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, comprising a combination of ibuprofen and phenylephrine or pharmaceutically acceptable salts thereof as active ingredients, as well as hypromellose, xanthan gum, liquid maltitol, glycerol, and water. The composition is stable, has good organoleptic 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 treating symptoms of influenza and the common cold, particularly in adults and children over 7 years of age.

Description

Technical Field

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

[0002] Existing technology

[0003] The combined use of analgesics and decongestants to relieve symptoms associated with the common cold or flu, such as headache, fever, sinus pressure, and mild body aches, is a well-known treatment strategy.

[0004] For example, one specific approach 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 primarily works by acting directly on alpha-adrenergic receptors and is an oral nasal decongestant.

[0005] To date, the ibuprofen / phenylephrine combination is only available on the market as a solid oral dosage form, and it is worth noting that all available drugs are intended for use only in adults and children aged 12 years and older.

[0006] Therefore, for example, drugs " Congestion Relief (FDA, Pfizer) is an oral composition in tablet form containing 200 mg of ibuprofen and 10 mg of phenylephrine hydrochloride (HCl). The recommended dose is one tablet every 4 hours.

[0007] Similarly, the drug "Care Cold & Flu Relief" (UK, Thornton & Ross) is in film-coated tablet form, and each dose contains 200 mg of ibuprofen and 5 mg of phenylephrine HCl. Alternatively, film-coated tablets... (ES, Laboratorio Stada) also consists of a fixed-dose combination of 200 mg ibuprofen and 5 mg phenylephrine HCl. Alternatively, film-coated tablets. Day & Night Cold & Flu 200mg / 5mg tablets (UK, Reckitt Benckiser Healthcare). The recommended dose for these three medications is 2 tablets every 8 hours.

[0008] It has been recognized that the use of solid oral dosage forms may not be suitable for some patient groups who may have difficulty swallowing whole tablets or capsules, including pediatricians, the elderly, or patients with disabilities. For these patient groups, the use of liquid formulations is generally considered advantageous. Furthermore, liquid formulations are better suited for adjusting the dosage of the active ingredient according to the patient's age and for better control of the amount of medication administered. This is particularly important when the target treatment is children under 12 years of age.

[0009] However, the formulation of liquid pharmaceutical compositions is generally more difficult than that of solid compositions. For example, there are often more stability issues due to the closer interactions between the combined drugs and between the drugs and excipients. Specifically, phenylephrine is a readily degradable drug, especially in liquid formulations, and particularly prone to degradation at high temperatures.

[0010] Furthermore, the formulation of each specific drug combination must be considered as a particular and unique challenge to be solved, stemming from the complex interactions between the specific drugs to be combined and the excipients, and therefore cannot be solved by simply combining previously known formulations of each individual drug.

[0011] Furthermore, preparing palatable liquid formulations for drugs with unpleasant tastes is challenging. While unpleasant tastes can be easily masked in solid dosage forms by encapsulating the drug in gelatin capsules or using film-coated tablets, in liquid formulations, it's difficult to avoid direct contact between the unpleasant-tasting drug and the taste buds in the mouth upon ingestion. For example, ibuprofen is known for its particularly unpleasant bitter, burning taste, and phenylephrine also exhibits a characteristic bitterness.

[0012] Another additional challenge lies in the solubility of the drugs to be combined. For example, ibuprofen is almost insoluble in water, and although its pharmaceutically acceptable salts are more readily soluble, their use exacerbates palatability issues. Due to ibuprofen's poor water solubility, its aqueous formulations are typically suspensions in which ibuprofen particles must be in equilibrium to avoid aggregation and sedimentation. These phenomena occur frequently and are difficult to avoid.

[0013] From a pharmacokinetic perspective, there is a need for formulations that provide high bioavailability of the active substance and subsequent early and potent therapeutic effects. Drug bioavailability is primarily measured by the time to reach the maximum observed concentration in plasma (T0). 最大 ) and the observed maximum plasma concentration (C 最大 The bioavailability of drugs can be measured using [methods to be determined]. The formulation of liquid formulations presents more challenges in assessing drug bioavailability because the use of certain excipients (such as polyols) required to improve formulation stability and palatability may hinder the absorption rate of the active substance.

[0014] Therefore, it is not obvious to those skilled in the art that it is possible to formulate stable, sensorily acceptable liquid compositions containing ibuprofen and phenylephrine that provide adequate drug bioavailability.

[0015] There are some publicly available technologies that attempt to solve related problems.

[0016] Therefore, for example, international patent application WO2008 / 008944-A1 discloses a pharmaceutical suspension containing phenylephrine and at least one substantially water-insoluble active agent (particularly acetaminophen), with a pH of about 4 to about 6. The composition comprises a non-reducing sugar, a polyol, and a high-intensity sweetener as a sweetening system; the preferred sweetener is sorbitol, optionally combined with sucrose. A preferred thickening component comprises 0.1 to 0.25% (w / v) xanthan gum as a primary structural agent and a co-processed combination of microcrystalline cellulose and carboxymethyl cellulose as a secondary structural agent. No compositions containing a specific combination of phenylephrine and ibuprofen are disclosed.

[0017] International patent application WO2007 / 098128-A2 discloses an oral liquid pharmaceutical composition for phenylephrine containing a reduced amount of sorbitol to promote the stability of phenylephrine. Specifically, the composition comprises a combination of glycerol and sorbitol, wherein the amount of glycerol is up to about 45% w / v, preferably 18 to 30% w / v, and up to about 10% w / v, preferably 3 to 10% w / v, of sorbitol. Compositions containing a specific combination of phenylephrine and ibuprofen are not disclosed.

[0018] International patent application WO2006 / 022996-A2 generally discloses pharmaceutical compositions comprising a first drug and a second drug, both selected from decongestants, antitussives, expectorants, analgesics, and antihistamines, which provide effective plasma drug concentrations. Examples 2, 25, 45, 69, and 72 disclose suspensions comprising phenylephrine in combination with other drugs (i.e., with promethazine, codeine, carbetapentane, or diphenhydramine). The suspension formulation comprises a combination of the polyols sorbitol, glycerol, and xylitol as a sweetener, and a combination of colloidal anhydrous silica and hydroxyethyl cellulose as a suspending agent. No compositions comprising a specific combination of phenylephrine and ibuprofen are disclosed.

