MXPA00005547A - Rapidly absorbed liquid compositions containing an amine and a nsaid - Google Patents

Abstract

The present invention provides a method which provides for a faster absorption of pharmaceutically acceptable amines. The method provides a pharmaceutically acceptable amine in combination with a non-steroidal anti-inflammatory drug in a liquid form. A preferred embodiment employs pseudoephedrine and ibuprofen.

Description

RAPIDLY ABSORBED LIQUID COMPOSITIONS FIELD OF THE INVENTION This invention relates to medicaments containing a combination of an analgesic / antiinflammatory acid compound and a pharmacologically active amine. In a preferred embodiment, the present invention relates to the combination of materials in a liquid dosage form.

BACKGROUND OF THE INVENTION Products that combine multiple pharmaceutically active ingredients are commercially available throughout the world. Consumers purchase these medications because they alleviate several symptoms at the same time. For example, ibuprofen and pseudoephedrine are marketed in combination in solid forms such as tablets, capsules and powders for reconstitution. Ibuprofen is an effective analgesic / antipyretic agent, while pseudoephedrine is an effective decongestant. The combination of these two active ingredients is particularly effective in relieving headaches from sinusitis and cold and flu symptoms. The combinations of buprofen and pseudoephedrine are described in the patent of E.U.A. 4,552,899.

Although these products are known to be effective, consumers who use them look for quicker relief of symptoms. Therefore, there continues to be a great need to develop products that give quick relief to the consumer. Attempts have been made to improve the rate of onset of activity of several drugs by increasing their rate of absorption into the blood stream after oral administration. For example, PCT application W098 / 38983 describes a method for improving the rate of absorption of the analgesic paracetamol, by combining it with sodium bicarbonate in a tablet or capsule formulation at a specific weight ratio. Irwin et. to the. [J. Pharm. Sci, 58 (3), March 1969] demonstrated increased absorption of the quaternary ammonium compound, isopropamide, when administered in combination with a large molar excess of trichloroacetate in solution. Meyer and Manning [Pharm. Res. 15 (2), 1998] describe the use of hydrophobic ion pairing to increase the bioavailability of protein and peptide drugs that are not very liposoluble. It has now been unexpectedly found, that the absorption rate of a pharmaceutically active amine (such as pseudoephedrine), improves when the amine is formulated together with a non-steroidal anti-inflammatory acid drug (such as ibuprofen) in a liquid medium.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a method for increasing the absorption of a pharmacologically active amine, which comprises providing a pharmaceutically effective dose of the amine, and an effective dose of a non-steroidal anti-inflammatory agent together in a liquid medium to provide increased bioabsorption of the amine .

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the pharmacokinetic profiles for ibuprofen from liquid dosage forms. Figure 2 shows the pharmacokinetic profiles for pseudoephedrine from liquid dosage forms. Figure 3 shows the pharmacokinetic profiles for pseudoephedrine from solid dosage forms.

DETAILED DESCRIPTION OF THE INVENTION Nonsteroidal anti-inflammatory drugs, commonly referred to as NSAIDs for use in the present invention, are well known in the art. They can be selected from propionic acid derivatives, acetic acid derivatives, fenamic acid derivatives and biphenylcarboxylic acid derivatives. Accordingly, it is understood that the term "NSAID", as used herein, means any non-steroidal analgesic non-narcotic anti-inflammatory compound, including pharmaceutically acceptable salts thereof, that is within the classes of compounds described above. Acceptable salts include sodium, potassium, arginine, lysine, and the like. Specific examples of the propionic acid derivatives include ibuprofen, naproxen, naproxen sodium, fenoprofen, ketoprofen, and the like. Suitable acetic acid derivatives include indomethacin, zomepirac, sulindac, and the like. Suitable phenamic acid derivatives include mefenamic acid and sodium meclofenamate. Suitable biphenylcarboxylic acid derivatives include diflunisal and flufenisal. The preferred NSAIDs are ibuprofen, ketoprofen and naproxen. It is understood that aspirin is not included in the definition of NSAIDs as used in this invention. The dosage of the NSAID will vary according to the potency of the specific compound. Therapeutic doses for these analgesics are well known in the art, and can be found in the physician's cabinet references (Medical Economics Company, Montvale, NJ). The preferred dosage of the NSAID is 40 to 800 milligrams of buprofen every 4 to 6 hours. Pharmaceutically acceptable amines include primary, secondary and tertiary amines. Suitable pharmaceutically acceptable amines include pseudoephedrine, phenylpropanolamine, dextromethorphan, chlorpheniramine, diphenhydramine, loratadine, fexofenadine, and cytirazine, famotidine, ranitidine, cimetidine, and their pharmaceutically acceptable salts. The dosage of the amine will vary according to the potency of the specific compound. Therapeutic doses for these analgesics are well known in the art, and can be found in the physician's cabinet references (Medical Economics Company, Montvale, NJ). The preferred dosage of amine is 15 to 60 milligrams of pseudoephedrine every 4 to 6 hours, with the preferred combination being 100 milligrams of ibuprofen and 15 milligrams of pseudoephedrine per 5 milliliter dosage. The present invention contemplates the NSAID and the amine which is in any stable liquid form including, but not limited to, solutions, emulsions, dispersions, colloidal dispersions, suspensions, soft gelatine capsules filled with liquid, and the like. The liquids will utilize suitable emulsification, suspension, dispersion, stabilization or solubilization agents, and diluents that are well known in the art. As used herein, it is understood that stable liquid forms are systems that maintain acceptable physical, chemical and microbiological properties for at least 30 days, preferably at least 12 months, and more preferably at least 24 months in packing. Ordinary pharmaceutical under conditions encountered during the normal distribution and storage of the liquid product.

