RU2842648C1 - Liquid composition containing ibuprofen and phenylephrine - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: group of inventions relates to the pharmaceutical industry, specifically to a liquid pharmaceutical composition for oral administration, a method for its preparation, use, as well as to a method of treating flu and cold symptoms using said composition. Liquid pharmaceutical composition for oral administration in the form of a suspension containing: a) ibuprofen in amount of 2 wt./vol.% up to 6 wt./vol.%; b) phenylephrine or a pharmaceutically acceptable salt thereof in amount of 0.05 wt./vol.% up to 0.5 wt./vol.%, expressed as an equivalent amount of phenylephrine hydrochloride; c) hypromellose in amount of 0.3 wt./vol.% up to 1 wt./vol.%; d) xanthum gum in amount of 0.2 wt./vol.% up to 1 wt./vol.%; e) liquid maltitol in amount of 35 wt./vol.% up to 65 wt./vol.; f) glycerine in amount of 5 wt./vol. up to 15 wt./vol.; and g) water. Method for producing said composition, comprising the following steps: (i) mixing hypromellose, xanthum gum and one part liquid maltitol with one part of the total amount of water to obtain a homogeneous mixture; (ii) separately mixing ibuprofen, phenylephrine or a pharmaceutically acceptable salt thereof, glycerol and the remaining liquid maltitol with another part of the total amount of water to form a homogeneous mixture; (iii) adding the mixture from step (ii) to the mixture from step (i); (iv) adding remaining amount of water. Use of said composition for the treatment of flu and cold symptoms, such as fever, pain, inflammation of the throat, nasal and paranasal sinus congestion. Use of said composition for preparing a drug for treating symptoms of influenza and colds, such as fever, pain, inflammation of throat, nasal and sinus congestion. A method of treating cold and influenza symptoms, such as fever, pain, sore throat, nasal and paranasal sinus congestion involving the stage of administering a therapeutically effective dose of said composition into a patient in need thereof.

EFFECT: use of the group of inventions provides a liquid composition comprising phenylephrine and ibuprofen, which is stable, acceptable from an organoleptic point of view, suitable for use in pediatrics and geriatrics and capable of providing effective pharmacological activity and rapid absorption of both active ingredients for the rapid relief of symptoms of influenza and colds.

18 cl, 2 tbl, 3 ex

Description

Field of technology

The present invention relates to a liquid pharmaceutical composition in the form of a suspension containing a combination of ibuprofen and phenylephrine, which is stable and, in particular, suitable for the treatment of flu and cold (viral upper respiratory tract infection) symptoms in adults and children.

State of the art

The combined use of analgesics and decongestants to relieve symptoms associated with the common cold or flu, such as headache, fever, sinus pressure, and minor body aches, is a well-known therapeutic strategy.

One specific method is, for example, a combination of ibuprofen and phenylephrine. Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) with antipyretic and anti-inflammatory properties, while phenylephrine is a sympathomimetic amine that acts primarily by directly acting on α-adrenergic receptors and is an oral nasal decongestant.

To date, the ibuprofen/phenylephrine combination is only available on the market as solid oral dosage forms, and it is noteworthy that all available medications are only intended for adults and children aged 12 years and older.

For example, Advil® Congestion Relief (FDA, Pfizer) is an oral tablet formulation containing 200 mg of ibuprofen and 10 mg of phenylephrine hydrochloride (HCl). The recommended dose of this medication is 1 tablet taken every 4 hours.

Similarly, the medicine “Care Cold & Flu Relief” (UK, Thornton & Ross) is available as film-coated tablets, and each dose contains 200 mg ibuprofen and 5 mg phenylephrine hydrochloride. Or film-coated tablets, Grippostad® (ES, Laboratorio Stada) also consist of a fixed combination of 200 mg ibuprofen and 5 mg phenylephrine hydrochloride. Or film-coated tablets, Nurofen® Day & Night Cold & Flu 200 mg/5 mg tablets (UK, Reckitt Benckiser Healthcare). The recommended dose of these three medicines is 2 tablets taken every 8 hours.

It should be noted that the use of solid oral dosage forms may not be suitable for some groups of patients who may have difficulty swallowing whole tablets or capsules, including children, elderly patients or patients with disabilities. For these groups of patients, the use of liquid formulations is generally considered preferable. In addition, a liquid formulation may be more suitable for adjusting the dose of active substances depending on the age of the patient, as well as for better control over the amount of drug administered. This advantage is important when treatment is aimed at children under 12 years of age.

However, the preparation of liquid pharmaceutical compositions is usually associated with greater difficulties than the preparation of solid compositions. For example, there are usually more problems in terms of stability due to the closer interaction between the combined drugs and between the drugs and excipients. Phenylephrine is generally a drug that is easily degraded, particularly in liquid compositions, and especially at high temperatures.

In addition, the composition of each specific drug combination must be considered as a special, unique problem to be solved, arising from complex interactions between the specific combined drugs and excipients, and therefore cannot be solved by simply combining previously known compositions for each specific drug.

In addition, for medicinal substances having an unpleasant taste, it is also difficult to obtain palatable liquid compositions, since, while in solid compositions the unpleasant taste can be masked by simply filling gelatin capsules with the medicinal substance or forming it into film-coated tablets, in liquid compositions it is difficult to avoid direct contact of the medicinal substance having an unpleasant taste with the taste cells in the oral cavity when swallowing the medicinal product. Ibuprofen, for example, is known to have a particularly unpleasant bitter burning taste, with phenylephrine exhibiting a characteristic bitter taste.

Another additional difficulty is related to the solubility of the combined drugs. For example, ibuprofen is practically insoluble in water, and although its pharmaceutically acceptable salts may be more soluble, their use will complicate problems related to taste characteristics. As a result of the poor solubility of ibuprofen in water, its aqueous preparations are usually suspensions in which the ibuprofen particles must be in equilibrium to avoid aggregation and sedimentation. These phenomena occur frequently and are difficult to exclude.

From the pharmacokinetic point of view, it is necessary to have a composition that ensures high bioavailability of the active substance and subsequent early and strong therapeutic effect. The bioavailability of a drug is measured mainly by the time to reach the maximum concentration observed in plasma (T _max ) and the maximum observed concentration in plasma (C _max ). With regard to the bioavailability of a drug, the production of liquid preparations is associated with great difficulties, since the use of some excipients necessary to improve the stability and taste of the composition, such as polyols, can reduce the rate of absorption of the active substances.

Therefore, it is not obvious to a person skilled in the art that the composition of the liquid composition containing ibuprofen and phenylephrine is stable, organoleptically acceptable and ensures adequate bioavailability of the drug.

There are some disclosures in the prior art that attempt to solve related problems.

For example, international patent application WO 2008/008944-A1 describes pharmaceutical suspensions comprising phenylephrine and at least one substantially water-insoluble active substance, in particular acetaminophen, which have a pH of from about 4 to about 6. The compositions contain non-reducing sugars, polyhydric alcohols and high intensity sweeteners as sweeteners; a preferred sweetener is sorbitol, optionally combined with sucrose. A preferred thickening agent includes 0.1-0.25% (w/v) xanthan gum as a primary structuring agent and a co-processed combination of microcrystalline cellulose and carboxymethylcellulose as a secondary structuring agent. Compositions containing a specific combination of phenylephrine and ibuprofen are not described.

