MXPA99005310A - Therapeutic agents - Google Patents

Abstract

An ibuprofen composition yielding an aqueous preparation having a pH of less than 7 on the addition of water to said composition which comprises one or more medicaments including an ibuprofen medicament which forms an ibuprofen active ingredient having a melting point less than 100°C, when combined with water to give an aqueous preparation having a pH of less than 7 and a phospholipid material intimately mixed with the ibuprofen medicament. The phospholipid material is capable of forming an aqueous preparation comprising an emulsion or dispersion comprising an aqueous phase substantially free of said ibuprofen active ingredient and a discrete phase consisting essentially of said phospholipid material and insoluble pharmacologically active ingredient including said ibuprofen active ingredient on the addition of water to said composition. The invention also provides aqueous drink preparations (especially heated emulsions) produced thereform and a process to prepare said aqueous drink preparations.

Description

AQUEOUS DRINKING COMPOSITION COMPRISING IBUPRQFEN Description of the invention: This invention relates to compositions useful for producing an aqueous drinking preparation containing ibuprofen, the aqueous drinking preparations produced therefrom, and a process for preparing aqueous drinking preparations. . Ibuprofen, that is, 2- (4-isobutylphenyl) propionic acid is a medically well known drug with analgesic, anti-inflammatory and antipyretic properties. This, usually sold in the form of racemic ibuprofen (equal amounts of the S (+) -ibuprofen and R (-) -ibuprofen enantiomers) can also be found in the purified form of any enantiomer, especially S (+) - ibuprofen , which is recognized as the active form of racemic ibuprofen. Ibuprofen is also available in salt form, for example, the sodium or lysine salt of ibuprofen. Ibuprofen is available under prescription (for example, Brufen (RTM)), mainly for the treatment of pain and anti-inflammatory conditions, including rheumatoid arthritis, alkylosing spondylitis, osteoarthritis, postoperative pain, postpartum pain and soft tissue damage, generally in doses of up to 3200 mg per day. Ibuprofen is also available as an over-the-counter drug (for example, Nurofen (RTM)), REF. 30488 mainly for the treatment of symptoms of pain and fever, including headache, migraine, rheumatic pain, muscle pain, back pain, neuralgia, dysmenorrhea, dental pain and colds and catarrh, generally in doses of up to 1200 mg per day. The compositions containing ibuprofen are usually provided in unit doses to give 200 mg, 400 mg, 600 mg or 800 mg of ibuprofen. If it is desired to formulate a composition containing ibuprofen, which, with the addition of cold or hot water (preferably hot water) forms a liquid product acceptable for ingestion by the patient. Such products have particular utility in the treatment of pain and the treatment of coughs and colds, but may be desirable in any therapeutic area where it is convenient to administer ibuprofen as a beverage. The problem is to provide a low-cost, easily formulated ibuprofen composition that forms a satisfactory drinking product only by the addition of hot or cold water, ie, without requiring the patient to perform extra steps before or after the treatment. addition of water to the ibuprofen composition. Previously it has not been easy to provide compositions containing ibuprofen, which, with the addition of hot water, produce satisfactory aqueous drinking preparations easily to be administered substantially immediately to the patient. One of the problems associated with ibuprofen is that when it dissolves, ibuprofen has an unpleasant taste and a subsequent undesirable burning sensation in the mouth and throat. Although ibuprofen dissolves more readily in water at a pH higher than 7, an aqueous drinking preparation containing ibuprofen with a pH greater than 7 does not provide an acceptable taste product, unless additional excipients are added to mask the taste. To avoid the cost of, and the formulation problems associated with the incorporation of ingredients to mask the taste in the composition to allow an acceptable tasting beverage product, it is desired, therefore, to keep the ibuprofen undissolved. Consequently, the composition of ibuprofen should be formulated to ensure that with the addition of water to it, the ibuprofen remains as a discrete phase separated from the aqueous phase in the preparation of aqueous drinking. In addition, it is desired to be able to formulate a product containing ibuprofen, which is adapted, after the addition of water at any temperature, to form a satisfactory aqueous drinking preparation, which is ready to be administered substantially immediately to the patient. This includes the addition of cold water and water at an elevated temperature, including its boiling temperature. The formulation of a product containing ibuprofen, which is adapted to form an aqueous drinking preparation in combination with cold water, is advantageous, since cold water is readily available from the tap. On the other hand, the formulation of a product containing ibuprofen, which is adapted to form an aqueous drinking preparation in combination with hot water, is advantageous for the treatment of conditions such as cough and colds, where it is desirable to administer ibuprofen. in the form of a hot drink. It has been a particular problem to formulate a product containing ibuprofen capable of producing an aqueous drinking preparation in combination with water at a temperature above the melting point of ibuprofen. The particular problem "that arises with racemic ibuprofen is that it has a melting point in the range of 75-77 ° C. The melting point of S (+) - ibuprofen is even lower, about 55 ° C. Consequently, when combined with cold water, ibuprofen is in solid form, whereas when combined with hot water, for example, above the melting point of the drug (ie, 77 ° C for racemic ibuprofen), Ibuprofen is in liquid form. Thus, means must be provided to ensure that not only the ibuprofen forms a discrete solid phase with the water at a temperature lower than its melting point, but that it is able to form and maintain a satisfactory