Liquid composition comprising ibuprofen and phenylephrine

Abstract

The present invention relates to a liquid pharmaceutical composition for oral administration in the form of a suspension, which composition comprises a combination of ibuprofen and phenylephrine or a pharmaceutically acceptable salt thereof as active substances, as well as hypromellose, xanthan gum, liquid maltitol, glycerol and water. The composition is stable, has good sensory properties, and exhibits an excellent pharmacokinetic profile, providing rapid absorption of the drug. The present invention also relates to the use of the composition for the treatment of the symptoms of influenza and the common cold, in particular for the treatment of the symptoms of influenza and the common cold in adults and children over 7 years of age.

Description

TECHNICAL FIELD

[0001] The present invention relates to a liquid pharmaceutical composition in the form of a suspension comprising a combination of ibuprofen and phenylephrine, which is stable and particularly suitable for treating the symptoms of influenza and the common cold in adults and children. PRIOR ART

[0002] The combined use of an analgesic and a decongestant to relieve symptoms associated with the common cold or influenza (such as headache, fever, sinus pressure, and mild body aches) is a well-known treatment strategy.

[0003] For example, a particular method is the 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 mainly by direct action on α-adrenergic receptors and is an oral nasal decongestant.

[0004] So far, the combination of ibuprofen / phenylephrine has only been available on the market as solid oral dosage forms, and it is noteworthy that all available drugs are only intended for adults and children 12 years of age and older.

[0005] Thus, for example, the drug " Congestion Relief" (FDA, Pfizer) is an oral composition in the form of a tablet containing 200 mg of ibuprofen and 10 mg of phenylephrine hydrochloride (HCl). The recommended dose of this drug is 1 tablet every 4 hours.

[0006] Similarly, the drug "Care Cold&Flu Relief" (UK, Thornton&Ross) is in the form of film-coated tablets, and each dose contains 200 mg of ibuprofen and 5 mg of phenylephrine HCl. Alternatively, the film-coated tablets (ES, Laboratorio Stada) also consist of a fixed-dose combination of 200 mg of ibuprofen and 5 mg of phenylephrine HCl. Alternatively, the film-coated tablets Day&Night Cold&Flu 200mg / 5mg tablets (UK, ReckittBenckiser Healthcare). The recommended dose of these three drugs is 2 tablets every 8 hours.

[0007] It has been recognized that the use of solid oral dosage forms may not be suitable for some patient populations who may have difficulty swallowing whole tablets or capsules, including pediatric, elderly, or disabled patients. For these patient populations, the use of liquid dosage forms is generally considered advantageous. Additionally, liquid dosage forms may be more suitable for adjusting the dose of the active substance according to the patient's age and for better controlling the amount of the administered drug. This is crucial when the target of the treatment is children less than 12 years old.

[0008] However, the formulation of liquid pharmaceutical compositions is generally more difficult than that of solid compositions. For example, there are usually more problems with stability because of the closer interactions between the combined drugs and between the drugs and excipients. Specifically, phenylephrine is a drug that is prone to degradation, especially in liquid dosage forms and particularly at high temperatures.

[0009] Furthermore, the formulation of each specific drug combination must be regarded as a specific and unique challenge to be solved, arising from the complex interactions within the specific drugs to be combined and the excipients, and thus cannot be solved by simply combining the previously known formulations of each individual drug.

[0010] In addition, for drugs with an unpleasant taste, the preparation of palatable liquid dosage forms is also challenging because, when in solid dosage forms, the unpleasant taste can be simply masked by filling the drug into gelatin capsules or by film-coated tablet formulations, while in liquid dosage forms, it is difficult to avoid the direct contact of the drug with unpleasant taste with oral taste cells during drug ingestion. For example, ibuprofen is known for having a particularly unpleasant bitter and burning taste, and phenylephrine also shows a characteristic bitter taste.

[0011] Another additional difficulty lies in the solubility of the drugs to be combined. For example, ibuprofen is poorly soluble in water, and although its pharmaceutically acceptable salts are more soluble, their use exacerbates the palatability problem. Due to the poor water solubility of ibuprofen, their aqueous formulations are usually suspensions, in which ibuprofen particles must be in equilibrium to avoid aggregation and sedimentation phenomena. These phenomena occur frequently and are not easily avoided.

[0012] From a pharmacokinetic perspective, there is a need for such formulations that provide a high bioavailability of the active substance and subsequent early and potent therapeutic effects. Drug bioavailability is mainly measured by the time (T 最大 ) to reach the maximum concentration observed in plasma and the maximum plasma concentration (C 最大 ) observed. Regarding the bioavailability of drugs, the formulation of liquid dosage forms poses more difficulties because the use of certain excipients (such as polyols) required to improve the stability and palatability of the formulation may hinder the absorption rate of the active substance.

[0013] Thus, it would not be obvious to the person skilled in the art to formulate a stable, sensorially acceptable liquid composition containing ibuprofen and phenylephrine which provides adequate drug bioavailability.

[0014] There are some disclosures in the prior art that attempt to address related problems.

[0015] Thus, for example, International Patent Application WO2008 / 008944-A1 discloses a pharmaceutical suspension containing phenylephrine and at least one substantially water-insoluble active agent (in particular paracetamol), having a pH value of from about 4 to about 6. The composition contains a non-reducing sugar, a polyol and a high-intensity sweetener as a sweetening system; the preferred sweetener is sorbitol, which is optionally combined with sucrose. The preferred thickening component contains from 0.1 to 0.25% (w / v) of xanthan gum as the main structuring agent and a co-processed combination of microcrystalline cellulose and carboxymethyl cellulose as the secondary structuring agent. A composition containing a specific combination of phenylephrine and ibuprofen is not disclosed.

[0016] International Patent Application WO2007 / 098128-A2 discloses an oral liquid pharmaceutical composition of phenylephrine containing a reduced amount of sorbitol to promote the stability of phenylephrine. Specifically, the composition contains a combination of glycerol and sorbitol, wherein the amount of glycerol is at most about 45% w / v, preferably 18 to 30% w / v of glycerol, and at most about 10% w / v of sorbitol, preferably 3 to 10% w / v of sorbitol. A composition containing a specific combination of phenylephrine and ibuprofen is not disclosed.

[0017] International Patent Application WO2006 / 022996-A2 generally discloses a pharmaceutical composition containing a first drug and a second drug, both of which are selected from decongestants, cough suppressants, expectorants, analgesics and antihistamines, which provide effective drug plasma concentrations. Examples 2, 25, 45, 69 and 72 disclose suspensions containing phenylephrine in combination with other drugs (i.e. with promethazine, codeine, carbetapentane or diphenhydramine). The suspension formulation contains a combination of the polyols sorbitol, glycerol and xylitol as sweeteners, and a combination of colloidal anhydrous silica and hydroxyethyl cellulose as suspending agents. A composition containing a specific combination of phenylephrine and ibuprofen is not disclosed.

[0018] International Patent Application WO2008 / 008364 - A2 discloses an oral liquid pharmaceutical composition comprising phenylephrine and polyethylene glycol substantially free of aldehydes, which has a reduced tendency for phenylephrine degradation. The composition is also palatable. The provided examples further comprise a combination of glycerol, sorbitol, and micronized sucralose as a sweetening system. No stability data for phenylephrine are provided. A composition comprising a specific combination of phenylephrine and ibuprofen is not disclosed.

