Patent Description:
Paracetamol a para-aminophenol derivative provides analgesic, antipyretic and weak anti-inflammatory activity. It is widely used over-the-counter analgesic and antipyretic. It is commonly used for the relief of headaches and other minor aches and pains as well as fever. It is also used in combination with opioid analgesics for the management of severe pain such as post-surgical pain and providing palliative care in advanced cancer patients.

Paracetamol 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 parenteral routes are the most preferred routes of administration. ) The parenteral route of administration is preferred due to the issue of rapid degradation and poor absorption of drug following oral administration. Further, the parenteral 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 relief from the symptoms.

In case of emergency or when patients are unconscious or unable to accept oral medications, the parenteral route is the preferred route. Drug absorption after parenteral delivery is rapid and, blood levels attained are more favourable than those achieved by oral dosage forms.

Other advantages of the parenteral formulations of paracetamol are that they can be administered before or during the surgery thereby permitting the initiation of effective analgesia in the early phase of the postoperative period. ) These injections avoid first-pass hepatic exposure and metabolism via portal 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.

Despite the advantages of the parenteral formulations of paracetamol, very few options of parenteral formulations of paracetamol are available in the market. The key reasons for their non-availability are the drug's poor aqueous solubility and instability in presence of water,.

Most of the formulations of Paracetamol 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 specific infusion rate etc the manufacturing cost of these formulations is relatively high.

<CIT> and <CIT> disclose stable aqueous pharmaceutical compositions comprising paracetamol for parenteral administration, wherein the concentration of Paracetamol in the composition is <NUM>/ml and therefore the said compositions are suitable only for administration via Intra-Venous (IV) infusion. <CIT> discloses ready to use stable injectable formulations wherein the concentration of Paracetamol is upto <NUM>/ml for administration only by IV infusion route.

<CIT> is related to pharmaceutical compositions of Paracetamol comprising atleast <NUM>% w/v of Paracetamol in anhydrous PEG200. Viscosities of these compositions are of the order of <NUM> Cps and are therefore have limited use through parenteral route only upon dilution.

IN1746/MUM/<NUM> relates to injectable formulations of Paracetamol only upto <NUM>% prepared in a solvent system of Glycofurol & water. These formulations provide only upto <NUM> of drug in <NUM>.

<CIT> discloses non-aqueous injectable formulations of Paracetamol using alcohol and polyethylene glycol. These injections are formulated in non-aqueous solvents and are not in the ready-to-use form. The non-aqueous formulations disclosed in the said reference are not suitable for intramuscular (IM) administration without dilution with aqueous fluid.

In <CIT>, column <NUM> lines <NUM> to <NUM> mentions aqueous formulations of paracetamol injections with the Paracetamol concentrations in the range of <NUM>/ml to <NUM>/ml in dilute solutions and <NUM>/ml to <NUM>/ml in concentrated solutions. However in column <NUM> of the same reference specification, the said US patent also states the following:
"Using this solution composed of a solvent mixture constituted by <NUM>% of propyleneglycol, by <NUM>% of polyethylene-glycol <NUM> and by <NUM>% of water (solution no <NUM>), it is possible to dissolve about <NUM>/ml of paracetamol at <NUM>° C. Choosing a concentration of <NUM>/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 <NUM>/ml result in injectables in which no recrystallization occurs. The inventors of US'<NUM> themselves admit and illustrate by way of examples that the formulations containing Paracetamol concentration upto <NUM>/ml remain stable. There is no enabling disclosure or teaching of whether concentrations as high as <NUM>/ml will yield an injectable where no recrystallization occurs. It is not obvious whether concentrations in the range <NUM>/ml to <NUM>/ml would be workable based on the teachings of US'<NUM>.

When the formulations disclosed in the specification of US'<NUM> with high concentration of paracetamol (≥ <NUM>/ml) were prepared by us and diluted to obtain a dose of <NUM> gm in not more than <NUM>, (i.e. to provide the concentration of atleast <NUM>/ml), the drug crystallised out of these solutions in <NUM> to <NUM> minutes. These formulations are therefore not appropriate for slow IV bolus administration after dilution, as crystals appear within <NUM> minutes of dilution. The results of our studies are summarised below:.

