Patent Description:
Paracetamol is a common analgesic and antipyretic drug, which is considered as first-line therapy for the management of fever and mild-to-moderate pain, also in paediatrics.

Liquid oral formulations of paracetamol are recommended for paediatric use, because they are easy to administer and because they allow convenient selection of the correct dose for each particular paediatric patient.

Liquid oral formulations in the form of oral solutions are particularly suitable, as they ensure a complete active ingredient uniformity and, therefore, an accurate dosing, as well as a quick absorption. However, paracetamol has an unpleasant bitter taste, which needs to be masked in order to be acceptable by children and thus to provide its therapeutic value for the paediatric population. Taste masking of paracetamol oral solutions may be challenging, particularly for formulations comprising high concentration of paracetamol. Furthermore, other formulation requirements must be fulfilled, such as the physic and chemical stability, microbiological integrity, as well as a suitable viscosity to allow convenient dosage of the formulation.

Several proposals have been disclosed in the art for the formulation of taste-masked paracetamol oral solutions.

On the one hand, several formulations are available in the market for high-concentration paracetamol solutions. For example, the commercial product Apiretal® <NUM>/ml is a paracetamol aqueous solution comprising polietilenglicol <NUM> and glycerol as cosolvents and sodium saccharin as sweetener, as well as flavouring and colouring agents.

Also, different proposals have been disclosed in the prior art. For example, the international patent application <CIT> discloses sugar free aqueous paracetamol solutions comprising a solubilizing agent containing polyethylene glycol, a thickening agent containing xanthan gum, and a sweetening system containing sucralose and a mixture of polyols including glycerol, sorbitol and xylitol. The polyethylene glycol used as solubilizing agent has preferably a high molecular weight, greater than <NUM>, typically, PEG <NUM> or PEG <NUM>.

The international patent application <CIT> discloses liquid high-concentration paracetamol formulations. The formulations comprise a solvent system for dissolving paracetamol, which contains polyvinylpyrrolidone, polyethylene glycol, water and, optionally, other solvents such as propylene glycol, polysorbate <NUM> and a sugar alcohol, such as glycerol or sorbitol.

The international patent application <CIT> discloses pharmaceutically acceptable taste masked liquid formulations comprising releatively large amount of unpleasant tasting medicines, wherein the taste masking effect is based on the use of a high-weight polyethylene glycol, of molecular weight of about <NUM>-<NUM>, which is melted before being added to the formulation.

The international patent application <CIT> discloses paracetalmol taste-masked semi-solid gel compositions, which are based on the use of a carbomer as gelling agent, as it provides high yield value and shear thinning quality to the gel composition.

The European patent application <CIT> discloses pharmaceutical compositions in semisolid form and a device for their administration comprising a squeezable container. For example, a semisolid paracetamol formulation having a viscosity of <NUM> cps is disclosed, comprising <NUM>% paracetamol, which is thickened with sodium carboxymethyl cellulose.

Despite the different proposals available in the art, there is still the need for further high-concentration formulations of paracetamol in the form of solution, which have improved organoleptical properties for effectively masking the bitter taste of paracetamol.

The object of the invention is a paracetamol oral solution.

Another aspect of the invention is the paracetamol oral solution for use in therapy.

The object of the present invention is a liquid pharmaceutical oral solution, which comprises:.

wherein the pharmaceutical oral solution has a weight ratio of low-weight polyethylene glycol plus glycerine to water comprised between <NUM>:<NUM> and <NUM>:<NUM>, and a weight ratio of glycerine to low-weight polyethylene glycol comprised between <NUM>:<NUM> and <NUM>:<NUM>.

The authors of the present invention have developed a paracetamol liquid pharmaceutical composition in the form of aqueous solution, wherein, thanks to the use of low-weight polyethylene glycol and glycerin as solubilizing substances, combined with sodium carboxymethyl cellulose as viscosizing agent, provides a slightly viscose solution which is easily dispensable and effectively masks the bitter taste of paracetamol.

The concentration of the ingredients in the paracetamol oral solution are generally expressed herein as mg/ml, meaning milligrams of the specified component per millilitre of the final oral paracetamol solution.

