxicity with Paracétamol injection 1000 mg/4 ml when administered as intravenous infusion in diluted form with water for injection for 14 days in rabbits.

The results of the preclinical studies conducted by the applicant confirmed that the formulations of the présent invention are capable of being administered through IV bolus route of administration in their undiluted form as well as through slow IV bolus route of administration over 2 to 5 minutes when diluted with water for injection to a final volume upto 20 ml.

Non-limiting examples of the formulations of the présent invention are provided herein below

Example 1

Ingrédients	Amount (mg/ml)	Percentage %
Paracétamol	250	25% w/v
Glycofurol	353	35.3% w/v
Ethyl alcohol	240	24% w/v
Plasdone C 17	20	2% w/v
Water for Injection	Qs to 1 ml	Qs to 100%

The viscosity of the above formulation (undiluted) was 18 CPS when measured by 5 Ostwald viscomctcr at 25°C.

When 4 ml (Volume équivalent to 1 gm) of the above formulation was diluted with water for injections upto a final volume of 20 ml, no recrystallization of drug was observed at 25°C up to duration of 8 minutes after dilution and at 20°C up to duration of 5 minutes after dilution.

Example 2:

Ingrédients	Amount (mg/ml)	Percentage %
Paracétamol	250	25% w/v
Glycofurol	300	30.0% w/v
Ethyl alcohol	300	30% w/v
Plasdone C 30	25	2.5% w/v
Water for Injection	Qs to 1 ml	Qs to 100%

The viscosity of the above formulation (undiluted) was 15 CPS when measured by Ostwald viscomcter at 25°C.

When 4 ml (Volume équivalent to 1 gm) of the above formulation was diluted with water for injections upto a final volume of 20 ml, no recrystallization of drug was observed 15 at 25°C up to duration of 8 minutes after dilution and at 20°C up to duration of 5 minutes after dilution.

Exainple 3:

Ingrédients	Amount (nig/nil)	Percentage %
Paracétamol	250	25% w/v
Glycofurol	353	35.3% w/v
Ethyl alcohol	240	24% w/v
Plasdone C 17	30	3% w/v
Water for Injection	Qs to 1 ml	Qs to 100%

The viscosily of the above formulation (undiluted) was 19.46 CPS when measured by Ostwald viscometer at 25°C.

When 4 ml (Volume équivalent to 1 gm) of the above formulation was diluted with 5 water for injections upto a final volume of 20 ml, no recrystallization of drug was observed at 25°C up to duration of 9 minutes after dilution and at 20°C up to duration of 8 minutes after dilution.

Example 4:

Ingrédients	Amount (mg/ml)	Percentage %
Paracétamol	250	25% w/v
Glycofurol	353	35.3% w/v
Ethyl alcohol	240	24% w/v
Plasdone C 17	40	4% w/v
Water for Injection	Qs to 1 ml	Qs to 100%

The viscosity of the above formulation (undiluted) was 20.94 CPS when measured 10 by Ostwald viscometer at 25°C.

When 4 ml (Volume équivalent to 1 gm) ofthe above formulation was diluted with water for injections upto a final volume of 20 ml, no recrystallization of drug was observed at 25°C up to duration of 11 minutes after dilution and al 20°C up to duration of 8 minutes after dilution

Example 5:

Ingrédients	Amount (mg/nil)	Percentage %
Paracétamol	250	25 %w/v
Glycofurol	353	35.3 %w/v
Eihyl alcohol	224	22.4 %w/v
Plasdone C 17	20	2 %w/v
N-Mcthyl Pyrollidone	20.6	2.06 %w/v
Water for Injection	Qs to 1 ml	Qs to 100%

The viscosity of the above formulation (undiluted) was 16.73 CPS when measured by Ostwald viscometer at 25°C.

When 4 ml (Volume équivalent to 1 gm) of the above formulation was diluted with water for injections up to a final volume of 20 ml, no recrystallization of drug was observed at 25°C up to duration of 20 minutes after dilution.

Example 6:

Ingrédients	Amount (mg/ml)	Percentage %
Paracétamol	250	25 %w/v
Glycofurol	353	35.3 %w/v
Ethyl alcohol	160	16 %w/v
Plasdone C 17	20	2 %w/v
N-Methyl Pyrollidone	103	10.3
Water for Injection	Qs to 1 ml	Qs to 100%

The viscosity of the above formulation (undiluted) was 16.46 CPS when measured by Ostwald viscometer at 25°C.

