WO2005065674A1 - Pharmaceutical composition of 2-(4-isobutylphenyl) propionic acid - Google Patents

Pharmaceutical composition of 2-(4-isobutylphenyl) propionic acid Download PDF

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WO2005065674A1
WO2005065674A1 PCT/US2004/039770 US2004039770W WO2005065674A1 WO 2005065674 A1 WO2005065674 A1 WO 2005065674A1 US 2004039770 W US2004039770 W US 2004039770W WO 2005065674 A1 WO2005065674 A1 WO 2005065674A1
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ibuprofen
arginine
aqueous solution
pharmaceutical composition
molar ratio
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PCT/US2004/039770
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French (fr)
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Leo Pavliv
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Cumberland Pharmaceuticals, Inc.
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Publication of WO2005065674A1 publication Critical patent/WO2005065674A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

  • the present invention relates to a pharmaceutical composition for oral or injectable (parenteral) use containing 2-(4-isobutylphenyl) propionic acid and a basic amino acid, and more particularly, where the amino acid is arginine.
  • Nonproprietary Name is ibuprofen, is a well-known anti-inflammatory drug having a molecular weight of 206.28 and the following chemical structure:
  • Ibuprofen is readily available as the racemic mixture ((RS)-Ibuprofen) of the two enantiomers, (R)-Ibuprofen and (S)-Ibuprofen. Even though the (S) enantiomer is the biologically active form, most preparations contain the racemic mixture since the (R) enantiomer is converted to the active (S) form in- vivo.
  • ibuprofen will be used to indicate any one of the (R) enantiomer, the (S) enantiomer, or the racemate.
  • Many amino acids, including arginine, are available as both the D and L forms.
  • arginine will indicate the D or L form of arginine or a mixture of (D)-arginine and (L)-arginine.
  • Arginine has a molecular weight of 174.20.
  • ibuprofen has many advantages over other analgesics such as aspirin and acetaminophen, it is very poorly soluble in water.
  • U.S. Pat. No. 6,005,005 appears to describe a liquid composition for oral use containing ibuprofen and arginine.
  • the approaches described in the patents discussed above have, among others, the disadvantage of requiring the formation of a salt before solubilization, where the salt must be isolated and tested prior to producing the dosage form.
  • the ibuprofen formulations resulting from those processes have at least a 1:1 molar ratio of amino acid to ibuprofen. It is beneficial from both a cost and development point to not have to form a salt and isolate and test it prior to producing the dosage form. It is also beneficial in most cases to minimize the amount of non- active components, including salts, used in therapeutic products in order to minimize potential side effects.
  • an embodiment of the present invention is a pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen, wherein the molar ratio of arginine to ibuprofen is less than 1:1, and wherein the pH of the solution is less than about 7.8.
  • Another embodiment of the present invention is a method of making a pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen, wherein the molar ratio of arginine to ibuprofen is less than 1:1, and wherein the pH of the solution is less than about 7.8.
  • Still other embodiments of the present invention are directed to methods of treating pain, inflammation, fever, and/or other conditions alleviated by ibuprofen comprising administering a pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen, wherein the molar ratio of arginine to ibuprofen is less than 1:1, and wherein the pH of the solution is less than about 7.8.
  • the Figure shows plasma concentration-time curves for 400 mg oral and intravenous ibuprofen.
  • a liquid composition of ibuprofen can be produced by combining ibuprofen with arginine at molar ratios that minimize the amount of arginine necessary to solubilize the ibuprofen.
  • a pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen, wherein the molar ratio of arginine to ibuprofen is less than 1:1.
  • a pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen, wherein the molar ratio of arginine to ibuprofen is less than about 0.98: 1.
  • the molar ratio of arginine to ibuprofen is from about 0.10: 1 to about 0.999: 1. In a further embodiment of the invention, the molar ratio of arginine to ibuprofen is from about 0.97:1 to about 0.98:1. In yet other embodiments of the invention, the molar ratio of arginine to ibuprofen is about 0.97:1 or about 0.92:1 or about 0.60: 1 or about 0.99: 1.
  • the molar ratio of arginine to ibuprofen is about 0.90:1 or about 0.91:1 or about 0.93:1 or about 0.94:1 or about 0.95:1 or about 0.96:1 or about 0.98:1.
  • a liquid composition of ibuprofen can be produced by combining ibuprofen with arginine at molar ratios that minimize the amount of arginine necessary to solubilize the ibuprofen, and that achieve a composition having a pH that is suitable for injection.
  • another embodiment of the invention is a pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen, wherein the pH is less than about 7.8.
  • the pharmaceutical composition comprises an aqueous solution of arginine and ibuprofen, wherein the pH is from about 7.6 to about 7.8.
  • a further embodiment of the invention is a pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen, wherein the pH is about 7.6.
  • the pH of the solution is about 7.3 or about 7.4 or about 7.5 or about 7.7.
  • the present inventor has further discovered a method of making a pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen in a molar ratio of less than 1:1, wherein the method comprises the following: adding arginine to water, mixing until the arginine is dissolved to form an arginine solution, adding ibuprofen to the arginine solution, and mixing until the ibuprofen is dissolved to form the aqueous solution of arginine and ibuprofen, optionally adding sufficient water to result in the desired concentration of ibuprofen, and optionally separating any precipitate using standard methods such as filtration or centrifugation.