[0019] International patent application WO2008 / 008364-A2 discloses an oral liquid pharmaceutical composition comprising phenylephrine and substantially aldehyde-free polyethylene glycol, 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 sweetener system. No stability data for phenylephrine are provided. No compositions comprising a specific combination of phenylephrine and ibuprofen are disclosed.

[0020] Therefore, there remains a need for liquid formulations containing a combination of phenylephrine and ibuprofen that are stable, sensorily acceptable, suitable for pediatric populations, and capable of providing effective pharmacological activity and rapid absorption of both active ingredients to provide rapid relief of symptoms of influenza and the common cold.

[0021] Purpose of the invention

[0022] The object of the present invention is a liquid pharmaceutical composition comprising a combination of ibuprofen and phenylephrine.

[0023] Another aspect of the present invention is a method for preparing the composition.

[0024] Another aspect of the present invention is a liquid pharmaceutical composition for medical use comprising a combination of ibuprofen and phenylephrine.

[0025] Invention Details

[0026] The object of the present invention is a liquid pharmaceutical composition in suspension form for oral administration, comprising:

[0027] a) Ibuprofen, in doses ranging from 2% w / v to 10% w / v;

[0028] b) Phenylephrine or a pharmaceutically acceptable salt thereof, in an amount of 0.005% w / v to 2% w / v, expressed as equivalents of phenylephrine hydrochloride;

[0029] c) Hydroxypropyl methylcellulose, in an amount of 0.1% w / v to 5% w / v;

[0030] d) Xanthan gum, in an amount of 0.05% w / v to 4% w / v;

[0031] e) Liquid maltitol;

[0032] f) Glycerin; and

[0033] g) Water.

[0034] The authors of this invention have developed an aqueous liquid pharmaceutical composition in suspension form comprising a combination of ibuprofen and phenylephrine as active ingredients, exhibiting optimal physicochemical characteristics, particularly high stability and good sensory properties. Furthermore, this formulation possesses excellent pharmacokinetic properties, providing extremely rapid absorption of both drugs and optimal bioavailability.

[0035] In this specification and in the claims, unless the context clearly indicates otherwise, nouns without quantifiers are intended to include the plural form as well. Furthermore, numerical values ​​preceded by the terms "about" or "approximately" are intended to include exact specified values ​​and specific variations around such values, i.e., variations of ±5% of the quantity. Numerical ranges defined by lower and upper endpoints are also intended to include the endpoints.

[0036] Unless otherwise stated, the percentages disclosed for each component of the composition are by weight / volume (%w / v), i.e., the number of grams of each component in 100 ml of the composition.

[0037] The excipients used to prepare the compositions 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. Furthermore, commonly used excipients and procedures for preparing the compositions are described in the book JP. Remington and ARGenaro, Remington, The Science and Practice of Pharmacy, 2009. th edition, Lippincott, Williams & Wilkins, Philadelphia, 2000 [ISBN: 0-683-306472] or in the book ME Aulton and KMG Taylor, Aulton's Pharmaceutics, the design and manufacture of medicines, 4 th edition, Churchill Livingstone Elsevier, 2013 [ISBN: 978-0-7020-4290-4].

[0038] Ibuprofen

[0039] Ibuprofen is the International Nonproprietary Name (INN) for the compound (RS)-2-(4-(2-methylpropyl)phenyl)propionic acid.

[0040] Ibuprofen is a well-known member of the nonsteroidal anti-inflammatory drug (NSAID) family and has analgesic, antipyretic, and anti-inflammatory properties.

[0041] In the context of this invention, the term "ibuprofen" does not specifically refer to racemic ibuprofen (RS), or (S)-ibuprofen and (R)-ibuprofen, or mixtures of (R) and (S) forms in any proportion. Preferably, the ibuprofen used in the pharmaceutical compositions of this invention is selected from the group consisting of (RS)-ibuprofen and (S)-ibuprofen.

[0042] Furthermore, the term ibuprofen also includes any hydrated and solvated form, as well as any crystalline and amorphous form. Preferably, crystalline ibuprofen is used.

[0043] Ibuprofen is commercially available and can also be prepared, for example, according to the procedure described in UK patent application GB-A-971700. For example, the resolution of ibuprofen to its enantiomers is described in the article Brushan et al. Resolution of enantiomers of ibuprofen by liquid chromatography: a review, Biomed. Chromatogr., 1998, 12(6), 309.

[0044] Ibuprofen is an acidic molecule containing a carboxylic acid moiety and is poorly soluble in water.

[0045] Ibuprofen can be used in treatment in both its acidic free form and as its pharmaceutically acceptable salts (e.g., arginine ibuprofen, lysine ibuprofen, or ibuprofen sodium). In the context of this invention, ibuprofen is preferably used in its acidic free form.

[0046] The size of the ibuprofen particles used to prepare the composition is not critical, but is preferably less than 150 μm to minimize aggregation and sedimentation, and thus improve the long-term stability and homogeneity of the suspension. More preferably, the size of the ibuprofen particles is 5 μm to 100 μm, even more preferably 10 μm to 60 μm, even more preferably 20 μm to 50 μm, and even more preferably 30 μm to 45 μm.

[0047] The particle size of ibuprofen granules can be quantified by known methods, such as by sieving through a sieve of appropriate size.

[0048] The concentration of ibuprofen in the composition of the present invention is 2% to 10%, preferably 2% to 8%, more preferably 2% to 7%, even more preferably 2% to 6%, even more preferably 2% to 5%, even more preferably 3% to 5%, and even more preferably about 4%, expressed as a w / v percentage. In one embodiment, the concentration of ibuprofen 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%, even more preferably greater than 3% to 6%, and even more preferably greater than 3% to 5%, expressed as a w / v percentage. In one embodiment, the concentration of ibuprofen in the composition of the present invention is 3.3% to 10%, preferably 3.3% to 8%, more preferably 3.3% to 7%, even more preferably 3.3% to 6%, and even more preferably 3.3% to 5%, expressed as a w / v percentage.