[0019] Accordingly, there is still a need to provide a liquid preparation comprising a combination of phenylephrine and ibuprofen that is stable, sensorially acceptable, suitable for the pediatric population, and capable of providing effective pharmacological activity and rapid absorption of both active ingredients in order to provide rapid relief of the symptoms of influenza and the common cold.

[0020] Object of the Invention

[0021] The object of the present invention is a liquid pharmaceutical composition comprising a combination of ibuprofen and phenylephrine.

[0022] Another aspect of the present invention is a method for preparing the composition.

[0023] Another aspect of the present invention is a liquid pharmaceutical composition comprising a combination of ibuprofen and phenylephrine for medical use. Detailed Description of the Invention

[0025] The object of the present invention is a liquid pharmaceutical composition for oral administration in the form of a suspension, which comprises:

[0026] a) ibuprofen in an amount of 2% w / v to 10% w / v;

[0027] b) phenylephrine or a pharmaceutically acceptable salt thereof in an amount of 0.005% w / v to 2% w / v, expressed as the equivalent of phenylephrine hydrochloride;

[0028] c) hypromellose in an amount of 0.1% w / v to 5% w / v;

[0029] d) xanthan gum in an amount of 0.05% w / v to 4% w / v;

[0030] e) liquid maltitol;

[0031] f) glycerol; and

[0032] g) water.

[0033] The inventors of the present invention have developed an aqueous liquid pharmaceutical composition in the form of a suspension, which contains a combination of ibuprofen and phenylephrine as active ingredients, has optimal physicochemical characteristics, and in particular, is very stable and has good sensory properties. In addition, the preparation also has excellent pharmacokinetic properties, providing extremely rapid absorption of both drugs and optimal bioavailability.

[0034] In this specification and in the claims, unless the context clearly indicates otherwise, a noun without a quantifier means that the plural form is also included. In addition, a numerical value preceded by the term "about" or "approximately" is intended to include the exact specified value and specific variations around such a value, that is, a variation of ±5% of the quantity. A numerical range defined by a lower endpoint and an upper endpoint means that the endpoints are also included.

[0035] Unless otherwise stated, the percentages disclosed for each component of the composition are weight / volume (% w / v), that is, the number of grams of each component in 100 ml of the composition.

[0036] The excipients used to prepare 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 R.C. Rowe, P.J. Sheskey and P.J. Weller, Handbook of Pharmaceutical Excipients, Sixth Edition, Pharmaceutical Press, 2009. In addition, the common excipients and procedures for preparing the composition are described in the book J.P Remington and A.R. Genaro, Remington The Science and Practice of Pharmacy, 20 th edition, Lippincott, Williams & Wilkins, Philadelphia, 2000 [ISBN: 0-683-306472] or in the book M.E. Aulton and K.M.G. Taylor, Aulton’s Pharmaceutics, the design and manufacture of medicines, 4 th edition, Churchill Livingstone Elsevier, 2013 [ISBN: 978-0-7020-4290-4].

[0037] Ibuprofen

[0038] Ibuprofen is the International Nonproprietary Name (INN) of the compound (RS)-2-(4-(2-methylpropyl)phenyl)propanoic acid.

[0039] Ibuprofen is a member of the well-known non-steroidal anti-inflammatory drugs (NSAIDs) and has analgesic, antipyretic and anti-inflammatory properties.

[0040] In the context of the present invention, the term "ibuprofen" does not unambiguously refer to racemic ibuprofen (RS), and (S)-ibuprofen and (R)-ibuprofen, or mixtures of the (R) and (S) forms in any proportion. Preferably, the ibuprofen used in the pharmaceutical compositions of the present invention is selected from the group consisting of (RS)-ibuprofen and (S)-ibuprofen.

[0041] Furthermore, the term ibuprofen also includes any hydrated and solvated forms, as well as any crystalline and amorphous forms. Preferably, crystalline ibuprofen is used.

[0042] Ibuprofen is commercially available and can also be prepared, for example, according to the procedure described in British patent application GB-A-971700. For example, the resolution of ibuprofen into its enantiomers is described in the article by Brushan et al. Resolution of enantiomers of ibuprofen by liquid chromatography: a review, Biomed. Chromatogr., 1998, 12(6), 309.

[0043] Ibuprofen is an acidic molecule containing a carboxylic acid moiety and is poorly soluble in water.

[0044] Ibuprofen can be used in therapy in both its acidic free form and as its pharmaceutically acceptable salts (such as ibuprofen arginine, ibuprofen lysine or sodium ibuprofen, etc.). In the context of the present invention, ibuprofen is preferably used in its acidic free form.

[0045] The size of the ibuprofen particles for preparing the composition is not critical, but is preferably less than 150 μm to minimize aggregation and sedimentation phenomena and thus improve the long-term stability and homogeneity of the suspension. The size of the ibuprofen particles is more preferably from 5 μm to 100 μm, still more preferably from 10 μm to 60 μm, still more preferably from 20 μm to 50 μm, and still more preferably from 30 μm to 45 μm.

[0046] The particle size of the ibuprofen particles can be quantified by known methods, for example by sieving through a sieve of a suitable size.

[0047] The concentration of ibuprofen present in the composition of the present invention is from 2% to 10%, preferably from 2% to 8%, more preferably from 2% to 7%, still more preferably from 2% to 6%, still more preferably from 2% to 5%, still more preferably from 3% to 5%, and still more preferably about 4%, expressed as a w / v percentage. In one embodiment, the concentration of ibuprofen present in the composition of the present invention is greater than 3% to 10%, preferably greater than 3% to 8%, more preferably greater than 3% to 7%, still more preferably greater than 3% to 6%, and still more preferably greater than 3% to 5%, expressed as a w / v percentage. In one embodiment, the concentration of ibuprofen present in the composition of the present invention is from 3.3% to 10%, preferably from 3.3% to 8%, more preferably from 3.3% to 7%, still more preferably from 3.3% to 6%, and still more preferably from 3.3% to 5%, expressed as a w / v percentage.

[0048] Phenylephrine

[0049] Phenylephrine is the International Nonproprietary Name (INN) for the compound 3-[(1R)-1-hydroxy-2-(methylamino)ethyl]phenol ((R)-(-)-phenylephrine, CAS 61-76-7).

[0050] In the context of the present invention, the term "phenylephrine" does not unambiguously refer to the common R-form, as well as the racemic or S-form. Preferably, (R)-(-)-phenylephrine is used.

[0051] Furthermore, the term phenylephrine also includes any hydrated and solvated forms, as well as any crystalline and amorphous forms thereof. Preferably, crystalline phenylephrine is used.

[0052] Phenylephrine is a basic compound containing a secondary amine group. Phenylephrine can be used in its free base form or in the form of its pharmaceutically acceptable salts. Pharmaceutically acceptable salts of phenylephrine include non-toxic acid addition salts.

[0053] In one embodiment of the present invention, phenylephrine is used as a salt, for example, an addition salt selected from those with 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.

[0054] In one embodiment of the present invention, the pharmaceutically acceptable salts of phenylephrine are selected from hydrochloride (phenylephrine hydrochloride), hydrobromide (phenylephrine hydrobromide), and bitartrate (phenylephrine bitartrate).