  • the resulting product is a clear, colorless solution that can readily be passed through a 0.2 micron filter.
  • the pH of the resulting solution can be adjusted using techniques known in the art to achieve a desired pH, for example a pH similar to that of blood.
  • the resulting solution can be terminally sterilized or lyophilized.
  • the ibuprofen can be added prior to the arginine, or the arginine and ibuprofen can be added at the same time.
  • the pH of the solution can be adjusted by adding additional arginine or ibuprofen to achieve the desired pH.
  • an aqueous solution of arginine and ibuprofen is prepared that results in a molar ratio of less than 1:1, and then additional arginine is added to achieve a pH of about 7.6 to about 7.8.
  • the present inventor has further discovered a method of treating a condition chosen from pain, inflammation, fever, and/or other conditions alleviated by ibuprofen comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen, wherein the molar ratio of arginine to ibuprofen is less than 1:1.
  • the present inventor has discovered a method of treating a condition chosen from pain, inflammation, fever, and or other conditions alleviated by ibuprofen comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen, wherein pH of the aqueous solution is less than about 7.8.
  • Other conditions alleviated by ibuprofen include, but are not limited to, patent ductus arteriosis and certain forms of cancer.
  • the pharmaceutical composition may be administered by injection (intravenous or intramuscular) or orally. Dosages of the pharmaceutical composition range from about 5 to about 1000 mg of ibuprofen in the pharmaceutical composition and can be determined by one of ordinary skill in the art.
  • the dosage is from about 100 to about 800 mg of ibuprofen in the pharmaceutical composition. In a further embodiment, the dosage is about 400 mg of ibuprofen in the pharmaceutical composition, hi still another embodiment, the dosage of the pharmaceutical composition is from about 5 to about 10 mg/kg, and in a further embodiment the dosage of the pharmaceutical composition is about 7.5 mg/kg.
  • the following examples represent specific embodiments of the foregoing discovery, and they are not representative of the entire scope of the invention.
  • the ibuprofen and arginine used in the examples are United States Pharmacopoea grade, but other pharmaceutically acceptable materials can be utilized.
  • Example 1 [019] Add 8.2 kg of arginine to approximately 80 liters of water for injection and mix until dissolved.
  • Example 3 Lower concentrations of arginine can be used to prepare the ibuprofen solution. Add 3.8 kg of arginine to approximately 80 liters of water for injection and mix until dissolved. Add 7.5 kg of ibuprofen to the arginine solution and mix until dissolved. Add a sufficient quantity of water to equal 100 liters, resulting in a 75mg/mL solution having a molar ratio of 0.60: 1 (arginine ⁇ buprofen). The product can be passed through a 0.2 micron filter resulting in a clear colorless solution. The pH of the resulting solution can be adjusted to achieve a desirable pH.
  • Example 4 Higher concentrations of arginine can be used to prepare the ibuprofen solution. Add 8.43 g of arginine to 80 mL of water for injection and mix until dissolved. Add 10 g of ibuprofen to the arginine solution and mix until dissolved. Add a sufficient quantity of water to equal 100 mL, resulting in a lOOmg/mL solution having a molar ratio of 0.99:1 (arginine buprofen). The product results in a clear, colorless, solution that can readily be passed through a 0.2 micron filter. The pH of the resulting solution can be adjusted to achieve a desirable pH.
  • Example 5 [023] 4.384 kg of arginine were added to approximately 45 liters of water for injection and mixed until dissolved. 5.62 kg of ibuprofen were added to the arginine solution and mixed until dissolved. The pH of the resulting solution was approximately 7.4, but could be adjusted to achieve somewhat lower or higher pH's as desired. A sufficient quantity of water was added to the resulting solution to equal 56.2 liters, resulting in a 100 mg/mL solution having a molar ratio of 0.92:1 (arginine:ibuprofen). The product resulted in a clear, colorless solution that could readily be passed through a 0.2 micron filter. The solution was terminally sterilized to assure that the product was sterilized.
  • Example 6 In an attempt to demonstrate similar pharmacokinetics between a 60 minute infusion of intravenous ibuprofen solubilized with arginine as in Example 5 and oral ibuprofen (in the form of Advil® Liqui-Gels®), volunteers received single oral or intravenous doses (200 mg, 400 mg, or 800 mg) of either oral or intravenous ibuprofen product. Blood samples were collected at specified times relative to the start of dosing, and plasma ibuprofen concentrations were measured.
  • Example 7 [027] Add 8.2 kg of arginine to approximately 60 liters of water for injection and mix until dissolved. Add 10.0 kg of ibuprofen to the arginine solution and mix until resulting solution is clear and ibuprofen has been dissolved. Add additional arginine to achieve a pH of about 7.6 to about 7.8.
  • Example 8 Five aqueous solutions of arginine and ibuprofen were prepared, each with a different molar ratio of arginine to ibuprofen.
  • the first column of Table 2 identifies the molar ratio of each aqueous solution.