[0049] Phenylephrine

[0050] Phenylephrine is the international non-proprietary name (INN) of the compound 3-[(1R)-1-hydroxy-2-(methylamino)ethyl]phenol ((R)-(-)-phenylephrine, CAS 61-76-7).

[0051] In the context of this invention, the term "phenylephrine" does not specifically refer to the common R-form, nor to the racemic or S-form. Preferably, (R)-(-)-phenylephrine is used.

[0052] Furthermore, the term phenylephrine also includes any hydrated and solvated form, as well as any crystalline and amorphous form thereof. Preferably, crystalline phenylephrine is used.

[0053] Norepinephrine is a basic compound containing a secondary amine group. Norepinephrine can be used in its free basic form or as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts of norepinephrine include non-toxic acid addition salts.

[0054] In one embodiment of the invention, norepinephrine is used as a salt, for example, selected from addition salts of 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.

[0055] In one embodiment of the invention, the pharmaceutically acceptable salt of norepinephrine is selected from hydrochloride (norepinephrine hydrochloride), hydrobromide (norepinephrine hydrobromide) and tartrate (norepinephrine tartrate).

[0056] In a preferred embodiment, norepinephrine hydrochloride is used.

[0057] The concentration of phenylephrine or its pharmaceutically acceptable salt in the composition of the present invention is 0.005% to 2%, preferably 0.01% to 1%, more preferably 0.05% to 0.5%, even more preferably 0.08% to 0.2%, and even more preferably about 0.1%, expressed in equivalents of phenylephrine hydrochloride, and expressed as w / v percentage.

[0058] The statement "expressed in equivalent weight of phenylephrine hydrochloride" means that if phenylephrine is added as a free base or as a salt different from hydrochloride, the amount of phenylephrine is converted to the equivalent weight of an equimolar amount of phenylephrine hydrochloride. Therefore, for example, if a 0.82 mg / ml free phenylephrine base (molecular weight 167.205 g / mol) is used, the concentration of phenylephrine "expressed in equivalent weight of phenylephrine hydrochloride (molecular weight 203.66 g / mol)" would be 1 mg / ml or 0.1% w / v. Moreover, similar calculations can be performed for other salts in a similar manner, as is well known to those skilled in the art.

[0059] In this specification and claims, the amount and concentration of phenylephrine are always expressed as equivalents or concentrations of phenylephrine hydrochloride.

[0060] Thickener / Suspending Agent

[0061] The compositions of the present invention comprise a combination of xanthan gum and hydroxypropyl methylcellulose (hydroxypropyl methylcellulose), which are used as suspending agents and thickeners.

[0062] Hydroxypropyl methylcellulose (also known as hydroxypropyl methylcellulose or HPMC) is a well-known cellulose derivative used in pharmaceutical formulations. Hydroxypropyl methylcellulose 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, all of which are suitable for the compositions of the present invention.

[0063] Xanthan gum is also a well-known pharmaceutical excipient, primarily used as a suspending agent in the preparation of suspensions and as a thickener. 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 also contains D-glucuronic acid, and is prepared as a sodium, potassium, or calcium salt. It is widely available commercially.

[0064] The authors of this invention have unexpectedly discovered that the combination of xanthan gum and hydroxypropyl methylcellulose as a suspending / thickening system, and the combination of polyol glycerol and maltitol, provides the composition with excellent physicochemical stability and also results in improved absorption of the active ingredients and optimal sensory properties.

[0065] In one embodiment, hydroxypropyl methylcellulose (referred to as hydroxypropyl methylcellulose type 2910) with a hydroxypropoxy content of 7.0 to 12% is used.

[0066] The proportion of hydroxypropyl methylcellulose in the composition is 0.1% to 5%, preferably 0.2% to 2%, more preferably 0.3% to 1%, even more preferably 0.4% to 0.6%, and even more preferably about 0.5%, expressed as w / v percentage.

[0067] The proportion of xanthan gum in the composition is 0.05% to 4%, preferably 0.1% to 2%, more preferably 0.2% to 1%, even more preferably 0.3% to 0.6%, and even more preferably about 0.4%, expressed as w / v percentage.

[0068] The weight ratio of hydroxypropyl methylcellulose to xanthan gum is typically 2:1 to 1:1, preferably 1.5:1 to 1:1, and more preferably, the weight ratio of hydroxypropyl methylcellulose to xanthan gum in the composition is about 1.25:1.

[0069] polyols

[0070] The composition of the present invention comprises a combination of the polyol glycerol and liquid maltitol.

[0071] Glycerin (or glycerol or propane-1,2,3-triol) is a known pharmaceutically acceptable excipient, commonly used in oral liquid formulations as a sweetener, co-solvent, or viscosity enhancer.

[0072] Maltitol is a disaccharide (4-O-α-D-glucanosyl-D-glucanol).

[0073] Liquid maltitol is an aqueous solution of D-maltitol. According to the current European Pharmacopoeia, it is commonly used as a pharmaceutical excipient. This pharmacopoeia specifies that the liquid maltitol must contain at least 68% w / w and no more than 85% w / w of solids, ≥50% w / w of D-maltitol, and no more than 8% w / w of sorbitol, as well as trace amounts of hydrogenated oligosaccharides and polysaccharides. According to the United States Pharmacopeia, maltitol solutions, on an anhydrous basis, contain at least 50% w / w of D-maltitol and no more than 8.0% w / w of D-sorbitol.

[0074] Typically, for example, liquid maltitol contains about 50% w / w to about 55% w / w of D-maltitol (based on the total weight of anhydrous matter); and the content of sorbitol is typically about 2% w / w to about 7% w / w, preferably about 3% w / w to about 5% w / w (also based on the total weight of anhydrous matter); the content of water is typically 20 to 30% w / w, preferably about 25% w / w; and the total solids content is typically about 70% w / w to about 80% w / w, preferably about 75% w / w.

[0075] Therefore, it should be understood that the compositions of the present invention inherently also contain a small amount of sorbitol, as well as other small amounts of sugars present together with maltitol in the "liquid maltitol" excipient used. Thus, whenever the formulation described in this specification and claims is described as containing a specific amount of "liquid maltitol," it should be understood that, in addition to maltitol, it also contains a small proportion of sorbitol and other sugars within a specific range.