The excipients used for preparing the composition of the present invention are well known in the art, and are widely available, and are described, for example, in the reference book <NPL>]. Also, common excipients and procedures for preparing the compositions are described in the book<NPL>] or in the book <NPL>].

Paracetamol is a well-known analgesic and anti-pyretic drug, also known as acetaminophen or as N-acetyl-para-aminophenol (<NPL>). It is an odourless white crystalline solid of bitter taste.

The amount of paracetamol in the oral solution according to the present invention is comprised in the range <NUM>-<NUM>/ml, i.e., expressed as milligrams of paracetamol per millilitre of solution. Preferably, it is comprised between <NUM>/ml and <NUM>/ml, more preferably comprised between <NUM>/ml and <NUM>/ml and still more preferably is about <NUM>/ml.

Paracetamol is poorly soluble in water, with a reported solubility of less than <NUM>/g in water at <NUM> (e.g., as reported in <NPL>).

The paracetamol oral solution according to the present invention comprises low-weight polyethylene glycol and glycerine, which act as solubilizers for paracetamol. Both are well-known pharmaceutical excipients.

As is well-known, polyethylene glycol, also known as macrogol, is prepared by polymerization of ethylene oxide and is commercially available over a wide range of molecular weights, depending on the number of oxyethylene groups.

Low-weight polyethylene glycol, as used herein, typically means a polyethylene glycol having an average molecular weight comprised between about <NUM> and <NUM>. Typically, the polyethylene glycol is selected from PEG <NUM>, PEG <NUM>, PEG <NUM>, PEG, PEG <NUM>, PEG <NUM>, PEG <NUM>, and mixtures thereof, preferably is selected from PEG <NUM>, PEG <NUM>, PEG <NUM>, PEG <NUM>, PEG <NUM>, and mixtures thereof, more preferably is selected from PEG <NUM>, PEG <NUM>, PEG <NUM> and mixtures thereof, and still more preferably is PEG <NUM>.

The polyethylene glycols of said molecular weight ranges are characterized in that they are liquid at room temperature (i.e. at about <NUM>). Therefore, alternatively, low-weight polyethylene glycol, as used herein, also means a polyethylene glycol which is liquid at room temperature.

In an embodiment, the polyethylene glycol is PEG <NUM>.

Generally, the total content of solubilizing agents, i.e., of polyethylene glycol plus glycerine, in the paracetamol solution amounts to from about <NUM>/ml to about <NUM>/ml, preferably from <NUM>/ml to <NUM>/ml, more preferably from <NUM>/ml to <NUM>/ml and still more preferably from <NUM>/ml to <NUM>/ml.

The weight ratio glycerin:polyethylene glycol is generally comprised between <NUM>:<NUM> and <NUM>:<NUM>, preferably comprised between <NUM>:<NUM> and <NUM>:<NUM>, more preferably comprised between <NUM>:<NUM> and <NUM>:<NUM>, still more preferably comprised between <NUM>:<NUM> and <NUM>:<NUM>, and still more preferably is about <NUM>:<NUM>.

Carboxymethylcellulose sodium (NaCMC), also known as carmellose sodium is used in the paracetamol oral solution according to the present invention, as viscosizing agent.

Carboxymethylcellulose sodium is a well-known excipient, which is widely available from different commercial suppliers, for example, from the company Ashland under the trademarks Aqualon® or Blanose®; or from Nouryon under the trademark Akucell®, among many others.

It is available in different grades, typically classified as being of low, medium or high viscosity, depending on the average molecular weight of the NaCMC and its degree of substitution.

All types and grades of NaCMC are suitable to be used in the present composition. Preferred is low and medium viscosity NaCMC, typically providing viscosities approximately comprised between <NUM> and <NUM> mPa·s in aqueous solution at <NUM>% w/v, measured at about <NUM>. More preferred is a NaCMC providing viscosity comprised between <NUM> mPa·s and <NUM> mPa·s, more preferably comprised between <NUM> mPa·s and <NUM> mPa·s in aqueous solution at <NUM>% w/v, measured at about <NUM>. The viscosity can be measured as described in the monograph of carboxymethylcellulose sodium of the European Pharmacopoeia <NUM>.