[0055] In a preferred embodiment, phenylephrine hydrochloride is used.

[0056] The concentration of phenylephrine or a pharmaceutically acceptable salt thereof in the composition of the present invention is from 0.005% to 2%, preferably from 0.01% to 1%, more preferably from 0.05% to 0.5%, still more preferably from 0.08% to 0.2%, and still more preferably about 0.1%, expressed as the equivalent of phenylephrine hydrochloride and expressed as a w / v percentage.

[0057] The expression "expressed as the equivalent of phenylephrine hydrochloride" means that if phenylephrine is added as the free base or as a salt other than hydrochloride, the amount of phenylephrine is converted to the equivalent weight of an equimolar amount of phenylephrine hydrochloride. Thus, for example, if 0.82 mg / ml of phenylephrine free base (molecular weight 167.205 g / mol) is used, the concentration of phenylephrine "expressed as the equivalent of phenylephrine hydrochloride (molecular weight 203.66 g / mol)" will be 1 mg / ml or 0.1% w / v. Moreover, similar calculations can be made for other salts in a similar manner, which is well known to those skilled in the art.

[0058] In this specification and the claims, the amount and concentration of phenylephrine are always expressed as the equivalent or concentration of phenylephrine hydrochloride.

[0059] Thickening agent / suspending agent

[0060] The composition of the present invention comprises a combination of xanthan gum and hypromellose (hydroxypropyl methylcellulose), which is used as a suspending agent and a thickening agent.

[0061] Hypromellose (also known as hydroxypropyl methylcellulose or HPMC) is a well-known cellulose derivative used in pharmaceutical formulations. Hypromellose can be described as partially O-methylated and O-(2-hydroxypropylated) cellulose. It is available in several grades with different viscosities and degrees of substitution, and all of them are suitable for the composition of the present invention.

[0062] Xanthan gum is also a well-known pharmaceutical excipient, which is mainly used as a suspending agent for preparing suspensions and 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 main hexose units, and contains D-glucuronic acid, and is prepared as the sodium salt, potassium salt or calcium salt. It is widely commercially available.

[0063] The authors of the present invention unexpectedly found that the combination of xanthan gum and hypromellose as a suspending / thickening system, and the combination of the polyols glycerol and maltitol, provide excellent physicochemical stability to the composition and also result in improved absorption of the active ingredient and optimal sensory properties.

[0064] In one embodiment, hypromellose having a hydroxypropoxy content of 7.0 to 12% (referred to as hypromellose type 2910) is used.

[0065] The proportion of hypromellose in the composition is from 0.1% to 5%, preferably from 0.2% to 2%, more preferably from 0.3% to 1%, still more preferably from 0.4% to 0.6%, and even more preferably about 0.5%, expressed as a w / v percentage.

[0066] The proportion of xanthan gum in the composition is from 0.05% to 4%, preferably from 0.1% to 2%, more preferably from 0.2% to 1%, still more preferably from 0.3% to 0.6%, and even more preferably about 0.4%, expressed as a w / v percentage.

[0067] The weight ratio of hypromellose:xanthan gum is generally 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.

[0068] Polyol

[0069] The composition of the present invention comprises a combination of the polyol glycerol and liquid maltitol.

[0070] Glycerol (or glycerin or propane-1,2,3-triol) is a known pharmaceutically acceptable excipient which is commonly used as a sweetening agent, co-solvent or viscosity enhancer in oral liquid formulations.

[0071] Maltitol is a disaccharide (4-O-α-D-glucopyranosyl-D-glucitol).

[0072] Liquid maltitol is an aqueous solution of D-maltitol which, in accordance with the current European Pharmacopoeia, is commonly used as a pharmaceutical excipient and which stipulates that: the solid matter of liquid maltitol is not less than 68% w / w and not more than 85% w / w, the content of D-maltitol is ≥50% w / w, it contains not more than 8% w / w of sorbitol, and it also contains small amounts of hydrogenated oligosaccharides and polysaccharides. According to the United States Pharmacopoeia, maltitol solution contains not less than 50% w / w of D-maltitol on an anhydrous basis, and not more than 8.0% w / w of D-sorbitol.

[0073] Generally speaking, for example, liquid maltitol contains about 50% w / w to about 55% w / w of D-maltitol (with reference to the total weight of the anhydrous substance); and the content of sorbitol is usually about 2% w / w to about 7% w / w, preferably about 3% w / w to about 5% w / w (also with reference to the total weight of the anhydrous substance); the water content is usually 20 to 30% w / w, preferably about 25% w / w, and the total solid matter is usually about 70% w / w to about 80% w / w, preferably about 75% w / w.

[0074] Therefore, it should be understood that the compositions of the present invention inherently also contain a small amount of sorbitol, as well as other minor sugars present in the "liquid maltitol" excipient used together with maltitol. Therefore, whenever the formulations described in the present specification and claims are described as containing a specific amount of "liquid maltitol", it should be understood that in addition to maltitol, a small proportion of sorbitol and other sugars within a specific amount range are also included.

[0075] If necessary, calculating the amount of maltitol present in the composition and the remaining amount of sorbitol is entirely within the skills of those skilled in the pharmaceutical art.

[0076] Liquid maltitol is commonly used as a sweetening agent in oral liquid formulations and also as a suspending agent.

[0077] Maltitol is generally considered an "active excipient" because it modifies intestinal motility by increasing peristaltic movements and reducing the residence time of the active substance in the intestinal lumen.

[0078] Generally speaking, the proportion of liquid maltitol in the composition is 30% to 70%, preferably 35% to 65%, more preferably 45% to 55%, and still more preferably about 50%, expressed as a w / v percentage.

[0079] Generally speaking, the proportion of glycerol in the composition is 5% to 15%, preferably 7% to 13%, more preferably 9% to 11%, and still more preferably about 10%, expressed as a w / v percentage.

[0080] The weight ratio of liquid maltitol:glycerol in the pharmaceutical compositions of the present invention is generally 10:1 to 1:1, preferably 7:1 to 3:1, and more preferably about 5:1.

[0081] As disclosed above, the combination of the polyols glycerol and maltitol, and the combination of xanthan gum and hypromellose as a suspending / thickening system provide the composition with excellent physicochemical stability, a fast-acting effect of the active ingredient, improved ibuprofen absorption, and optimal sensory properties.

[0082] Additional optional ingredients

[0083] pH regulator

[0084] The composition of the present invention may contain a pH regulator to maintain the pH of the suspension within a desired pH range. The pH of the composition is generally from 2 to 7, preferably from 2 to 6, more preferably from 2.5 to 5, still more preferably from 3 to 4.5, still more preferably from 3.3 to 4.3, still more preferably from 3.5 to 4, and still more preferably from 3.5 to 3.9.

[0085] The amount of the pH regulator in the composition is such that it is sufficient to provide the desired degree of pH value, which can be easily adjusted by those skilled in the art. If present, the pH regulator is usually present in an amount of about 0.1% to about 2%, expressed as a w / v percentage.