[0076] If necessary, calculating the amount of maltitol present in the composition and the amount of residual sorbitol is entirely within the skill range of a person skilled in the art of pharmaceutical technology.

[0077] Liquid maltitol is commonly used as a sweetener in oral liquid formulations and also as a suspending agent.

[0078] Maltitol is often considered an "active excipient" because it alters intestinal motility by increasing peristaltic movement and reducing the residence time of active substances in the intestinal lumen.

[0079] Generally, the proportion of liquid maltitol in the composition is 30% to 70%, preferably 35% to 65%, more preferably 45% to 55%, and even more preferably about 50%, expressed as w / v percentage.

[0080] Generally, the proportion of glycerol in the composition is 5% to 15%, preferably 7% to 13%, more preferably 9% to 11%, and even more preferably about 10%, expressed as w / v percentage.

[0081] The weight ratio of liquid maltitol to glycerol in the pharmaceutical composition of the present invention is generally 10:1 to 1:1, preferably 7:1 to 3:1, and more preferably about 5:1.

[0082] As disclosed above, the combination of polyol glycerol and maltitol, along with the combination of xanthan gum and hydroxypropyl methylcellulose as a suspending / thickening system, provides the composition with excellent physicochemical stability, fast-acting effect of the active ingredient, enhanced ibuprofen absorption, and optimal sensory properties.

[0083] Other optional ingredients

[0084] pH adjuster

[0085] The compositions of the present invention may contain a pH adjuster to maintain the pH of the suspension within a desired pH range. The pH of the composition is typically 2 to 7, preferably 2 to 6, more preferably 2.5 to 5, even more preferably 3 to 4.5, even more preferably 3.3 to 4.3, even more preferably 3.5 to 4, and even more preferably 3.5 to 3.9.

[0086] The amount of pH adjuster in the composition is sufficient to provide the desired pH level, which can be easily adjusted by those skilled in the art. If present, the pH adjuster is typically present in an amount of about 0.1% to about 2%, expressed as a w / v percentage.

[0087] pH adjusters can be, for example, acidifying agents such as citric acid, acetic acid, hydrochloric acid, lactic acid, phosphoric acid, or sulfuric acid, and / or alkalizing agents such as ammonia solution, diethanolamine, monoethanolamine, potassium bicarbonate, sodium bicarbonate, potassium citrate, sodium citrate, sodium bicarbonate, or sodium borate. Preferably, the pH adjuster is, for example, a buffer such as a citrate buffer, acetate buffer, citrate-phosphate buffer, Tris buffer, or phosphate buffer, etc.

[0088] The preferred buffer is a citrate buffer, which is typically prepared from 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 anhydrous citric acid to sodium citrate in a weight ratio of about 1.5:1.

[0089] preservative

[0090] The composition may contain a preservative to ensure its protection against microbial contamination. Suitable preservatives are, for example, butylparaben, ethylparaben, methylparaben, propylparaben, benzoic acid, benzalkonium chloride, benzyl chloride, benzyl alcohol, bromonitol, chlorhexidine, chlorocresol, xylene, imidazoline, cresol, phenol, sodium benzoate, sorbic acid, or thimerosal.

[0091] As is well known in the art, the amount of preservative typically depends on the specific preservative used and can generally range from about 0.001% to about 5%, expressed as a w / v percentage. Those skilled in the art should have no difficulty selecting the appropriate amount in each case, as disclosed in the references in the art.

[0092] In one embodiment of the 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.

[0093] sweeteners

[0094] Optionally, the composition may include a sweetener to enhance the sweetness of the polyol mixture; in particular, a strong sweetener may be used. A strong sweetener generally refers to a non-nutritive, high-intensity sweetener, which is typically about 100 to about 13,000 times sweeter than sucrose.

[0095] Suitable strong sweeteners for use in the compositions of the present invention are, for example, acesulfame potassium, alitane, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, kiwifruit protein, or mixtures thereof.

[0096] The amount of sweetener can vary widely depending on the sweetness intensity of the sweetener, but is typically 0.0001% to 0.5% w / v.

[0097] In one embodiment, the composition comprises sodium saccharin, typically in an amount of 0.01% w / v to 0.5% w / v.

[0098] In one embodiment, the composition comprises kiwifruit sweet protein, typically in an amount of 0.0001% w / v to 0.01% w / v.

[0099] In one embodiment, the composition comprises sodium saccharin and kiwifruit protein, wherein the amount of sodium saccharin is from 0.01% w / v to 0.5% w / v, and the amount of kiwifruit protein is from 0.0001% w / v to 0.01% w / v.

[0100] Flavor enhancer

[0101] Some sodium salts, such as sodium chloride, sodium acetate, or sodium gluconate, are inhibitors of bitterness and enhance other desired tastes and flavors, such as sweetness.

[0102] Therefore, in one embodiment, the composition of the present invention comprises a flavor enhancer selected from sodium chloride, sodium acetate, sodium gluconate, and mixtures thereof, preferably comprising sodium chloride.

[0103] The amount of flavor enhancers, such as sodium chloride, in the composition is typically from about 0.1% w / v to about 5% w / v.

[0104] Flavoring agents

[0105] The composition may optionally additionally include flavoring agents for imparting a pleasant flavor and / or odor to the composition. Suitable flavoring agents include natural and artificial flavorings. Natural flavorings include natural oils and extracts from plants, leaves, flowers, and fruits. Some suitable flavorings are, for example, menthol, cinnamon, clove, anise, eucalyptus, peppermint, spearmint, thyme, vanilla, chocolate, and fruit flavorings 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, as well as combinations thereof.

[0106] The amount of flavoring agent can be easily adjusted by a skilled formulator, depending on the specific flavoring agent and the desired sensory effect. Generally, the amount of flavoring agent (if present in the composition) is from about 0.001% w / v to about 0.1% w / v.

[0107] Composition

[0108] Water is the primary solvent in the formulation. Purified water is typically used. The exact percentage of water is not quantified because it is adjusted to a specific final volume to provide the desired concentration of each component.