When 4 ml (Volume équivalent to 1 gm) of the above formulation was diluted with water for injections up to a final volume of 20 ml, no recrystallization of drug was observed at 25°C up to duration of 20 minutes after dilution.

Example 7:

Ingrédients	Amount (mg/ml)	Percentage %
Paracétamol	250	25 %w/v
Glycofurol	353	35.3 %w/v
Ethyl alcohol	80	8 %w/v
Plasdone C 17	20	2 %w/v
N-Methyl Pyrollidone	206	20.6 %w/v
Water for Injection	Qs to 1 ml	Qs to 100%

The viscosity of the above formulation (undiluted) was 22.94 CPS when measured by Ostwald viscometer at 25°C.

When 4 ml (Volume équivalent to 1 gm) of the above formulation was diluted with water for injections up to a final volume of 20 ml, no recrystallization of drug was observed at 25°C up to duration of 20 minutes after dilution.

Example 8:

Ingrédients	Amount (mg/ml)	Percentage %
Paracétamol	250	25 %w/v
Glycofurol	270	27 %w/v
Ethyl alcohol	240	24 %w/v
Plasdone C 17 •	20	2 %w/v
N-Melhyl Pyrollidone	61.8	6.18 %w/v
Water for Injection	Qs to 1 ml	Qs to 100%

The viscosity of the above formulation (undiluted) was 15.1 CPS when measured by Ostwald viscometer at 25°C.

When 4 ml (Volume équivalent to 1 gm) of the above formulation was diluted with water for injections up to a final volume of 20 ml, no recrystallization of drug was observed at 25°C up to duration of 20 minutes after dilution.

Example 9:

Ingrédients	Amount (mg/ml)	Percentage %
Paracétamol	250	25 %w/v
Glycofurol	244.9	24.49 %w/v
Ethyl alcohol	240	24 %w/v
Plasdone C 17	20	2 %w/v
N-Mcthyl Pyrollidone	103	10.3 %w/v
Water for Injection	Qs to 1 ml	Qs to 100%

The viscosity of the above formulation (undiluted) was 11.76 CPS when measured by Ostwald viscometer at 25°C.

When 4 ml (Volume équivalent to 1 gm) of the above formulation was diluted with water for injections up to a final volume of 20 ml, no recrystallization of drug was observed at 25°C up to duration of 20 minutes after dilution.

Example 10:

Ingrédients	Amount (mg/ml)	Percentage %
Paracétamol	250	25 %w/v
Glycofurol	270	27 %w/v
Ethyl alcohol	240	24 %w/v
N-Mcthyl Pyrollidone	61.8	6.18 %w/v
Water for Injection	Qs to 1 ml	Qs to 100%

The viscosity of the above formulation (undiluted) was 13.2 CPS when measured by Ostwald viscometer at 25°C.

When 4 ml (Volume équivalent to 1 gm) of the above formulation was diluted with water for injections up to a final volume of 20 ml, no recrystallization of drug was observed at 25°C up to duration of 8 minutes after dilution.

Example 11:

Ingrédients	Amount (mg/ml)	Percentage %
Paracétamol	250	25 %w/v

Glycofurol	353	35.3 %w/v
Plasdone C 17	20	2 %wh
N-Mcthyl Pyrollidone	309	30.9 %w/v
Water for Injection	Qs to 1 ml	Qs to 100%

The viscosity of the above formulation (undiluted) was 30.22 CPS when measured by Ostwald viscometer at 25°C.

When 4 ml (Volume équivalent to 1 gm) of the above formulation was diluted with water for injections up to a final volume of 20 ml, no rccrystallization of drug was observed 5 at 25°C up to duration of 20 minutes after dilution.

Example 12:

Ingrédients	Amount (mg/ml)	Percentage %
Paracétamol	250	25 %w/v
Ethyl alcohol	240	24 %w/v
Plasdone C 17	20	2 %w/v
N-Methyl Pyrollidone	257.5	25.75 %w/v
Water for Injection	Qs to 1 ml	Qs to 100%

The viscosity of the above formulation (undiluted) was 8.41 CPS when measured by Ostwald viscometer at 25°C.

When 4 ml (Volume équivalent to 1 gm) of the above formulation was diluted with water for injections up to a final volume of 20 ml, no recrystallization of drug was observed at 25°C up to duration of 20 minutes after dilution.