International patent application WO 2007/098128-A2 describes liquid pharmaceutical compositions for oral use based on phenylephrine, containing reduced amounts of sorbitol to improve the stability of phenylephrine. In particular, the compositions contain a combination of glycerol and sorbitol, wherein the amount of glycerol is up to about 45% w/v, preferably from 18 to 30% w/v glycerol and up to about 10% w/v sorbitol, preferably from 3 to 10% w/v sorbitol. Compositions containing a specific combination of phenylephrine and ibuprofen are not described.

International patent application WO 2006/022996-A2 describes, in general, pharmaceutical compositions comprising a first drug substance and a second drug substance, both selected from decongestants, antitussives, expectorants, analgesics and antihistamines, which provide effective drug concentrations in the plasma. Examples 2, 25, 45, 69 and 72 describe suspensions containing phenylephrine in combination with other drugs, namely promethazine, codeine, carbetapentane or diphenhydramine. The suspension formulations include a combination of sorbitol polyols, glycerol and xylitol as sweeteners and a combination of colloidal anhydrous silicon dioxide and hydroxyethylcellulose as suspending agents. Compositions containing a specific combination of phenylephrine and ibuprofen are not described.

International patent application WO 2008/008364-A2 describes oral liquid pharmaceutical compositions comprising phenylephrine and substantially aldehyde-free polyethylene glycol, which have a reduced tendency to degrade phenylephrine. The compositions also have an attractive taste. The examples provided additionally include a combination of glycerol, sorbitol and micronized sucralose as a sweetener. No stability data are provided for phenylephrine. Compositions containing a specific combination of phenylephrine and ibuprofen are not described.

Thus, there is currently a need to provide liquid compositions containing a combination of phenylephrine and ibuprofen that are stable, organoleptically acceptable, suitable for pediatric use and capable of providing effective pharmacological activity and rapid absorption of both active ingredients to provide rapid relief of flu and cold symptoms.

Purpose of the invention

The aim of the invention is a liquid pharmaceutical composition containing a combination of ibuprofen and phenylephrine.

Another aspect of the invention is a method for producing the composition.

Another aspect of the invention is a liquid pharmaceutical composition comprising a combination of ibuprofen and phenylephrine for use in medicine.

Detailed description of the invention

The aim of the present invention is a liquid pharmaceutical composition for oral use in the form of a suspension, containing:

a) ibuprofen in an amount of 2 to 10% w/v;

b) phenylephrine or a pharmaceutically acceptable salt thereof in an amount of from 0.005% to 2% w/v, expressed as an equivalent amount of phenylephrine hydrochloride;

c) hypromellose in an amount of 0.1 to 5% w/v;

d) xanthan gum in an amount of 0.05 to 4% w/v;

e) liquid maltitol;

f) glycerin; and

g) water.

The inventors of the present invention have developed an aqueous liquid pharmaceutical composition in the form of a suspension containing, as active substances, a combination of ibuprofen and phenylephrine, which has optimal physicochemical characteristics, in particular, it is distinguished by exceptional stability and good organoleptic properties. In addition, the composition also has excellent pharmacokinetic properties, ensuring very rapid absorption of both medicinal substances and optimal bioavailability.

In the present description, as well as in the claims, expressions in the singular also include plural forms, unless the context clearly indicates otherwise. In addition, numerical values preceded by the term "about" or "approximately" include the exact stated value, as well as a certain deviation from this value, i.e., a deviation or ±5% from the stated amount. It is intended that numerical ranges defined by lower and upper limit values also include the stated limit values.

Unless otherwise stated, the percentages described for each component of the composition correspond to the ratio of weight to volume (% w/v), i.e. grams of each component per 100 ml of the composition.

Excipients used to prepare the composition of the present invention are well known in the art, widely available and described, for example, in RC Rowe, PJ Sheskey and PJ Weller, Handbook of Pharmaceutical Excipients, Sixth Edition, Pharmaceutical Press, 2009. In addition, general excipients and formulation procedures are described in JP Remington and AR Genaro, Remington The Science and Practice of Pharmacy , ^20th edition, Lippincott, Williams & Wilkins, Philadelphia, 2000 [ISBN: 0-683-306472] or in ME Aulton and KMG Taylor, Aulton's Pharmaceutics, the design and manufacture of medicines, ^4th edition, Churchill Livingstone Elsevier, 2013 [ISBN: 978-0-7020-4290-4].

Ibuprofen

Ibuprofen is the international nonproprietary name (INN) of the compound (RS)-2-(4-(2-methylpropyl)phenyl)propanoic acid.

Ibuprofen is a well-known non-steroidal anti-inflammatory drug (NSAID) and has analgesic, antipyretic and anti-inflammatory properties.

In the context of the present invention, the term “ibuprofen” refers equally to racemic ibuprofen (RS), and to (S)-ibuprofen and (R)-ibuprofen or to mixtures (R) And (S) forms in any ratio. Preferably, the ibuprofen used in the pharmaceutical composition of the present invention is selected from the group consisting of (RS)-ibuprofen and (S)-ibuprofen.

In addition, the term ibuprofen also includes any hydrated and solvated form, as well as any crystalline and amorphous form. Crystalline ibuprofen is preferably used.

Ibuprofen is commercially available and can also be prepared, for example, according to the procedure described in UK Patent Application GB-A-971700. The resolution of ibuprofen into its enantiomers is described, for example, in Brushan et al. Resolution of enantiomers of ibuprofen by liquid chromatography: a review , Biomed. Chromatogr., 1998, 12 (6), 309.

Ibuprofen is an acidic molecule consisting of a carboxylic acid group and is poorly soluble in water.

Ibuprofen can be used in therapy both in its acid-free form and in the form of its pharmaceutically acceptable salt, such as, inter alia, ibuprofen arginate, ibuprofen lysinate or ibuprofen sodium. In the context of the present invention, ibuprofen is preferably used in its acid-free form.

The particle size of ibuprofen used to obtain the composition is not critical, but is preferably less than 150 μm in order to minimize aggregation and sedimentation phenomena and, accordingly, improve the long-term stability and homogeneity of the suspension. The particle size of ibuprofen is more preferably from 5 μm to 100 μm, even more preferably from 10 μm to 60 μm, even more preferably from 20 μm to 50 μm, and even more preferably from 30 μm to 45 μm.

The particle size of ibuprofen can be quantitatively determined by known methods, for example by sieving through a sieve of the appropriate size.

The concentration of ibuprofen present in the composition of the invention is from 2% to 10%, preferably from 2% to 8%, more preferably from 2% to 7%, even more preferably from 2% to 6%, even more preferably from 2% to 5%, even more preferably from 3% to 5% and even more preferably about 4%, expressed as a percentage by weight and volume. In one embodiment, the concentration of ibuprofen present in the composition of the invention is from greater than 3% to 10%, preferably from greater than 3% to 8%, more preferably from greater than 3% to 7%, even more preferably from greater than 3% to 6% and even more preferably from greater than 3% to 5%, expressed as a percentage by weight and volume. In one embodiment, the concentration of ibuprofen present in the composition of the invention is from 3.3% to 10%, preferably from 3.3% to 8%, more preferably from 3.3% to 7%, even more preferably from 3.3% to 6% and even more preferably from 3.3% to 5%, expressed as a percentage by weight and volume.

Phenylephrine

Phenylephrine is the international nonproprietary name (INN) of the compound 3-[(1R)-1-hydroxy-2-(methylamino)ethyl]phenol ((R)-(-)-phenylephrine, CAS 61-76-7).

In the context of the present invention, the term "phenylephrine" refers equally to both the conventional R-form and the racemic or S- form. Preferably, (R)-(-)-phenylephrine is used.

In addition, the term phenylephrine also includes any hydrated and solvated form thereof, as well as any crystalline and amorphous form thereof. Crystalline phenylephrine is preferably used.