[0109] The compositions of this invention are in the form of suspensions. As is known in pharmaceutical formulations, suspensions are two-phase systems consisting of insoluble or immiscible solids dispersed in a liquid. The average particle size of the dispersed solid particles is typically from about 1.0 nm to about 150 μm, without agglomerates. Ibuprofen is a poorly soluble drug that primarily constitutes the solid dispersion phase of the suspension.

[0110] In one embodiment, the present invention relates to a liquid pharmaceutical composition for oral administration in the form of a suspension, comprising:

[0111] 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%, 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;

[0112] 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, even more preferably 0.08% w / v to 0.2% w / v, and even more preferably, in an amount of about 0.1% w / v, expressed as equivalent to phenylephrine hydrochloride;

[0113] c) Hydroxypropyl methylcellulose, 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, even more preferably 0.4% w / v to 0.6% w / v, and even more preferably about 0.5% w / v;

[0114] 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, even more preferably 0.3% w / v to 0.6% w / v, and even more preferably about 0.4% w / v;

[0115] e) Liquid maltitol, typically in an amount 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 even more preferably about 50% w / v;

[0116] f) Glycerin, typically in an amount 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 even more preferably about 10% w / v;

[0117] g) Water;

[0118] h) Optionally, the pH adjuster is preferably selected from citrate buffers, acetate buffers, citrate-phosphate buffers, Tris buffers, and phosphate buffers, more preferably citrate buffers;

[0119] i) Optionally, the preservative 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 sodium benzoate;

[0120] j) Optionally, the sweetener is preferably selected from acesulfame potassium, alitane, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, kiwifruit protein, and mixtures thereof, more preferably a mixture of sodium saccharin and kiwifruit protein;

[0121] k) Optionally, a flavor enhancer, selected from sodium chloride, sodium acetate or sodium gluconate, preferably sodium chloride, is used, and the amount is typically from 0.1% w / v to 5% w / v;

[0122] l) Optionally, the flavoring agent is preferably used in an amount of 0.001% w / v to 0.1% w / v.

[0123] Preferably, the composition comprises at least one of optional ingredients h) to l).

[0124] The specific composition in this embodiment consists essentially of the ingredients listed above.

[0125] In one embodiment, the present invention relates to a liquid pharmaceutical composition for oral administration in the form of a suspension, comprising:

[0126] 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%, 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;

[0127] 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, even more preferably 0.08% w / v to 0.2% w / v, and even more preferably, in an amount of about 0.1% w / v, expressed as equivalent to phenylephrine hydrochloride;

[0128] c) Hydroxypropyl methylcellulose, 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, even more preferably 0.4% w / v to 0.6% w / v, and even more preferably about 0.5% w / v;

[0129] 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, even more preferably 0.3% w / v to 0.6% w / v, and even more preferably about 0.4% w / v;

[0130] e) Liquid maltitol, typically in an amount 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 even more preferably about 50% w / v;

[0131] f) Glycerin, typically in an amount 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 even more preferably about 10% w / v;

[0132] g) Water;

[0133] h) pH adjuster, preferably selected from citrate buffer, acetate buffer, citrate-phosphate buffer, Tris buffer and phosphate buffer, more preferably citrate buffer;

[0134] 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;

[0135] j) Optionally, the sweetener is preferably selected from acesulfame potassium, alitane, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, kiwifruit protein, and mixtures thereof, more preferably a mixture of sodium saccharin and kiwifruit protein;

[0136] k) Optionally, a flavor enhancer, selected from sodium chloride, sodium acetate, or sodium gluconate, preferably sodium chloride, is used, typically in an amount of 0.1% w / v to 5% w / v; and

[0137] l) Optionally, the flavoring agent is preferably used in an amount of 0.001% w / v to 0.1% w / v.

[0138] The specific composition in this embodiment consists essentially of the ingredients listed above.

[0139] In one embodiment, the present invention relates to a liquid pharmaceutical composition for oral administration in the form of a suspension, comprising:

[0140] 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%, 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;

[0141] 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, even more preferably 0.08% w / v to 0.2% w / v, and even more preferably, in an amount of about 0.1% w / v, expressed as equivalent to phenylephrine hydrochloride;

[0142] c) Hydroxypropyl methylcellulose, 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, even more preferably 0.4% w / v to 0.6% w / v, and even more preferably about 0.5% w / v;

[0143] 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, even more preferably 0.3% w / v to 0.6% w / v, and even more preferably about 0.4% w / v;

[0144] e) Liquid maltitol, typically in an amount 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 even more preferably about 50% w / v;

[0145] f) Glycerin, typically in an amount 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 even more preferably about 10% w / v;

[0146] g) Water;

[0147] h) pH adjuster, preferably selected from citrate buffer, acetate buffer, citrate-phosphate buffer, Tris buffer and phosphate buffer, more preferably citrate buffer;

[0148] 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;

[0149] j) A sweetener, preferably selected from acesulfame potassium, alitane, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, kiwifruit protein, and mixtures thereof, more preferably a mixture of sodium saccharin and kiwifruit protein;

[0150] k) Optionally, a flavor enhancer, selected from sodium chloride, sodium acetate, or sodium gluconate, preferably sodium chloride, is used, typically in an amount of 0.1% w / v to 5% w / v; and

[0151] l) Optionally, the flavoring agent is preferably used in an amount of 0.001% w / v to 0.1% w / v.

[0152] The specific composition in this embodiment consists essentially of the ingredients listed above.