It is clear from the above that these formulations are unsuitable for administration through the injectable route. Our studies unequivocally establish and confirm the admission of the inventors of US'<NUM> that the concentrated formulations of the said US patent are indeed unstable due to re-crystallisation of the drug.

<CIT> discloses high concentration aqueous formulations of paracetamol which deliver <NUM> of the drug in a volume of injection as low as <NUM> to <NUM> maintaining the viscosity in the range of <NUM> to <NUM> CPs when measured by Ostwald viscometer at <NUM>. 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 these formulations. We carried out detailed pre-clinical toxicity studies of the formulations disclosed in <CIT>.

Repeated dose intravenous toxicity studies were carried out in <NUM> Swiss Albino Mice and <NUM> New Zealand White Rabbits for <NUM> consecutive days. The test solution of the paracetamol injections disclosed in <CIT> were prepared and administered through intravenous route (tail vein) without any dilution at the dose levels of <NUM> (Low), <NUM> (Mid) and <NUM> (high) µL/<NUM> gm body wt of the Swiss Albino Mice. These formulations caused severe adverse effects at the site of injection and animals from low and mid dose Paracetamol treated groups were less affected when compared to high dose Paracetamol treated groups. Further, when these formulations were administered through marginal ear veins of New Zealand White Rabbits at the dose level of <NUM>, <NUM> and <NUM>µL/<NUM> body weight/day, they caused adverse effects at the site of injection. The findings of our studies in mice and rabbit suggest that the formulation of paracetamol disclosed in <CIT> when administered without any dilution through IV bolus route, are not tolerated even at the lowest dose. They cause severe phlebitis and are not suitable for intravenous bolus administration in humans.

When these formulations are diluted to achieve <NUM> gm of drug in <NUM> of formulation, precipitation of the drug sets in thereby making it unsuitable for administion through slow IV bolus route.

Some of the paracetamol injections disclosed in the prior art are non-aqueous and therefore not in ready-to use form. Further a severe limitation of prior art formulations is viscosities > <NUM> Cps which may cause tissue damage and pain at the site of injections. Through the present specification, the viscosity unit <NUM> Cps corresponds to <NUM> Pa s.

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

It is not possible to dilute the concentrated formulations known in the art to a volume of about <NUM> which can enable their administration through slow intravenous bolus route wherein the entire dose of the drug (e. g <NUM> gm in <NUM> ) is injected within <NUM> minutes, preferably in <NUM> 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 Paracetamol which are not only stable and suitable for administration through IM & IV infusion route but are also suitable for administration through slow intravenous bolus injections route but exhibiting minimal or no effects. In addition to providing stable high concentration solutions, these ready to use formulations must have viscosities of < <NUM> Pa s (< <NUM> Cps), preferably < <NUM> Pa s (< <NUM> Cps) at room temperature.

There exists a need to provide stable formulations which, enable administration of the therapeutic dose of <NUM> gm in a volume not more than <NUM> with viscosities < <NUM> Pa·s (<<NUM> Cps), preferably < <NUM> Pa·s (< <NUM> Cps) at room temperature, thereby rendering them suitable for administration through slow intravenous bolus route upon dilution with aqueous fluids over and above the Intramuscular, Intravenous infusion routes.

The main object of the present invention is to provide high concentration injectable formulations of paracetamol which when diluted with aqueous fluids are capable of providing a dose of <NUM> gm of the drug in not more than <NUM> without any crystallisation of drug for a duration of atleast <NUM> minutes after dilution.

It is yet another object of the present invention to provide high concentration stable aqueous injections of paracetamol which, when diluted with aqueous fluids to deliver <NUM> gm of drug in not more than <NUM> of the formulation, are suitable for being administered through slow intravenous bolus route.