emulsion with the addition of hot water ( >77 ° C), while ibuprofen is undergoing the fusion process. Furthermore, if hot water is used, it is necessary to maintain the ibuprofen as a discrete, homogeneous, uniformly distributed phase throughout the beverage during the period in which the beverage can be administered to the patient, for example up to 30 minutes. During this period, it is likely that the ibuprofen will cool and solidify. It is also required to keep ibuprofen as a discrete phase. In this way, an ibuprofen composition is required, which, simply by adding water (preferably hot water), is capable of forming a satisfactory aqueous drinking preparation containing ibuprofen, and in which, the ibuprofen can be maintained as a discrete phase when it is in the solid state or in the liquid state. In addition, it is also desirable to provide an ibuprofen composition which forms an aqueous taste preparation of pleasant taste substantially immediately upon addition of water, thereby avoiding any waiting time and minimizing the need for extra steps, such as the agitation. Compositions of ibuprofen adapted to form drinking products with the addition of hot water have already been proposed above. For example, WO 93/20850 describes compositions to which hot water may be added. However, this description requires significant formulation steps to prepare a soluble ibuprofen-beta-cyclodextrin complex, which dissolves with the addition of water. The formation of a dispersion of ibuprofen with cold water has already been proposed previously (see European Patent Applications Nos. 284167 and 390369). However, the compositions described therein are not adapted to provide satisfactory aqueous preparations with the addition of hot water due to the formation of an oily film of molten ibuprofen on the surface of the water. Other proposals have also been made to maintain ibuprofen as a discrete phase in an aqueous preparation. For example, microcapsules, in which NSAIDs are encapsulated within a polymeric wall, described in WO 95/05166. Although those can be formulated as liquid aqueous suspensions, they do not indicate that it would be appropriate to add hot water to these microcapsules. Also such microcapsules require complex preparation steps which seek to avoid the composition of the present invention. Other means for maintaining ibuprofen as a discrete phase are described in European Patent Application 274870 which discloses NSAID drugs such as ibuprofen which can be formulated with surfactants such as polyethoxylated nonionic fatty acid esters or sorbitan to give compositions forming micelles The surfactant is required in a considerable excess (ie greater than five times the amount of active ingredient). This is not satisfactory for the drug of relatively high doses such as ibuprofen (eg dose of 100-400mg) due to the large amount of surfactant required. The formation of liposomes has been proposed using phospholipid materials in which a drug is encapsulated in a liposome (a membrane of two lipid layers) in an aqueous formulation. See, for example, European Patent Application 622072 which describes the formation of liposomes based on yolk lecithin and soybean lecithin as the lipids, which dispersion contains at least one hydroxy acid and at least one amino acid to stabilize the liposomal dispersion. However, the encapsulation of a drug in the two-layer membrane also requires complex preparation steps which seek to avoid the compositions of the present invention. It has also been proposed to form emulsions containing phospholipids in which the active ingredient is mixed with a lipid material in the oil phase. For example, European Patent Application No. 700678 discloses a stable lipid emulsion comprising (a) an oily component such as vegetable oils and / or synthetic or semi-synthetic glycerides, (b) an emulsifying agent containing yolk lecithin and / or soy lecithin, (c) water, (d) drug, (e) citric acid and (f) selected amino acids. The patent US 5110606 also describes an emulsion comprising as the internal phase a drug contained in particular polar liquid carriers, the internal phase is dispersed in a lower alkyl ester of an external phase of Cu-Ci? Fatty acid. using lecithin as an emulsifying agent, where the ratio of the components is 1-20% polar fluid, 33-70% fatty ester and 20-60% lecithin. These methods describe relatively complex steps and / or a significant number of formulation excipients to formulate those aqueous preparations. It is not disclosed how to formulate a simple ibuprofen composition that can be used to provide a stable aqueous preparation with the addition of hot water and to maintain the ibuprofen at a discrete stage taking into account its melting point characteristics. The formation of an emulsion with molten ibuprofen and a surfactant has been proposed. However, Japanese Patent Application 52111533 discloses that it is first necessary to add the ibuprofen to a surfactant solution derived from polyoxyethylene in hot water followed by heating the mixture to melt the ibuprofen and then cooling to produce the precipitation of the ibuprofen. The ibuprofen is then collected and dried and then taken for further formulation. This description does not suggest that an aqueous formulation of satisfactory unit doses could be produced to be administered substantially immediately to a patient by simply adding hot water to a composition comprising the active ingredient. It has also been proposed in WO 9420072 that low melting point drugs such as ibuprofen can be melted with a lipid material such as lecithin and add hot water, but this also involves a complex process in which the solid lipid is melted; stabilizers are added to both the lipid and the dispersion media or to the dispersion medium only; the drug is then incorporated into the lipid particles (optionally by melting) and the dispersion medium is heated to the melting temperature; finally the molten lipid compound containing the drug is emulsified in the dispersion medium, preferably by high speed homogenization. This description also does not suggest providing an emulsion-forming composition which produces an aqueous drinking formulation, substantially immediately after the addition of hot water.