The amount of NaCMC is adjusted accordingly to provide a suitable viscosity to the final formulation. Typically, the viscosity of the paracetamol solution according to the invention is comprised between about <NUM> mPa·s and about <NUM> mPa·s, preferably comprised between about <NUM> mPa·s and about <NUM> mPa·s, measured at about <NUM>.

The viscosity measurements can be made using a Brookfield Viscometer.

In one embodiment, the amount of NaCMC in the composition is comprised between <NUM>/ml and <NUM>/ml, preferably comprised between <NUM>/ml and <NUM>/ml, more preferably comprised between <NUM>/ml and <NUM>/ml, for example, about <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM>/ml.

Optionally, the composition may comprise a sweetening agent to improve the palatability of the paracetamol solution.

Typically, a non-nutritive high-intensity sweetener is used, for example, selected from aspartame, acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, saccharin sodium, sucralose, thaumatin, and mixtures thereof. Preferably, the sweetening agent is selected from saccharin, saccharin sodium, sucralose and neohesperidin, and mixtures thereof, and more preferably is selected from sucralose, neohesperidin, and mixtures thereof.

The amount of the sweetening agent may widely vary depending on the sweetening intensity of the agent, but generally is comprised in the range <NUM>/ml to <NUM>/ml, preferably from <NUM>/ml to <NUM>/ml.

In a preferred embodiment, the sweeter agent is a mixture of sucralose and neohesperidin. According to this embodiment, sucralose is typically added in a concentration of from about <NUM>/ml to <NUM>/ml, preferably from <NUM>/ml to <NUM>/ml, more preferably from <NUM>/ml to <NUM>/ml, and still more preferably in a concentration of about <NUM>/ml; and neohesperidin is typically added in a concentration in the range <NUM>/ml to <NUM>/ml, preferably <NUM>/ml to <NUM>/ml.

The composition may optionally additionally comprise a flavouring agent for providing a pleasant flavour and/or odour to the composition. Suitable flavouring agents include natural and artificial flavours. Some suitable flavours are, for example, menthol, cinnamon, clove, anise, eucalyptus, peppermint, spearmint, thyme, vanilla, chocolate, sugar flavour, fruit flavours, such as cherry flavour, grape flavour, orange flavour, banana flavour, strawberry flavour, lemon flavour, apple flavour, peach flavour, raspberry flavour, pineapple flavour and apricot flavour among many others, and combinations thereof.

A preferred flavouring agent is a combination of sugar flavour with a fruit flavour, for example, with cherry flavour, strawberry flavour, peach flavour, raspberry flavour or apricot flavour.

The amount of flavouring agent can be easily adjusted by the skilled formulator, depending on the specific flavouring agent and the desired organoleptic effect. Typically, the amount of flavouring agent, if present in the composition, ranges from about <NUM>/ml to about <NUM>/ml.

The paracetamol oral solution may also contain a colouring agent to improve its appearance and make the product more organoleptically appealing.

Any colouring agent suitable for use in foods or pharmaceuticals may be used, as are well known in the art, for example, those disclosed in the "Coloring Agents" section of the Handbook of Pharmaceutical Ingredients op.

The selection of a suitable colouring agent and its appropriate concentration is routine for the skilled in pharmaceutical formulation.

Suitable colouring agents include, for example, curcumin (E100), riboflavin (E101), tartrazine (E102), quinoline yellow (E104), sunset yellow FCF (E110), carmine cochineal (E120), amaranth (E123), ponceau 4R (E124), erythrosine (E127), allura red AC (E129), indigo carmine (E132), clorophylls (E140), or caramel (E150), among many others.

The paracetamol oral solution according to the present invention comprises glycerol, which is also an antimicrobial preservative. Therefore, in general, there is no need of an additional preservative to ensure the protection of the composition against microbial contamination.

Optionally, an additional preservative may be added, for example, butyl paraben, sodium butyl paraben, ethyl paraben, sodium ethyl paraben, methyl paraben, sodium methyl paraben, propyl paraben, sodium propyl paraben, benzoic acid, sodium benzoate, potassium benzoate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, chlorhexidine, chlorocresol, chloroxylenol, imidurea, cresol, phenol, sorbic acid, potassium sorbate or thimerosal, for example, among others, or mixtures thereof.