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

The present invention provides stable high concentration aqueous injections of paracetamol which when diluted with aqueous fluids to not more than <NUM>, remain stable and are suitable for administration through slow intravenous route.

An injectable formulation of the present invention comprises
<NUM>/ml paracetamol in a solvent system comprising.

The another solvent is preferably selected from N-methyl pyrrolidone, dimethylacetamide, transcutol, cyclodextrin, or mixtures thereof.

The amount of glycofurol in the formulations is less than or equal to <NUM> % w/v, preferably less than or equal to <NUM> % w/v of the formulation. The amount of lower chain alcohol is less than or equal to <NUM> % w/v, preferably less than or equal to <NUM> % w/v of the formulation. The amount of another solvent in the formulations is less than or equal to <NUM> % v/v of the formulation.

The stabiliser is selected from grades of polymeric compounds such as plasdone for example plasdone C <NUM>, plasdone C <NUM> or its combination thereof. The amount of stabiliser is <NUM> % w/v to <NUM> % w/v of the formulation.

In one embodiment the injectable containing <NUM> paracetamol in <NUM>. In another embodiment, the dose of <NUM> of drug can be delivered in a volume of <NUM>. In another embodiment, the dose of <NUM> gm can be delivered in a volume of <NUM>. 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 <NUM> gm of Paracetamol in <NUM> of the formulation without any recrystallization for atleast upto <NUM> minutes after dilution, in another embodiment, such formulations do not exhibit recrystallization in atleast <NUM> to <NUM> 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 formulations also provide the option of dilution with large volume of aqueous fluids in order to deliver the drug through intravenous infusion route.

These formulations result in complete solubilisation of Paracetamol. The formulations containing <NUM> gm of drug when diluted with aqueous fluids upto <NUM>, do not exhibit and recrystallization atleast up to <NUM> minutes after dilution, more preferably up to a period of atleast <NUM> minutes after dilution.

Injectable formulations comprising <NUM>/ml of paracetamol, the solvent system of the present invention with a stabiliser in a specified range provides injectable formulations which on dilution with aqueous fluids up to <NUM> of formulation, are suitable for slow IV bolus route of administration with significantly minimised side effects such as phlebitis.

The formulations of the present invention are stable throughout the shelf life of the formulations. In the present invention, water is used in a quantity sufficient to make up the final volume of the formulation. Water to make up the final volume in these formulations is less than or equal to <NUM> % w/v, preferably less than or equal to <NUM> % w/v of the formulations.

The said formulations of the present 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 parenteral carriers known in the art such that a dose of <NUM> gm of Paracetamol is delivered in <NUM> volume of the final formulation.

In another embodiment of the present formulations, suitable auxiliary ingredients 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 be selected from monothioglycerol, sodium metabisulphite. The pH modifier(s) the formulation can be selected from sodium hydroxide, hydrochloric acid. The buffer(s) of the formulation can be selected from dibasic sodium phosphate, monobasic sodium phosphate.

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

The viscosity of the present formulations in their undiluted form is in the range of <NUM> Pa·s to <NUM> Pa·s (<NUM> to <NUM> CPs) when measured by Ostwald viscometer at <NUM>. The viscosity of the preferred embodiments of the present formulations in their undiluted form ranges from <NUM> Pa·s to <NUM> Pa·s (<NUM> to <NUM> CPs) at <NUM>. This feature of the formulations of the present invention not only provides the advantage of less or no pain and no tissue damage at the site of injection when administered in undiluted form intra-muscularly but also leads to less or no pain when administered upon dilution upto <NUM> via slow IV bolus route over a period of <NUM> to <NUM> minutes.

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

The study was aimed to assess toxicity of paracetamol injection <NUM>/<NUM> (<NUM>/ml) in rats and mice after repeated administration for <NUM> days. The animals were selected, conditioned, and exposed administered the test compound through Intra venous undiluted bolus injection at three dosage levels (<NUM>, <NUM>, <NUM>/kg) and observed for <NUM> days.