Example 13:

Ingrédients	Amount (mg/ml)	Percentage %
Paracétamol	250	25 %w/v
Ethyl alcohol	160	16 %w/v
N-Methyl Pyrollidone	439.6	43.96 %w/v
Water for Injection	Qs to 1 ml	Qs to 100%

The viscosity of the above formulation (undiluted) was 9.29 CPS when measured by Ostwald viscomcter at 25°C.

When 4 ml (Volume équivalent to 1 gm) of the above formulation was diluted with water for injections up to a final volume of 20 ml, no rccrystallization of drug was observed 5 at 25°C up to duration of 20 minutes after dilution.

Example 14:

Ingrédients	Amount (mg/ml)	Percentage %
Paracétamol	250	25 %w/v
Ethyl alcohol	80	8 %w/v
Plasdone C 17	20	2 %w/v
N-Methyl Pyrollidone	412	41.2 %w/v
Water for Injection	Qs to 1 ml	Qs to 100%

The viscosity of the above formulation (undiluted) was 11.12 CPS when measured by Ostwald viscometer at 25°C.

When 4 ml (Volume équivalent to 1 gm) of the above formulation was diluted with 10 water for injections up to a final volume of 20 ml, no recrystallization of drug was observed at 25°C up to duration of 20 minutes after dilution.

Example 15:

Ingrédients	Amount (mg/ml)	Percentage %
Paracétamol	250	25 %w/v
Ethyl alcohol	80	8 %w/v
N-Methyl Pyrollidone	542.6	54.26 %w/v
Water for Injection	Qs to 1 ml	Qs to 100%

The viscosity of the above formulation (undiluted) was 10.61 CPS when measured by Ostwald viscometer at 25°C.

When 4 ml (Volume équivalent to 1 gm) of the above formulation was diluted with water for injections up to a final volume of 20 ml, no recrystallization of drug was observed at 25°C up to duration of 20 minutes after dilution.

Example 16:

Ingrédients	Amount (mg/ml)	Percentage %
Paracétamol	250	25 %w/v
Plasdonc C 17	20	2 %w/v
N-Methyl Pyrollidone	386.2	38.62 %w/v
Water for Injection	Qs to 1 ml	Qs to 100%

The viscosity of the above formulation (undiluted) was 10.24 CPS when measured by Ostwald viscomcter at 25°C.

When 4 ml (Volume équivalent to 1 gm) of the above formulation was diluted with water for injections up to a final volume of 20 ml, no reciystallization of drug was observed at 25°C up to duration of 20 minutes after dilution.

Example 17:

Ingrédients	Amount (mg/ml)	Percentage %
Paracétamol	250	25 %w/v
Glycofurol	150	15 %w/v
Ethyl alcohol	250	25 %w/v
Plasdone C 17	20	2 %w/v
N-Methyl Pyrollidone	248	24.8 %w/v
Water for Injection	Qs to 1 ml	Qs to 100%

The viscosity of the above formulation (undiluted) was 12.6 CPS when measured by Ostwald viscomcter at 25°C.

When 4 ml (Volume équivalent to 1 gm) of the above formulation was diluted with water for injections up to a final volume of 20 ml, no recrystallization of drug was observed at 25°C up to duration of 20 minutes after dilution.

Example 18:

Ingrédients	Amount (mg/ml)	Percentage %
Paracétamol	250	25 %w/v
Glycofurol	200	20 %w/v

» 19

Ethyl alcohol	300	30 %w/v
Plasdone C 17	20	2 %w/v
N-Methyl Pyrollidone	156	15.6 %w/v
Water for Injection	Qs to 1 ml	Qs to 100%

The viscosity of the above formulation (undiluted) was 14.5 CPS when measured by Ostwald viscometer at 25°C.

When 4 ml (Volume équivalent to 1 gm) of the above formulation was diluted with water for injections up to a final volume of 20 ml, no rccrystallization of drug was observed 5 at 25°C up to duration of 20 minutes after dilution.

Example 19:

Ingrédients	Amount (mg/ml)	Percentage %
Paracétamol	250	25 %w/v
Glycofurol	353	35.3 %w/v
Elhyl alcohol	200	20 %w/v
Plasdone C 17	50	5 %w/v
N-Methyl Pyrollidone	32.5	3.25 %w/v
Water for Injection	Qs to 1 ml	Qs to 100%

The viscosity of the above formulation (undiluted) was 21.1 CPS when measured by Ostwald viscometer at 25°C.

