Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2000-08-04
2003-11-04
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S439000, C424S488000, C514S261100, C514S262100, C514S264110
Reexamination Certificate
active
06641843
ABSTRACT:
The present invention relates to novel pharmaceutical compositions of (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol.
(1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol and its antiviral use, particularly against HIV infections is described in European Patent Specification Number 0434450. The succinate salt of (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol is described in WO96/06844. The hemisulfate salt of (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol is described in WO98/52949.
(1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol (also known as 1592U89) is currently under clinical investigation as an anti-HIV pharmaceutical agent. There exists a need for the compound to be prepared in solution form, for example for pediatric use.
Solutions of (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol are bitter-tasting and therefore require the addition of sweeteners and taste-maskers. However, formulation of (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol in solution is difficult because materials containing a —COOH group present problems with (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol compatibility. For example, glucose forms an adduct with the compound by replacing the methanol group on the cyclopentyl ring of (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol. (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol has been found to be incompatible with sucrose (which degrades to glucose and fructose) as well as glucose.
Solutions of (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol containing sorbitol result in a color change and the formation of dark colored particulates at pH 4.5-6.5.
In addition, propylene glycol concentration appears to have an influence on color formation, with higher levels of propylene glycol (10%) causing color formation.
We have found that sorbitol or saccharin or a combination of sorbitol and saccharin are compatible with (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol and do not lead to the formation of adducts with it. In addition, lowering the pH to about 4.0 eliminates the color change and the formation of particulates. We have also found that combinations of fructose, acesulfame and saccharin are compatible with (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol. In addition, we have found that abacavir is stable in pH ranges of about 2.0 to about 4.5 and about 6.6 to 7.5. Advantageously, the pH may be 3.8 to 4.5. We have also found that the addition of a metal chelator, for example citrate, improves the stability of abacavir in solution.
According to a first aspect of the invention there is provided a pharmaceutical composition comprising (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol and sorbitol at a range of pH from about 2.0 to about 4.5, advantageously pH 4.0. In an alternative embodiment, there is provided a pharmaceutical composition comprising (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol and saccharin at a range of pH from about 2.0 to about 4.5, advantageously pH 4.1. The pharmaceutical composition may comprise both sorbitol and saccharin at a range of pH from about 2.0 to about 4.5, advantageously pH 4.1.
A further aspect of the invention includes compositions comprising (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol and sorbitol and/or saccharin at a pH range of about 6.6 to about 7.5, advantageously pH 7.0. Compositions at about pH 7 may include propylene glycol or other suitable solubilizer to improve solubility.
According to another aspect of the invention there is provided a pharmaceutical composition comprising (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol and a sweetening agent compatible with said (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol at a pH range of about 2.0 to about 4.5.
In a further aspect of the invention there is provided a pharmaceutical composition comprising (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol and fructose, acesulfame, and saccharin at a range of pH from about 2.0 to about 4.5, advantageously pH 4.0. Alternatively, the compositions may be formulated at a pH range of about 6.6 to 7.5, advantageously pH 7.0.
According to a further aspect of the present invention there is provided a pharmaceutical composition comprising (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol, sorbitol, saccharin and citrate at a range of pH from about 2.0 to about 4.5. The citrate ion concentration may advantageously be in the range of about 0.01M to about 0.13M. Advantageously, sodium citrate and citric acid may be used.
The compositions of the present invention may also comprise one or more pharmaceutically acceptable organic solvents, for example, propylene glycol, polypropylene glycol, polyethylene glycol, and the like; pharmaceutically acceptable alcohols, for example ethanol or 2-(2-ethoxyethoxy)ethanol and the like; antioxidants, for example, edetate disodium, malic acid, fumaric acid, or sodium metabisulfite, and the like; pharmaceutically acceptable acids, for example, hydrochloric acid, acetic acid, citric acid, sulfuric acid, and the like; and oils or surfactants, and the like.
The compositions of the present invention may also comprise other pharmaceutically acceptable sweetening agents and/or flavoring agents, for example, aspartame, sucralose, and the like and/or cherry flavor, artificial banana flavor, caramel, chocolate mint flavor, grape flavor, wild cherry flavor, raspberry flavor, strawberry flavor, citrus flavor, orange flavor, pineapple flavor, citrus lime flavor, citrus cream flavor, cherry vanilla flavor, creme de menthe flavor and the like.
According to the present invention, any ester of hydroxybenzoate (parabens) or combination of such esters may be used, including methyl and propyl paraben and butyl and propyl paraben combinations. Sodium benzoate (0.02-0.5% w/v) or potassium sorbate (0.05-0.2% w/v) may be used as preservatives.
In a further aspect of the present invention, there is provided (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol compositions containing methyl paraben and propyl paraben. For oral solutions and suspensions, the range of methyl paraben concentration may be 0.15-0.2% (1.5 mg/mL to 2 mg/mL) and the range of propyl paraben concentration may be 0.01% to 0.02% (0.1 to 0.2 mg/mL).
According to a further aspect of the present invention, any suitable buffer may be used to provide a pH>5.5. Advantageously, sodium citrate or phosphate may be used. To achieve a pH range of about 2.0 to about 4.5, advantageously citrate, fumarate, glutarate, malate, maleate, tartrate or acetate may be used.
Included in the invention are the pharmaceutically acceptable salts, esters, or salts of such esters of (1S,4R)-cis-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol, or any other compound which, upon administration of a safe and therapeutically effective amount of the compound to a human subject, is capable of providing (directly or indirectly) the antivirally active metabolite or residue thereof.
Preferred esters in accordance with the invention are independently selected from the following group: (1) carboxylic acid esters in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from
Di Nola-Baron Liliana
Fix Amy H.
SmithKline Beecham Corporation
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