All animals were observed for abnormal clinical signs and behavioural changes; morbidity and mortality; changes in body weight and food consumption throughout the study period. At the end of study (i.e. <NUM> days), the animals were also evaluated for haematological and biochemical estimations and histopathology of different organs for determination of toxicity.

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

The result concluded that surprisingly no toxicity was observed in rats and mice when undiluted Paracetamol formulation (<NUM>/<NUM>) was injected by intravenous bolus route of administration. This is in contrast with the results of the study conducted for the formulations in <CIT> which were not tolerated through IV bolus route even at low dose.

The objective of this study was to assess the local and systemic toxicity in rabbits from <NUM> days repeated administration of Paracetamol Injection (<NUM>/<NUM>), prepared as per the present invention with a special emphasis on identifying target organs toxicities.

In this study, animals were randomly assigned to four treatment groups. Each group comprised of two female rabbits. Two groups (<NUM> & <NUM>) were given vehicle (Placebo) for Paracetamol Injection (<NUM>/<NUM>) diluted upto <NUM> with water for injection. Other two groups (<NUM> & <NUM>) were given Paracetamol Injection (<NUM>/<NUM>) diluted upto <NUM> with water for injection. <NUM> & <NUM> groups were treated with their respective treatments as once a day dose at volume of <NUM>/ <NUM> Rabbit. <NUM> & <NUM> groups were treated with their respective treatments in divided doses administered four times a day (<NUM>/<NUM> each time). The diluted injections were administered as slow intravenous infusion at <NUM>/kg dose level within <NUM> to <NUM> minutes.

All the animals 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 <NUM>, <NUM>, and <NUM>. Feed consumption was calculated on weekly basis. At the end of experiment (Day <NUM>), all surviving animals were sacrificed and gross pathology data was recorded.

At the end of study (i.e. <NUM> days), the animals were evaluated for gross pathology and histopathology of different organs including site of injection for determination of toxicity. The result showed no local or systemic toxicity with Paracetamol injection <NUM>/<NUM> when administered as intravenous infusion in diluted form with water for injection for <NUM> days in rabbits.

The results of the preclinical studies conducted by the applicant confirmed that the formulations of the present 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 <NUM> to <NUM> minutes when diluted with water for injection to a final volume upto <NUM>.

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

The viscosity of the above formulation (undiluted) was <NUM> Pa s (<NUM> CPs) when measured by Ostwald viscometer at <NUM>.

When <NUM> (volume equivalent to <NUM> gm) of the above formulation was diluted with water for injections upto a final volume of <NUM>, no recrystallization of drug was observed at <NUM> up to duration of <NUM> minutes after dilution and at <NUM> up to duration of <NUM> minutes after dilution.

The viscosity of the above formulation (undiluted) was <NUM> Pa·s (<NUM> CPs) when measured by Ostwald viscometer at <NUM>.

When <NUM> (volume equivalent to <NUM> gm) of the above formulation was diluted with water for injections upto a final volume of <NUM>, no recrystallization of drug was observed at <NUM> up to duration of <NUM> minutes after dilution and at <NUM> up to duration of <NUM> minutes after dilution.

When <NUM> (volume equivalent to <NUM> gm) of the above formulation was diluted with water for injections up to a final volume of <NUM>, no recrystallization of drug was observed at <NUM> up to duration of <NUM> minutes after dilution.

Claim 1:
An injectable formulation of paracetamol comprising:
<NUM>/ml paracetamol in a solvent system comprising
(a) less than or equal to <NUM>% w/v glycofurol,
(b) less than or equal to <NUM>% w/v lower chain alcohol selected from the group comprising ethyl alcohol, iso-propyl alcohol, or mixture thereof,
(c) <NUM>% to <NUM>% w/v stabilizer selected from Plasdone C <NUM>, Plasdone C <NUM> or its combination thereof,
(d) optionally another solvent selected from N-methyl pyrrolidone, cyclodextrin, dimethylacetamide, transcutol, or mixtures thereof; and
(e) water to make up the volume of the formulation.