  • compositions comprising arginine and ibuprofen and their associated pH

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Abstract

The present invention provides a pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen, wherein the molar ratio of arginine to ibuprofen is less than 1:1, as well as a method of making the same. The present invention also provides a pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen, wherein the solution has a pH of less than about 7.8, as well as a method of making the same. The present invention also provides a method of treating a condition chosen from pain, inflammation, fever, and/or other conditions alleviated by ibuprofen comprising administering a pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen, wherein the molar ratio of arginine to ibuprofen is less than 1:1, and wherein the molar ratio of arginine to ibuprofen is selected to achieve a pH of less than about 7.8.

Description

PHARMACEUTICAL COMPOSITION OF 2-(4- ISOBUTYLPHENYL) PROPIONIC ACID [001] This application is a continuation-in-part application of Application No. 09/985,246, which is hereby incorporated by reference in its entirety. [002] The present invention relates to a pharmaceutical composition for oral or injectable (parenteral) use containing 2-(4-isobutylphenyl) propionic acid and a basic amino acid, and more particularly, where the amino acid is arginine.
Background of Invention [003] 2-(4-isobutylphenyl) propionic acid, whose International
Nonproprietary Name is ibuprofen, is a well-known anti-inflammatory drug having a molecular weight of 206.28 and the following chemical structure:
Figure imgf000002_0001
(Merck Index 12th ed., n4925, page 839). Originally patented in the 1960's, ibuprofen is now marketed generically, as well as under the tradenames of Motrin®, Advil®, and Nuprin® for the treatment of pain, inflammation, and fever. [004] Ibuprofen is readily available as the racemic mixture ((RS)-Ibuprofen) of the two enantiomers, (R)-Ibuprofen and (S)-Ibuprofen. Even though the (S) enantiomer is the biologically active form, most preparations contain the racemic mixture since the (R) enantiomer is converted to the active (S) form in- vivo. For simplicity, hereinafter the term "ibuprofen" will be used to indicate any one of the (R) enantiomer, the (S) enantiomer, or the racemate. [005] Many amino acids, including arginine, are available as both the D and L forms. For simplicity, hereinafter the term "arginine" will indicate the D or L form of arginine or a mixture of (D)-arginine and (L)-arginine. Arginine has a molecular weight of 174.20. [006] Although ibuprofen has many advantages over other analgesics such as aspirin and acetaminophen, it is very poorly soluble in water. Thus, certain dosage forms of ibuprofen, especially oral or injectable liquids, have been difficult to develop. Several U.S. patents have addressed this problem. [007] For example, U.S. Pat. No. 4,309,421 appears to describe water- soluble complexes of ibuprofen and phospholipids suitable for parenteral administration. U.S. Pat. Nos. 4,859,704 and 4,861,797 appear to describe the synthesis of alkali metal salts of ibuprofen for preparing a liquid ibuprofen formulation. [008] Other U.S. patents appear to address this problem by preparing an ibuprofen salt with a basic amino acid as the active pharmaceutical ingredient and then solubilizing the salt to produce a liquid dosage form. [009] For example, U.S. Pat. No. 5,200,558 appears to describe enhanced analgesic effects of S (+) ibuprofen as salts of L and D amino acids, including arginine, in various dosage forms, including as an injectable solution. U.S. Pat. No. 4,279,926 appears to describe the use of basic amino acid salts of propionic acids for relieving pain and treating inflammatory conditions. Similarly, U.S. Pat. No. 5,463,117 appears to describe the preparation of salts of ibuprofen with basic amino acids. Finally, U.S. Pat. No. 6,005,005 appears to describe a liquid composition for oral use containing ibuprofen and arginine. [010] However, the approaches described in the patents discussed above have, among others, the disadvantage of requiring the formation of a salt before solubilization, where the salt must be isolated and tested prior to producing the dosage form. Additionally, the ibuprofen formulations resulting from those processes have at least a 1:1 molar ratio of amino acid to ibuprofen. It is beneficial from both a cost and development point to not have to form a salt and isolate and test it prior to producing the dosage form. It is also beneficial in most cases to minimize the amount of non- active components, including salts, used in therapeutic products in order to minimize potential side effects. Furthermore, for injectable products it is beneficial to produce a liquid dosage form of ibuprofen having a pH similar to that of blood (pH 7.4). Finally, it is beneficial for an injectable and oral product to have similar pharmacokinetics to minimize the need for dosage adjustments. Summary of the Invention [011] The present invention utilizes arginine to solubilize ibuprofen during the manufacture of the pharmaceutical product instead of using a salt form of ibuprofen. Thus, an embodiment of the present invention is a pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen, wherein the molar ratio of arginine to ibuprofen is less than 1:1, and wherein the pH of the solution is less than about 7.8. Another embodiment of the present invention is a method of making a pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen, wherein the molar ratio of arginine to ibuprofen is less than 1:1, and wherein the pH of the solution is less than about 7.8. Still other embodiments of the present invention are directed to methods of treating pain, inflammation, fever, and/or other conditions alleviated by ibuprofen comprising administering a pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen, wherein the molar ratio of arginine to ibuprofen is less than 1:1, and wherein the pH of the solution is less than about 7.8.
Brief Description of the Figure [012] The Figure shows plasma concentration-time curves for 400 mg oral and intravenous ibuprofen.