[0153] In one embodiment, the present invention relates to a liquid pharmaceutical composition for oral administration in the form of a suspension, comprising:

[0154] 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%, 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;

[0155] 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, even more preferably 0.08% w / v to 0.2% w / v, and even more preferably, in an amount of about 0.1% w / v, expressed as equivalent to phenylephrine hydrochloride;

[0156] c) Hydroxypropyl methylcellulose, 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, even more preferably 0.4% w / v to 0.6% w / v, and even more preferably about 0.5% w / v;

[0157] 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, even more preferably 0.3% w / v to 0.6% w / v, and even more preferably about 0.4% w / v;

[0158] e) Liquid maltitol, typically in an amount 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 even more preferably about 50% w / v;

[0159] f) Glycerin, typically in an amount 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 even more preferably about 10% w / v;

[0160] g) Water;

[0161] h) pH adjuster, preferably selected from citrate buffer, acetate buffer, citrate-phosphate buffer, Tris buffer and phosphate buffer, more preferably citrate buffer;

[0162] 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;

[0163] j) A sweetener, preferably selected from acesulfame potassium, alitane, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, kiwifruit protein, and mixtures thereof, more preferably a mixture of sodium saccharin and kiwifruit protein;

[0164] k) Flavor enhancer, selected from sodium chloride, sodium acetate or sodium gluconate, preferably sodium chloride, in an amount typically from 0.1% w / v to 5% w / v, and

[0165] l) Optionally, the flavoring agent is preferably used in an amount of 0.001% w / v to 0.1% w / v.

[0166] The specific composition in this embodiment consists essentially of the ingredients listed above.

[0167] In one embodiment, the present invention relates to a liquid pharmaceutical composition for oral administration in the form of a suspension, comprising:

[0168] 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%, 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;

[0169] 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, even more preferably 0.08% w / v to 0.2% w / v, and even more preferably, in an amount of about 0.1% w / v, expressed as equivalent to phenylephrine hydrochloride;

[0170] c) Hydroxypropyl methylcellulose, 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, even more preferably 0.4% w / v to 0.6% w / v, and even more preferably about 0.5% w / v;

[0171] 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, even more preferably 0.3% w / v to 0.6% w / v, and even more preferably about 0.4% w / v;

[0172] e) Liquid maltitol, typically in an amount 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 even more preferably about 50% w / v;

[0173] f) Glycerin, typically in an amount 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 even more preferably about 10% w / v;

[0174] g) Water;

[0175] h) pH adjuster, preferably selected from citrate buffer, acetate buffer, citrate-phosphate buffer, Tris buffer and phosphate buffer, more preferably citrate buffer;

[0176] 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;

[0177] j) A sweetener, preferably selected from acesulfame potassium, alitane, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, kiwifruit protein, and mixtures thereof, more preferably a mixture of sodium saccharin and kiwifruit protein;

[0178] k) Flavor enhancer, selected from sodium chloride, sodium acetate or sodium gluconate, preferably sodium chloride, in an amount typically from 0.1% w / v to 5% w / v, and

[0179] l) Flavoring agent, preferably in an amount of 0.001% w / v to 0.1% w / v.

[0180] The specific composition in this embodiment consists essentially of the ingredients listed above.

[0181] The preferred characteristics of the different components of these compositions are disclosed in the relevant paragraphs above in this specification (ibuprofen, phenylephrine, thickeners / suspending agents, polyols and other optional ingredients).

[0182] In another embodiment, in any of the above embodiments, the concentration of ibuprofen 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%, even more preferably greater than 3% to 6%, and still more preferably greater than 3% to 5%, expressed as a w / v percentage. More specifically, the concentration of ibuprofen in the composition of the present invention is 3.3% to 10%, preferably 3.3% to 8%, more preferably 3.3% to 7%, even more preferably 3.3% to 6%, and still more preferably 3.3% to 5%, expressed as a w / v percentage.

[0183] In a preferred composition, the weight ratio of ibuprofen to phenylephrine is about 40:1 (based on the weight of equivalent phenylephrine hydrochloride, regardless of the form of phenylephrine used), for example, a composition comprising about 4% w / v ibuprofen and about 0.1% w / v phenylephrine or a pharmaceutically acceptable salt thereof (expressed as equivalent concentration of phenylephrine hydrochloride), or a composition comprising about 2% w / w ibuprofen and about 0.05% w / w phenylephrine or a pharmaceutically acceptable salt thereof (expressed as equivalent concentration of phenylephrine hydrochloride). Using these compositions, doses may be administered, for example, as follows: 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, wherein the amount of phenylephrine is expressed as the equivalent weight of phenylephrine hydrochloride.

[0184] In another preferred composition, the weight ratio of ibuprofen to phenylephrine is about 20:1 (also calculated by the weight of equivalent phenylephrine hydrochloride), for example, a composition comprising about 4% w / v ibuprofen and about 0.2% w / v phenylephrine or a pharmaceutically acceptable salt thereof (expressed as an equivalent concentration of phenylephrine hydrochloride). Using these compositions, doses can be administered, for example, as follows: 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.

[0185] Preparation method

[0186] Another aspect of the present invention is a method for preparing the composition.

[0187] A suitable method for preparing the composition of the present invention includes the following steps:

[0188] (i) A portion of liquid maltitol, hydroxypropyl methylcellulose and xanthan gum are mixed with a portion of the total water volume to obtain a homogeneous mixture;

[0189] (ii) The remaining portion of ibuprofen, phenylephrine or its pharmaceutically acceptable salt, glycerol and liquid maltitol are separately mixed with another portion of the total water volume to obtain a homogeneous mixture;

[0190] (iii) Add the mixture from step (ii) to the mixture from step (i);

[0191] (iv) Add the remaining water.

[0192] All components 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 with a heating jacket.

[0193] 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 water volume.

[0194] When the composition contains preservatives, pH adjusters, and / or flavor enhancers, these are preferably added in this step, preferably pre-dissolved in water, followed by the addition of hydroxypropyl methylcellulose, xanthan gum, and liquid maltitol. When the composition contains sweeteners, they may also be added in this step in the same manner.

[0195] Typically, the mixture obtained in step (i) has a gel-like appearance. Typically, after adding hydroxypropyl methylcellulose 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.

[0196] In step (ii), the amount of water used to prepare the second mixture is not critical and can be, for example, about 5% to about 25% of the total water volume.

[0197] The mixture obtained in step (ii) is a suspension.

[0198] When the composition contains a flavoring agent, it may be added, for example, after step (iii) and before step (iv), so that the flavoring agent and optionally a sweetener (if present) may be dissolved in a portion of water (e.g., about 0.5% to 5% of the total water content of the composition) and added to the mixture obtained in step (iii).