Phenylephrine is a basic compound containing a secondary amino group. Phenylephrine can be used in the form of a free base or as a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts of phenylephrine include non-toxic acid addition salts.

In one embodiment of the invention, phenylephrine is used in the form of a salt, for example selected from acid addition salts such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, salicylic acid, tartaric acid, glutamic acid, succinic acid, methanesulfonic acid and benzenesulfonic acid.

In one embodiment of the invention, the pharmaceutically acceptable salt of phenylephrine is selected from the hydrochloride salt (phenylephrine hydrochloride), the hydrobromide salt (phenylephrine hydrobromide) and the bitartrate salt (phenylephrine bitartrate).

In one preferred embodiment, phenylephrine hydrochloride is used.

The concentration of phenylephrine or a pharmaceutically acceptable salt thereof in the composition of the invention is from 0.005% to 2%, preferably from 0.01% to 1%, more preferably from 0.05% to 0.5%, even more preferably from 0.08% and 0.2%, and even more preferably is about 0.1%, expressed as an equivalent amount of phenylephrine hydrochloride in percentage by weight and volume.

The expression "expressed as an equivalent amount of phenylephrine hydrochloride" means that if phenylephrine was added as a free base or as a salt other than the hydrochloride, the amount of phenylephrine is converted to the equivalent weight of an equimolar amount of phenylephrine hydrochloride. Thus, for example, if phenylephrine free base is used at a concentration of 0.82 mg / ml (molecular weight 167.205 g / mol), then the concentration of phenylephrine, "expressed as an equivalent amount of phenylephrine hydrochloride" (molecular weight 203.66 g / mol), will be 1 mg / ml or 0.1 w / v %. Also, similar calculations can be made for other salts in a similar manner well known to those skilled in the art.

In the present description, as well as in the claims, the amounts and concentrations of phenylephrine are always expressed as an equivalent amount or concentration of phenylephrine hydrochloride.

Thickener/suspending agent

The composition of the present invention includes a combination of xanthan gum and hypromellose (hydroxypropyl methylcellulose), which act as suspending agents and thickening agents.

Hypromellose (also known as hydroxypropyl methylcellulose or HPMC) is a well-known cellulose derivative used in pharmaceuticals. Hypromellose can be described as partially O-methylated and O-(2-hydroxypropylated) cellulose. It is available in several grades, differing in viscosity and degree of substitution, all of which are suitable for use in the composition of the present invention.

Xanthan gum is also a well-known pharmaceutical excipient, which is mainly used as a suspending agent for the preparation of suspensions and also as a thickening agent. Xanthan gum can be described as a high molecular weight polysaccharide gum. It contains D-glucose and D-mannose as the dominant hexose units, along with D-glucuronic acid, and is obtained as sodium, potassium or calcium salt. It is widely available commercially.

The present inventors have unexpectedly found that the combination of xanthan gum and hypromellose as a suspending/thickening system, together with a combination of glycerol and maltitol polyols, provides excellent physicochemical stability of the composition, as well as improved absorption of active ingredients and optimal organoleptic properties.

In one embodiment, hypromellose with a hydroxypropoxy content of 7.0 to 12% (known as hypromellose type 2910) is used.

The relative content of hypromellose in the composition, expressed as a percentage by weight and volume, is from 0.1% to 5%, preferably from 0.2% to 2%, more preferably from 0.3% to 1%, even more preferably from 0.4% to 0.6% and even more preferably is about 0.5%.

The relative content of xanthan gum in the composition, expressed as a percentage by weight and volume, is from 0.05% to 4%, preferably from 0.1% to 2%, more preferably from 0.2% to 1%, even more preferably from 0.3% to 0.6% and even more preferably about 0.4%.

The weight ratio of hypromellose:xanthan gum is usually from 2:1 to 1:1, preferably from 1.5:1 to 1:1, and more preferably the weight ratio of hypromellose:xanthan gum in the composition is about 1.25:1.

Polyols

The composition according to the invention includes a combination of glycerol polyols and liquid maltitol.

Glycerol (or glycerol or propane-1,2,3-triol) is a known pharmaceutically acceptable excipient that typically acts as a sweetener, co-solvent or thickening agent in oral liquid compositions.

Maltitol is a disaccharide (4-O-α-D-glucopyranosyl-D-glucitol).

Liquid maltitol is an aqueous solution of D-maltitol which is commonly used as a pharmaceutical excipient, according to the current European Pharmacopoeia, which states that liquid maltitol contains not less than 68% w/w and not more than 85% w/w solids, that the D-maltitol content is ≥50% w/w, that it contains not more than 8% w/w sorbitol and that it additionally contains minor amounts of hydrogenated oligo- and polysaccharides. According to the US Pharmacopoeia, maltitol solution contains not less than 50% w/w D-maltitol on an anhydrous basis and not more than 8.0% w/w D-sorbitol.

Typically, for example, liquid maltitol contains from about 50% w/w to about 55% w/w of D-maltitol relative to the total weight of the anhydrous substance; and the sorbitol content is typically from about 2% w/w to about 7% w/w, preferably from about 3% w/w to about 5% w/w, also relative to the total weight of the anhydrous substance; the water content is typically in the range of 20-30% w/w, preferably about 25% w/w, and the total solids content is typically in the range of from about 70% w/w to about 80% w/w, preferably about 75% w/w.

It is thus understood that the compositions of the present invention themselves also contain small amounts of sorbitol and other minor saccharides that are present together with maltitol in the excipient "liquid maltitol" used. Therefore, whenever the present description and claims state that the compositions contain a certain amount of "liquid maltitol", it should be understood that, in addition to maltitol, small relative amounts of sorbitol and other saccharides in the stated quantitative ranges are also included.

A person skilled in the art of pharmaceutical technology can, if necessary, determine the amount of maltitol and the residual amount of sorbitol present in the compositions.

Liquid maltitol is used in liquid oral formulations, typically as a sweetener and also as a suspending agent.

Maltitol is often considered an “active excipient” because it alters intestinal motility by increasing peristaltic movements and reducing the residence time of active substances in the intestinal lumen.

Typically, the relative content of liquid maltitol in the composition, expressed as a percentage by weight and volume, is from 30% to 70%, preferably from 35% to 65%, more preferably from 45% to 55% and even more preferably about 50%.

Typically, the relative content of glycerol in the composition, expressed as a percentage by weight and volume, is from 5% to 15%, preferably from 7% to 13%, more preferably from 9% to 11%, and even more preferably is about 10%.

The weight ratio of liquid maltitol:glycerol in the pharmaceutical composition of the invention is typically from 10:1 to 1:1, preferably from 7:1 to 3:1, and more preferably about 5:1.

As stated above, the combination of glycerol and maltitol polyols, together with the combination of xanthan gum and hypromellose as a suspending/thickening system, provides excellent physicochemical stability of the composition, fast-acting effect of the active ingredients and improved absorption of ibuprofen, as well as optimal organoleptic properties.

Additional optional ingredients

pH adjusting agent

In order to maintain the pH of the suspension in the desired range, the composition of the present invention may contain a pH adjusting agent. Typically, the pH of the composition is from 2 to 7, preferably from 2 to 6, more preferably from 2.5 to 5, even more preferably from 3 to 4.5, even more preferably from 3.3 to 4.3, even more preferably from 3.5 to 4, and even more preferably from 3.5 to 3.9.

The amount of pH adjusting agent in the composition is sufficient to provide the desired pH value, which can be easily adjusted by a person skilled in the art. If the pH adjusting agent is present, it is typically present in an amount, expressed as a percentage by weight and volume, in the range of from about 0.1% to about 2%.

