Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1997-03-26
2001-07-03
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S488000, C424S499000, C424S501000, C424S494000, C424S497000, C424S457000, C424S468000
Reexamination Certificate
active
06254889
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a solid dispersion and a solid dispersion dosage form of a xanthine derivative or a pharmacologically allowable salt thereof which exhibits an antagonistic activity relative to the adenosine A1 receptor, and which has a diuretic activity, a kidney-protecting activity, a bronchodilating activity, a cerebral function-improving activity, an anti-dementia activity, or the like.
BACKGROUND ART
In general, drugs which are slightly soluble in water and have high crystallinity have low bioavailability since they have low solubility and low disolution rate in the gastrointestinal tract. Hitherto, in order to improve their absorbability, several methods for finely grinding drug crystals or for transforming them into amorphous substances have been examined.
By fine-grinding, however, particle diameters become irregular between lots, or inter-particle force is enhanced to cause agglomeration.
As a method for obtaining amorphous substances, grinding or forming a solid dispersion are considered. Drug crystals which can become amorphous by grinding are limited. Further, it has been known that solubility and absorbability of a slightly water-soluble compound are improved by dispersing it in a polymer to form a solid dispersion.
As to xanthine derivatives or pharmacologically allowable salts thereof, which are slightly soluble, however, solid dispersions or solid dispersion dosage forms are not yet known.
DISCLOSURE OF THE INVENTION
The present invention relates to a solid dispersion comprising a xanthine derivative or a pharmacologically allowable salt thereof and a polymer, the xanthine derivative [hereinafter referred to as compound (I)] being represented by the following formula (I).
(In the above formula, R
1
and R
2
are the same or different, and represent substituted or unsubstituted lower alkyl groups, and Q represents a hydrogen atom or a hydroxyl group.)
Furthermore, the present invention relates to a solid dispersion dosage form comprising a xanthine derivative of a compound (I) or a pharmacologically allowable salt thereof and a polymer.
In the definition of the formula (I), the lower alkyl groups are straight or branched groups having 1 to 6 carbon atoms, and examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a neopentyl group, and a hexyl group. As to substituent groups of the substituted lower alkyl groups, examples include a hydroxyl group and an acetyl group.
The pharmacologically allowable salts of compounds (I) include pharmacologically allowable acid addition salts, metal salts, ammonium salts, organic amine addition salts, and amino acid addition salts.
Examples of pharmacologically allowable acid addition salts of compounds (I) include inorganic acid salts such as hydrochlorides, sulfates, phosphates; and organic acid salts such as acetates, maleates, fumarates, tartrates, and citrates. Examples of pharmacologically allowable metal salts include alkali metal salts such as lithium salts, sodium salts, and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; aluminum salts; and zinc salts. Examples of pharmacologically allowable ammonium salts include salts of ammonium or tetramethyl ammonium. Examples of pharmacologically allowable organic amine addition salts include addition salts of morpholine or piperidine. Examples of pharmacologically allowable amino acid addition salts include addition salts of lysine, glycine, phenylalanine, glutamic acid, and aspartic acid.
Compounds (I) or pharmacologically allowable salts thereof can be produced according to the method described in Japanese Unexamined Patent Publication No. 3-173889.
Practical examples of compounds (I) are shown in Table 1.
TABLE 1
Compound No.
R
1
R
2
X
1
n-C
3
H
7
n-C
3
H
7
2
n-C
3
H
7
n-C
3
H
7
3
n-C
3
H
7
n-C
3
H
7
4
n-C
3
H
7
5
n-C
3
H
7
In the solid dispersion or the solid dispersion dosage form, a compound (I) or a pharmacologically allowable salt thereof is contained at 1 to 50% by weight, and preferably, 3 to 10% by weight.