Detailed Description of the Invention [013] The present inventor has discovered that a liquid composition of ibuprofen can be produced by combining ibuprofen with arginine at molar ratios that minimize the amount of arginine necessary to solubilize the ibuprofen. Thus, one embodiment of the present invention is a pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen, wherein the molar ratio of arginine to ibuprofen is less than 1:1. Another embodiment of the invention is a pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen, wherein the molar ratio of arginine to ibuprofen is less than about 0.98: 1. In another embodiment of the invention, the molar ratio of arginine to ibuprofen is from about 0.10: 1 to about 0.999: 1. In a further embodiment of the invention, the molar ratio of arginine to ibuprofen is from about 0.97:1 to about 0.98:1. In yet other embodiments of the invention, the molar ratio of arginine to ibuprofen is about 0.97:1 or about 0.92:1 or about 0.60: 1 or about 0.99: 1. In still yet other embodiments of the invention, the molar ratio of arginine to ibuprofen is about 0.90:1 or about 0.91:1 or about 0.93:1 or about 0.94:1 or about 0.95:1 or about 0.96:1 or about 0.98:1. [014] The present inventor has further discovered that a liquid composition of ibuprofen can be produced by combining ibuprofen with arginine at molar ratios that minimize the amount of arginine necessary to solubilize the ibuprofen, and that achieve a composition having a pH that is suitable for injection. Thus, another embodiment of the invention is a pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen, wherein the pH is less than about 7.8. In yet another embodiment of the invention, the pharmaceutical composition comprises an aqueous solution of arginine and ibuprofen, wherein the pH is from about 7.6 to about 7.8. A further embodiment of the invention is a pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen, wherein the pH is about 7.6. In still other embodiments, the pH of the solution is about 7.3 or about 7.4 or about 7.5 or about 7.7. [015] The present inventor has further discovered a method of making a pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen in a molar ratio of less than 1:1, wherein the method comprises the following: adding arginine to water, mixing until the arginine is dissolved to form an arginine solution, adding ibuprofen to the arginine solution, and mixing until the ibuprofen is dissolved to form the aqueous solution of arginine and ibuprofen, optionally adding sufficient water to result in the desired concentration of ibuprofen, and optionally separating any precipitate using standard methods such as filtration or centrifugation. The resulting product is a clear, colorless solution that can readily be passed through a 0.2 micron filter. The pH of the resulting solution can be adjusted using techniques known in the art to achieve a desired pH, for example a pH similar to that of blood. Finally, the resulting solution can be terminally sterilized or lyophilized. [016] Alternatively, the ibuprofen can be added prior to the arginine, or the arginine and ibuprofen can be added at the same time. Moreover, the pH of the solution can be adjusted by adding additional arginine or ibuprofen to achieve the desired pH. For example, in one embodiment of the invention, an aqueous solution of arginine and ibuprofen is prepared that results in a molar ratio of less than 1:1, and then additional arginine is added to achieve a pH of about 7.6 to about 7.8. [017] The present inventor has further discovered a method of treating a condition chosen from pain, inflammation, fever, and/or other conditions alleviated by ibuprofen comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen, wherein the molar ratio of arginine to ibuprofen is less than 1:1. Additionally, the present inventor has discovered a method of treating a condition chosen from pain, inflammation, fever, and or other conditions alleviated by ibuprofen comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen, wherein pH of the aqueous solution is less than about 7.8. Other conditions alleviated by ibuprofen include, but are not limited to, patent ductus arteriosis and certain forms of cancer. The pharmaceutical composition may be administered by injection (intravenous or intramuscular) or orally. Dosages of the pharmaceutical composition range from about 5 to about 1000 mg of ibuprofen in the pharmaceutical composition and can be determined by one of ordinary skill in the art. In one embodiment, the dosage is from about 100 to about 800 mg of ibuprofen in the pharmaceutical composition. In a further embodiment, the dosage is about 400 mg of ibuprofen in the pharmaceutical composition, hi still another embodiment, the dosage of the pharmaceutical composition is from about 5 to about 10 mg/kg, and in a further embodiment the dosage of the pharmaceutical composition is about 7.5 mg/kg. [018] The following examples represent specific embodiments of the foregoing discovery, and they are not representative of the entire scope of the invention. The ibuprofen and arginine used in the examples are United States Pharmacopoea grade, but other pharmaceutically acceptable materials can be utilized. Example 1 [019] Add 8.2 kg of arginine to approximately 80 liters of water for injection and mix until dissolved. Add 10.0 kg of ibuprofen to the arginine solution and mix until dissolved. Add a sufficient quantity of water to equal 100 liters, resulting in a lOOmg/mL solution having a molar ratio of 0.97: 1 (arginine:ibuprofen). The product results in a clear, colorless, solution that can readily be passed through a 0.2 micron filter. The pH of the resulting solution is approximately 7.4 and can be adjusted to achieve somewhat lower or higher pH's as desired. The solution can further be terminally sterilized to minimize the likelihood of a non-sterile product. Example 2 [020] Lower concentrations of ibuprofen can be prepared by using lesser amounts of arginine and ibuprofen. Add 41 g of arginine to approximately 80 liters of water for injection and mix until dissolved. Add 50 g of ibuprofen to the arginine solution and mix until dissolved. Add a sufficient quantity of water to equal 100 liters, resulting in a 0.5mg/mL solution having a molar ratio of 0.97:1 (arginine buprofen). The product results in a clear, colorless, solution that can readily be passed through a 0.2 micron filter. The pH of the resulting solution can be adjusted to achieve a desirable pH.