These descriptions suggest that when the fusion characteristics of ibuprofen are taken into account, complex formulation steps are necessary to form an emulsion of this drug. They do not provide suggestions as to how to provide a relatively simple low-cost composition to which hot water can be added to provide an acceptable taste product without the characteristic oily film of ibupro'fen occurring on the surface of the water. Now an ibuprofen composition capable of forming a discrete phase containing only ibuprofen and a certain phospholipid material has been found, which can be easily formulated giving an acceptable taste, a stable aqueous preparation substantially immediately after the addition of hot water or cold to the composition of ibuprofen. The composition comprises an intimate combination of a medicament of ibuprofen and a phospholipid material and is adapted to form an acid preparation when combined with water at a temperature in the range of 0-100 ° C. In this specification, certain expressions have the meanings set forth below. 'Drug' means any pharmacologically active substance that provides a therapeutic effect.The drugs can be formed in different ionic species when they are in an aqueous medium at acidic pH, thus, we refer to them as * pharmacologically active ingredients "being the form of the medicament when dissolved, dispersed or emulsified in water at a pH of less than 7. 'Ibuprofen composition', means a pharmaceutical composition containing the medicament ibuprofen, which, when combined with water at a temperature in the range of 0- 100 ° C produces an aqueous preparation having a pH of less than 7. 'Active ingredient of ibuprofen', means the form of ibuprofen having a melting point lower than 100 ° C, which is present in the discrete phase of a aqueous acid preparation after the ibuprofen composition has been combined with water at a temperature in the range of 0-100 ° C. 'Ibuprofen medicament', means the form of ibuprofen, which is present in the composition of ibuprofen, and which forms the active ingredient of ibuprofen when an aqueous preparation having a pH of less than 7 is formed, combining the composition of ibuprofen with water at a temperature in the range of 0-100 ° C. The ibuprofen medication may, therefore, be ibuprofen itself or a derivative of ibuprofen, which forms the active ingredient of ibuprofen when combined with water at a temperature of the range of 0-100 ° C to give an aqueous preparation having a pH of less than 7. Such derivatives include, but are not limited to, salts, optical isomers and hydrates.Saline additives form ibuprofen as the active ingredient of ibuprofen in si tu, with the addition of water at a pH less than 7. Suitable salts of ibuprofen include alkali metal salts such as sodium and potassium salts, amino acid salts such as lysine or arginine salts nina, or amine salts, such as the meglumine salt. The ibuprofen can be in racemic form or in the form of S (+) - and R (-) enantiomers or mixtures of these enantiomers. The preferred enantiomer is S (+) - ibuprofen, which is recognized to be the therapeutically effective enantiomer. The present invention also applies to the anhydrous and hydrated forms of the medicament ibuprofen, for example, the monohydrate and dihydrate of a salt (for example, the sodium salt) of ibuprofen. Preferably, the medicament ibuprofen 'comprises racemic ibuprofen or substantially pure S (+) - ibuprofen, more preferably racemic ibuprofen. "Aqueous preparation" means the preparation that is intended to be ingested by the patient, produced when the ibuprofen composition is combined with water at a temperature in the range of 0-100 ° C. The aqueous preparation comprises an aqueous phase substantially free of an ingredient. active of ibuprofen and a discrete phase which incorporates substantially all of the active ingredient of ibuprofen.The aqueous phase may contain soluble pharmacologically active ingredients dissolved therein.The aqueous preparation may be in the form of a dispersion of the active ingredient of ibuprofen. dispersion", means that the active ingredient of ibuprofen is suspended in solid form when the dispersed phase is evenly distributed throughout the aqueous phase. When another, higher melting, insoluble, pharmacologically active ingredient is used, when hot water is added a dispersion may be formed, wherein the active ingredient of the liquefied ibuprofen is mixed with the solid pharmacologically active ingredient. The dispersed phase consists essentially of the insoluble pharmacologically active ingredient, including the active ingredient of ibuprofen and the phospholipid material. The aqueous preparation may also be in the form of an emulsion of the active ingredient of ibuprofen. By the term 'emulsion' is meant an oil-in-water emulsion, in which the active ingredient of ibuprofen, optionally with another liquid pharmacologically active ingredient, is suspended in liquid form as the oil phase uniformly distributed through the aqueous phase. The oil phase consists essentially of insoluble pharmacologically active ingredient, including the active ingredient of ibuprofen and the phospholipid material 'Discrete', means that the phase containing the insoluble pharmacologically active ingredient which includes the active ingredient of ibuprofen, is separated and distinguished from the aqueous phase. The active ingredient of ibuprofen does not dissolve in the aqueous phase. However, it is uniformly dispersed throughout the aqueous phase. This is maintained as a separate and distinct phase from the aqueous phase by the phospholipid material. As defined herein, the discrete phase consists essentially of insoluble pharmacologically active ingredient, including the active ingredient of ibuprofen and its phospholipid material. 'Insoluole', means insoluble in water at a pH of less than 7. The present invention provides an ibuprofen composition comprising one or more medicaments, including an ibuprofen medicament, which forms an active ingredient of ibuprofen having a point of melting less than 100 ° C when combined with water to give an aqueous preparation having a pH of less than 7, characterized in that the composition produces an aqueous preparation having a pH of less than 7, with the addition of water to the composition , and comprising a phospholipid material intimately mixed with the ibuprofen medicament, the phospholipid material is capable of forming an aqueous preparation (eg, comprising an emulsion or dispersion) comprising an aqueous phase substantially free of the active ingredient of ibuprofen and a phase Discrete consisting essentially of the phospholipid material and insoluble pharmacologically active ingredient that includes the ingredient active of ibuprofen with the addition of water to the composition. In a further aspect, the present invention provides a unit dose aqueous preparation comprising an aqueous phase and a discrete phase comprising (a) an active ingredient of ibuprofen, which has a melting point of less than 100 ° C and (b) ) a phospholipid material capable of forming the active ingredient of ibuprofen in a discrete phase or in combination with water, characterized in that the aqueous preparation has a pH of less than 7, and because the aqueous phase is essentially free of the active ingredient of ibuprofen and because the discrete phase consists essentially of the phospholipid material and the insoluble pharmacologically active ingredient which includes the active ingredient of ibuprofen. The particular advantages achieved by the present invention are the provision of a composition that can be easily formulated by the manufacturer, and an acceptable taste drinking product that can be prepared very easily by the patient together with the use of minimal amounts of excipients homogenizers. It is especially advantageous that a hot beverage can be prepared by simply adding hot water to the ibuprofen composition. The present invention, also provides a liquid formulation whose absorption of ibuprofen in the body is optimized, ie, that the ibuprofen phase is evenly distributed throughout the aqueous preparation. Racemic ibuprofen and S (+) - ibuprofen are the preferred active ibuprofen ingredients. When the active ingredient of ibuprofen is racemic ibuprofen, the added water should preferably be at a temperature in the range of 80-100 ° C, preferably 90-100 ° C. When the active ingredient of ibuprofen is S (+) - ibuprofen, the added water should preferably be at a temperature in the range of 60-100 ° C, preferably 80-100 ° C. Preferably, when the aqueous phase is at a temperature above the melting point of the active ingredient of ibuprofen, the discrete oil phase consists essentially of the phospholipid material and the active ingredient of liquid ibuprofen. More preferably, the discrete oil phase consists essentially of the phospholipid material and ibuprofen, either as racemic ibuprofen or S (+) - ibuprofen.

