MXPA99000128A - Composition of ibuprophene - Google Patents

Abstract

The present invention relates to fumaric acid added in sufficient amounts to reduce the burning aftertaste commonly associated with derivatives of propionic acid.

Description

COMPOSITION OF IBUPROPHENE BACKGROUND OF THE INVENTION The present invention relates to compositions of ibuprofen, more specifically to an ibuprofen composition with reduced burning characteristics. Many flavors and sweeteners have been added to medications to make them more palatable and disguise the burning and aftertaste, which is common with many medications. Despite numerous efforts to find an effective means of eliminating this ardor, there is a continuing need for a method that effectively eliminates the burning sensation with medicaments, preferably the burning can be reduced to a level such as a chewable composition can provide. Ibuprofen is a well-known drug that has a non-palatable burning sensation in the mouth and throat after being ingested Japanese Patent Application 9 (1997) -2949 assigned to American Home Products seeks to eliminate the non-palatable aftertaste by providing only one enantiomer The patent application describes the separation of ibuprofen from its racemic mixture to form an orally administered drug composition, containing only S (+) - ibuprofen and essentially not containing R (-) - ibuprofen Although this binding may provide a more palatable form of ibuprofen, the separation and isolation of the enantiomers is difficult, US Patent 4,762,702 discloses ibuprofen particles covered by a layer of hydrocolloid and fumaric acid.The preferred hydrocolloid composition includes xanthan gum and / or malto dextrin The resulting product is an effervescent mixture, which is dried in vacuum. Ie this method, since it overcomes the defects of the previous preparations in the technology due to the coverage of ibuprofen crystals by means of hydrocolloid in the presence of fumaric acid. Despite the description of the above-mentioned patent and application, a simpler and less expensive method provides an ibuprofen composition with disguised flavor.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides propionic acid derivatives with fumaric acid in an amount of about 50 to about 150% of the amount of the propionic acid derivative. The present invention provides sufficient fumaric acid to reduce the burning aftertaste of propionic acid, in the absence of a hydrocolloid agent. In a preferred embodiment, the fumaric acid composition derived from propionic acid is provided in a chewable form. A method for inhibiting the burning aftertaste of propionic acid derivatives by providing an effective amount of fumaric acid is also provided by the present invention.

DETAILED DESCRIPTION OF THE INVENTION The propionic acid derivatives are a well-known class of analgesic compounds. As used herein, it is understood that the propionic acid derivatives include, but are not limited to, ibuprofen, naproxen-benoxaprofen, naproxen-sodium, flurbiprofen, fenoprofen, fembuprofen, ketoprofen-indoprofen, pirprofen, carpofen, oxaprofen, pranoprofen, microprofen. , dioxaprofen, suproprofen, alminoprofen, thiaprofenic acid, fluprofen, and bucilloxic acid. The structural form is set forth in U.S. Patent 4,923,898 incorporated herein by reference. Propionic acid derivatives, as defined herein, are defined as pharmaceutically acceptable non-steroidal anti-inflammatory / analgesic drugs having a free -CH (CH 3) COOH or -CH 2 CH 2 COOH group or a group of pharmaceutically acceptable salts, such as -CH (CH 3) COO-Na + or CH2CH2COO-Na +, which typically bind directly or through a carbonyl functionality to an aromatic ring system. The acetic acid derivatives to be used herein include, but are not limited to, indomethacin, sulindac, tolmetin, diclofenac, fenclofenac, alsoclofenac, ibufenac, isoxepac, furofenac, thiopinac, zidometacin, aceminetacin, fentiazac, clidanac and oxepinac. The structurally related acetic acid derivatives have a similar analgesic and anti-inflammatory properties included within the scope of the invention which includes tometin, sulindac, indomethacin, diclofenac, alclofenac, fenclicosic acid and ibufenac. The propionic acid derivatives are typically administered on a daily scale of from about 50 to about 2000 milligrams, preferably from about 100 to 1600 and more preferably from about 200 to about 1200 milligrams. Ibuprofen is widely used, it is well known as a non-steroidal anti-inflammatory and a propionic acid derivative. Ibuprofen is chemically known as 2- (4-isobutylphenyl) ropionic acid. As used herein, it is understood that ibuprofen includes a 2- (4-isobutylphenyl) -propionic acid, as well as pharmaceutically acceptable salts. Suitable ibuprofen salts include arginine, lysine, histidine, as well as other salts described in U.S. Pat. No. 4,279,926, 4,873,231, 5,424,075, 5,510,385, the contents of which are incorporated herein by reference. Fumaric acid is a pharmaceutically acceptable and widely available acid. The concentration of fumaric acid present to inhibit the burning of the propionic acid derivative will vary in the amount of desired reduction in ardor. Generally, the level of fumaric acid is from about 50 to about 150 weight percent of the dose of the propionic acid derivative. Typically, the level of fumaric acid is from about 60 to about 100% by weight of the level of the propionic acid derivative and more preferably from about 70 to about 90% by weight of the dose level of the propionic acid derivative. Contrary to what has been taught in the above descriptions, the present invention does not require the incorporation of a hydrocolloid material to be effective. The present invention can be included in the following modalities. The simplest and preferred embodiment is the incorporation of fumaric acid into a matrix, that is, it is provided freely and randomly in a mixture. In this embodiment, the propionic acid derivative, preferably ibuprofen, and fumaric acid, are provided in a matrix in the form of a caplet, tablet or capsule. In another embodiment of the invention, ibuprofen and fumaric acid are provided in a granulation. Typically, this includes the mixture of the propionic acid derivative, fumaric acid, as well as sugars, binders, water and other ingredients which together use a well-known equipment in the technology. For example, U.S. Patent No. 5,429,825 discloses rotofusion granulation methods, the contents being incorporated herein by reference as set forth in its entirety. The mixture is then dried and ground.