The NSAID will be dissolved or suspended, but preferably suspended, while the amine will be substantially dissolved in the liquid medium. As used herein, suspensions are understood to be a system in which the small particles are more or less uniformly dispersed in a liquid medium. The suspensions will use suitable suspending and dispersing agents that are well known in the art; see, for example, the patent of E.U.A. No. 5,375,659, the contents of which are incorporated herein by reference. Examples of such suspension materials include, but are not limited to, polycarbohydrates such as cellulose derivatives, starch and starch derivatives, xanthan gum, carrageenan, locust bean gum, and the like, wetting agents such as sodium lauryl sulfate and alkyl polyoxyethylene sulfates; sulfonates such as quaternary ammonium compounds; nonionic materials such as polyoxyethylene fatty alcohol ethers, sorbitan fatty esters and polyoxyethylene sorbitan fatty acid esters. A preferred system such as that described in the U.S.A. No. 5,374,659, is formed of xanthan gum, pregelatinized starch and polyoxyethylene monooleate. Other agents are described in Remmington's Pharmaceutical Sciences, fifteenth edition, Osal and Hoover editors, 1975. Suspending agents are used at levels of from about 0.1 to about 5% by weight, preferably from about 0.25 to about 3, and more preferably from about 0.5 to about 2% by weight. Water is the preferred solvent system, although any pharmaceutically acceptable solvent can be used. The compositions of the present invention may also contain, in addition to the NSAID and amine components, other pharmaceutically active ingredients including antihistamines, decongestants, antitussives and expectorants. Typically, these pharmaceutically active ingredients are provided in their effective dosages which are known; see, for example, the patent of E.U.A. 4,552,889. The compositions of the present invention have an increased drug exposure of the amine to humans in the early periods after dosing, comparatively with other amine compositions. Early drug exposure is measured by the area under the blood, plasma or serum concentration curve from when the drug is consumed up to 1 or 2 hours later (AUC 1H or AUC 2). The total drug exposure is the area under the curve that is extrapolated to infinite time (AUC INFINITE) - A comparative study has shown an increased early exposure of amine (AUC 1H and AUC 2) with respect to that obtained in the absence of an amount of an NSAID in liquid form. The compositions of the present invention give an early exposure of amine in the consumer bloodstream during the first hour (AUC 1H) which is about 10% higher, preferably more than about 40% higher, and more preferably greater than about 80% higher that the early exposure of drug from the same amine from a liquid product of a single ingredient. In addition, the compositions herein give an early exposure of amine in the consumer bloodstream during the first two hours (AUC 2H) which is approximately 10% higher, preferably greater than approximately 20% higher, and more preferably greater than approximately 40% greater than the early exposure of the same amine drug from a single ingredient liquid product. In addition, the compositions according to the present invention have an increased CMAX, wherein CMAX is the maximum concentration of the amine in blood, plasma or serum, which occurs earlier comparatively with other liquid amine compositions. This change also indicates the increased rate or absorption improvement of the pharmaceutically acceptable amine, comparatively with amines in the absence of the NSAID. The compositions of the present invention give a maximum amine concentration in the consumer bloodstream of about 10% higher, preferably more than about 12.5% higher, and more preferably more than about 15% greater than the maximum concentration of the same amine from a liquid product of a single ingredient. In addition, the compositions according to the present invention provide total exposure of amine (AUC INFINITE) which is equal to that provided by amines in the absence of the NSAID, indicating that there is no decrease in the general level of absorption of the pharmaceutically acceptable amine. While not wishing to be limited by any theory, it is thought that the present invention works due to the formation of an ion pair in the liquid medium. This ionic pairing apparently does not form with the solid dosage forms. Ionic pairing allows the amine drugs to be delivered more efficiently and rapidly into the blood stream, thus providing greater early drug exposure and higher peak concentrations more rapidly comparatively with the amine in the absence of the NSAID in liquid form or with the amine in the presence of the NSAID in solid form. Therefore, the present invention will provide the consumer with a faster onset of activity for the pharmacologically active amine. The following examples are provided to better illustrate the claimed invention, but do not limit the same to the examples provided below. As used herein, it is understood that mg means milligrams, ng means nanograms, kg means kilograms and ml means milliliters.