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 alkalizing agent such as an ammonia solution, diethanolamine, monoethanolamine, potassium bicarbonate, sodium bicarbonate, potassium citrate, sodium citrate, sodium bicarbonate or sodium borate, for example. Preferably, the pH adjusting agent is a buffering agent such as, inter alia, a citrate buffer, an acetate buffer, a citrate-phosphate buffer, a Tris buffer or a phosphate buffer.

A preferred buffering agent is a citrate buffer, which can typically be prepared from citric acid and sodium citrate, for example using anhydrous citric acid and sodium citrate in a weight ratio of from 2:1 to 1:2, preferably from 2:1 to 1:1, and more preferably in a weight ratio of anhydrous citric acid to sodium citrate of about 1.5:1.

Preservative

The composition may contain a preservative to ensure its protection against microbial contamination. Suitable preservatives are, among others, for example, butylparaben, ethylparaben, methylparaben, propylparaben, benzoic acid, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, chlorhexidine, chlorocresol, chloroxylenol, imidurea, cresol, phenol, sodium benzoate, sorbic acid or thimerosal.

The amount of preservative typically depends on the particular preservative used, as is well known in the art, and typically, expressed as a percentage by weight and volume, may be from about 0.001% to about 5%. A person skilled in the art will have no difficulty in selecting the appropriate amount in each case, as described in reference books in the art.

In one embodiment of the invention, the composition comprises a preservative. Preferably, the preservative is selected from butylparaben, propylparaben, benzyl alcohol and sodium benzoate, more preferably, the preservative is selected from sodium benzoate and benzyl alcohol, and even more preferably, the preservative is sodium benzoate, which is typically used in an amount of from 0.02 to 0.5% w/v.

Sweeteners

Optionally, the composition may contain a sweetener to enhance the sweetening effect of the polyol mixture, in particular, an intense sweetener may be used. Intense sweeteners usually mean non-caloric high-intensity sweeteners, which are usually 100-13,000 times sweeter than sucrose.

Suitable intense sweeteners for use in the present composition are, for example, acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, thaumatin or mixtures thereof.

The amount of sweetener may vary widely depending on the intensity of the sweetening agent, but is typically between 0.0001% and 0.5% w/v.

In one embodiment, the composition comprises sodium saccharin, typically in an amount of from 0.01 to 0.5 w/v%.

In one embodiment, the composition comprises thaumatin, typically in an amount of from 0.0001% w/v to 0.01% w/v.

In one embodiment, the composition comprises sodium saccharin and thaumatin, wherein the amount of sodium saccharin is from 0.01% w/v to 0.5% w/v and the amount of thaumatin is from 0.0001% w/v to 0.01% w/v.

Flavor enhancers

Some sodium salts, such as sodium chloride, sodium acetate, or sodium gluconate, are bitter taste inhibitors and enhance other desirable tastes and aromas, such as sweetness.

Therefore, in one embodiment, the composition of the present invention comprises a flavour enhancer selected from sodium chloride, sodium acetate, sodium gluconate and mixtures thereof, preferably comprising sodium chloride.

The amount of flavor enhancer, such as sodium chloride, in the composition is typically in the range of from about 0.1% w/v to about 5% w/v.

Flavors

The composition may optionally further comprise a flavoring agent to impart a pleasant taste and/or smell to the composition. Suitable flavoring agents include natural and artificial flavoring agents. Natural flavoring agents include natural oils and extracts of plants, leaves, flowers and fruits. Some suitable flavoring agents are, among many others, for example, menthol, cinnamon, cloves, anise, eucalyptus, peppermint, spearmint, thyme, vanilla, chocolate, fruit flavoring agents such as cherry flavoring, grape flavoring, orange flavoring, banana flavoring, strawberry flavoring, lemon flavoring, apple flavoring, peach flavoring, raspberry flavoring, pineapple flavoring and apricot flavoring and combinations thereof.

The amount of flavoring agent can be easily adjusted by a skilled formulator depending on the particular flavoring agent and the desired organoleptic effect. Typically, the amount of flavoring agent, if present in the composition, is in the range of about 0.001% w/v to about 0.1% w/v.

Compositions

Water is the main solvent of the composition. Purified water is usually used. The exact percentage of water is not determined, since it is adjusted to a certain final volume to ensure the desired concentration of each ingredient.

The composition of the present invention is in the form of a suspension. A suspension, as is well known in pharmaceutical formulations, is a two-phase system consisting of an undissolved or immiscible solid dispersed in a liquid. The dispersed solid particles may have an average particle size typically from about 1.0 nm to about 150 μm, without agglomerates. Ibuprofen is a poorly soluble drug that primarily constitutes the solid dispersed phase of the suspension.

In one embodiment, the present invention relates to a liquid pharmaceutical composition for oral administration in the form of a suspension, which comprises:

a) ibuprofen in an amount of 2% to 10% w/v, preferably 2% to 8% w/v, more preferably 2% to 7%, even more preferably 2% to 6%, even more preferably 2% to 5%, even more preferably 3% w/v to 5% w/v and even more preferably in an amount of about 4% w/v;

b) phenylephrine or a pharmaceutically acceptable salt thereof in an amount of from 0.005% w/v to 2% w/v, preferably from 0.01% w/v to 1% w/v, more preferably from 0.05% w/v to 0.5% w/v, even more preferably from 0.08% w/v to 0.2% w/v and even more preferably in an amount of about 0.1% w/v, expressed as an equivalent amount of phenylephrine hydrochloride;

c) hypromellose in an amount of from 0.1% w/v to 5% w/v, preferably from 0.2% w/v to 2% w/v, more preferably from 0.3% w/v to 1% w/v, even more preferably from 0.4% w/v to 0.6% w/v and even more preferably about 0.5% w/v;

d) xanthan gum in an amount of from 0.05% w/v to 4% w/v, preferably from 0.1% w/v to 2% w/v, more preferably from 0.2% w/v to 1% w/v, even more preferably from 0.3% w/v to 0.6% w/v and even more preferably about 0.4% w/v;

e) liquid maltitol, typically in an amount of from 30% to 70% w/v, preferably from 35% w/v to 65% w/v, more preferably from 45% w/v to 55% w/v and even more preferably about 50% w/v;

f) glycerol, usually in an amount of from 5% to 15% w/v, preferably from 7% w/v to 13% w/v, more preferably from 9% w/v to 11% w/v and even more preferably about 10% w/v;

g) water;

h) optionally a pH adjusting agent, preferably selected from citrate buffer, acetate buffer, citrate-phosphate buffer, Tris buffer and phosphate buffer, more preferably citrate buffer;

i) optionally a preservative, preferably selected from butylparaben, propylparaben, benzyl alcohol and sodium benzoate, more preferably selected from benzyl alcohol and sodium benzoate, and more preferably sodium benzoate;

j) optionally a sweetener, preferably selected from acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, thaumatin and mixtures thereof, more preferably a mixture of sodium saccharin and thaumatin;

k) optionally a flavour enhancer selected from sodium chloride, sodium acetate or sodium gluconate, preferably sodium chloride, typically in an amount of from 0.1% w/v to 5% w/v;

l) optionally a flavouring agent, preferably in an amount of from 0.001% to 0.1% w/v.

wherein the composition preferably comprises at least one of the optional ingredients h) to l).

The specific composition in this embodiment essentially consists of the above listed ingredients.