The ground product is, then, a suitable way to be compressed into a tablet. Preferably, the disintegrants are added to the mixture to aid in the release of the active ingredients to the user. In a highly preferred embodiment, propionic acid and fumaric acid are found in a chewable tablet available to those who have difficulty swallowing a tablet. In another embodiment of the present invention, the fumaric and propionic acids are provided in the presence of a non-hydrocolloid binder. Preferably, the non-hydrocolloid binder is a pharmaceutically acceptable wax or fat. Suitable fats and waxes include glyceryl monostearate, hydrogenated tallow, myristyl alcohol, myristic acid, stearyl alcohol, substituted monoglycerides, substituted diglycerides, substituted triglycerides, beeswax, carnuaba wax, Japan wax, acetylate monoglycerides, and the like. Combinations of two or more of the non-colloidal agglutinators can be used. Preferably, the melting point of the non-colloidal binders of the invention have a melting temperature of from about 30 to about 100 C, most preferably from about 40 to about 85 C. The non-hydrocolloid binder is made by melting the wax first or fat and then mixing the combination of ibuprofen and fumaric acid. The combination is then milled to the appropriate size and compressed into tablets, using techniques well known to those skilled in the art. The formulation of the present invention may also contain pharmaceutically acceptable excipients, fillers, flavors, diluents, lubricants, disintegration agents, suspending agents, stabilizers, binders, colorants, vehicles and the like. For example, suitable carriers include lactose, starch, dicalcium phosphate, calcium sulfate, kaolin, mannitol and powdered sugar. Typical binders include starch gelatin, sugars such as dextrose, mannitol, xylitol, sorbitol, maltodextrin, fructose, sucrose, melases, lactose and natural and synthetic gums, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, polyethylene glycol, ethylcellulose and waxes. The lubricants include boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol and the like. Typical disintegrators include starch derived from wood, corn, potato, rice, methylcellulose, magnesium silicates, aluminum silicates, sucrose, dextrose, bad odexture, agar, benoite, alginic acid, wood products, guar gum, citrus pulp , sodium lauryl sulfate and the like. The present invention may be provided in liquid form, e.g., elixir, suspension or syrup. Liquid formulations are prepared using pharmaceutically acceptable manufacturing methods and surfactants, dispersants and diluents known in the art. Preferably, the present invention is provided in caplets, capsules, tablets and most preferably in chewable form. As used herein, it is understood that the burning in this specification means the aftertaste, commonly identified as metallic, observed when taking ibuprofen. This aftertaste is different from the bitter taste, since the addition of a sweetener is not effective in reducing the aftertaste. Alternatively the ibuprofen / fumaric acid composition may be added at appropriate levels to beverages, foods and other edible compositions that may be desired. It is also anticipated that the ibuprofen / fumaric acid compositions of the present invention may also be used in veterinary applications. Without wishing to be bound by any other theory, the incorporation of fumaric acid to the propionic acid derivative reduces the burning characteristic of aftertaste by sufficiently acidifying the saliva to maintain the protonated form of the propionic acid derivative. The protonated form of the propionic acid derivative has low solubility and hence has a lower irritation to the throat mucosa. Unlike other acidulants, fumaric acid dissolves slowly, so its bitter taste is minimized in the mouth, but it is enough to acidify the throat. Other pharmaceutically acceptable acids, such as citric, malic and tartaric acid, are much more soluble than fumaric acid. These and other acids quickly spread an unacceptable bitter taste in the mouth. The dissolution is so rapid that the bitter taste is perceived long before the saliva is sufficiently acidified. The invention will now be illustrated by means of the following examples, but it is not intended to be limited to them alone. In these examples, it is understood that, unless otherwise noted, all parts are in percent by weight.