EXAMPLE 1 One study included 24 healthy subjects, 10 men and 14 women, aged 18 to 55 years. Subjects underwent three treatments in cross-over experiments, and study periods were separated by a minimum of one week for drug failure. The subjects were reported at the clinical site the afternoon before each study period, and remained cloistered until after the last blood sample was collected 14 hours after dosing. Treatment A was a dose of the test suspension, which consisted of 7.5 mg / kg of ibuprofen and 1125 mg / kg of pseudoephedrine hydrochloride (ingredients provided in Table 1), prepared as described in the U.S. patent. 5,621, 005, example 1, additionally with pseudoephedrine hydrochloride added after the addition step of buprofen. Treatment B was a infant suspension dose of buprofen Motrin® (McNeil Consumer Healthcare) which consisted of 7.5 mg / kg ibuprofen. The treatment was a dose of nasal decongestant infant Sudafed® (Warner Lambert), which consisted of 1,125 mg / kg of pseudoephedrine.

TABLE 1 Formula of suspension of treatment A Ingredients (% by weight) GNP USP 10.0 Xanthan gum N 0.18 Pregelatinized starch 1.5 Sucrose NF 35.0 Colors 0.0038 Polysorbate 80 NF 0.05 Artificial flavors 0.893 Ibuprofen USP 2.0 Pseudoephedrine hydrochloride USP 0.30 Sodium benzoate NF 0.20 Citric acid USP 0.18 Purified water USP 64.2 After overnight fasting, the subjects ingested the product, and immediately drank 177.42 ml of water. There were seven ml of blood before dosing and 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 14 hours after dosing. The plasma was removed from the blood samples, and quantified for ibuprofen and pseudoephedrine separately using two specific methods of high performance liquid chromatography (HPLC). The following single dose pharmacokinetic parameters for plasma ibuprofen and pseudoephedrine were determined using non-compartmentalized methods: early drug exposure up to 1 hour (AUC IH), early drug exposure up to 2 hours (AUC), area under the time-concentration curve in plasma extrapolated to infinity (AUC INFINITE), and maximum plasma concentration (CMAX) - The rate of drug absorption is reflected by AUC 1H, AUC 2 and CMAX- The averages of the parameters of ibuprofen and pseudoephedrine were analyzed separately creating a cross-over experiment of two treatments and three periods. The means for the combination product and ibuprofen and pseudoephedrine alone were compared by analysis of variance (ANOVA). From the ANOVA, statistically significant differences are detected in the means for p values less than 0.05. Figure 1 shows the average profiles of plasma ibuprofen concentrations over time for the combination suspension of ibuprofen-pseudoephedrine and the Motrin® suspension. They are similarly shaped and virtually superimposed, indicating no change in the rate of absorption of ibuprofen when combined with an amine. Figure 2 shows the average pseudoephedrine profiles for the combination suspension of ibuprofen-pseudoephedrine and Sudafed® liquid. The amine was absorbed at a faster rate from the combination suspension than from the commercialized liquid, which is reflected by a steeper slope and a higher maximum concentration. This observation was unexpected, since the pseudoephedrine is dissolved as the hydrochloride salt in the liquid carrier of both products. The results of the data analysis for pseudoephedrine are summarized in Table 2, which clearly demonstrates that the rate of absorption of the amine was increased by ibuprofen in the liquid dosage form. The exemplary composition of the present invention increased the early exposure of amine in humans by approximately 93% during the first hour (AUC -), and approximately 54% during the first two hours (AUC 2H), comparatively with the liquid product of amine of a single ingredient. This difference was highly significant from the statistical point of view, since both values of p were equal to 0.0001. In addition, the average concentration of pseudoephedrine in plasma from the liquid combination product reached a maximum 18% higher, and occurred one hour before, comparatively with the Sudafed® liquid. These last differences were statistically significant.

TABLE 2 Results of the pseudoephedrine (PSE) study NS = not statistically significant.