Example 3 [021] Lower concentrations of arginine can be used to prepare the ibuprofen solution. Add 3.8 kg of arginine to approximately 80 liters of water for injection and mix until dissolved. Add 7.5 kg of ibuprofen to the arginine solution and mix until dissolved. Add a sufficient quantity of water to equal 100 liters, resulting in a 75mg/mL solution having a molar ratio of 0.60: 1 (arginineύbuprofen). The product can be passed through a 0.2 micron filter resulting in a clear colorless solution. The pH of the resulting solution can be adjusted to achieve a desirable pH. Example 4 [022] Higher concentrations of arginine can be used to prepare the ibuprofen solution. Add 8.43 g of arginine to 80 mL of water for injection and mix until dissolved. Add 10 g of ibuprofen to the arginine solution and mix until dissolved. Add a sufficient quantity of water to equal 100 mL, resulting in a lOOmg/mL solution having a molar ratio of 0.99:1 (arginine buprofen). The product results in a clear, colorless, solution that can readily be passed through a 0.2 micron filter. The pH of the resulting solution can be adjusted to achieve a desirable pH. Example 5 [023] 4.384 kg of arginine were added to approximately 45 liters of water for injection and mixed until dissolved. 5.62 kg of ibuprofen were added to the arginine solution and mixed until dissolved. The pH of the resulting solution was approximately 7.4, but could be adjusted to achieve somewhat lower or higher pH's as desired. A sufficient quantity of water was added to the resulting solution to equal 56.2 liters, resulting in a 100 mg/mL solution having a molar ratio of 0.92:1 (arginine:ibuprofen). The product resulted in a clear, colorless solution that could readily be passed through a 0.2 micron filter. The solution was terminally sterilized to assure that the product was sterilized.
Example 6 [024] In an attempt to demonstrate similar pharmacokinetics between a 60 minute infusion of intravenous ibuprofen solubilized with arginine as in Example 5 and oral ibuprofen (in the form of Advil® Liqui-Gels®), volunteers received single oral or intravenous doses (200 mg, 400 mg, or 800 mg) of either oral or intravenous ibuprofen product. Blood samples were collected at specified times relative to the start of dosing, and plasma ibuprofen concentrations were measured. The following pharmacokinetic parameters were calculated: Cmax(maximum concentration), AUC0- 12 (area under the curve from initial time to 12 hours), AUCo-∞, (area under the curve from initial time to infinity), Tmaχ (time of maximum concentration), kei (elimination constant), and tι/2(half life). Statistical analyses were performed on the plasma concentration data and pharmacokinetic parameters were calculated for the 12 patients on each of the three doses examined. [025] The plasma concentration-time profiles for both oral and intravenous administration of ibuprofen were observed to be very similar. The concentration-time data for the 400-mg oral and intravenous doses are shown in the Figure to illustrate this result. On the basis of the ibuprofen concentration-time data, the following pharmacokinetic parameters were calculated (Table 1).
Table 1. Pharmacokinetic Parameters After Oral and Intravenous Administration of Ibuprofen
Figure imgf000010_0001
Data shown are mean + standard deviation.
[026] The linearity of ibuprofen pharmacokinetics after oral and intravenous administration was analyzed. The results indicated that for both intravenous ibuprofen and oral ibuprofen, AUCo-ι2, AUCo-∞, and Cmax increased in an appropriately linear manner with dose. Example 7 [027] Add 8.2 kg of arginine to approximately 60 liters of water for injection and mix until dissolved. Add 10.0 kg of ibuprofen to the arginine solution and mix until resulting solution is clear and ibuprofen has been dissolved. Add additional arginine to achieve a pH of about 7.6 to about 7.8. Add a sufficient quantity of water to equal 100 liters, resulting in a 100 mg/mL ibuprofen solution. The product results in a clear, colorless, solution that can readily be passed through a 0.2 micron filter. The solution can further be terminally sterilized to minimize the likelihood of a non- sterile product.
Example 8 [028] Five aqueous solutions of arginine and ibuprofen were prepared, each with a different molar ratio of arginine to ibuprofen. The first column of Table 2 identifies the molar ratio of each aqueous solution. In order to prepare each of those solutions, the amount of arginine (in grams) identified in the second column of Table
2 was added to approximately 15 to 20 mL of water while stirring until the arginine was completely dissolved. Next, for each solution, 2.500 g of ibuprofen was added, as indicated in the third column of Table 2, and mixed until dissolved. Finally, a sufficient amount of water was added to each solution to attain a final volume of 25 mL for each solution. The concentrations of all solutions were lOOmg/mL ibuprofen. The five solutions were visually compared, and all resulted in clear colorless aqueous solutions with no visible precipitate. A standard pH meter calibrated with appropriate pH standards was then used to measure the pH of each solution. The results are shown for each solution in the final column of Table 2.