In the case that an additional preservative is used, the amount selected will be based on the specific preservative and typically may range from about <NUM>/ml to about <NUM>/ml.

The pH of the paracetamol solution according to the present invention is generally around neutrality, typically the pH value is comprised between <NUM> and <NUM>, preferably comprised between <NUM> and <NUM>.

In general, such pH is obtained without the need to use any pH adjuster. Optionally, if required, pH adjusting agent may be added in order to adjust the pH value to the preferred range. In such case, the amount and type of the pH adjusting agent to be used will be easily determined by the skilled in the art.

As is well-known in the art, the pH adjusting agent may be an acidifying agent, such as citric acid, acetic acid, hydrochloric acid, lactic acid, phosphoric acid, or sulfuric acid, for example, and/or an alkalinizing agent, such as ammonia solution, diethanolamine, monoethanolamine, potassium bicarbonate, sodium bicarbonate, potassium citrate, sodium citrate, sodium bicarbonate, or sodium borate, for example. Said acidifying and alkalinizing agents can be used in combination, as buffering system, generally comprising an acid and its conjugated base, as is well-known in the art.

Another component of the paracetamol oral solution is water, which is used as solvent. Typically, purified water for pharmaceutical use is used, which is available commercially, commonly obtained by distillation, ion exchange or reverse osmosis from drinkable water. The amount of water is typically adjusted to provide the desired concentration of every ingredient, as discussed above.

Generally, the weight ratio of the solubilizing agents, i.e., of polyethylene glycol plus glycerine, to water in the paracetamol solution is comprised between <NUM>:<NUM> and <NUM>:<NUM>, preferably comprised between <NUM>:<NUM> and <NUM>:<NUM>, more preferably comprised between <NUM>:<NUM> and <NUM>:<NUM>, and still more preferably is about <NUM>:<NUM>.

The present invention provides a pharmaceutical oral solution. The term solution is understood in its ordinary meaning as known in the art, i.e., a homogeneous, molecular, mixture of two or more components. In particular, the solid paracetamol, as well as the solid excipients of the formulation, are dissolved in the solvent system comprising the low-weight polyethylene glycol, glycerin and water. The term oral solution means that the paracetamol solution is for oral administration.

The paracetamol solution of the present invention can be prepared using standard procedures, by simple mixture of the components.

A clear solution is obtained by thoroughly mixing the above stated ingredients in a suitable vessel provided with a stirring system, such as a blade stirrer. In order to obtain an optimal and uniform viscosizing effect, the NaCMC is preferably previously dispersed, for example in glycerin, before being incorporated, typically as the last step of the process, followed by high shear mixing of the resulting solution.

The paracetamol oral solution of the invention can be filled into a standard multiple-dose primary container suitable for oral liquid pharmaceutical dosage forms, such glass or plastic bottle, typically provided with a suitable dose measure system, such as a graded vessel or spoon, or a syringe.

The paracetamol solution is a clear, homogeneous solution, slightly viscous, which can be easily dispensed according to the required dose.

As shown in the Examples, the solution is stable and has outstanding organoleptic properties. The comparative palatability assay disclosed in Example <NUM> shows that the paracetamol oral solution according to the present invention was found organoleptically superior, compared to a commercial paracetamol oral solution (Apiretal® <NUM>/ml oral solution).

In view of these properties, the paracetamol oral solution is suitable to be used in therapy, particularly for treating the paediatric patients. In particular, the paracetamol oral solution can be used for the treatment of fever and mild-to-moderate pain.

Therefore, another aspect of the present invention is the paracetamol oral solution for use in therapy, in particular, for use in the treatment of fever and/or mild-to-moderate pain, preferably in the paediatric patient.

The paediatric patient, as used herein, typically includes children from <NUM> to about <NUM> years.

The skilled practitioner will have no difficulties in determining the most suitable dose, according to the common medical guidelines. Typically, paracetamol is administered to the paediatric patient in daily doses of about <NUM>/kg, distributed in <NUM>-<NUM> daily administrations.