COMPARATIVE EXAMPLE 2 One study included 24 healthy men, aged 18 to 50 years. The subjects were subjected to cross-over experiments in four treatments, and the study periods were separated by a minimum of one week for drug failure. Subjects were reported at the clinical site the afternoon before each study period, and remained cloistered until after the last blood sample was collected 24 hours after dosing. Treatment A was a combination tablet that contained 200 mg of ibuprofen and 30 mg of pseudoephedrine. Treatment B was a Nuprin® (Bristol-Meyers) tablet containing 200 mg of ibuprofen. Treatment D was a Sudafed® tablet (Warner Lambert) containing 30 mg of pseudoephedrine. After overnight fasting, the subjects ingested the product, and immediately drank 200 ml of water. 8 ml of blood was collected before dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after dosing. Plasma was removed from the blood samples, and quantified for ibuprofen and pseudoephedrine separately using, respectively, high performance liquid chromatography and gas chromatography. The following single-dose pharmacokinetic parameters for plasma ibuprofen and pseudoephedrine were determined using non-compartmentalized methods: early drug exposure up to 1 hour (AUC 1H), early drug exposure up to 2 hours (AUC 2H), area under the time-concentration in plasma extrapolated to infinity (AUC INFINITE), and maximum concentration in plasma (CMAX) - The rate of drug absorption is reflected by (AUC IH), (AUC 2H) and (CMAX) - They were analyzed separately Means of the parameters of ibuprofen and pseudoephedrine creating a cross experiment in three treatments and four periods. The means for the combination product and ibuprofen or pseudoephedrine alone were compared by analysis of variance (ANOVA). From the ANOVA, statistically significant differences are detected in the means for p values less than 0.05. The average profiles of pseudoephedrine for the ibuprofen-pseudoephedrine combination tablet and for the Sudafed® tablet dosed alone and with a NUPRIN® tablet are shown in Figure 3. They are similarly shaped and virtually superimposed, indicating that buprofen did not change the absorption rate of pseudoephedrine when formulated into a solid dosage form. The results of the data analysis for pseudoephedrine are summarized in Tables 3 and 4, which clearly demonstrate that the rate of absorption of the amine was not affected by ibuprofen when formulated as a tablet. There were no statistically significant differences between any of the following means: AUC IH, AUC 2H, AUC INFINITO and CMAX- TABLE 3 Results of the pseudoephedrine (PSE) study, comparing treatments A and B NS = not statistically significant.

TABLE 4 Results of the pseudoephedrine (PSE) study, comparing treatments A and D NS = not statistically significant.

Claims (17)

NOVELTY OF THE INVENTION CLAIMS

1. A method for providing increased absorption of a pharmaceutically acceptable amine in the blood of a human, characterized in that it comprises providing a pharmacologically effective dosage of a pharmaceutically acceptable amine and an effective amount of a non-steroidal antiinflammatory acid drug in stable liquid form.

2. The method according to claim 1, further characterized in that the increased absorption is indicated by AUC IH (early drug exposure) which is at least approximately 10% greater than the early drug exposure of the same amine from a single ingredient liquid.

3. The method according to claim 1, further characterized in that the increased absorption is indicated by AUC 2 (early drug exposure) which is at least about 10% greater than the early drug exposure of the same amine from a single ingredient liquid.

4. The method according to claim 1, further characterized in that the increased absorption is indicated by a CMAX (maximum concentration) that is at least about 10% greater than the CMAX of the same amine from a liquid of a only ingredient.

5. The method according to claim 1, further characterized in that the stable liquid form is a suspension.

6. The method according to claim 1, further characterized in that the amine is pseudoephedrine.

7. The method according to claim 1, further characterized in that the non-steroidal anti-inflammatory drug is ibuprofen.

8. The method according to claim 6, further characterized in that the pseudoephedrine is provided on a scale of about 15 mg to about 60 mg per dosage unit.

9. The method according to claim 6, further characterized in that the pseudoephedrine is provided on a scale of about 15 mg to about 45 mg per dosage unit.

10. The method according to claim 7, further characterized in that the ibuprofen is provided in an amount of about 40 mg to about 800 mg per dosage unit.

11. The method according to claim 7, further characterized in that the ibuprofen is provided in an amount of about 40 mg to about 300 mg per dosage unit.

12. The method according to claim 1, further characterized in that the amine is pseudoephedrine at approximately 15 milligrams, and the non-steroidal anti-inflammatory is ibuprofen provided at a level of approximately 100 milligrams per 6 ml.

13. The method according to claim 1, further characterized in that the human is an infant.

14. A composition comprising a pharmacologically effective amount of a pharmaceutically acceptable amine and a pharmacologically effective amount of a non-steroidal anti-inflammatory drug, said amine and said non-steroidal antiinflammatory drug being provided in a stable liquid form.

15. The composition according to claim 14, further characterized in that the stable liquid form is a suspension.

16. The composition according to claim 14, further characterized in that the non-steroidal anti-inflammatory drug is ibuprofen, and the pharmaceutically acceptable amine is pseudoephedrine.

17. The composition according to claim 16, further characterized in that the ibuprofen is provided at a dosage of about 100 milligrams, and the pseudoephedrine is provided at a dosage of about 15 milligrams per 6 ml.