EXAMPLE 1 Chewable tablets containing 100 milligrams (mg) of ibuprofen were prepared either with 70 mg of fumaric acid or without fumaric acid. Chewable tablets, which do not contain fumaric acid were used as a control. A tasting panel of 18 individuals was asked to chew two control tablets and mark the burning of the throat on a scale of 1 to 9 (highest level). After one hour, the tablets containing the ibuprofen-acid combination smokers were chewed and the individuals were asked to mark the results using the same scale of 1-9. Individuals classified the control tablets as moderately high as a 7 on a 9-point scale, while the tablets containing the combination of ibuprofen-fumaric acid were classified as moderately low, in a 3 or 4 on a 9-point scale.

EXAMPLE 2 It was found that the following formulation is effective to eliminate subsequent burning. 100 milligrams (mg) of ibuprofen, 1.76 mg of dye, 84 mg of microcrystalline cellulose, 11 mg of sweetener, 4 mg of second sweetener, 2 mg of flavoring, 6 mg of lubricant, 465 mg of excipient, 65 mg of acid fumaric EXAMPLE 3 Two individuals were used to determine the effective level of fumaric acid in a dose of 100 milligrams of ibuprofen. Individuals classified the composition of ibuprofen-fumaric acid in the following scale. Burning intensity: extremely high, 9; very high 8, moderately high 7, slightly high 6, neither high nor low 5, slightly low 4, moderately low 3, very low 2, extremely low 1, no bitter taste or burning 0. The average score of the test results were reported as follows: 30 mg of fumaric acid 7 40 mg of fumaric acid 6 50 mg of fumaric acid 3 60 mg of fumaric acid 1 This example demonstrates that 50 mg of fumaric acid by weight per 100 mg of ibuprofen was effective for reduce the burning aftertaste caused by ibuprofen.

Claims (9)

NOVELTY OF THE INVENTION CLAIMS

1. A composition administered orally, including an analgesically effective amount of propionic acid and from about 50 to about 150 weight percent fumaric acid in the absence of a hydrocolloid.

2. The composition according to claim 1, further characterized in that the propionic acid is ibuprofen.

3. The composition according to claim 1, further characterized in that the fumaric acid / propionic acid is provided in a chewable tablet.

4. The composition according to claim 2, which is in the form of a chewable tablet.

5. The composition according to claim 1, further characterized in that the ibuprofen and fumaric acid are ingested as liquid.

6. - A method for reducing the aftertaste of propionic acid compositions including: providing an analgesically effective amount of propionic acid derivatives; mixing from about 50 to about 150 weight percent fumaric acid based on the weight of the propionic acid derivative characterized in that the fumaric acid and the propionic acid derivative are mixed in the absence of a hydrocolloid.

7. The method according to claim 6, further characterized in that the propionic acid derivative is ibuprofen.

8. The method according to claim 6, further characterized in that the fumaric acid and the propionic acid derivative are mixed in a granulation process.

9. The method according to claim 8, further characterized in that the granulation process is conducted with a non-hydrocolloid binder.