The aqueous preparation formed with the addition of water to the ibuprofen composition comprises an aqueous phase and also a discrete phase incorporating the active ingredient ibuprofen. The aqueous phase comprises a sufficient amount of water to form a beverage. The amount of water to be added to the ibuprofen composition is, therefore, such that it provides an acceptable aqueous drinking preparation. The lower amount of the amount of water, is usually determined by the dose of ibuprofen, for example, a low dose, such as 100 mg requires less water to form a uniform dispersion or emulsion than a 400 mg dose of ibuprofen. The upper end of the interval is determined by the amount of water a person prepares to drink a single unit dose. Generally, it is anticipated that the amount of water will be in the range of 10 ml-500 ml, more preferably 50-300 ml, more preferably 100-250 ml. The phospholipid material provides the interface between the water and the active ingredient of ibuprofen, so that the discrete phase is stable and retains its homogeneous microfine structure in the aqueous phase. The phospholipid material and the optional surfactants provide the interface between the discrete phase and the external aqueous phase. The phospholipid material suspends the active ingredient of ibuprofen as a discrete phase in the aqueous phase.

Other suspended or dispersed components may also be present in the aqueous preparation in addition to the discrete phase consisting essentially of the insoluble pharmacologically active ingredient. Preferably, the ibuprofen composition contains only water-soluble excipients other than the medicament or medicaments, so that all excipients dissolve in the water when combined with the ibuprofen composition. However, it may contain insoluble materials such as certain cellulose materials, which are dispersed in the aqueous phase and are not part of the discrete phase, consisting essentially of phospholipid material and insoluble pharmacologically active ingredient, including the active ingredient of ibuprofen. Such other ingredients can help to stabilize the emulsion and / or modify the viscosity of the emulsion. Preferably, the medically available ibuprofen is the only substantially insoluble drug employed, and more preferably is the only substantially insoluble component in the ibuprofen composition. The amount of the ibuprofen medication in the ibuprofen composition will depend on the treatment regimen required. The administration of the aqueous preparation obtained from the ibuprofen composition can be only once a day, or it can be several times a day, for example 2-4 times a day, depending on the treatment required. Each unit dose of the ibuprofen composition suitably contains the ibuprofen medicament in an amount to give an equivalent dose of 50-800 mg of ibuprofen, preferably 100-400 mg and more preferably 100-200 mg of ibuprofen per unit dose. When S (+) - ibuprofen is used alone, those amounts can be reduced, for example, suitably 25-800 mg, preferably 50-300 mg, and more preferably 100-200 mg S (+) - ibuprofen If required, two or more unit doses (eg, tablets, granule sachets, tablespoons) of ibuprofen composition can be taken and water added to them. Thus, the ibuprofen composition may contain the ibuprofen medicament in smaller amounts than the amounts given above, so that more than one unit dose of the ibuprofen compositions may be used. If desired, an additional medication may be used. The pharmacologically active ingredient, produced from the additional medicament with the addition of water to provide an aqueous acidic preparation, could be dissolved or dispersed in either the discrete phase or the aqueous phase. The soluble pharmacologically active ingredient or ingredients, will be part of the aqueous phase. The insoluble pharmacologically active ingredient or ingredients will form the discrete phase. Examples of additional medicaments include any ingredient commonly used in a cough or cold remedy, for example, an antihistamine derivative, caffeine or other xanthine, a cough suppressant, a decongestant, a spreader, a muscle relaxant, a vitamin and a coanalgesic, such as codeine, or other NSAIDs or combinations thereof. Suitable antihistamines that are preferably non-sedating include acrivastine, astemizole, azatadine, azelastine bromodiphenylhydramine, brompheniramine, carbinoxamine, cetiricin, chlorpheniramine, cyproheptadine, dexbromfeniramine, dexchlorpheniramine, diphenhydramine, ebastine, cetotifen, yodoxamide, loratidine, levocubastine, mequitacin, oxatomide, fenindamina, feniltoloxamina, pyrilamina, setastina, tazifilina, temelastina, terfenadina, tripelennamina or triprolidina. Suitable cough suppressors include caramifen, codeine (codeine phosphate) or dextromethorphan. Suitable decongestants include pseudoephedrine, phenylpropanolamine and phenylephrine. Suitable specifiers include guaifenesin, potassium citrate, potassium guaiacolsulfonate, potassium sulfate, and terpine hydrate. Suitable vitamins include vitamin C. Preferably, a water-soluble medicament is employed, so that the additional medicament is present in the aqueous phase of the liquid preparation. The amounts of those other pharmacologically active ingredients to be used are those known in the art. For the guidelines of the appropriate dose, reference is made to the MIMS, the Physicians Desk Register and the OTC Manual. The ratio of aqueous phase to discrete phase will depend on the dose of the ibuprofen medication used, but suitably, the ratio of the aqueous phase to the discrete phase will fall within the range of 10000: 1 to 1: 1 parts by weight, more preferably from 5000: 1 to 100: 1 and more preferably from 2000: 1 to 500: 1 parts by weight. The water may be added in a ratio to the ibuprofen composition of 10000: 1 to 1: 1 parts by weight, preferably 5000: 1 to 100: 1 parts by weight, most preferably 2000: 1 to 500: 1 parts by weight Depending on the nature of the ibuprofen medication, the required dose and the form of the ibuprofen composition, the ibuprofen medicament can form 1-99% by weight, desirably 2-80% by weight of the ibuprofen composition. The ibuprofen composition may be in solid form (e.g., tablets, powders, granules, etc.) or in liquid form. When the ibuprofen composition is in the form of a tablet, preferably the ibuprofen medicament is present in a degree of 50-80% by weight, especially 55-70% by weight, of the composition. When the ibuprofen composition is in the form of the powder, for example as a fine powder or as granules, preferably the ibuprofen medicament is present in a degree of 3-20% by weight, especially 4-10% by weight , of the composition. When the ibuprofen composition is in the form of a liquid concentrate, preferably the ibuprofen medicament comprises 1-10% by weight, more preferably 2-5% by weight, of the composition. The selected phospholipid material is capable of forming the active ingredient of ibuprofen in a discrete phase when combined with water to give an aqueous preparation having a pH of less than 7 at any temperature between 0 and 100 ° C. When the water is at a temperature of, or less than, the melting point of the lower melting insoluble drug (usually the active ingredient of ibuprofen), a dispersion will be formed in which the dispersed phase consists essentially of the phospholipid material and the insoluble pharmacologically active ingredient includes the active ingredient of ibuprofen. When the water is at a temperature above the melting point of the highest melting point insoluble drug (usually the active ingredient of ibuprofen), an emulsion will be formed in which the oil phase consists essentially of phospholipid material and insoluble pharmacologically active ingredient, including the active ingredient of ibuprofen. The phospholipid material includes natural phospholipids, as well as synthetic ones. We prefer to use lecithin materials or phosphatide materials. Examples include soy lecithin, egg lecithin, vegetable lecithin, and hydrogenated thereof, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, diacetylphosphate, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylcholine and sphingomyelin. Lecithin is a complex mixture of phosphatides, which consists mainly of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol, combined with various amounts of other substances, such as triglycerides, fatty acids and carbohydrates separated from a crude vegetable source. The composition of lecithin varies according to the source and degree of purification. For example, lecithin contains 69% phosphatidincoline and 24% phosphatidylethanolamine, while soy lecithin contains these ingredients in amounts of 21% and 22% respectively, along with 19% phosphatidylinositol. Lecithins are practically insoluble in water, but when mixed with water, they hydrate to form emulsions. Particular advantages are obtained by using the natural lecithin materials identified above (see also the Excipients Manual, 2a. 1994 edition, Ed A Wade and P J Weller). Preferably, a single phospholipid material is used, more preferably a natural lecithin. In a particularly preferred aspect, we use soy lecithin. A further advantage is found in the fact that only a small portion of the phospholipid material is necessary to obtain the aqueous preparations of the present invention. Preferably, the phospholipid material is used to a degree less than 10% by weight of the active ingredient of ibuprofen according to the present invention. This is advantageous when it is desired to formulate dosage forms with minimal excipients. The amount of phospholipid will depend on the form of the ibuprofen composition and the nature and dosage of the ibuprofen medication. Preferred compositions comprise the phospholipid material in an ibuprofen medicament ratio of 0.001: 1 to 0.5: 1 parts by weight, more preferably 0.01: 1 to 0.3: 1 parts by weight, most preferably 0.02: 1 to 0.2: 1 parts by weight, especially 0.03 to 0.07 parts by weight. Preferred compositions contain a phospholipid material in an amount of less than 10% by weight, for example 0.01-5% by weight, more preferably 0.025-2% by weight of the ibuprofen composition, especially 0.1-1.5% by weight of the composition of ibuprofen.