In one embodiment, the present invention relates to a liquid pharmaceutical composition for oral administration in the form of a suspension, which comprises:

a) ibuprofen in an amount of 2% to 10% w/v, preferably 2% to 8% w/v, more preferably 2% to 7%, even more preferably 2% to 6%, even more preferably 2% to 5%, even more preferably 3% w/v to 5% w/v and even more preferably in an amount of about 4% w/v;

b) phenylephrine or a pharmaceutically acceptable salt thereof, in an amount of from 0.005% w/v to 2% w/v, preferably from 0.01% w/v to 1% w/v, more preferably from 0.05% w/v to 0.5% w/v, even more preferably from 0.08% w/v to 0.2% w/v and even more preferably in an amount of about 0.1% w/v, expressed as an equivalent amount of phenylephrine hydrochloride;

c) hypromellose in an amount of from 0.1% w/v to 5% w/v, preferably from 0.2% w/v to 2% w/v, more preferably from 0.3% w/v to 1% w/v, even more preferably from 0.4% w/v to 0.6% w/v and even more preferably about 0.5% w/v;

d) xanthan gum in an amount of from 0.05% w/v to 4% w/v, preferably from 0.1% w/v to 2% w/v, more preferably from 0.2% w/v to 1% w/v, even more preferably from 0.3% w/v to 0.6% w/v and even more preferably in an amount of about 0.4% w/v;

e) liquid maltitol, typically in an amount of from 30% to 70% w/v, preferably from 35% w/v to 65% w/v, more preferably from 45% w/v to 55% w/v and even more preferably in an amount of about 50% w/v;

f) glycerol, usually in an amount of from 5% to 15% w/v, preferably from 7% w/v to 13% w/v, more preferably from 9% w/v to 11% w/v and even more preferably about 10% w/v;

g) water;

h) a pH adjusting agent, preferably selected from citrate buffer, acetate buffer, citrate-phosphate buffer, Tris buffer and phosphate buffer, more preferably citrate buffer;

i) a preservative, preferably selected from butylparaben, propylparaben, benzyl alcohol and sodium benzoate, more preferably selected from benzyl alcohol and sodium benzoate, and more preferably sodium benzoate;

j) optionally a sweetener, preferably selected from acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, thaumatin and mixtures thereof, more preferably a mixture of sodium saccharin and thaumatin;

k) optionally a flavour enhancer selected from sodium chloride, sodium acetate or sodium gluconate, preferably sodium chloride, typically in an amount of from 0.1% w/v to 5% w/v; and

l) optionally a flavouring agent, preferably in an amount of from 0.001% to 0.1% w/v.

The specific composition in this embodiment essentially consists of the above listed ingredients.

In one embodiment, the present invention relates to a liquid pharmaceutical composition for oral administration in the form of a suspension, which comprises:

a) ibuprofen in an amount of 2% to 10% w/v, preferably 2% to 8% w/v, more preferably 2% to 7%, even more preferably 2% to 6%, even more preferably 2% to 5%, even more preferably 3% w/v to 5% w/v and even more preferably in an amount of about 4% w/v;

b) phenylephrine or a pharmaceutically acceptable salt thereof, in an amount of from 0.005% w/v to 2% w/v, preferably from 0.01% w/v to 1% w/v, more preferably from 0.05% w/v to 0.5% w/v, even more preferably from 0.08% w/v to 0.2% w/v and even more preferably in an amount of about 0.1% w/v, expressed as an equivalent amount of phenylephrine hydrochloride;

c) hypromellose in an amount of from 0.1% w/v to 5% w/v, preferably from 0.2% w/v to 2% w/v, more preferably from 0.3% w/v to 1% w/v, even more preferably from 0.4% w/v to 0.6% w/v and even more preferably in an amount of about 0.5% w/v;

d) xanthan gum in an amount of from 0.05% w/v to 4% w/v, preferably from 0.1% w/v to 2% w/v, more preferably from 0.2% w/v to 1% w/v, even more preferably from 0.3% w/v to 0.6% w/v and even more preferably in an amount of about 0.4% w/v;

e) liquid maltitol, typically in an amount of from 30% to 70% w/v, preferably from 35% w/v to 65% w/v, more preferably from 45% w/v to 55% w/v and even more preferably in an amount of about 50% w/v;

f) glycerol, usually in an amount of from 5% to 15% w/v, preferably from 7% w/v to 13% w/v, more preferably from 9% w/v to 11% w/v, and even more preferably in an amount of about 10% w/v;

g) water;

h) a pH adjusting agent, preferably selected from citrate buffer, acetate buffer, citrate-phosphate buffer, Tris buffer and phosphate buffer, more preferably citrate buffer;

i) a preservative, preferably selected from butylparaben, propylparaben, benzyl alcohol and sodium benzoate, more preferably selected from benzyl alcohol and sodium benzoate, and more preferably sodium benzoate;

j) a sweetener, preferably selected from acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, thaumatin and mixtures thereof, more preferably a mixture of sodium saccharin and thaumatin;

k) optionally a flavour enhancer selected from sodium chloride, sodium acetate or sodium gluconate, preferably sodium chloride, typically in an amount of from 0.1% w/v to 5% w/v; and

l) optionally a flavouring agent, preferably in an amount of from 0.001% to 0.1% w/v.

The specific composition in this embodiment essentially consists of the above listed ingredients.

In one embodiment, the present invention relates to a liquid pharmaceutical composition for oral administration in the form of a suspension, which comprises:

a) ibuprofen in an amount of 2% to 10% w/v, preferably 2% to 8% w/v, more preferably 2% to 7%, even more preferably 2% to 6%, even more preferably 2% to 5%, even more preferably 3% w/v to 5% w/v and even more preferably in an amount of about 4% w/v;

b) phenylephrine or a pharmaceutically acceptable salt thereof, in an amount of from 0.005% w/v to 2% w/v, preferably from 0.01% w/v to 1% w/v, more preferably from 0.05% w/v to 0.5% w/v, even more preferably from 0.08% w/v to 0.2% w/v and even more preferably in an amount of about 0.1% w/v, expressed as an equivalent amount of phenylephrine hydrochloride;

c) hypromellose in an amount of from 0.1% w/v to 5% w/v, preferably from 0.2% w/v to 2% w/v, more preferably from 0.3% w/v to 1% w/v, even more preferably from 0.4% w/v to 0.6% w/v and even more preferably in an amount of about 0.5% w/v;

d) xanthan gum in an amount of from 0.05% w/v to 4% w/v, preferably from 0.1% w/v to 2% w/v, more preferably from 0.2% w/v to 1% w/v, even more preferably from 0.3% w/v to 0.6% w/v and even more preferably in an amount of about 0.4% w/v;

e) liquid maltitol, typically in an amount of from 30% to 70% w/v, preferably from 35% w/v to 65% w/v, more preferably from 45% w/v to 55% w/v and even more preferably about 50% w/v;

f) glycerol, usually in an amount of from 5% to 15% w/v, preferably from 7% w/v to 13% w/v, more preferably from 9% w/v to 11% w/v and even more preferably about 10% w/v;

g) water;

h) a pH adjusting agent, preferably selected from citrate buffer, acetate buffer, citrate-phosphate buffer, Tris buffer and phosphate buffer, more preferably citrate buffer;

i) a preservative, preferably selected from butylparaben, propylparaben, benzyl alcohol and sodium benzoate, more preferably selected from benzyl alcohol and sodium benzoate, and more preferably sodium benzoate;

j) a sweetener, preferably selected from acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, thaumatin and mixtures thereof, more preferably a mixture of sodium saccharin and thaumatin;

k) a flavour enhancer selected from sodium chloride, sodium acetate or sodium gluconate, preferably sodium chloride, typically in an amount of from 0.1% w/v to 5% w/v, and

l) optionally a flavouring agent, preferably in an amount of from 0.001% to 0.1% w/v.