Table 2. Compositions comprising arginine and ibuprofen and their associated pH
Figure imgf000011_0001
[029] The results of the comparative test illustrated in Table 2 show that the presently claimed invention, i.e., compositions comprising an aqueous solution of arginine and ibuprofen, wherein the molar ratio of arginine to ibuprofen is less than 1:1, unexpectedly resulted in solutions exhibiting both: (1) complete dissolution of ibuprofen and (2) pH values of less than 7.8. This unexpected result is in contrast to the compositions with a molar ratio of equal to or greater than 1:1, which yielded pH values of greater than or equal to 7.8.

Claims

I claim:
1. A pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen, wherein the pH of the aqueous solution of arginine and ibuprofen is less than about 7.8.
2. The pharmaceutical composition of claim 1, wherein the aqueous solution of arginine and ibuprofen has been terminally sterilized.
3. The pharmaceutical composition of claim 1, wherein the aqueous solution of arginine and ibuprofen has been lyophilized.
4. The pharmaceutical composition of claim 1, wherein the ibuprofen is (RS)- Ibuprofen.
5. The pharmaceutical composition of claim 1, wherein the ibuprofen is (S)- Ibuprofen.
6. The pharmaceutical composition of claim 1, wherein the arginine is L- arginine.
7. The pharmaceutical composition of claim 1, wherein the arginine is D- arginine.
8. The pharmaceutical composition of claim 1, wherein the molar ratio of arginine to ibuprofen is less than about 0.98: 1.
9. The pharmaceutical composition of claim 8, wherein the molar ratio of arginine to ibuprofen is from about 0.97:1 to about 0.98:1.
10. The pharmaceutical composition of claim 9, wherein the molar ratio of arginine to ibuprofen is about 0.98: 1.
11. The pharmaceutical composition of claim 8, wherein the molar ratio of arginine to ibuprofen is about 0.95:1.
12. The pharmaceutical composition of claim 1, wherein the pH of the aqueous solution of arginine and ibuprofen is from about 7.6 to about 7.8.
13. The pharmaceutical composition of claim 12, wherein the pH of the aqueous solution of arginine and ibuprofen is about 7.6.
14. The pharmaceutical composition of claim 12, wherein the pH of the aqueous solution of arginine and ibuprofen is about 7.7.
15. A method of making a pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen, the method comprising dissolving arginine and ibuprofen in water to form the aqueous solution of arginine and ibuprofen, wherein the molar ratio of arginine to ibuprofen is less than 1:1.
16. The method of claim 15, wherein the molar ratio of arginine to ibuprofen is less than about 0.98:1.
17. The method of claim 16, wherein the molar ratio of arginine to ibuprofen is from about 0.97:1 to about 0.98:1.
18. The method of claim 17, wherein the molar ratio of arginine to ibuprofen is about 0.98:1.
19. The method of claim 16, wherein the molar ratio of arginine to ibuprofen is about 0.95:1.
20. The method of claim 15, further comprising adding additional arginine or ibuprofen so that the pH of the aqueous solution of arginine and ibuprofen is from about 7.6 to about 7.8.
21. The method of claims 20, wherein the pH of the aqueous solution of arginine and ibuprofen is about 7.6.
22. The method of claims 20, wherein the pH of the aqueous solution of arginine and ibuprofen is about 7.7.
23. The method of claim 15, further comprising terminally sterilizing the aqueous solution of arginine and ibuprofen.
24. The method of claim 15, further comprising lyophilizing the aqueous solution of arginine and ibuprofen.
25. The method of claim 15, wherein the ibuprofen is (RS)-Ibuprofen.
26. The method of claim 15, wherein the ibuprofen is (S)-Ibuprofen.
27. The method of claim 15, wherein the arginine is L-arginine.
28. The method of claim 15, wherein the arginine is D-arginine.
29. A pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen prepared according to the method of claim 15.
30. A pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen prepared according to the method of claim 20.
31. A method of treating a condition chosen from pain, inflammation, fever, and patent ductus arteriosis, comprising administering to a patient in need thereof an effective amount of an aqueous solution of arginine and ibuprofen, wherein the pH of the aqueous solution of arginine and ibuprofen is less than about 7.8.
32. The method of claim 31, wherein the molar ratio of arginine to ibuprofen is less than about 0.98:1.
33. The method of claim 32, wherein the molar ratio of arginine to ibuprofen is from about 0.97:1 to about 0.98:1.
34. The method of claim 33, wherein the molar ratio of arginine to ibuprofen is from about 0.98:1.
33. The method of claim 32, wherein the molar ratio of arginine to ibuprofen about 0.95:1.
36. The method of claim 31, wherein the pH of the aqueous solution of arginine and ibuprofen is from about 7.6 to about 7.8.