A frequent advantage is that of using one or more non-phospholipid surfactants in combination with the phospholipid material to achieve the desired emulsifying effect. Advantageously, solid surfactants are used at room temperature. Examples include, but are not limited to, one or more ingredients such as sodium lauryl sulfate, sorbitan esters, polyoxyethylene alkyl ethers, poloxamer, polyoxyethylene derivatives and castor oil, polyoxyethylene sorbitan fatty acid esters. Preferably, sodium lauryl sulfate is used as the surfactant. Conveniently, the surfactant is used in an amount of less than 10%, for example 0.01-5% by weight, more preferably 0.025-2% by weight, especially 0.1-1.5% by weight of the ibuprofen composition. . Preferably, if a surfactant is included in the composition, it will be present in a ratio to the phospholipid material from 10: 1 to 1:10 parts by weight, preferably from 5: 1 to 1: 5 parts by weight. The aqueous preparations formed according to the invention are acidic, ie they have a pH of less than 7. It has been found that by ensuring that the aqueous preparation is at an acid pH and that the active ingredient of ibuprofen is maintained within the Discreet, a pleasant drinking formulation is provided. In some cases, the formed preparation will have a pH of 7 or less, due to the choice of the active ingredients and the optional excipients used. However, when salts of ibuprofen or other selected derivatives are likely to produce a pH greater than 7, for example, sodium or potassium salts, the ibuprofen composition should contain an acid component that provides an aqueous preparation having a pH of 7. or less. Commonly, when water is added to such an ibuprofen composition, the ibuprofen would precipitate and form an unsatisfactory dispersion. However, according to this invention, ibuprofen is converted into the discrete phase by the phospholipid material. Accordingly, in a preferred aspect, the incorporation of suitable amounts of an acidic component ensures that the resulting aqueous preparation has an acidic pH. In this way, a more preferred component of the ibuprofen composition is an acid component. Such a component ensures that the liquid preparation formed with the addition of water has a pH of less than 7, preferably less than 6, more preferably less than 5, and more preferably less than 4.5. Examples of acid components include one or more of the citric acid, tartaric acid or malic acid, or salts thereof, such as sodium citrate. Preferably, the acid component is a buffer system used to maintain the pH below 7 during administration. Examples of suitable buffer systems include citric acid, together with sodium citrate. When the acid component is used, it can suitably form up to 35% of the dosage form, for example, 1-30% by weight, preferably 5-28% by weight, or preferably 10-25 % by weight of the ibuprofen composition. This can be used in a ratio of ibuprofen medication of 1:20 to 20: 1 parts by weight, preferably 1:10 to 10: 1 parts by weight, most preferably from 8: 1 to 1: 1 parts by weight. weight. The ibuprofen composition may be in solid or liquid form, and may contain other pharmaceutically acceptable excipients, as necessary to produce a suitable composition, dispersion and emulsion. It is preferred to use a water soluble carrier material to contain the ibuprofen medicament and phospholipid material to aid in the formation of the aqueous preparation. The carrier material is intimately mixed with the ibuprofen medicament and the phospholipid material in the ibuprofen composition, so that the materials form a homogenous mixture. Examples of water soluble carriers include sugars, including monosaccharides, polysaccharides and sugar alcohols, for example castor sugar, sorbitol, mannitol, xylitol, maltodextrin, lactose, sucrose, fructose, dextrin, glucose and cyclodextrin, as well as polyethylene glycols. The amount of water-soluble carrier, preferably the sugar component used, will depend on the form of the composition and the dose needed. Suitably up to a degree of 1-99% w / w of the ibuprofen composition can be used, preferably 5-80% w / w, more preferably 10-70% w / w and so more preferable 20-65% w / w of the ibuprofen composition. When in the form of a liquid, the medicine ibuprofen can be dissolved or suspended in the solvent to form a syrup or concentrate. Water can be added to the syrup or concentrate to form the liquid drinking preparation. Liquid carriers suitable for combination with the active ingredient include edible alcohols, glycols and oil. In addition, the liquid ibuprofen composition may also comprise viscosity modifiers, gelling agents, flavors, sweeteners and colorants. Preferably, the ibuprofen composition is in solid form, for example as a powder, granules or tablets. Optional formulation aids, such as disintegrants, for example, croscarmellose sodium, starch and starch derivatives (preferable in an amount of up to 10% by weight, for example 1-10% by weight, more preferably 2- 8% by weight of the composition), a binder, for example, polyvinylpyrrolidone, HPMC, starch and its derivatives (preferably in an amount of up to 5% by weight, for example 1-5% by weight, more preferably 2-4% by weight of the composition), tacking adjuvants, such as a compressible binder, for example microcrystalline cellulose (preferably in an amount of up to 20% by weight, for example 5-20% by weight of the composition) , a flow aid such as colloidal silica and silica derivatives (preferably in an amount of up to 3% by weight, for example 0.1-3% by weight, more preferably 0.5-2% by weight of the composition), a lubricant such as stearic acid or stearic acid magnesium content (preferably in an amount of up to 3% by weight, for example 0.1-3% by weight, more preferably 0.5-2% by weight, of the composition), and flavoring adjuvants, sweeteners, adjuvants of dyes, etc., as required. The discrete phase, which may be the dispersed phase in a dispersion, or the oil phase in an emulsion, may optionally include a minimum portion of water-insoluble material, a material for the present invention, such as a lipid or other hydrophobic, suspended ingredient in the active ingredient. Examples are well known to those skilled in the art and include mono, di and triglycerides and long chain fatty acids, fatty acid esters, waxes, vegetable oils, insoluble cellulose materials and insoluble crosslinked polyvinylpyrrolidone. Such materials can suitably form up to 10% by weight of the active ingredient, for example 0-5% by weight of the active ingredient. Preferred compositions do not contain or contain negligible amounts of such materials. The aqueous preparation is formed by combining the ibuprofen composition with water at any temperature in the range of 0-100 ° C. If ibuprofen is the only medicine or any other medication used that has a higher melting point, when the ibuprofen composition is combined with water at a temperature below the melting point, the active ingredient of ibuprofen will form an aqueous preparation in form of a dispersion. In most cases, the water will be at a temperature in the range of 5-50 ° C, more preferably 10-30 ° C. When it is at temperatures above room temperature (for example, more than about 25 ° C), the water will need to be heated. By combining the water with the composition, the aqueous preparation is formed substantially immediately and is ready for immediate administration to the patient. When the ibuprofen composition is combined with hot water at a temperature above the melting point of the active ingredient of ibuprofen, an aqueous preparation is formed, wherein the active ingredient of ibuprofen is in liquid form. The composition of ibuprofen by itself does not require a preheating step before mixing with hot water. In many cases, the active ingredient of ibuprofen will have the lowest melting point and most drugs have a melting point above 100 ° C. The water temperature, when combined with the ibuprofen composition, is in the range defined by the melting point of the active ingredient of ibuprofen and the boiling point of water. Preferably, the water is at a temperature in the range of at least 5 ° C to 10 ° C above the melting point of the active ingredient of ibuprofen and 100 ° C. In most cases, the water will be at a temperature in the range of 50-100 ° C, preferably 60-100 ° C, more preferably 70-100 ° C and more preferably 80-100 ° C. C. After combining the hot water with the ibuprofen composition, the aqueous preparation is formed substantially immediately, and is ready for immediate administration to the patient as