[0086] The pH regulator can be, for example, an acidifying agent such as citric acid, acetic acid, hydrochloric acid, lactic acid, phosphoric acid or sulfuric acid, and / or a basifying agent such as ammonia solution, diethanolamine, monoethanolamine, potassium bicarbonate, sodium bicarbonate, potassium citrate, sodium citrate, sodium bicarbonate or sodium borate. Preferably, the pH regulator is a buffer such as citrate buffer, acetate buffer, citrate-phosphate buffer, Tris buffer or phosphate buffer, etc.

[0087] The preferred buffer is citrate buffer, which can generally be prepared with citric acid and sodium citrate, for example, using anhydrous citric acid and sodium citrate in a weight ratio of 2:1 to 1:2, preferably 2:1 to 1:1, and more preferably a weight ratio of anhydrous citric acid to sodium citrate of about 1.5:1.

[0088] Preservative

[0089] The composition may contain a preservative to ensure protection against microbial contamination. Suitable preservatives are, for example, butyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, benzoic acid, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, chlorhexidine, chlorocresol, chloroxylenol, imidurea, cresol, phenol, sodium benzoate, sorbic acid or thimerosal, etc.

[0090] As is well known in the art, the amount of the preservative usually depends on the specific preservative used and can generally be from about 0.001% to about 5%, expressed as a w / v percentage. Those skilled in the art should have no difficulty in selecting the appropriate amount in each case, as disclosed in the reference books in the art.

[0091] In one embodiment of the present invention, the composition comprises a preservative. Preferably, the preservative is selected from butyl paraben, propyl paraben, 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 0.02 to 0.5% w / v.

[0092] Sweetening agent

[0093] Optionally, the composition may comprise a sweetening agent to enhance the sweetening effect of the polyol mixture. In particular, a strong sweetening agent may be used. Strong sweetening agents generally refer to those non-nutritive high-intensity sweetening agents, which are typically about 100 to about 13,000 times sweeter than sucrose.

[0094] Suitable strong sweetening agents for use in the compositions of the present invention are, for example, acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, miraculin, or mixtures thereof.

[0095] The amount of the sweetening agent can vary widely depending on the sweetening intensity of the sweetening agent, but is typically from 0.0001% to 0.5% w / v.

[0096] In one embodiment, the composition comprises sodium saccharin, typically in an amount of 0.01% w / v to 0.5% w / v.

[0097] In one embodiment, the composition comprises miraculin, typically in an amount of 0.0001% w / v to 0.01% w / v.

[0098] In one embodiment, the composition comprises sodium saccharin and miraculin, wherein the amount of sodium saccharin is from 0.01% w / v to 0.5% w / v, and the amount of miraculin is from 0.0001% w / v to 0.01% w / v.

[0099] Flavour enhancer

[0100] Some sodium salts, such as sodium chloride, sodium acetate or sodium gluconate, are inhibitors of bitterness and enhance other desired tastes and flavours, such as sweetness.

[0101] Thus, in one embodiment, the compositions of the present invention comprise a flavour enhancer selected from sodium chloride, sodium acetate, sodium gluconate, and mixtures thereof, preferably comprising sodium chloride.

[0102] The amount of the flavour enhancer, such as sodium chloride, in the composition is typically from about 0.1% w / v to about 5% w / v.

[0103] Flavour corrective agent

[0104] The composition may optionally further comprise a flavoring agent for imparting a pleasant flavor and / or odor to the composition. Suitable flavoring agents include natural and artificial flavors. Natural flavors include natural oils, as well as extracts from plants, leaves, flowers, and fruits. Some suitable flavors are, for example, menthol, cinnamon, clove, anise, eucalyptus, peppermint, spearmint, thyme, vanilla, chocolate, fruit flavors such as cherry flavor, grape flavor, orange flavor, banana flavor, strawberry flavor, lemon flavor, apple flavor, peach flavor, raspberry flavor, pineapple flavor, and apricot flavor, etc., and combinations thereof.

[0105] The amount of the flavoring agent can be easily adjusted by a skilled formulator, depending on the specific flavoring agent and the desired sensory effect. Generally speaking, the amount of the flavoring agent (if present in the composition) is from about 0.001% w / v to about 0.1% w / v.

[0106] Composition

[0107] Water is the main solvent of the preparation. Generally speaking, purified water is used. The exact percentage of water is not quantified because it is adjusted to a certain final volume to provide the desired concentration of each ingredient.

[0108] The composition of the present invention is in the form of a suspension. As is well known in pharmaceutical preparations, a suspension is a two-phase system consisting of insoluble or immiscible solids dispersed in a liquid. The average particle size of the dispersed solid particles can generally be from about 1.0 nm to about 150 μm, without aggregates. Ibuprofen is a poorly soluble drug, which mainly constitutes the solid dispersed phase of the suspension.

[0109] In one embodiment, the present invention relates to a liquid pharmaceutical composition for oral administration in the form of a suspension, which comprises:

[0110] a) Ibuprofen in an amount of 2% w / v to 10% w / v, preferably 2% w / v to 8% w / v, more preferably 2% to 7%, still more preferably 2% to 6%, still more preferably 2% to 5%, still more preferably 3% w / v to 5% w / v, and still more preferably, an amount of about 4% w / v;

[0111] b) Phenylephrine or a pharmaceutically acceptable salt thereof in an amount of 0.005% w / v to 2% w / v, preferably 0.01% w / v to 1% w / v, more preferably 0.05% w / v to 0.5% w / v, still more preferably 0.08% w / v to 0.2% w / v, and still more preferably, an amount of about 0.1% w / v, expressed as the equivalent of phenylephrine hydrochloride;

[0112] c) Hypromellose in an amount of 0.1% w / v to 5% w / v, preferably 0.2% w / v to 2% w / v, more preferably 0.3% w / v to 1% w / v, still more preferably 0.4% w / v to 0.6% w / v, and still more preferably about 0.5% w / v;

[0113] d) Xanthan gum in an amount of 0.05% w / v to 4% w / v, preferably 0.1% w / v to 2% w / v, more preferably 0.2% w / v to 1% w / v, still more preferably 0.3% w / v to 0.6% w / v, and still more preferably about 0.4% w / v;

[0114] e) Liquid maltitol in an amount of generally 30% w / v to 70% w / v, preferably 35% w / v to 65% w / v, more preferably 45% w / v to 55% w / v, and still more preferably about 50% w / v;

[0115] f) Glycerol in an amount of generally 5% w / v to 15% w / v, preferably 7% w / v to 13% w / v, more preferably 9% w / v to 11% w / v, and still more preferably about 10% w / v;

[0116] g) Water;

[0117] h) Optionally, a pH adjuster, which is preferably selected from citrate buffers, acetate buffers, citrate-phosphate buffers, Tris buffers, and phosphate buffers, more preferably a citrate buffer;

[0118] i) Optionally, a preservative, which is preferably selected from butyl paraben, propyl paraben, benzyl alcohol, and sodium benzoate, more preferably selected from benzyl alcohol and sodium benzoate, and still more preferably sodium benzoate;

[0119] j) Optionally, a sweetening agent, preferably selected from acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, miraculin, and mixtures thereof, more preferably a mixture of sodium saccharin and miraculin;

[0120] k) Optionally, a flavor enhancer selected from sodium chloride, sodium acetate or sodium gluconate, preferably sodium chloride, in an amount generally from 0.1% w / v to 5% w / v;

[0121] l) Optionally, a flavor correcting agent, preferably in an amount from 0.001% w / v to 0.1% w / v.