[0199] The composition can be filled into a suitable bottle, typically a polyethylene terephthalate (PET) amber bottle, fitted with a suitable cap, preferably a child-proof cap, usually a high-density polyethylene (HDPE) cap.

[0200] The package may also contain a measuring device for dispensing the desired dose of the composition, such as a graduated cup or an oral syringe.

[0201] Alternatively, the composition can be filled into single-dose sachets, adding an appropriate volume to deliver the desired dose, 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 the concentration of the composition. Suitable sachets for liquid compositions can be made of, for example, laminated materials, such as polyester / aluminum / polyester / polyethylene (PET / Alu / PET / PE).

[0202] Use of the composition

[0203] The composition according to the invention has optimal sensory properties, thus completely masking the bitterness of ibuprofen and norepinephrine, as well as the burning sensation usually associated with ibuprofen.

[0204] Furthermore, as disclosed in Example 2, although it is known that phenylephrine is highly susceptible to degradation, stability tests conducted have determined that the composition according to the invention is very stable. Therefore, under all storage conditions—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 content of both active substances, ibuprofen and phenylephrine, remained between 95% and 105%, and degradation products from the active substances were less than 0.1%.

[0205] Furthermore, the composition remained physically stable under these storage conditions, and no aggregation or precipitation was detected. This is important for ensuring the correct dosage of the active ingredient is administered throughout the entire shelf life of the pharmaceutical product.

[0206] In addition, in pharmacokinetic comparison tests, healthy subjects were administered the composition of the present invention at a dose of 400 mg ibuprofen and 10 mg phenylephrine hydrochloride, or the reference drug (2 tablets). Day & Night Cold & Flu 200mg / 5mg tablets (Reckitt Benckiser Healthcare, UK) also contain the same dose of the active ingredient, both administered as a single dose, and it was found that the bioavailability of ibuprofen was higher in those taking the composition of the invention than in those taking the reference drug, with approximately 10% higher ibuprofen absorption in the former group. This was considered unexpected because the composition of the invention contains maltitol, an active excipient known to enhance gastric motility and reduce the duration of drug presence in the intestinal lumen, and therefore lower rather than higher bioavailability was expected.

[0207] Furthermore, such comparative tests also showed that both ibuprofen and phenylephrine reached their observed maximum concentrations in plasma (T0). 最大 The effect was faster in those subjects taking the composition according to the invention than in those subjects taking the reference drug. Therefore, ibuprofen's T... 最大 About 1 hour less (i.e., T) 最大 The value was 1.0 hour, compared to 2.0 hours for ibuprofen (the reference compound), and the T value for norepinephrine was also lower. 最大 Approximately 0.34 hours less (i.e., T) 最大 The value is 0.33 hours, compared to 0.67 hours for phenylephrine in the reference compound. This unexpectedly faster absorption will also provide a faster therapeutic effect, thus making the compositions of the present invention fast-acting drugs, providing a favorable environment for early and potent therapeutic effects.

[0208] Another advantage of the compositions of the present invention compared to commercial solid oral formulations is dosage 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, about 1 mg to about 10 or 15 mg of phenylephrine (expressed as phenylephrine hydrochloride equivalent), and other options.

[0209] This dosage flexibility allows for customized dosages based on symptom severity and patient age, particularly for pediatric patients. In this way, for example, children aged 7 to 9 years can take 200 mg ibuprofen and 5 mg phenylephrine, children aged 10 to 12 years can take 300 mg ibuprofen and 7.5 mg phenylephrine, and adults and the elderly can take 400 mg ibuprofen and 10 mg phenylephrine, where the amount of phenylephrine is expressed as the equivalent weight of phenylephrine hydrochloride.

[0210] Therefore, another aspect of the invention is a composition as defined above, used in medicine, particularly for treating symptoms of influenza and the common cold, such as fever, pain, sore throat, nasal congestion, and sinus congestion. The compositions of the invention are suitable for such use in adults, including older adults, and in children, particularly children over 7 years of age. In one embodiment, this use is for adults and children over 7 years of age.

[0211] Another aspect of the invention is a method for treating symptoms of influenza and the common cold, such as fever, pain, sore throat, nasal congestion, and sinus congestion, comprising the step of administering a therapeutically effective dose of the composition according to the invention to a patient in need. The patient may be an adult, including elderly patients, or a child, particularly children over 7 years of age. In one embodiment, the method is used to treat adults and children over 7 years of age.

[0212] Another aspect of the invention is the use of the compositions of the invention as defined above in the preparation of a medicament for treating symptoms of influenza and the common cold, such as fever, pain, sore throat, nasal congestion, and sinus congestion. This treatment can be administered to any patient in need, including both adults (including older adults) and children (particularly children over 7 years of age). In one embodiment, the treatment is used for both adults and children over 7 years of age.

[0213] Example

[0214] Example 1: A suspension formulation containing ibuprofen and phenylephrine HCl

[0215] The compositions according to the present invention are prepared using the ingredients listed in the following table:

[0216]

[0217] The hydroxypropyl methylcellulose used is hydroxypropyl methylcellulose 15cP (alternative 2910). The particle size of ibuprofen is 40 μm.

[0218] To prepare the composition, a stainless steel reactor equipped with a stirring system and a heating mantle was filled with purified water, approximately 30% of the final batch volume. Sodium benzoate, anhydrous citric acid, sodium citrate, sodium saccharin, and sodium chloride were gradually added to the reactor under continuous stirring until completely dissolved. Subsequently, hydroxypropyl methylcellulose was added under stirring until completely dispersed, followed by the addition of xanthan gum. The mixture was then maintained under stirring for approximately 3 hours until gelled, followed by the addition of approximately half of the liquid maltitol.

[0219] Approximately 10% of the total water volume was added to a second stainless steel reactor equipped with a stirrer and heating jacket. Then, under stirring, glycerol, the remaining liquid maltitol, phenylephrine HCl, and ibuprofen were gradually added until a homogeneous suspension was obtained. This suspension was then mixed with the contents of the first reactor under stirring until a homogeneous suspension was obtained.

[0220] Fill the second stainless steel reactor with about 2% of the total water volume, and add orange flavoring and kiwi sweet protein while stirring until completely dissolved. Add this solution to the suspension previously prepared in the main reactor.