long as the temperature of the liquid is not too hot. If necessary, the aqueous preparation can be stirred after being combined with hot water to aid in the formation of the emulsion. If the water has been heated to its boiling point, the patient may wish to wait a short time (for example 5-10 minutes), while the aqueous preparation is cooled to an acceptable temperature for administration. Preferably, the aqueous preparation is formed by placing a unit dose of the ibuprofen composition (e.g., in solid form, e.g., a tablet or granule, or in liquid form, e.g. a liquid concentrate) in a receptacle and adding the Water. This is a very simple way of administering the active ingredient and forms another particular advantage of the present invention. Alternatively, a unit dose of the ibuprofen composition may be added to a receptacle that already contains water. Preferably, the water is added directly to the ibuprofen composition. In another aspect, the invention provides a process for producing a unit dose aqueous preparation comprising an aqueous phase substantially free of ibuprofen and a discrete phase incorporating ibuprofen, characterized by the step of combining an ibuprofen composition comprising an intimate mixture of: (a) ) one or more drugs, including an ibuprofen medication, which forms an active ingredient of ibuprofen having a melting point below 100 ° C when combined with water to give an aqueous preparation having a pH of less than 7, ( b) a phospholipid material, capable of forming the active ingredient of ibuprofen in a discrete phase in combination with the composition of ibuprofen with water; and if required, (c) an acid component adapted to produce an aqueous preparation having a pH less than 7; with water, wherein the combination of the water with the ibuprofen composition causes the aqueous preparation to have a pH of less than 7, formed substantially immediately, wherein the discrete phase consists essentially of the phospholipid material and the insoluble pharmacologically active ingredient which includes the active ingredient of ibuprofen. In a preferred process, an emulsion is provided by combining the ibuprofen composition with water at a temperature above the melting point of the active ingredient of ibuprofen. In addition, preferably, a process for emulsifying an active ibuprofen ingredient in an aqueous medium is provided which comprises the steps of: (1) heating an amount of water to a temperature in the range defined by the melting point of the active ibuprofen and the boiling point of water; (2) combining the hot water with an ibuprofen composition comprising an intimate mixture of (a) a medicament of ibuprofen which forms an active ingredient of ibuprofen having a melting point below 100 ° C when combined with water to give an aqueous preparation having a pH of less than 7, (b) a phospholipid material capable of emulsifying the active ibuprofen ingredient with the combination of the ibuprofen composition with water at a temperature in the range defined by the melting point of the active ingredient of ibuprofen and the boiling point of water, and optionally, if required, (c) an acid component adapted to produce an aqueous preparation in the form of an emulsion having a pH of less than 7. Where the combination of the The composition of ibuprofen with the hot water produces the substantially immediate formation of a uniform aqueous emulsion having a pH of less than 7 wherein the oil phase consists essentially of the phospholipid material and the active ingredient of ibuprofen. Preferred aqueous preparations in the form of emulsions formed according to the invention are formed as uniform microfine emulsions substantially immediately after the addition of water at a temperature at or above the melting point of the active ingredient of ibuprofen. Furthermore, after cooling, when the active ibuprofen ingredient solidifies, the solid particles do not coalesce but are retained in the form of a fine dispersion. This is an advantage since, if boiling water is used to produce the aqueous preparation in the form of an emulsion, the patient may require that the aqueous preparation be cooled to a temperature below the melting point of the active ibuprofen ingredient before drinking. It has been found that such dispersions formed from the aqueous emulsions of the present invention are stable for up to 24 hours. Aqueous preparations of the present invention comprising emulsions or dispersions are pleasantly flavored and therapeutically effective. Since they are present in an aqueous preparation, they are thus available for absorption after ingestion by swallowing the product to be drunk. Ibuprofen and its derivatives are mainly anti-inflammatory, analgesic and antipyretic agents, but have also been proposed for other therapeutic uses, for example to treat perodontal bone loss, pruritus, Alzheimer's disease, etc. The aqueous preparations of the present invention are therefore indicated for use in the treatment of all therapeutic uses for which ibuprofen is effective, including rheumatoid arthritis, osteoarthritis and ankylosing spondylitis, seronegative arthropathies, periarticular diseases and soft tissue damage. . They can also be used in the treatment of postoperative pain, po-st-parto pain, dental pain, dysmenorrhea, headache, migraine, rheumatic pain, muscle pain, back pain, neuralgia and / or musculoskeletal pain or the pain or discomfort associated with the following : respiratory infections, colds or influenza, gout or stiffness in the morning. Accordingly, in a further aspect the present invention provides a method for obtaining a therapeutic response, preferably an anti-inflammatory, analgesic and / or antipyretic response, which comprises administering to a person in need thereof an aqueous unit dose preparation. comprising an aqueous phase and a discrete phase comprising (a) an active ingredient of ibuprofen having a melting point of less than 100 ° C and (b) a phospholipid material capable of forming the active ingredient of ibuprofen in a discrete phase after combining with water, characterized in that the aqueous preparation has a pH of less than 7 and because the aqueous phase is essentially free of the active ingredient of ibuprofen and because the discrete phase consists essentially of phospholipid material and insoluble pharmacologically active ingredient which includes the active ingredient of ibuprofen In another aspect the invention provides a process for preparing an ibuprofen composition adapted to provide an aqueous preparation having an aqueous phase substantially free of ibuprofen and a discrete ibuprofen phase after the addition of water at a temperature in the range of 0-100. ° C, which comprises: (a) forming an intimate mixture of one or more drugs, including an ibuprofen medication, which forms an active ingredient of ibuprofen having a melting point below 100 ° C after the combination of the ibuprofen medication with Water to give an aqueous preparation having a pH less than 7, with a phospholipid material capable of forming an aqueous preparation comprising an emulsion or dispersion, wherein the discrete phase consists essentially of the phospholipid material and insoluble pharmacologically active ingredient which includes an ingredient active of ibuprofen, optionally with other excipients; and (b) formulating the mixture in a unit dose composition. In the formulation of the composition, the process of combining and mixing can be in a single step with all the solid components introduced in a mixer and mixed until a homogeneous mixture is achieved. Alternatively, the ibuprofen can be granulated with the phospholipid material together with another surfactant and optionally other ingredients, to form a granule which can then be dried and then combined with the remaining excipients to form a homogeneous mixture. Alternatively, the granules can be milled to form a powder which is combined with the remaining excipients to form a homogeneous mixture. The granulation or mixing step can be carried out either dry or with a liquid binder, such as a solvent system containing polyvinylpyrrolidone or with an aqueous binder such as ethanol in water. These can then be fed directly into suitable storage media such as powder or granules (for example in sachets) or fed to tabletting machines to compress them into tablets. The invention is illustrated by the following non-limiting Examples. In the Examples, soy lecithin is distributed by Lucas Meyer, Germany under the brand name Emultop®. Egg lecithin is also distributed by Lucas Meyer, Germany.