37. The method of claim 36, wherein the pH of the aqueous solution of arginine and ibuprofen is about 7.6.
38. The method of claim 36, wherein the pH of the aqueous solution of arginine and ibuprofen is about 7.7.
39. The method of claim 31, wherein the administration occurs via intravenous injection.
40. The method of claim 31, wherein the administration occurs via intramuscular injection.
41. The method of claim 31 , wherein the administration occurs orally.
42. The method of claim 31, wherein the effective amount is from about 100 mg to about 800 mg of ibuprofen.
43. The method of claim 42, wherein the effective amount is about 400 mg of ibuprofen.
44. The method of claim 31, wherein the effective amount is about 7.5 mg/kg of ibuprofen.
45. The method of claim 31, wherein the condition is pain.
46. The method of claim 31, wherein the condition is inflammation.
47. The method of claim 31 , wherein the condition is fever.
48. The method of claim 31, wherein the condition is patent ductus arteriosis.
PCT/US2004/039770 2003-12-19 2004-12-17 Pharmaceutical composition of 2-(4-isobutylphenyl) propionic acid WO2005065674A1 (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102160852A (en) * 2010-02-23 2011-08-24 付正香 Ibuprofen injection and preparation method thereof
WO2011144677A1 (en) 2010-05-18 2011-11-24 Spain Pharma, S.A. Pharmaceutical composition of ibuprofen for injection
CN102871957A (en) * 2011-02-21 2013-01-16 陕西合成药业有限公司 Dexibuprofen intravenous administration preparation and preparation method thereof
CN108158980A (en) * 2016-12-07 2018-06-15 浙江普利药业有限公司 Arginine Ibuprofen parenteral solution and preparation method thereof

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040132823A1 (en) * 2001-11-02 2004-07-08 Leo Pavliv Pharmaceutical composition of 2-(4-isobutylphenyl) propionic acid
ES2823249T3 (en) * 2009-03-12 2021-05-06 Cumberland Pharmaceuticals Inc Ibuprofen administration intravenously
US20110028556A1 (en) * 2009-07-31 2011-02-03 Cumberland Pharmaceuticals, Inc. Treating critically ill patients with intravenous ibuprofen
US8735452B2 (en) * 2009-07-15 2014-05-27 Cumberland Pharmaceuticals Inc. Treating patients with intravenous ibuprofen
US8871810B2 (en) 2009-07-15 2014-10-28 Cumberland Pharmaceuticals Inc. Treating critically ill patients with intravenous ibuprofen
EP2636406B1 (en) * 2012-02-20 2015-08-12 Pharmaceutical Solutions Industry Ltd Ibuprofen Intravenous Infusion
CN106890137B (en) * 2012-03-16 2020-09-25 坎伯兰医药品股份有限公司 Injectable ibuprofen formulations
US9072661B2 (en) 2012-03-16 2015-07-07 Cumberland Pharmaceuticals Inc. Injectable ibuprofen formulation
US9072710B2 (en) 2012-03-16 2015-07-07 Cumberland Pharmaceuticals Inc. Injectable ibuprofen formulation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003039532A1 (en) * 2001-11-02 2003-05-15 Cumberland Pharmaceuticals Inc. Pharmaceutical composition of 2-(4-isobutylphenyl) propionic acid
US20040132823A1 (en) * 2001-11-02 2004-07-08 Leo Pavliv Pharmaceutical composition of 2-(4-isobutylphenyl) propionic acid

Family Cites Families (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6021570B2 (en) * 1978-07-04 1985-05-28 三共株式会社 Method for manufacturing high concentration preparations of DOPAs
US4439452A (en) * 1979-02-14 1984-03-27 Seymour Enrenpreis Class of analgesics and/or anti-inflammatory agents consisting of inhibitors of breakdown of endogenous enkephalin and/or endorphin, and combinations of said analgesics with antipyretic, anti-inflammatory (aspirin-type) drugs
DE2914788A1 (en) * 1979-04-11 1980-10-16 Nattermann A & Cie PARENTERAL APPLICABLE, STABLE DRUG SOLUTIONS WITH ANTI-INFLAMMATORY EFFECT
US4337273A (en) * 1980-05-15 1982-06-29 Thomas Jefferson University Methods of increasing coronary blood flow through vasodilation by flurbiprofen
US4282252A (en) * 1980-05-15 1981-08-04 Thomas Jefferson University Method of increasing coronary blood flow with ibuprofen
US4346108A (en) * 1981-06-22 1982-08-24 The Upjohn Manufacturing Company M Method for preventing adhesion formation
US4701470A (en) * 1982-12-06 1987-10-20 The Upjohn Company Treatment of Type II Herpes virus with ibuprofen
US4439450A (en) * 1983-06-30 1984-03-27 The Upjohn Manufacturing Company M Treatment of the blood-brain barrier with ibuprofen
DE3328401A1 (en) * 1983-08-05 1985-02-21 Merckle GmbH, 7902 Blaubeuren INJECTABLE SOLUTION FOR TREATING INFLAMMATION
US4472420A (en) * 1983-08-18 1984-09-18 Methodist Hospital Of Indiana, Inc. Method for treatment of shock
EP0284612B1 (en) * 1986-01-30 1991-07-24 University of Utah Treatment of bone loss
IT1213301B (en) * 1986-07-14 1989-12-20 Zambon Spa COMPOSITIONS FOR THE TREATMENT OF SYNDROMES FROM ISCHEMIA AND REPERFUSION