[0122] Preferably, the composition comprises at least one of the optional components h) to l).

[0123] The specific composition in this embodiment consists essentially of the ingredients listed above.

[0124] In one embodiment, the present invention relates to a liquid pharmaceutical composition for oral administration in the form of a suspension, which comprises:

[0125] a) Ibuprofen, in an amount from 2% w / v to 10% w / v, preferably from 2% w / v to 8% w / v, more preferably from 2% to 7%, still more preferably from 2% to 6%, still more preferably from 2% to 5%, still more preferably from 3% w / v to 5% w / v, and still more preferably, in an amount of about 4% w / v;

[0126] b) Phenylephrine or a pharmaceutically acceptable salt thereof, in an amount 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, still more preferably from 0.08% w / v to 0.2% w / v, and still more preferably, in an amount of about 0.1% w / v, expressed as the equivalent of phenylephrine hydrochloride;

[0127] c) Hypromellose, in an amount 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, still more preferably from 0.4% w / v to 0.6% w / v, and still more preferably about 0.5% w / v;

[0128] d) Xanthan gum, in an amount 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, still more preferably from 0.3% w / v to 0.6% w / v, and still more preferably about 0.4% w / v;

[0129] e) Liquid maltitol, the amount of which is generally 30% w / v to 70% w / v, preferably 35% w / v to 65% w / v, more preferably 45% w / v to 55% w / v, and still more preferably about 50% w / v;

[0130] f) Glycerol, the amount of which is generally 5% w / v to 15% w / v, preferably 7% w / v to 13% w / v, more preferably 9% w / v to 11% w / v, and still more preferably about 10% w / v;

[0131] g) Water;

[0132] h) A pH regulator, which is preferably selected from citrate buffers, acetate buffers, citrate-phosphate buffers, Tris buffers, and phosphate buffers, more preferably a citrate buffer;

[0133] i) A preservative, which is preferably selected from butyl paraben, propyl paraben, benzyl alcohol, and sodium benzoate, more preferably selected from benzyl alcohol and sodium benzoate, and still more preferably sodium benzoate;

[0134] j) Optionally, a sweetening agent, which is preferably selected from acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, miraculin, and mixtures thereof, more preferably a mixture of sodium saccharin and miraculin;

[0135] k) Optionally, a flavor enhancer, which is selected from sodium chloride, sodium acetate, or sodium gluconate, preferably sodium chloride, the amount of which is generally 0.1% w / v to 5% w / v; and

[0136] l) Optionally, a flavoring agent, the amount of which is preferably 0.001% w / v to 0.1% w / v.

[0137] The specific composition in this embodiment consists essentially of the ingredients listed above.

[0138] In one embodiment, the present invention relates to a liquid pharmaceutical composition for oral administration in the form of a suspension, which comprises:

[0139] a) Ibuprofen, the amount of which is 2% w / v to 10% w / v, preferably 2% w / v to 8% w / v, more preferably 2% to 7%, still more preferably 2% to 6%, still more preferably 2% to 5%, still more preferably 3% w / v to 5% w / v, and still more preferably, the amount is about 4% w / v;

[0140] b) phenylephrine or a pharmaceutically acceptable salt thereof, in an amount of 0.005% w / v to 2% w / v, preferably 0.01% w / v to 1% w / v, more preferably 0.05% w / v to 0.5% w / v, still more preferably 0.08% w / v to 0.2% w / v, and still more preferably, in an amount of about 0.1% w / v, expressed as the equivalent of phenylephrine hydrochloride;

[0141] c) hypromellose, in an amount of 0.1% w / v to 5% w / v, preferably 0.2% w / v to 2% w / v, more preferably 0.3% w / v to 1% w / v, still more preferably 0.4% w / v to 0.6% w / v, and still more preferably about 0.5% w / v;

[0142] d) xanthan gum, in an amount of 0.05% w / v to 4% w / v, preferably 0.1% w / v to 2% w / v, more preferably 0.2% w / v to 1% w / v, still more preferably 0.3% w / v to 0.6% w / v, and still more preferably about 0.4% w / v;

[0143] e) liquid maltitol, in an amount generally of 30% w / v to 70% w / v, preferably 35% w / v to 65% w / v, more preferably 45% w / v to 55% w / v, and still more preferably about 50% w / v;

[0144] f) glycerol, in an amount generally of 5% w / v to 15% w / v, preferably 7% w / v to 13% w / v, more preferably 9% w / v to 11% w / v, and still more preferably about 10% w / v;

[0145] g) water;

[0146] h) a pH regulator, which is preferably selected from citrate buffers, acetate buffers, citrate-phosphate buffers, Tris buffers, and phosphate buffers, more preferably a citrate buffer;

[0147] i) a preservative, which is preferably selected from butyl p-hydroxybenzoate, propyl p-hydroxybenzoate, benzyl alcohol, and sodium benzoate, more preferably selected from benzyl alcohol and sodium benzoate, and still more preferably sodium benzoate;

[0148] j) a sweetener, which is preferably selected from acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, miraculin, and mixtures thereof, more preferably a mixture of sodium saccharin and miraculin;

[0149] k) optionally, a flavor enhancer, which is selected from sodium chloride, sodium acetate, or sodium gluconate, preferably sodium chloride, in an amount generally of 0.1% w / v to 5% w / v; and

[0150] l) Optionally, a flavoring agent, the amount of which is preferably from 0.001% w / v to 0.1% w / v.

[0151] The specific composition in this embodiment consists essentially of the ingredients listed above.

[0152] In one embodiment, the present invention relates to a liquid pharmaceutical composition for oral administration in the form of a suspension, which comprises:

[0153] a) Ibuprofen, the amount of which is from 2% w / v to 10% w / v, preferably from 2% w / v to 8% w / v, more preferably from 2% to 7%, still more preferably from 2% to 6%, still more preferably from 2% to 5%, still more preferably from 3% w / v to 5% w / v, and still more preferably, the amount is about 4% w / v;

[0154] b) Phenylephrine or a pharmaceutically acceptable salt thereof, the amount of which is 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, still more preferably from 0.08% w / v to 0.2% w / v, and still more preferably, the amount is about 0.1% w / v, expressed in terms of the equivalent of phenylephrine hydrochloride;

[0155] c) Hypromellose, the amount of which is 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, still more preferably from 0.4% w / v to 0.6% w / v, and still more preferably about 0.5% w / v;

[0156] d) Xanthan gum, the amount of which is 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, still more preferably from 0.3% w / v to 0.6% w / v, and still more preferably about 0.4% w / v;

[0157] e) Liquid maltitol, the amount of which is generally from 30% w / v to 70% w / v, preferably from 35% w / v to 65% w / v, more preferably from 45% w / v to 55% w / v, and still more preferably about 50% w / v;

[0158] f) Glycerol, the amount of which is generally from 5% w / v to 15% w / v, preferably from 7% w / v to 13% w / v, more preferably from 9% w / v to 11% w / v, and still more preferably about 10% w / v;

[0159] g) Water;

[0160] h) A pH adjuster, which is preferably selected from citrate buffers, acetate buffers, citrate-phosphate buffers, Tris buffers, and phosphate buffers, more preferably a citrate buffer;

[0161] i) A preservative, which is preferably selected from butyl paraben, propyl paraben, benzyl alcohol, and sodium benzoate, more preferably selected from benzyl alcohol and sodium benzoate, and even more preferably is sodium benzoate;

[0162] j) A sweetening agent, which is preferably selected from acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, miraculin, and mixtures thereof, more preferably a mixture of sodium saccharin and miraculin;

[0163] k) A flavor enhancer, which is selected from sodium chloride, sodium acetate, or sodium gluconate, preferably sodium chloride, and the amount thereof is usually 0.1% w / v to 5% w / v, and

[0164] l) Optionally, a flavoring agent, and the amount thereof is preferably 0.001% w / v to 0.1% w / v.