Example 1 Ibuprofen 200mg Castor sugar 2500mg Citric acid 50Omg Sodium citrate 40Omg Flavoring 40Omg Sodium lauryl sulfate lOmg Dyestuff agent lOmg Sweetener 42mg Soy lecithin lOmg The ibuprofen and the soy lecithin were milled together and then mixed with the remaining powder excipients until a homogeneous mixture was obtained. The mixture was then packed in sachets to give 200mg of ibuprofen per sachet. The contents of the bags were placed at a rate and 200ml of substantially boiling water was added. The ibuprofen was melted and emulsified immediately to form a satisfactory drinking formulation. The emulsified phase was presented as small droplets evenly distributed throughout the beverage to give a smooth, slightly turbid homogeneous appearance. No oil film of ibuprofen was formed on the surface. The formulation was allowed to cool slightly and was then ready to be administered to the patient as a beverage. The emulsion was kept in cooling (for example for 30 minutes). 200ml of cold water was added to an additional bag containing the previous composition. A dispersion was immediately formed to give a satisfactory drinking product. Small amounts of hot water (eg> 85 ° C), warm (40-85 ° C), or colder water (for example <40 ° C), such as 150ml, 100ml and 50ml may be added to the mixture granulate to form an emulsion / dispersion. The granular mixture can also be prepared by granulating the ibuprofen, soy lecithin and sodium lauryl sulfate in a high speed mixer using aqueous ethanol as the granulating liquid. The resulting granules can then be dried and ground to produce a fine powder. The powder can be added to the remaining excipients and mixed until a homogeneous mixture is obtained. The mixture can then be packed into bags to give 200 mg of ibuprofen per pouch.