The specific composition in this embodiment essentially consists of the above listed ingredients.

In one embodiment, the present invention relates to a liquid pharmaceutical composition for oral administration in the form of a suspension, which comprises:

a) ibuprofen in an amount of 2% to 10% w/v, preferably 2% to 8% w/v, more preferably 2% to 7%, even more preferably 2% to 6%, even more preferably 2% to 5%, even more preferably 3% w/v to 5% w/v and even more preferably in an amount of about 4% w/v;

b) phenylephrine or a pharmaceutically acceptable salt thereof, in an amount of from 0.005% w/v to 2% w/v, preferably from 0.01% w/v to 1% w/v, more preferably from 0.05% w/v and 0.5% w/v, even more preferably from 0.08% w/v to 0.2% w/v and even more preferably in an amount of about 0.1% w/v, expressed as an equivalent amount of phenylephrine hydrochloride;

c) hypromellose in an amount of from 0.1% w/v to 5% w/v, preferably from 0.2% w/v to 2% w/v, more preferably from 0.3% w/v to 1% w/v, even more preferably from 0.4% w/v to 0.6% w/v and even more preferably in an amount of about 0.5% w/v;

d) xanthan gum from 0.05% w/v to 4% w/v, preferably from 0.1% w/v to 2% w/v, more preferably from 0.2% w/v to 1% w/v, even more preferably from 0.3% w/v to 0.6% w/v and even more preferably in an amount of about 0.4% w/v;

e) liquid maltitol, typically in an amount of from 30% to 70% w/v, preferably from 35% w/v to 65% w/v, more preferably from 45% w/v to 55% w/v and even more preferably in an amount of about 50% w/v;

f) glycerol, usually in an amount of from 5% to 15% w/v, preferably from 7% w/v to 13% w/v, more preferably from 9% w/v to 11% w/v, and even more preferably in an amount of about 10% w/v;

g) water;

h) a pH adjusting agent, preferably selected from citrate buffer, acetate buffer, citrate-phosphate buffer, Tris buffer and phosphate buffer, more preferably citrate buffer;

i) a preservative, preferably selected from butylparaben, propylparaben, benzyl alcohol and sodium benzoate, more preferably selected from benzyl alcohol and sodium benzoate, and more preferably sodium benzoate;

j) a sweetener, preferably selected from acesulfame potassium, alitame, neohesperidin, dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, thaumatin and mixtures thereof, more preferably a mixture of sodium saccharin and thaumatin;

k) a flavour enhancer selected from sodium chloride, sodium acetate or sodium gluconate, preferably sodium chloride, typically in an amount of from 0.1% w/v to 5% w/v, and

l) a flavoring agent, preferably in an amount of from 0.001% to 0.1% w/v.

The specific composition in this embodiment essentially consists of the above listed ingredients.

Preferred characteristics of the various components of these compositions are described above in this description in the relevant paragraphs (ibuprofen, phenylephrine, thickening/suspending agent, polyols and additional optional ingredients).

In another embodiment, in any of the above embodiments, the concentration of ibuprofen present in the composition of the invention, expressed as a percentage by weight and volume, is from greater than 3% to 10%, preferably from greater than 3% to 8%, more preferably from greater than 3% to 7%, even more preferably from greater than 3% to 6% and even more preferably from greater than 3% to 5%. More particularly, the concentration of ibuprofen present in the composition of the invention, expressed as a percentage by weight and volume, is from 3.3% to 10%, preferably from 3.3% to 8%, more preferably from 3.3% to 7%, even more preferably from 3.3% to 6% and even more preferably from 3.3% to 5%.

In a preferred composition, the weight ratio of ibuprofen:phenylephrine is about 40:1 (calculated based on the weight of the equivalent amount of phenylephrine hydrochloride, regardless of the form of phenylephrine used), such as in compositions containing about 4% w/v ibuprofen and about 0.1% w/v phenylephrine or a pharmaceutically acceptable salt thereof, wherein the amount is expressed as an equivalent concentration of phenylephrine hydrochloride, or in compositions containing about 2% w/w ibuprofen and about 0.05% w/w phenylephrine or a pharmaceutically acceptable salt thereof, wherein the amount is expressed as an equivalent concentration of phenylephrine hydrochloride. With these compositions, for example, a dose of about 100 mg ibuprofen and about 2.5 mg phenylephrine, or about 200 mg ibuprofen and about 5 mg phenylephrine, or about 300 mg ibuprofen and about 7.5 mg phenylephrine, or about 400 mg ibuprofen and about 10 mg phenylephrine can be administered, where the amount of phenylephrine is expressed as the equivalent weight of phenylephrine hydrochloride.

In another preferred composition, the weight ratio of ibuprofen:phenylephrine is about 20:1 (also calculated taking into account the weight of the equivalent amount of phenylephrine hydrochloride), for example in compositions containing about 4% w/v ibuprofen and about 0.2% w/v phenylephrine or a pharmaceutically acceptable salt thereof, wherein the amount is expressed as an equivalent concentration of phenylephrine hydrochloride. Using these compositions, it is possible to administer, for example, a dose of about 100 mg ibuprofen and about 5 mg phenylephrine, or about 200 mg ibuprofen and about 10 mg phenylephrine, or about 400 mg ibuprofen and about 20 mg phenylephrine, wherein the amount of phenylephrine is expressed as an equivalent weight of phenylephrine hydrochloride.

Method of obtaining

Another aspect of the invention is a method for producing the composition.

A suitable method for producing a composition according to the invention comprises the following steps:

(i) mixing hypromellose, xanthan gum and one part liquid maltitol with one part total water to obtain a homogeneous mixture;

(ii) separately mixing ibuprofen, phenylephrine or a pharmaceutically acceptable salt thereof, glycerol and the remainder of the liquid maltitol with another portion of the total amount of water to obtain a homogeneous mixture;

(iii) adding the mixture from step (ii) to the mixture from step (i);

(iv) adding the rest of the water.

All ingredients are added under continuous stirring. For example, steps (i) and (ii) can be carried out in stainless steel reactors equipped with a stirring system and, preferably, also a heating jacket.

In step (i), the precise relative content of water used to obtain the first mixture is not critical and may be, for example, from about 15% to about 50% of the total amount of water.

In case the composition contains a preservative, a pH adjusting agent and/or a flavour enhancer, they are preferably added at this stage, preferably pre-dissolved in water, before adding hypromellose, xanthan gum and liquid maltitol. If the composition contains a sweetener, it can also be added at this stage in a similar manner.

Typically, the mixture obtained in step (i) has a gel-like appearance. Typically, after adding hypromellose and xanthan gum, the mixture is stirred for about 2 to 6 hours, preferably with heating to about 40-80°C, until a gel-like mixture is obtained. Preferably, maltitol is then added.

In step (ii), the amount of water used to obtain the second mixture is also not critical and may be, for example, from about 5% to about 25% of the total amount of water.

The mixture obtained in step (ii) is a suspension.

In the case where the composition contains a flavouring agent, it can be added, for example, after step (iii) and before step (iv), so that the flavouring agent and, optionally, the sweetener, if present, can be dissolved in one part of water (for example, from about 0.5% to 5% of the total amount of water of the composition) and added to the mixture obtained in step (iii).