[0165] The specific composition in this embodiment consists essentially of the ingredients listed above.

[0166] In one embodiment, the present invention relates to a liquid pharmaceutical composition for oral administration in the form of a suspension, which comprises:

[0167] a) Ibuprofen, and the amount thereof is 2% w / v to 10% w / v, preferably 2% w / v 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, the amount is about 4% w / v;

[0168] b) Phenylephrine or a pharmaceutically acceptable salt thereof, and the amount thereof is 0.005% w / v to 2% w / v, preferably 0.01% w / v to 1% w / v, more preferably 0.05% w / v to 0.5% w / v, even more preferably 0.08% w / v to 0.2% w / v, and even more preferably, the amount is about 0.1% w / v, expressed in terms of the equivalent of phenylephrine hydrochloride;

[0169] c) Hypromellose, and the amount thereof is 0.1% w / v to 5% w / v, preferably 0.2% w / v to 2% w / v, more preferably 0.3% w / v to 1% w / v, even more preferably 0.4% w / v to 0.6% w / v, and even more preferably is about 0.5% w / v;

[0170] 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, still more preferably from 0.3% w / v to 0.6% w / v, and even more preferably about 0.4% w / v;

[0171] e) liquid maltitol, in an amount generally of from 30% w / v 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;

[0172] f) glycerol, in an amount generally of from 5% w / v 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;

[0173] g) water;

[0174] h) a pH regulator, preferably selected from citrate buffers, acetate buffers, citrate - phosphate buffers, Tris buffers, and phosphate buffers, more preferably a citrate buffer;

[0175] i) a preservative, preferably selected from butyl paraben, propyl paraben, benzyl alcohol, and sodium benzoate, more preferably selected from benzyl alcohol and sodium benzoate, and even more preferably sodium benzoate;

[0176] j) a sweetening agent, preferably selected from acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, miraculin, and mixtures thereof, more preferably a mixture of sodium saccharin and miraculin;

[0177] k) a flavor enhancer selected from sodium chloride, sodium acetate, or sodium gluconate, preferably sodium chloride, in an amount generally of from 0.1% w / v to 5% w / v, and

[0178] l) a flavor corrective agent, in an amount preferably of from 0.001% w / v to 0.1% w / v.

[0179] The specific compositions in this embodiment consist essentially of the ingredients listed above.

[0180] The preferred characteristics of the different components of these compositions are as disclosed in the relevant paragraphs above in this specification (ibuprofen, phenylephrine, thickening / suspending agents, polyols, and additional optional ingredients).

[0181] In another embodiment, in any of the above embodiments, the concentration of ibuprofen present in the composition of the present invention is greater than 3% to 10%, preferably greater than 3% to 8%, more preferably greater than 3% to 7%, still more preferably greater than 3% to 6%, and even more preferably greater than 3% to 5%, expressed as a w / v percentage. More specifically, the concentration of ibuprofen present in the composition of the present invention is 3.3% to 10%, preferably 3.3% to 8%, more preferably 3.3% to 7%, still more preferably 3.3% to 6%, and even more preferably 3.3% to 5%, expressed as a w / v percentage.

[0182] In a preferred composition, the weight ratio of ibuprofen:phenylephrine is about 40:1 (calculated based on the weight of phenylephrine hydrochloride in equivalent, regardless of the form of phenylephrine used). For example, a composition containing about 4% w / v ibuprofen and about 0.1% w / v phenylephrine or a pharmaceutically acceptable salt thereof (expressed as the equivalent concentration of phenylephrine hydrochloride), or a composition containing about 2% w / w ibuprofen and about 0.05% w / w phenylephrine or a pharmaceutically acceptable salt thereof (expressed as the equivalent concentration of phenylephrine hydrochloride). Using these compositions, doses such as the following can be administered: 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, where the amount of phenylephrine is expressed as the equivalent weight of phenylephrine hydrochloride.

[0183] In another preferred composition, the weight ratio of ibuprofen:phenylephrine is about 20:1 (also calculated based on the weight of phenylephrine hydrochloride in equivalent), for example, a composition containing about 4% w / v ibuprofen and about 0.2% w / v phenylephrine or a pharmaceutically acceptable salt thereof (expressed as the equivalent concentration of phenylephrine hydrochloride). Using these compositions, doses such as the following can be administered: 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, where the amount of phenylephrine is expressed as the equivalent weight of phenylephrine hydrochloride.

[0184] Preparation method

[0185] Another aspect of the present invention is a method for preparing the composition.

[0186] Suitable methods for preparing the composition of the present invention include the following steps:

[0187] (i) Mix a part of liquid maltitol, hypromellose, and xanthan gum with a part of the total amount of water to obtain a homogeneous mixture;

[0188] (ii) Separately mix ibuprofen, phenylephrine or a pharmaceutically acceptable salt thereof, glycerol, and the remaining part of liquid maltitol with another part of the total amount of water to obtain a homogeneous mixture;

[0189] (iii) Add the mixture of step (ii) to the mixture of step (i);

[0190] (iv) Add the remaining water.

[0191] All ingredients are added under continuous stirring. For example, steps (i) and (ii) can be carried out in a stainless steel reactor equipped with a stirring system and preferably also equipped with a heating jacket.

[0192] In step (i), the exact proportion of water used to prepare the first mixture is not critical and can be, for example, about 15% to about 50% of the total amount of water.

[0193] When the composition contains a preservative, a pH regulator, and / or a flavor enhancer, they are preferably added in this step, preferably pre-dissolved in water and then hypromellose, xanthan gum, and liquid maltitol are added. When the composition contains a sweetener, it can also be added in this step in the same manner.

[0194] Generally speaking, the mixture obtained in step (i) has a gel-like appearance. Generally speaking, after adding hypromellose and xanthan gum, the mixture is stirred for about 2 to 6 hours, preferably under heating at about 40 to 80 °C, until a gel-like mixture is obtained. Maltitol is preferably added subsequently.

[0195] In step (ii), the amount of water used to prepare the second mixture is also not critical and can be, for example, about 5% to about 25% of the total amount of water.

[0196] The mixture obtained in step (ii) is a suspension.

[0197] When the composition contains a flavoring agent, it can be added, for example, after step (iii) and before step (iv). Thus, the flavoring agent and optionally a sweetener (if present) can be dissolved in a part of water (for example, about 0.5% to 5% of the total amount of water of the composition) and added to the mixture obtained in step (iii).