Examples 2-5 In the same manner as described in Example 1, a granular mixture of ibuprofen containing a derivative thereof was prepared.

Results: Examples 2-3 The contents of the bag were placed at a rate and 200ml of very hot water (> 95 ° C) was added. The ibuprofen melted and emulsified immediately to form a satisfactory drinking formulation. The emulsified phase was present as small droplets evenly distributed throughout the beverage to give a slightly turbid homogeneous, satisfactory appearance. No oil film of ibuprofen was formed. The formulation was allowed to cool slightly and was ready to be administered to the patient as a beverage. The emulsion was kept cool (for example for 30 minutes).

EXAMPLE 4 After the addition of 200 ml of boiling water, a satisfactory coarse emulsion was formed with the majority of the emulsified ibuprofen phase located in the upper portion of the beverage. The oily ibuprofen film was not present on the surface of the beverage.

EXAMPLE 5 After the addition of 200ml of boiling water, a satisfactory coarse emulsion was formed with the majority of the emulsified ibuprofen phase located in the upper portion of the beverage. The oily ibuprofen film was not present. An excess of egg lecithin on the surface was also visible.

It was preferred to use egg lecithin in an amount between 20 and 40 mg in the composition of Example 4, for example 3Omg.

Examples 6-11 The following active ingredients were mixed as a dry powder with the granular mixture of Example 1.

Results Mixtures of the Examples were placed separately in rates and 200ml of hot water (> 90 ° C) was added. The ibuprofen melted and immediately emulsified to form a satisfactory drinking formulation. The emulsified phase was present as small droplets distributed evenly throughout the beverage to give the homogeneous appearance slightly cloudy, satisfactory. An oily film of ibuprofen was not formed. The formulation was allowed to cool slightly and was then ready to be administered to the patient as a beverage. The emulsion was kept cool (for example for 30 minutes).

Example 12 In each of Examples 1-11, sorbitol can be used as a sugar replacement.

Example 13 In each of Examples 1-12, malic acid can be used as a replacement for citric acid.

Example 14 Each of Examples 1-13 may omit sodium lauryl sulfate.

Example 15 Each of Examples 1-14 may contain lOOmg, 300 or 400mg of racemic ibuprofen or S (+) - ibuprofen as a replacement for the 200mg of ibuprofen.

Example 16 The following composition can also be prepared as described in Example 1.

Ibuprofen 200 mg Citric acid 500 mg Soy lecithin 10 mg Microcrystalline cellulose 500 mg It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (13)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. An ibuprofen composition comprising one or more medicaments, including an ibuprofen medicament, which forms an active ingredient of ibuprofen having a melting point of less than 100 ° C, when combined with water to give an aqueous preparation having an pH less than 7, characterized in that the composition produces an aqueous preparation having a pH less than 7 after the addition of water to the composition, and comprises a phospholipid material intimately mixed with the ibuprofen medicament, the phospholipid material is capable of forming a aqueous preparation comprising an aqueous phase substantially free of the active ingredient of ibuprofen and a discrete phase consisting essentially of the phospholipid material and insoluble pharmacologically active ingredient, including the active ingredient of ibuprofen upon addition of water to the composition.

The composition according to claim 1, characterized in that, after combination with water at a temperature in the range of 80-100 ° C, it is adapted to form an emulsion containing a discrete oil phase consisting essentially of the phospholipid material and insoluble pharmacologically active ingredient, which includes the active ingredient of ibuprofen.

The composition according to any of claims 1 and 2, characterized in that the active ingredient of ibuprofen comprises ibuprofen or S (+) - ibuprofen.

4. The composition according to any of the preceding claims, characterized in that the ratio of phospholipid material to ibuprofen medication is in the range of 0.02: 1 to 0.2: 1 parts by weight.

5. The composition according to any of the preceding claims, characterized in that the phospholipid material comprises one or more natural lecithin materials.

6. The composition according to claim 5, characterized in that the phospholipid material comprises soy lecithin.

7. The composition according to any of the preceding claims, characterized in that it contains an acid component.

8. The composition according to any of the preceding claims, further characterized in that it contains a non-phospholipid surfactant.

9. A unit dose aqueous preparation comprising an aqueous phase and a discrete phase comprising (a) an active ingredient of ibuprofen having a melting point of less than 100 ° C and (b) a phospholipid material capable of forming the ingredient active of ibuprofen in a discrete phase after combining with water, characterized in that the aqueous preparation has a pH less than 7 and because the aqueous phase is essentially free of the active ingredient of ibuprofen and because the discrete phase consists essentially of phospholipid material and pharmacologically active ingredient insoluble that includes the active ingredient of ibuprofen.

10. The aqueous preparation according to claim 9, characterized in that when the aqueous phase is at a temperature higher than the melting point of the ibuprofen active ingredient, the discrete oil phase consists essentially of phospholipid material and liquid ibuprofen active ingredient.

11. The aqueous preparation according to any of claims 9 to 10, characterized in that the aqueous phase contains an additional drug useful in a cough and / or cold remedy that includes an antihistamine, a cough suppressant, a decongestant , a spreader, a muscle relaxant, caffeine, a vitamin, and a coanalgesic, or a mixture of them.

12. A process for producing a unit dose aqueous preparation comprising an aqueous phase substantially free of ibuprofen and a discrete phase incorporating ibuprofen, characterized by the step of combining an ibuprofen composition comprising an intimate mixture of: (a) a or more medications, including an ibuprofen medication, which forms an active ingredient of ibuprofen that has a melting point of less than 100 ° C when combined with water to give an aqueous preparation having a pH of less than 7, (b) a material phospholipid capable of forming the active ibuprofen ingredient in a discrete phase after combining the composition of ibuprofen with water; and, if required, (c) an acid component adapted to produce an aqueous preparation having a pH of less than 7.; with water, wherein the combination of the water with the ibuprofen composition produces an aqueous preparation having a pH of less than 7 which is formed substantially immediately, wherein the discrete phase consists essentially of phospholipid material and insoluble pharmacologically active ingredient, which includes the active ingredient of ibuprofen. ' The process according to claim 12 for producing an aqueous emulsion by combining the composition of ibuprofen with water at a temperature above the melting point of the active ingredient of ibuprofen. !4. The use of a preparation according to any of claims 9 to 11 in the manufacture of a medicament for treating inflammation, pain and / or fever.