[0221] The final product is a white or nearly white viscous suspension with a characteristic orange odor. The pH is approximately 3.8.

[0222] Fill the product into 100 and 150 ml PET amber bottles equipped with graduated cups and oral syringes.

[0223] Example 2: Stability Data

[0224] According to the ICH guidelines applicable to four 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), long-term and accelerated stability studies were conducted on the product of Example 1, with three batches of product in their final containers (i.e., 100 and 150 ml) and only one batch in both container sizes under additional refrigeration conditions (2 to 8°C).

[0225] The stability of the product was evaluated over a period of up to 36 months based on the following parameters: appearance, pH, viscosity, ibuprofen dissolution, particle size in terms of sedimentation and particle size of suspended particles (without agglomerates), ibuprofen determination (HPLC), norepinephrine HCl determination (HPLC), ibuprofen related substances (HPLC), and norepinephrine HCl related substances (HPLC).

[0226] The results obtained show the optimal values ​​for all evaluated parameters, which determined the stability of the product under all batches and conditions, and therefore led to the conclusion that the product does not require any special storage conditions.

[0227] Analysis of impurities associated with norepinephrine revealed that all impurity levels were very low across all batches and under all conditions, with no reportable impurity levels (<0.5%) in any case.

[0228] Furthermore, analysis of impurities associated with ibuprofen showed that all impurity levels were very low across all batches and under all conditions, with no reportable amounts (<0.1%).

[0229] In addition, a photostability study (ICH Q1B) was conducted on one batch of the product. The study was conducted under the following conditions: 1.2 million lux and 200 watts / m². 2The product was irradiated with integrated UV energy. The following parameters were evaluated: description, pH, viscosity, ibuprofen dissolution, ibuprofen assay (HPLC), norepinephrine HCl assay (HPLC), sodium benzoate assay (HPLC), ibuprofen-related substances (HPLC), and norepinephrine HCl-related substances (HPLC). The product was found to be stable under the evaluation conditions; therefore, no special conditions are required.

[0230] Finally, a stability study was conducted on three production batches, analyzing the following parameters: appearance, pH, viscosity, ibuprofen dissolution, ibuprofen assay (HPLC), norepinephrine HCl assay (HPLC), sodium benzoate assay (HPLC), ibuprofen related substances (HPLC), norepinephrine HCl related substances (HPLC), microbiological quality, and antimicrobial preservation efficacy. The following conclusions were drawn: During use, the product maintained its physical properties and / or quantification / degradation in four climate zones for at least six months.

[0231] Example 3: Comparative Pharmacokinetic Study

[0232] 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.

[0233] The test product was the composition of Example 1, which was administered in a single dose (i.e., 10 ml of composition) containing 400 mg ibuprofen and 10 mg phenylephrine HCl.

[0234] The recommended dosage is two tablets. Day & Night Cold & Flu 200mg / 5mg tablets (UK, Reckitt Benckiser Healthcare) are also administered as a single dose, equivalent to 400mg ibuprofen and 10mg phenylephrine HCl.

[0235] Ci was determined for the enantiomers of ibuprofen in the composition of Example 1 and the reference drug. 最大 The average values ​​of AUC are shown in the table below:

[0236]

[0237] Ibuprofen T 最大 The average time was 1.0 hour for the composition of Example 1 and 2.0 hours for the reference drug.

[0238] T of norepinephrine 最大 The average time was 0.33 hours for the composition of Example 1 and 0.67 hours for the reference drug.

Claims

1. A liquid pharmaceutical composition in suspension form for oral administration, said composition comprising: a) Ibuprofen, in doses ranging from 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 equivalents of phenylephrine hydrochloride; c) Hydroxypropyl methylcellulose, 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) Glycerin; and g) Water.

2. The composition according to claim 1, characterized in that the phenylephrine is in the form of a salt selected from the following: 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 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 equivalents of phenylephrine hydrochloride.

6. The composition according to any one of claims 1 to 5, characterized in that the amount of hydroxypropyl methylcellulose is 0.2% w / v to 2% w / v, preferably 0.3% w / v to 1% w / v, more preferably 0.4% w / v to 0.6% w / v, and even more preferably about 0.5% w / v.

7. The composition according to any one of claims 1 to 6, characterized in that the amount of xanthan gum is 0.1% w / v to 2% w / v, preferably 0.2% w / v to 1% w / v, more preferably 0.3% w / v to 0.6% w / v, and even more preferably about 0.4% w / v.

8. The composition according to any one of claims 1 to 7, characterized in that the amount of liquid maltitol is 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 even more preferably about 50% w / v.

9. The composition according to any one of claims 1 to 8, characterized in that the amount of glycerol is 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 even more preferably about 10% w / v.

10. The composition according to any one of claims 1 to 9, characterized in that the composition comprises a pH adjuster to adjust the pH of the composition to a value of 2 to 6.

11. The composition according to any one of claims 1 to 10, characterized in that the composition comprises a preservative.

12. The composition according to any one of claims 1 to 11, characterized in that the composition comprises a sweetener selected from: acesulfame potassium, alitane, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sucralose, kiwifruit protein, and mixtures thereof, preferably, the sweetener being a mixture of sodium saccharin and kiwifruit protein.

13. The composition according to any one of claims 1 to 12, characterized in that the composition comprises sodium chloride, preferably in an amount of 0.1% w / v to about 5% w / v.

14. A method for preparing the composition according to claims 1 to 13, characterized in that the method comprises the following steps: (i) A portion of liquid maltitol, hydroxypropyl methylcellulose and xanthan gum are mixed with a portion of the total water volume to obtain a homogeneous mixture; (ii) The remaining portion of ibuprofen, phenylephrine or its pharmaceutically acceptable salt, glycerol and liquid maltitol are separately mixed with another portion of the total water volume to obtain a homogeneous mixture; (iii) Add the mixture from step (ii) to the mixture from step (i); (iv) Add the remaining water.

15. The composition according to claims 1 to 13, for medical use, preferably for treating symptoms of influenza and the common cold, such as fever, pain, sore throat, nasal congestion, and sinus congestion.