[0198] The composition can be filled in a suitable bottle, usually a polyethylene terephthalate amber bottle, which is equipped with a suitable cap, preferably a children-proof cap, usually a high-density polyethylene (HDPE) cap.

[0199] The package can also include a measuring device for dispensing the required dose of the composition, for example, a graduated cup or an oral syringe.

[0200] Alternatively, the composition can be filled into single-dose sachets, adding a suitable volume for delivering the required dose, for example, usually about 5 ml to about 10 ml, such as volumes of 5 ml, 7.5 ml or 10 ml. Other volumes can also be suitable, depending on the desired dose and the concentration of the composition. Suitable sachets for liquid compositions can be made of, for example, a laminated material, such as made of polyester / aluminum / polyester / polyethylene (PET / Alu / PET / PE).

[0201] Use of the composition

[0202] The composition according to the invention has optimal sensory properties, so the bitterness of ibuprofen and phenylephrine and the burning sensation usually associated with ibuprofen are completely masked.

[0203] In addition, as disclosed in Example 2, although it is known that phenylephrine is highly prone to degradation, the stability tests carried out have determined that the composition according to the invention is very stable. Thus, under all storage conditions, namely 25°C - 60% RH for 36 months, 30°C - 65% RH for 36 months, 30°C - 75% RH for 36 months, and 40°C - 75% RH for 6 months, the contents of the two active substances, ibuprofen and phenylephrine, are maintained between 95 and 105%, and the degradation products derived from the active substances are less than 0.1%.

[0204] Furthermore, the composition also remains physically stable under these storage conditions, and no aggregation or precipitation phenomena are detected. This is important for ensuring the administration of the correct dose of the active substance throughout the shelf life of the pharmaceutical product.

[0205] In addition, in a pharmacokinetic comparative test, the composition of the invention with a dose of 400 mg of ibuprofen and 10 mg of phenylephrine hydrochloride was administered to healthy subjects, or a reference drug (2 tablets Day&Night Cold&Flu 200mg / 5mg tablets, Reckitt Benckiser Healthcare, UK), which also contain the same dose of the active ingredient, both are administered once, and it has been found that the bioavailability of ibuprofen is higher in those subjects taking the composition of the present invention than in those taking the reference drug, with ibuprofen absorption being approximately 10% higher in the former. This is considered unexpected because the composition of the present invention contains maltitol, which is an active excipient known to enhance gastric motility and reduce the residence time of the drug in the intestinal lumen, and thus a lower rather than higher bioavailability was expected.

[0206] In addition, such comparative tests have also shown that the time (T 最大 ) to reach the maximum concentration observed in plasma for both ibuprofen and phenylephrine is faster in those subjects taking the composition according to the present invention than in those taking the reference drug. Thus, the T 最大 of ibuprofen is approximately 1 hour less (i.e., T 最大 value is 1.0 hour, compared to 2.0 hours for ibuprofen in the reference compound), and the T 最大 of phenylephrine is approximately 0.34 hour less (i.e., T 最大 value is 0.33 hour, compared to 0.67 hour for phenylephrine in the reference compound). This unexpected faster absorption will also provide a faster therapeutic effect, thus making the composition of the present invention a fast-acting drug, providing a favorable environment for early and potent therapeutic effects.

[0207] Another advantage of the composition of the present invention compared to commercial solid oral formulations is dose flexibility. Thus, for example, the dosage of ibuprofen can be, for example, from about 40 mg to about 400 or 600 mg, in combination with, for example, from about 1 mg to about 10 or 15 mg of phenylephrine (expressed as the equivalent of phenylephrine hydrochloride), and other options.

[0208] This dose flexibility allows for dosing to be customized according to the severity of the symptoms and the age of the patient, especially for pediatric patients. In this way, for example, children aged 7 to 9 years can take 200 mg of ibuprofen and 5 mg of phenylephrine, children aged 10 to 12 years can take 300 mg of ibuprofen and 7.5 mg of phenylephrine, and adults and the elderly can take 400 mg of ibuprofen and 10 mg of phenylephrine, where the amount of phenylephrine is expressed as the equivalent weight of phenylephrine hydrochloride.

[0209] Accordingly, another aspect of the present invention is a composition as defined above, which is used in medicine, particularly for treating the symptoms of influenza and common cold, such as fever, pain, sore throat, nasal congestion, and sinus congestion. The composition of the present invention is suitable for such use in adults, including elderly adults, and in children, particularly children over 7 years old. In one embodiment, the use is for adults and children over 7 years old.

[0210] Another aspect of the present invention is a method for treating the symptoms of influenza and common cold, such as fever, pain, sore throat, nasal congestion, and sinus congestion, which comprises the step of administering to a patient in need thereof a therapeutically effective dose of the composition according to the present invention. The patient can be an adult, including an elderly patient, or a child, particularly a child over 7 years old. In one embodiment, the method is for treating adults and children over 7 years old.

[0211] 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 treating the symptoms of influenza and common cold, such as fever, pain, sore throat, nasal congestion, and sinus congestion. The treatment can be directed to any patient in need thereof, including both adults (including elderly adults) and children (particularly children over 7 years old). In one embodiment, the treatment is for adults and children over 7 years old. Examples

[0212] Example 1: Suspension formulation containing ibuprofen and phenylephrine HCl

[0213] The composition according to the present invention is prepared using the ingredients listed in the following table:

[0214]

[0215] The hypromellose used is hypromellose 15 cP (type 2910 substitute). The particle size of ibuprofen is 40 μm.

[0216] For the preparation of the composition, a stainless steel reactor equipped with a stirring system and a heating jacket is filled with purified water equivalent to approximately 30% of the final batch, and sodium benzoate, anhydrous citric acid, sodium citrate, sodium saccharin, and sodium chloride are gradually added to the reactor under continuous stirring until completely dissolved. Subsequently, hypromellose is added under stirring until completely dispersed, and then xanthan gum is also added, and the mixture is kept under stirring for about 3 hours until gelation occurs, and then approximately half of the liquid maltitol is added.

[0217] A second stainless steel reactor equipped with stirring and a heating jacket is filled with approximately 10% of the total amount of water, and then glycerol, the remaining part of the liquid maltitol, phenylephrine HCl, and ibuprofen are gradually added under stirring until a homogeneous suspension is obtained. This suspension is mixed with the contents of the first reactor under stirring until a homogeneous suspension is obtained.

[0218] About 2% of the total water volume was filled into the second stainless steel reactor, and orange flavor and thaumatin were added with stirring until completely dissolved, and this solution was added to the suspension previously prepared in the main reactor.

[0219] The final product is a white or almost white viscous suspension with a characteristic orange flavor. The pH is about 3.8.

[0220] The product was filled into 100 and 150 ml PET amber bottles equipped with graduated cups and oral syringes.

[0221] Example 2: Stability data

[0222] Long-term and accelerated stability studies were carried out on the product of Example 1 according to the ICH guidelines applicable to 4 climate zones (25°C ± 2°C / 60% ± 5% RH, 30°C ± 2°C / 65% ± 5% RH, 30°C ± 2°C / 75% ± 5% RH and 40°C ± 2°C / 75% ± 5% RH), where 3 batches of the product were in their final containers (i.e., 100 and 150 ml), and for only one batch in two sizes of containers there was an additional refrigerated condition (2 to 8°C).