The composition may be filled into suitable containers, typically amber-coloured polyethylene terephthalate (PET) bottles, fitted with a suitable closure, preferably a child-resistant closure, typically high-density polyethylene (HDPE).

The packaging may also include a measuring device for dosing the required dose of the composition, such as a measuring cup or an oral syringe.

Alternatively, the composition may be filled into a single-dose sachet by adding a suitable volume to deliver the desired dose, such as volumes typically from about 5 ml to about 10 ml, such as 5 ml, 7.5 ml or 10 ml. Other volumes may also be suitable depending on the desired dose and concentration of the composition. Suitable sachets for liquid compositions may be made, for example, of laminated materials, such as polyester/aluminium/polyester/polythene (PET/aluminium/PET/PE).

Application of the composition

The composition of the present invention has optimal organoleptic properties, for example, the bitter taste of ibuprofen and phenylephrine, as well as the burning sensation usually associated with ibuprofen, are completely masked.

Furthermore, as shown in Example 2, the stability studies performed confirm that the composition of the present invention is extremely stable despite the fact that phenylephrine is known to be very susceptible to degradation. Thus, the content of both active substances, ibuprofen and phenylephrine, remained within 95-105%, and the degradation products obtained from the active substances were below 0.1% under all storage conditions, namely: at 25ºC and 60% relative humidity for 36 months, at 30ºC and 65% relative humidity for 36 months, at 30ºC and 75% relative humidity for 36 months and at 40ºC and 75% relative humidity for 6 months.

In addition, the formulation also remained physically stable under these storage conditions, and no aggregation or precipitation phenomena were observed. This is important to ensure that the correct dose of active ingredients is administered throughout the shelf life of the medicinal product.

Furthermore, in a comparative pharmacokinetic study, healthy subjects were administered either a single dose of the composition of the invention with a dose of 400 mg ibuprofen and 10 mg phenylephrine hydrochloride or a reference drug (2 tablets of Nurofen® Day & Night Cold & Flu 200 mg/5 mg tablets, Reckitt Benckiser Healthcare, UK), also containing a similar dose of the active ingredients, and it was found that the bioavailability of ibuprofen was higher in subjects taking the composition of the invention than in subjects taking the reference drug, with ibuprofen absorption being approximately 10% higher in the former. These results were unexpected since the present composition contains maltitol, an active excipient known to enhance gastric motility and reduce the residence time of drugs in the intestinal lumen, and accordingly a lower rather than higher bioavailability would be expected.

In addition, such a comparative test also showed that the time to reach the observed maximum plasma concentration (T _max ) of both ibuprofen and phenylephrine was shorter in subjects taking the composition of the present invention than in subjects taking the reference drug. Thus, T _max for ibuprofen was shorter by about 1 hour (i.e., the T _max value was 1.0 hour compared to 2.0 hours for ibuprofen in the control compound), and T _max for phenylephrine was shorter by 0.34 hours (i.e., the T _max value was 0.33 hours compared to 0.67 hours for phenylephrine in the control compound). This unexpected faster absorption also provides a faster therapeutic effect, thus making the present composition a fast-acting drug that provides a favorable environment for an early and strong therapeutic effect.

Another advantage of the present composition, compared with commercial solid oral compositions, is the flexibility of dosing. Thus, for example, among other variations, the administered dose of ibuprofen can vary from about 40 mg, for example, to about 400 or 600 mg, associated with about 1 mg to about 10 or 15 mg, for example, of phenylephrine (expressed as phenylephrine hydrochloride equivalent).

This flexibility in dosing allows the dose to be adapted to the severity of symptoms and the age of the patient, particularly for children. Thus, for example, children aged 7 to 9 years may take 200 mg ibuprofen and 5 mg phenylephrine, children aged 10 to 12 years may take 300 mg ibuprofen and 7.5 mg phenylephrine, and adults and the elderly may take 400 g ibuprofen and 10 mg phenylephrine, with the amount of phenylephrine being expressed as the equivalent mass of phenylephrine hydrochloride.

Accordingly, another aspect of the present invention is a composition as defined above for use in medicine, in particular for use in the treatment of flu and cold symptoms such as fever, pain, sore throat, nasal congestion and sinus congestion. The composition according to the invention is suitable for such use in both adults, including the elderly, and children, in particular children over 7 years of age. In one embodiment, the use is intended for adults and children over 7 years of age.

Another aspect of the invention is a method for treating flu and cold symptoms such as fever, pain, sore throat, nasal congestion and sinus congestion, comprising the step of administering a therapeutically effective dose of the composition of the present invention to a patient in need of such treatment. The patient may be an adult, including an elderly patient, or a child, in particular a child over 7 years of age. In one embodiment, the method is intended for treating adults and children over 7 years of age.

Another aspect of the present invention is the use of the composition of the present invention, as defined above, for the preparation of a medicament for the treatment of flu and cold symptoms, such as fever, pain, sore throat, nasal congestion and paranasal sinuses. The treatment can be directed to any patient in need of such treatment, including adults (including the elderly) and children (in particular, children over 7 years old). In one embodiment, the treatment is intended for adults and children over 7 years old.

Examples

Example 1: Suspension composition containing ibuprofen and phenylephrine HCl

The composition of the present invention was prepared using the ingredients listed in the following table:

Ingredient % (weight/volume) mg/ml Ibuprofen 4.0 40.0 Phenylephrine HCl 0,1 1.0 Hypromellose 0.5 5.0 Xanthan gum 0.4 4.0 Liquid maltitol 50.0 500,0 Glycerol 10.0 100,0 Anhydrous citric acid 0.74 7.4 Sodium citrate 0.52 5.2 Sodium chloride 0.1-5.0 1.0-50 Thaumatin 0.0001-0.01 0.001-0.1 Sodium saccharin 0.01-0.5 0.1-5.0 Sodium benzoate 0.02-0.5 0.2-5.0 Orange flavoring 0.001-0.1 0.01-1.0 Purified water in sufficient quantity in sufficient quantity 1.0 ml

The hypromellose used was hypromellose 15 cP (substitution type 2910). The particle size of ibuprofen was 40 µm.

To prepare the composition, a stainless steel reactor equipped with a stirring system and a heating jacket was filled with purified water in an amount equivalent to about 30% of the final mixture, and sodium benzoate, anhydrous citric acid, sodium citrate, sodium saccharin and sodium chloride were successively added to the reactor with continuous stirring until completely dissolved. Hypromellose was then added with stirring until completely dispersed, then xanthan gum was also added and the mixture was left with stirring for about 3 hours until a gel was formed, and then about half of the liquid maltitol was added.

A secondary stainless steel reactor equipped with a stirring system and a heating jacket was filled with water in an amount of approximately 10% of the total amount, then glycerol, the remaining amount of liquid maltitol, phenylephrine HCl and ibuprofen were added sequentially with stirring until a homogeneous suspension was obtained. This suspension was mixed with the contents of the first reactor with stirring until a homogeneous suspension was obtained.

The secondary stainless steel reactor was filled with water in an amount of approximately 2% of the total amount, orange flavoring and thaumatin were added with stirring until completely dissolved, and this solution was added to the suspension previously obtained in the main reactor.

The final product was a viscous suspension of white or almost white color with a characteristic orange odor. The pH value was about 3.8.

The product was filled into 100 and 150 ml amber PET bottles equipped with a measuring cup and an oral syringe.