In an embodiment, the paracetamol oral solution consists of:.

The invention relates to the following embodiments:.

A paracetamol solution according to the present invention, containing <NUM>/ml of paracetamol, was prepared with the ingredients disclosed in the following table:.

The sodium carboxymethyl cellulose used was a low-medium viscosity carboxymethylcellulose that provides a viscosity between <NUM> mPa·s and <NUM> mPa·s (<NUM> mPa·s) in aqueous solution at <NUM>% w/v. It conforms to the monograph for carmellose sodium in the current European Pharmacopoeia.

The solution was prepared as follows. In a stainless-steel reactor equipped with agitation system, PEG <NUM> was first mixed with a small part of water (about <NUM>% of total water), and paracetamol was then added and stirred until complete dissolution. The flavouring agents, sucralose, neohesperidin and colouring agent were subsequently added, dissolved in water, under continuous stirring. Sodium carboxymethylcellulose and glycerin were premixed in a separate vessel and added to the previous mix, the rest of water was added, to make up the final volume, and the obtained final mixture was maintained under high-shear mixing using a Cowles stirrer for about <NUM> minutes.

The obtained product was a clear red-coloured slightly viscous solution. The viscosity was <NUM> mPa·s, measured at <NUM> using a Visco Star Plus Viscometer, equipped with a number <NUM> spindle rotating at <NUM> rpm. The pH of the solution was <NUM>.

The paracetamol composition prepared in Example <NUM> was tested for physicochemical and microbiological integrity in a <NUM>-month stability assay, at <NUM> on the stove and at room temperature. At the end of this period, the product was tested and it was confirmed that all the required specifications (aspect, pH, viscosity, impurities, paracetamol concentration and microbiological integrity) were fulfilled.

The palatability of the composition of Example <NUM> was assessed, compared to the commercial product Apiretal® <NUM>/ml oral solution. The excipients of this product are PEG <NUM> and glycerol as solubilizing substances, sodium saccharin as sweetener, flavouring agents and water.

A comparative single-blind palatability study was designed, with <NUM> adult volunteers aged from <NUM> to <NUM>.

All participants tested both formulations, i.e., Example <NUM> according to the invention (formulation A), and comparative Apiretal® <NUM>/ml oral solution (formulation B). They were randomly assigned a specific sequence, so each volunteer received the samples in a specified order. About half of volunteers (group <NUM>, <NUM> subjects) received first the composition according to the invention, while the other half (group <NUM>, <NUM> subjects) received first the comparative formulation. The preparations were administered approximately <NUM> apart to allow time for taking and rating the preparation and cleaning the mouth.

Each volunteer was asked to rate the taste/texture of the compositions and their aftertaste using the following scale: "very good", "good", "average", "bad" and "very bad". They were also asked about their preference between both formulations.

The results of the preference selection between formulations are summarized in the following table:.

It was found that <NUM>% of the volunteers preferred the composition according to the invention. It was observed that the administration order had an influence in the preference, as shown in the results for groups <NUM> and <NUM>, but, nevertheless, a higher percentage for the composition of Example <NUM> was found in both groups.

The results of the taste/texture and aftertaste evaluation are shown in <FIG>, respectively. The rating scale numbering in the figures corresponds to: <NUM> (very good), <NUM> (good), <NUM> (average), <NUM> (bad) and <NUM> (very bad).

It could be appreciated better rating (<NUM> and <NUM> scores) for the composition of the present invention (formulation A) in both tests.

Claim 1:
A liquid pharmaceutical oral solution, which comprises:
a) paracetamol in an amount comprised between <NUM>/ml and <NUM>/ml;
b) low-weight polyethylene glycol;
c) glycerin;
d) carboxymethyl cellulose sodium; and
e) water,
wherein the pharmaceutical oral solution has a weight ratio of low-weight polyethylene glycol plus glycerine to water comprised between <NUM>:<NUM> and <NUM>:<NUM>, and a weight ratio of glycerine to low-weight polyethylene glycol comprised between <NUM>:<NUM> and <NUM>:<NUM>.