[0223] In view of the following parameters, the stability of the product was evaluated over a period of 36 months: appearance, pH, viscosity, ibuprofen dissolution, particle size with respect to sedimentation and particle size of suspended particles (no aggregates), ibuprofen determination (HPLC), phenylephrine HCl determination (HPLC), ibuprofen related substances (HPLC), and phenylephrine HCl related substances (HPLC).

[0224] The results obtained showed the best values for all the evaluated parameters, which determined the stability of the product for all batches and all conditions, and thus the following conclusion was drawn: The product does not require any special storage conditions.

[0225] Analysis of the impurities related to phenylephrine revealed that all impurity levels were very low for all batches and all conditions, and there was no reportable amount of impurities (<0.5%) in all cases.

[0226] In addition, analysis of the impurities related to ibuprofen showed that all impurity levels were very low for all batches and all conditions, and there was also no reportable amount (<0.1%).

[0227] In addition, a photostability study (ICH Q1B) was also carried out on one batch of the product. According to the determination conditions, at 1.2 million lux and 200 watts / m 2Irradiate the product with integrated UV energy. Evaluate the following parameters: description, pH, viscosity, ibuprofen dissolution, ibuprofen determination (HPLC), phenylephrine HCl determination (HPLC), sodium benzoate determination (HPLC), ibuprofen related substances (HPLC), and phenylephrine HCl related substances (HPLC). It was found that the product was stable to light under the evaluation conditions, so the product also does not require special conditions.

[0228] Finally, a use stability study was conducted on 3 production batches, and the following parameters were analyzed: appearance, pH, viscosity, ibuprofen dissolution, ibuprofen determination (HPLC), phenylephrine HCl determination (HPLC), sodium benzoate determination (HPLC), ibuprofen related substances (HPLC), phenylephrine HCl related substances (HPLC), microbiological quality, and antimicrobial preservative efficacy. The following conclusions were drawn: During use, the product was maintained under four climate zones without any loss of its physical properties and / or quantification / degradation for at least 6 months.

[0229] Example 3: Comparative pharmacokinetic study

[0230] A Phase I, randomized, open-label, single-dose, single-center study was conducted in 23 healthy male and female volunteers aged 18 to 55 years. The study was conducted under fasting conditions and a crossover design, with two phases, two sequences, and a wash-out period of at least 3 days.

[0231] The test product was the composition of Example 1, which was administered as a single dose (i.e., 10 ml of the composition) at a dose containing 400 mg of ibuprofen and 10 mg of phenylephrine HCl.

[0232] The reference drug was two Day&Night Cold&Flu 200 mg / 5 mg tablets (UK, Reckitt Benckiser Healthcare), which was also administered as a single dose, equivalent to 400 mg of ibuprofen and 10 mg of phenylephrine HCl.

[0233] The mean values of C 最大 and AUC determined for the ibuprofen enantiomers of the composition of Example 1 and the reference drug are shown in the following table:

[0234]

[0235] The T 最大 mean value for ibuprofen was 1.0 hour for the composition of Example 1 and 2.0 hours for the reference drug.

[0236] The T of phenylephrine 最大 The mean value is 0.33 hours for the composition of Example 1 and 0.67 hours for the reference drug.

Claims

1. A liquid pharmaceutical composition for oral administration in the form of a suspension, the composition comprising: a) Ibuprofen in an amount of 2% w / v to 10% w / v; b) Phenylephrine or a pharmaceutically acceptable salt thereof in an amount of 0.005% w / v to 2% w / v, expressed as the equivalent of phenylephrine hydrochloride; c) Hypromellose in an amount of 0.1% w / v to 5% w / v; d) Xanthan gum in an amount of 0.05% w / v to 4% w / v; e) Liquid maltitol; f) Glycerol; 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 hydrogen tartrate.

3. The composition according to claim 2, characterized in that the composition comprises phenylephrine hydrochloride.

4. The composition according to any one of claims 1 to 3, characterized in that the amount of ibuprofen is 3% w / v to 5% w / v.

5. The composition according to claim 1, characterized in that the amount of phenylephrine or a pharmaceutically acceptable salt thereof is 0.08% w / v to 0.2% w / v, expressed as the equivalent of phenylephrine hydrochloride.

6. The composition according to claim 1, characterized in that the amount of hypromellose is 0.2% w / v to 2% w / v.

7. The composition according to claim 1, characterized in that the amount of hypromellose is 0.3% w / v to 1% w / v.

8. The composition according to claim 1, characterized in that the amount of hypromellose is 0.4% w / v to 0.6% w / v.

9. The composition according to claim 1, characterized in that the amount of hypromellose is about 0.5% w / v.

10. The composition according to claim 1, characterized in that the amount of xanthan gum is 0.1% w / v to 2% w / v.

11. The composition according to claim 1, characterized in that the amount of xanthan gum is 0.2% w / v to 1% w / v.

12. The composition according to claim 1, characterized in that the amount of xanthan gum is 0.3% w / v to 0.6% w / v.

13. The composition according to claim 1, characterized in that the amount of xanthan gum is about 0.4% w / v.

14. The composition according to claim 1, characterized in that the amount of liquid maltitol is 30% w / v to 70% w / v.

15. The composition according to claim 1, characterized in that the amount of liquid maltitol is 35% w / v to 65% w / v.

16. The composition according to claim 1, characterized in that the amount of liquid maltitol is 45% w / v to 55% w / v.

17. The composition according to claim 1, characterized in that the amount of liquid maltitol is about 50% w / v.

18. The composition according to claim 1, characterized in that the amount of glycerol is 5% w / v to 15% w / v.

19. The composition according to claim 1, characterized in that the amount of glycerol is 7% w / v to 13% w / v.

20. The composition according to claim 1, characterized in that the amount of glycerol is from 9% w / v to 11% w / v.

21. The composition according to claim 1, characterized in that the amount of glycerol is about 10% w / v.

22. The composition according to claim 1, characterized in that the composition comprises a pH regulator to adjust the pH of the composition to a value of 2 to 6.

23. The composition according to claim 1, characterized in that the composition comprises a preservative.

24. The composition according to claim 1, characterized in that the composition comprises a sweetening agent selected from the group consisting of acesulfame potassium, alitame, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, miraculin, and mixtures thereof.

25. The composition according to claim 24, characterized in that the sweetening agent is a mixture of sodium saccharin and miraculin.

26. The composition according to claim 1, characterized in that the composition comprises sodium chloride.

27. The composition according to claim 26, characterized in that the amount of sodium chloride is from 0.1% w / v to about 5% w / v.

28. A method for preparing the composition according to any one of claims 1 to 27, characterized in that the method comprises the following steps: (i) Mixing a part of liquid maltitol, hypromellose, and xanthan gum with a 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 part of liquid maltitol with another part of the total amount of water to obtain a homogeneous mixture; (iii) Adding the mixture of step (ii) to the mixture of step (i); (iv) Adding the remaining water.

29. Use of the composition according to any one of claims 1 to 27 for the preparation of a medicament for treating the symptoms of influenza and common cold.

30. The use according to claim 29, characterized in that the symptoms of influenza and common cold are selected from the group consisting of fever, pain, sore throat, nasal congestion, and sinus congestion.

Images