Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-05
2004-02-24
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S484000, C548S486000, C424S451000
Reexamination Certificate
active
06696482
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides liquid, semi-solid or solid pharmaceutical formulations that improve the oral bioavailability of hydrophobic pharmaceutical agents, such as indolinone-, quinazoline-, and nitrothiazole-based compounds. Also provided are formulations for parenteral delivery of such hydrophobic pharmaceutical agents, as well as methods of making and using both types of formulations.
BACKGROUND OF THE INVENTION
The following description of the background of the invention is provided to aid in understanding the invention, but is not admitted to describe or constitute prior art to the invention.
Various methods are available for administering therapeutic agents to a patient. Such methods include, parenteral, oral, ocular, nasal, topical, and transmucosal administration. Variations of these different types of administrations exist. For example, parenteral administration includes intravenous, subcutaneous, intraperitoneal, intramuscular, and intramedullary injection. The chosen mode of administration should take into account the nature of the therapeutic compound and the illness being treated.
Certain potential pharmaceuticals are hydrophobic and typically have very low aqueous solubility and hence low oral bioavailability. Different techniques concerned with solubilizing hydrophobic compounds include those described by Praveen et al., U.S. Pat. No. 5,314,685, and Fernandes et al., U.S. Pat. No. 4,992,271, both of which are incorporated by reference herein in their entirety including any figures and drawings.
One measure of the potential usefulness of an oral formulation of a new pharmaceutical agent is the bioavailability observed after oral administration of the formulation. Various factors can affect the oral bioavailability of the drug. These factors include aqueous solubility, drug absorption throughout the gastrointestinal tract, dosage strength, and first pass effect. Aqueous solubility is one of the most important factors. The oral bioavailability of an aqueous solution formulation of a drug is generally used as the standard or the ideal bioavailability against which other oral formulations are measured. Formulations of drugs that increase the relative bioavailability of the drug as compared to an aqueous solution are desirable, especially with hydrophobic compounds.
SUMMARY OF THE INVENTION
The present invention features formulations (including formulations for oral administration as well as parenteral administration) for hydrophobic pharmaceutical agents, such as indolinone-, quinazoline-, or nitrothiazole-based compounds. Such formulations have advantageous solubility characteristics which allow for administration of hydrophobic pharmaceutical agents, such as indolinone-, quinazoline-, or nitrothiazole-based compounds, for pharmaceutical testing and therapy. Not only do such formulations overcome the solubility problems that have previously plagued the art, they have also been shown to produce a therapeutic effect in test animals.
Thus, a first aspect of the present invention features a formulation comprising: (a) one or more hydrophobic pharmaceutical agents, where the agents are independently selected from the group consisting of quinazoline-, nitrothiazole-, and indolinone-based compounds; (b) one or more polyoxyhydrocarbyl compounds; and (c) one or more pharmaceutically acceptable surfactants.
It is anticipated that the one or more hydrophobic pharmaceutical agents may include a combination of nitrothiazole-based compounds with quinazoline-based compounds, or nitrothiazole-based compounds with indolinone-based compounds, or quinazoline-based compounds with indolinone-based compounds. In addition, the one or more hydrophobic pharmaceutical agents may include a combination of indolinone-based compounds, for example 3-[(2,4-dimethylpyrrol-5-yl)methylene]-(5-amino)-2-indolinone, 3-[(2,4-dimethylpyrrol-5-yl)methylene]-(5-chloro)-2-indolinone, 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone, and 3-[(3-methylthiophenyl-5-yl)methylene]-(4-methyl)-2-indolinone. Another possibility is that the one or more hydrophobic pharmaceutical agents may include a combination of quinazoline-based compounds, for example 4-(3-bromophenyl)-6,7-dimethoxyquinazoline and 4-(3-chlorophenyl)-6,7-dimethoxyquinazoline. Or alternatively, the one or more hydrophobic pharmaceutical agents may include a combination of nitrothiazole-based compounds, for example some combination of 2-methyl-5-[(5-nitrothiazol-2-yl)mercapto]-1,3,4-thiadiazole; 1-benzyl-5-[(5-nitrothiazol-2-yl)mercapto]tetrazole; 2-[(5-nitrothiazol-2-yl)mercapto]-5-t-butyl-1,2,4-triazole; 3-[(5-nitrothiazol-2-yl)mercapto]-5-(thien-2-yl)-1,2,4-triazole; 3-[(5-nitrothiazol-2-yl)mercapto]-5-phenyl-1,2,4-triazole; and 4-allyl-3-hydroxy-5-[(5-nitrothiazole-2-yl)mercapto]-1,2,4-triazole.
The term “hydrophobic pharmaceutical agent” as used herein refers to compounds having a greater solubility in organic solvents of low polarity, such as long chain alcohols, than in aqueous solution. “Hydrophobic” means “water-hating” and is used herein to indicate weakly soluble in water and soluble in non-polar solvents. The formulations described by the present invention facilitate solubilization of hydrophobic compounds which readily dissolve in alcohols. Preferably, the hydrophobic compound is A insoluble in aqueous solution. More preferably, the compound has similar solubility characteristics in alcohols and aqueous solution to quinazoline-, nitrothiazole-, and indolinone-based compounds.
The term “compound” refers to the compound or a pharmaceutically acceptable salt, ester, amide, prodrug, isomer, or metabolite, thereof.
The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reacting a compound of the invention with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like, or with inorganic or organic bases such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, choline, n-methyl glucamine, diethylamine, procaine and the like.
The term “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs may be s easier to administer than the parent drug in some situations. For example, the prodrug may be bioavailable by oral administration but the parent is not, or the prodrug may improve solubility to allow for intravenous administration.
The term “polarity” as used herein refers to the dipole of a molecule. A “dipole” is two equal and opposite charges separated in space. A molecule is polar if it has a dipole, i.e. if the center of negative charge does not coincide with the center of positive charge. The dipole moment of a molecule, is equal to the magnitude of the charge multiplied by the distance between the centers of charge. It is possible to measure the dipole moments of molecules by methods well-known in the art. A low dipole moment indicates low polarity.
The term “quinazoline-based compound” refers to a quinazoline organic compound substituted with chemical substituents. Quinazoline compounds are of the general structure:
The term “substituted” refers to compounds of the invention that are derivatized with any number of chemical substituents, typically replacing one or more of the hydrogen atoms present in the compound's general structure.
The term “nitrothiazole-based compound” refers to a nitrothiazole organic compound substituted with chemical substituents. Nitrothiazole compounds are of the general structure:
The term “indolinone-based compound” refers to a indolinone organic compound substituted with chemical substituents. Indolinone compounds are of the general structure:
The term “polyoxyhydrocarbyl compound” as used herein refers to a water soluble ca
Shenoy Narmada
Wagner Gregory S.
Burrous Beth A.
Foley & Lardner
Kishore Gollamudi S.
Sugen Inc.
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