The polymer to be used in the present invention is not particularly limited so long as it can disperse compounds (I) or pharmacologically allowable salts thereof, and accordingly, several natural polymers and synthetic polymers can be used. Examples of polymers include rubber compounds such as gum arabic; gelatin; polysaccharides such as agar; cellulose compounds or derivatives thereof such as crystalline cellulose, micro crystalline cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, carboxymethyl ethyl cellulose, ethyl cellulose, and cellulose acetate phthalate; polyvinyl derivatives such as polyvinyl alcohol, polyvinyl pyrrolidone, and polyvinyl acetal diethylaminoacetate; aminoalkyl methacrylate copolymers such as aminoalkyl methacrylate copolymer E and aminoalkyl methacrylate copolymer RS; and methacrylate copolymers such as methacrylate copolymer L, methacrylate copolymer LD, and methacrylate copolymer S. Among these polymers, enteric-coating polymers are preferred. Examples of enteric-coating polymers include methacrylate copolymer L (trade name: Eudragit L100 and Eudragit L100-55; Röhm Pharma Co., Ltd.), hydroxypropylmethyl cellulose phthalate (trade name: hydroxypropylmethyl cellulose phthalate HP-55; Shin-Etsu Chemical Co., Ltd.), hydroxypropylmethyl cellulose acetate succinate, and carboxymethylethyl cellulose. Particularly, methacrylate copolymer L (trade name: Eudragit L100) is preferably used.
Such a polymer is contained in the solid dispersion or the solid dispersion dosage form at 3 to 50% by weight, and preferably, 9 to 10% by weight.
In the solid dispersion or the solid dispersion dosage form of the present invention, the blending ratio of a compound (I) to the polymer is 3:1 to 1:5 (by weight). In particular, when the content of a compound (I) or a pharmacologically allowable salt thereof is 3% by weight, the blending ratio is preferably 1:3, and when the content of a compound (I) or a pharmacologically allowable salt thereof is 10 to 20% by weight, the blending ratio is preferably 1:1.
The solid dispersion of the present invention can be prepared by a co-grinding method, a solvent method, a melting method, a heat-melt-kneading method, or the like.
In the co-grinding method, a compound (I) or a pharmacologically allowable salt thereof is mixed with a polymer using a mixer or the like, and the mixture is ground using a grinder or the like. In the solvent method, a compound (I) or a pharmacologically allowable salt thereof and a polymer are dissolved or dispersed in an organic solvent, and the organic solvent is then removed according to an ordinary method under reduced pressure or ordinary pressure.
The organic solvent to be used in the solvent method is not particularly limited so long as it can dissolve a compound (I) or a pharmacologically allowable salt thereof and a polymer. Examples of such organic solvents include aliphatic halogenated hydrocarbons, ketones, alcohols, ethers, aliphatic hydrocarbons, aromatic hydrocarbons, esters, organic acids, amides, and mixed solvents thereof. Examples of aliphatic halogenated hydrocarbons include methylene chloride, dichloroethane, and chloroform. Examples of ketones include acetone and methyl ethyl ketone. Examples of alcohols include methanol, ethanol, propanol, and butanol. Examples of ethers include diethyl ether, dibutyl ether, diisobutyl ether, dioxane, tetrahydrofuran, and ethylene glycol dimethyl ether. Examples of aliphatic hydrocarbons include n-hexane, cyclohexane, and n-heptane. Examples of aromatic hydrocarbons include benzene, toluene, and xylene. Examples of esters include ethyl acetate. Examples of organic acids include acetic acid and propionic acid. Examples of amides include dimethylformamide and dimethylacetamide. Aliphatic halogenated
Hayakawa Eiji
Ishikawa Yasuhiro
Kigoshi Makoto
Masada Tomoaki
Ueno Yasuhiko
Fitzpatrick ,Cella, Harper & Scinto
Kyowa Hakko Kogyo Co. Ltd.
Webman Edward J.
LandOfFree
Solid dispersion dosage form of amorphous xanthine... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Solid dispersion dosage form of amorphous xanthine..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Solid dispersion dosage form of amorphous xanthine... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2491682