When 4 ml (Volume équivalent to 1 gm) of the above formulation was diluted with 10 water for injections up to a final volume of 20 ml, no rccrystallization of drug was observed al 25°C up to duration of 20 minutes after dilution.

Example 20:

Ingrédients	Amount (mg/ml)	Percentage %
Paracétamol	250	25 %w/v
Glycofurol	400	40 %w/v
Ethyl alcohol	90	9 %w/v

Plasdone C 17	20	2 %w/v
N-Mcthyl Pyrollidone	164	16.4 %w/v
Water for Injection	Qs to 1 ml	Qs to 100%

The viscosity of the above formulation (undiluted) was 20.2 CPS when measured by Ostwald viscomctcr at 25°C.

When 4 ml (Volume équivalent to 1 gm) of the above formulation was diluted with water for injections up to a final volume of 20 ml, no recrystallization of drug was observed 5 at 25°C up to duration of 20 minutes after dilution.

The présent invention has surprisingly found that Injectable formulations comprising 250 mg/ml paracétamol or ils pharmaceutically acceptable sait, a solvent System comprising Glycofurol, Lower chain alcohol, a stabiliser, water which when diluted with aqueous fluids to not more titan 20 ml remain stable. In another embodiment of the présent formulation the 10 other solvent component may be used. These formulations are also suitable for slow IV bolus administration with minimised side effects such as phlebitis.

Claims (14)

1. A injectable formulation of Paracétamol comprising:

250 mg/ml Paracétamol or pharmaceutically acceptable salts thereof in a solvent System comprising glycofurol, a lower chain alcohol, a stabiliser, another solvent and water.

2. The injectable formulation of claim 1, wherein the viscosity of the formulation ranges from 5 to 35 CPs at 25°C, preferably 8 to 32 CPs.

3. The injectable formulation of claims 1-2, wherein the solvent System comprises glycofurol 0 - 40% w/v, lower chain alcohol 0 - 30% w/v, stabiliser 0 - 5% w/v, the other solvent 0-55% and water to make up the volume of the formulation.

4. The injectable formulation of claims 1-3, wherein the other solvent is selected from Surfactants, Cyclodextrins, Dimethylacetamide dérivatives, Transcutol, NMethyl Pyrollidone, or polyhydric alcohol(s) such as Propylene Glycol, Glycérine, Sorbitol and Poly ethylene glycols, or mixtures thereof.

5. The injectable formulation of claims 1-4, wherein the other solvent is most preferably selected from Surfactants, Cyclodextrins, Dimethylacetamide dérivatives, Transcutol, N-Methyl Pyrollidone.

6. The injectable formulation of claims 1-5, wherein the lower chain alcohol is selected from the group comprising ethyl alcohol, iso-propyl alcohol, and their like, or mixtures thereof.

7. The injectable formulation of claims 1-6, wherein the amount of water is < 50 % v/v, of the formulation.

8. The aqueous parentéral formulation of claims 1- 7, wherein the formulation further comprises auxiliary ingrédients such as antioxidant(s), pH modifier(s), buffcr(s), chelating agent(s), or any mixtures thereof.

« ' ²² *

9. The injectable formulation of daims 1-8, wherein the antioxidant(s) of the formulation are selected from a group comprising Monothioglycerol, sodium metabisulphite, or their like.

10. The injectable formulation of daims 1-9, wherein the pH modifîer(s) of the A

5 formulation are selected from a group comprising Sodium Hydroxide, hydrochloric acid, or their like.

11. The injectable formulation of daims 1-10, wherein the buffer(s) of the formulation are selected from a group comprising Dibasic sodium phosphate, monobasic sodium phosphate, or their like.

10

12. The injectable formulation of daims 1-11, wherein the formulation when diluted with the help of water for injection or conventional aqucous IV fluids such as normal saline, dextrose solution, or any other parentéral carriers, such that a dose of 1 gm of Paracétamol or its pharmaceutically acceptable sait is delivered in 20 ml volume of the final formulation, no crystals appear for a period of atleast 5 to 8 minutes.

15

13. The injectable formulation of daims 1-12, wherein the formulations are capable of administration via intra-muscular, intra-venous bolus, intravenous infusion as well as slow intra-venous bolus injection.

14. The injectable formulation of daims 1-13, wherein the slow intravenous bolus injection is stable from 2 to 10 minutes after dilution of the formulation.