Example 2: Stability data

The product of Example 1 was subjected to long-term and accelerated stability studies according to ICH (International Council for Harmonization) recommendations valid for 4 climate zones (25ºC±2ºC/60%±5% relative humidity, 30ºC±2ºC/65%±5% relative humidity, 30ºC±2ºC/75%±5% relative humidity and 40ºC±2ºC/75%±5% relative humidity) for 3 batches of the product in their final containers, i.e. 100 and 150 ml, and an additional refrigerated condition (2-8°C) for only one batch in both container sizes.

The stability of the product was assessed for 36 months taking into account the following parameters: appearance, pH, viscosity, ibuprofen dissolution, particle size by sedimentation and particle size in suspension (absence of agglomerates), ibuprofen assay (HPLC), phenylephrine HCl assay (HPLC), ibuprofen related substances (HPLC) and phenylephrine HCl related substances (HPLC).

The obtained results demonstrated optimal values for all the evaluated parameters, which confirmed the stability of the product for all batches and for all conditions, and accordingly it was concluded that the product does not require special storage conditions.

Analysis of impurities related to phenylephrine showed very low levels of all impurities across all lots and all conditions, with no detectable amounts of impurities (<0.5%) in all cases.

In addition, analysis of ibuprofen-related impurities showed very low levels of all impurities across all lots and all conditions, with no detectable amounts (<0.1%).

In addition, one batch of the product was also subjected to a photostability test (ICH Q1B). According to the test conditions, the product was irradiated with an intensity of 1.2 million lux and an integrated UV energy of 200 W/m ² . The following parameters were evaluated: description, pH value, viscosity, ibuprofen dissolution, ibuprofen assay (HPLC), phenylephrine HCl assay (HPLC), sodium benzoate assay (HPLC), ibuprofen related substances (HPLC) and phenylephrine HCl related substances (HPLC). The product demonstrated stability to light under the evaluated conditions, so it also does not require special conditions.

Finally, a stability study was conducted using 3 production lots analyzing the following parameters: appearance, pH value, viscosity, ibuprofen dissolution, ibuprofen assay (HPLC), phenylephrine HCl assay (HPLC), sodium benzoate assay (HPLC), ibuprofen related substances (HPLC), phenylephrine HCl related substances (HPLC), microbiological quality and antimicrobial preservation efficiency. It was concluded that, during use, the product is preserved without loss of its physical properties and/or quantification/degradation for at least 6 months in four climatic zones.

Example 3: Pharmacokinetic comparative study

A phase I, randomized, open-label, single-dose, single-center, fasting, inverted design with two periods, two sequences, and a washout period of at least 3 days was conducted in 23 healthy male and female volunteers aged 18 to 55 years.

The test product was the composition of Example 1, which was administered as a single dose containing 400 mg ibuprofen and 10 mg phenylephrine HCl (i.e., 10 mL of the composition).

The reference medicinal product was two Nurofen® Day & Night Cold & Flu 200 mg/5 mg tablets (UK, Reckitt Benckiser Healthcare), also taken once, equivalent to 400 mg ibuprofen and 10 mg phenylephrine hydrochloride.

The mean values determined for C _max and AUC for the ibuprofen enantiomers for the composition of Example 1 and for the reference medicinal product are presented in the following table:

Parameters R-ibuprofen S-ibuprofen Example 1 Reference drug Example 1 Reference drug C _max (ng/ml) 20464,84 18699,86 18021,21 15941,72 AUC _0-t (ng*h/ml) 62578,29 60768,06 65366,45 61261,66

The mean T _max for ibuprofen was 1.0 h for the formulation of Example 1 and 2.0 h for the reference drug product.

The mean T _max for phenylephrine was 0.33 h for the composition of Example 1 and 0.67 h for the reference drug product.

Claims (29)

1. A liquid pharmaceutical composition for oral administration in the form of a suspension, containing: a) ibuprofen in an amount from 2% w/v to 6% w/v; b) phenylephrine or a pharmaceutically acceptable salt thereof in an amount of from 0.05% w/v to 0.5% w/v, expressed as an equivalent amount of phenylephrine hydrochloride; c) hypromellose in an amount of from 0.3% w/v to 1% w/v; d) xanthan gum in an amount of from 0.2 w/v to 1 w/v%; e) liquid maltitol in an amount from 35% w/v to 65 w/v; f) glycerol in an amount of from 5 w/v to 15 w/v; and g) water. 2. The composition according to claim 1, characterized in that phenylephrine is in the form of a salt selected from phenylephrine hydrochloride, phenylephrine hydrobromide and phenylephrine bitartrate. 3. The composition according to claim 2, characterized in that it contains phenylephrine hydrochloride. 4. A composition according to any one of claims 1 to 3, characterized in that the amount of ibuprofen is from 3% w/v to 5% w/v. 5. A composition according to any one of claims 1 to 4, characterized in that the amount of phenylephrine or a pharmaceutically acceptable salt thereof is from 0.08% w/v to 0.2% w/v, expressed as an equivalent amount of phenylephrine hydrochloride. 6. The composition according to any one of claims 1 to 5, characterized in that the amount of hypromellose is from 0.4% w/v to 0.6% w/v and is preferably about 0.5% w/v, where “about” means a deviation of ±5% from the specified amount. 7. The composition according to any one of claims 1 to 6, characterized in that the amount of xanthan gum is from 0.3% w/v to 0.6% w/v and is preferably about 0.4% w/v, where “about” means a deviation of ±5% from the specified amount. 8. The composition according to any one of claims 1 to 7, characterized in that the amount of liquid maltitol is from 45% w/v to 55% w/v and is preferably about 50% w/v, where “about” means a deviation of ±5% from the specified amount. 9. The composition according to any one of claims 1 to 8, characterized in that the amount of glycerin is from 7% w/v to 13% w/v, preferably from 9% w/v to 11% w/v and more preferably about 10% w/v, where “about” means a deviation of ±5% from the specified amount. 10. A composition according to any one of claims 1 to 9, characterized in that it contains a pH regulating agent to bring the pH of the composition to a value of 2 to 6. 11. A composition according to any one of paragraphs 1-10, characterized in that it contains a preservative. 12. The composition according to any one of claims 1 to 11, characterized in that it contains a sweetener selected from acesulfame potassium, alitame, neohesperidin, dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, thaumatin and mixtures thereof, preferably the sweetener is a mixture of sodium saccharin and thaumatin. 13. A composition according to any one of claims 1 to 12, characterized in that it contains sodium chloride, preferably in an amount of from 0.1% w/v to about 5% w/v, where “about” means a deviation of ±5% from the specified amount. 14. A method for producing a composition according to paragraphs 1-13, characterized in that it includes the following stages: (i) mixing hypromellose, xanthan gum and one part liquid maltitol with one part total amount of water to obtain a homogeneous mixture; (ii) separately mixing ibuprofen, phenylephrine or a pharmaceutically acceptable salt thereof, glycerol and the remaining amount of liquid maltitol with another portion of the total amount of water to obtain a homogeneous mixture; (iii) adding the mixture from step (ii) to the mixture from step (i); (iv) adding the remaining amount of water. 15. The composition according to claims 1-13 for use in the treatment of flu and cold symptoms such as fever, pain, sore throat, nasal congestion and sinus congestion. 16. Use of the composition according to claims 1-13 for the treatment of flu and cold symptoms such as fever, pain, sore throat, nasal congestion and sinus congestion. 17. Use of the composition according to claims 1-13 for obtaining a medicinal product for treating symptoms of flu and colds, such as fever, pain, sore throat, nasal congestion and sinus congestion. 18. A method for treating flu and cold symptoms such as fever, pain, sore throat, nasal congestion and sinus congestion, comprising the step of administering a therapeutically effective dose of the composition of claims 1-13 to a patient in need of such treatment.