US4684666A (en) * 1986-08-19 1987-08-04 Haas Pharmaceuticals, Inc. Stabilized liquid analgesic compositions
US5519057A (en) * 1986-11-14 1996-05-21 Johnson & Johnson--Merck Pharmaceuticals Co. Ibuprofen-containing medicament
CA1319886C (en) * 1987-02-03 1993-07-06 Alberto Ferro Mixed micelle solutions
CA1324083C (en) * 1987-03-09 1993-11-09 Tetsu Miyoshi Pharmaceutical preparations containing non-steroidal anti-inflammatory agents
US4851444A (en) * 1987-07-10 1989-07-25 Analgesic Associates Onset-hastened/enhanced analgesia
US4980375A (en) * 1987-07-10 1990-12-25 Sterling Drug Inc. Onset-hastened/enhanced antipyretic response
US4861797A (en) * 1987-10-15 1989-08-29 Oratech Pharmaceutical Development Corporation Liquid ibuprofen compositions and methods of making them
US4859704A (en) * 1987-10-15 1989-08-22 Oratech Pharmaceutical Development Corporation Water soluble ibuprofen compositions and methods of making them
CH677606A5 (en) * 1988-07-12 1991-06-14 Aesculapius Pharma Sa
DE3838431A1 (en) * 1988-11-12 1990-05-17 Bayer Ag IBUPROFEN SHOWER PREPARATIONS
US4975465A (en) * 1989-03-28 1990-12-04 American Home Products Corporation Orally administrable ibuprofen compositions
US5100918A (en) * 1989-05-25 1992-03-31 Sterling Drug, Inc. Prevention or treatment of sunburn using the S(+) isomer of ibuprofen
NZ234143A (en) * 1989-06-28 1991-10-25 Mcneil Ppc Inc Aqueous pharmaceutical suspension formulation for administering substantially insoluble pharmaceutical agents
US5262179A (en) * 1989-09-13 1993-11-16 Nicholas Kiwi Pty Ltd. Non-effervescent ibuprofen compositions
US5460825A (en) * 1990-05-23 1995-10-24 Mcneil-Ppc, Inc. Taste mask coatings for preparing chewable pharmaceutical tablets
US5102668A (en) * 1990-10-05 1992-04-07 Kingaform Technology, Inc. Sustained release pharmaceutical preparation using diffusion barriers whose permeabilities change in response to changing pH
US5210099A (en) * 1991-02-11 1993-05-11 American Home Products Corporation Analgesic compositions
WO1992015332A1 (en) * 1991-03-04 1992-09-17 Warner-Lambert Company Novel salts/ion pairs of non-steroidal anti-inflammatory drugs in various dosage forms
US5192753A (en) * 1991-04-23 1993-03-09 Mcgeer Patrick L Anti-rheumatoid arthritic drugs in the treatment of dementia
US5145674A (en) * 1991-04-30 1992-09-08 The Dow Chemical Company Biologically-active compounds comprising a biologically-active anionic portion and a water-insoluble, inorganic cationic portion
US5179097A (en) * 1991-06-10 1993-01-12 Angres Isaac A Salts of non-steroidal anti-inflammatory carboxylic acids and anti-lipidemic carboxylic acids
US5264220A (en) * 1991-11-12 1993-11-23 Long David M Jr Method of extending the vascular dwell-time of particulate therapeutic and particulate diagnostic agents
US5332834A (en) * 1992-12-02 1994-07-26 Hoechst Celanese Corporation Racemization of an enantomerically enriched α-aryl carboxylic acid
US5310961A (en) * 1993-07-02 1994-05-10 Affinity Biotech, Inc. Neomorphic ibuprofen
US5466865A (en) * 1993-07-02 1995-11-14 Ibah, Inc. Neomorphic ibuprofen and methods of using same
US5672358A (en) * 1994-06-21 1997-09-30 Ascent Pharmaceuticals, Inc. Controlled release aqueous emulsion
IT1277741B1 (en) * 1995-12-28 1997-11-12 Dompe Spa PARENTERAL PHARMACEUTICAL COMPOSITIONS CONTAINING ALKYLAMMONIUM SALTS OF 2-ARYLPROPIONIC ACIDS
US5712310A (en) * 1996-06-14 1998-01-27 Alpharma Uspd, Inc. Suspension of substantially water-insoluble drugs and methods of their manufacture
GB9625589D0 (en) * 1996-12-10 1997-01-29 Boots Co Plc Therapeutic agents
US6342530B1 (en) * 2000-11-14 2002-01-29 Farmacon-Il, Llc Composition and method for parenteral administration of ibuprofen d,l- or l-lysine salt

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003039532A1 (en) * 2001-11-02 2003-05-15 Cumberland Pharmaceuticals Inc. Pharmaceutical composition of 2-(4-isobutylphenyl) propionic acid
US20040132823A1 (en) * 2001-11-02 2004-07-08 Leo Pavliv Pharmaceutical composition of 2-(4-isobutylphenyl) propionic acid

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102160852A (en) * 2010-02-23 2011-08-24 付正香 Ibuprofen injection and preparation method thereof
WO2011144677A1 (en) 2010-05-18 2011-11-24 Spain Pharma, S.A. Pharmaceutical composition of ibuprofen for injection
WO2011144766A1 (en) 2010-05-18 2011-11-24 Spain Pharma, S.A. Pharmaceutical composition of ibuprofen for injection
CN102871957A (en) * 2011-02-21 2013-01-16 陕西合成药业有限公司 Dexibuprofen intravenous administration preparation and preparation method thereof
CN108158980A (en) * 2016-12-07 2018-06-15 浙江普利药业有限公司 Arginine Ibuprofen parenteral solution and preparation method thereof

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