Fat emulsion containing xanthine derivative

Details Fat emulsion containing xanthine derivative Fat emulsion containing xanthine derivative

1999-03-24

2001-04-03

Kishore, Gollamudi S. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

C424S450000, C514S257000, C514S213010, C514S267000, C514S938000

Reexamination Certificate

active

06210687

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a fat emulsion containing a xanthine derivative or a pharmacologically acceptable salt thereof, which exhibits an adenosine A1 receptor antagonizing activity, and which has antihypertensive activity, diuretic activity, kidney-protecting activity, bronchiodilatary activity, brain function-improving activity and antidemential activity.
TECHNICAL BACKGROUND
Renal insufficiency, especially, acute renal insufficiency is such a serious disease that waste materials are accumulated in the blood owing to the deficiency of the renal function, and the development of an agent for preventing, curing or treating the renal insufficiency has been in demand. It is required to elucidate the renal function and to develope an appropriate treatment of the renal functional insufficiency.
It has been long known that xanthines such as caffeine, theophylline and the like possess diuretic activity. In recent years, studies have been made with respect to the diuretic activity of these xanthines, and it has been clarified that the xanthines act as an antagonist of an adenosine receptor. Further, in recent years, it has been discovered that 8-(3-noradamantyl)-1,3-dipropylxanthine (hereinafter sometimes referred to as “KW-3902”) exhibits an excellent adenosine receptor antagonizing activity, and this compound has been developed as a medicine having an antihypertensive activity, a diuretic activity and kidney-protecting activity (F. Suzuki et al., J. Med. Chem., 35, 3066 (1992)). KW-3902 has attracted attention as a medicine which is especially effective for treating acute renal insufficiency. This KW-3902 is deemed effective in the parenteral administration. KW-3902 is sparingly soluble in water, and it is difficult to produce its preparations. In addition, the compound is problematic in a long-term storage stability. Thus, the development thereof as a medicine has posed a serious problem.
Meanwhile, a fat emulsion (lipid microsphere) has been already clinically applied for feeding, and also studies to apply the fat emulsion to preparation of an antiinflammatory antalgic agent have been conducted (Mizushima et al., “SAISHIN IGAKU”, vol. 40, No. 9, pp. 1806-1813, 1985). However, medical ingredients which can be formulated with a fat emulsions are limited, and there have been problems that the stability thereof or the absorption of active ingredients varies depending on the ingredients, the amount, the physical form and the like of the fat emulsion.
DISCLOSURE OF THE INVENTION
The present inventors have conducted studies on production of pharmaceutical preparations of xanthine derivatives, especially 8-(polycycloalkyl)xanthines having excellent long-term storage stability, and have consequently found that pharmaceutical preparations which have high content of sparingly-soluble xanthine derivatives, which exhibit excellent long-term storage stability and which are especially suitable for parenteral administration are obtained through formulation using a fat emulsion.
The present invention is to provide a stable pharmaceutical preparation of a xanthine derivative or its pharmacologically acceptable salt suitable for parenteral administration. More specifically, the present invention is to provide a pharmaceutical preparation which contains a large amount of a xanthine derivative or its pharmacologically acceptable salt having antihypertensive activity, diuretic activity and kidney-protecting activity, which is especially useful as an agent for preventing, curing or treating renal insufficiency and which has excellent long-term storage stability. That is, the present invention is to provide a stable fat emulsion containing a 8-(polycycloalkyl)xanthine or its pharmacological acceptable salt.
The present invention relates to a fat emulsion containing a large amount of a xanthine derivative [hereinafter referred to as “Compound (I)”] represented by formula (I)
wherein R
1
and R
2
are the same or different and each represents a substituted or unsubstituted lower alkyl group, and Q represents hydrogen, a hydroxyl group or a hydroxyl group derivative or its pharmacologically acceptable salt, and having an excellent long-term storage stability.
In the definition of formula (I), the lower alkyl group includes linear or branched lower alkyl groups having from 1 to 8 carbon atoms, preferably from 1 to 6 carbon atoms, more preferably from 1 to 3 carbon atoms, such as methyl, ethyl, propyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl. Preferable are methyl, ethyl and n-propyl. Examples of the substituent of the substituted lower alkyl group include a hydroxyl, acyl group such as an acetyl group, a carbonyl group (O═) and lower alkoxy group. Of these substituents, a hydroxyl group and an acetyl group are preferable. The lower alkyl group of the lower alkoxy group means the same groups as mentioned above for the lower alkyl group.
Examples of the hydroxyl group derivative of the substituent Q include an acyloxy group such as an acetoxy group and a lower alkoxy group such as a methoxy group.
Examples of the pharmacologically acceptable salt of Compound (I) include an acid addition salt, a metal salt, an ammonium salt, an organic acid amine addition salt and an amino acid addition salt which are pharmacologically acceptable.
Examples of the pharmacologically acceptable acid addition salt of Compound (I) include inorganic acid salts such as a hydrochloride, a sulfate and a phosphate; and organic acid salts such as an acetate, a maleate, a fumarate, a tartrate and a citrate. Examples of the pharmacologically acceptable metal salt include alkali metal salts such as a lithium salt, a sodium salt and a potassium salt; alkaline earth metal salts such as a magnesium salt and a calcium salt; an aluminum salt; and a zinc salt. Examples of the pharmacologically acceptable ammonium salt include salts of ammonium and tetramethylammonium. Examples of the pharmacologically acceptable organic amine addition salt include addition salts of morpholine and piperidine. Examples of the pharmacologically acceptable amino acid addition salt include addition salts of lysine, glycine, phenylalanine, glutamic acid and aspartic acid.
Compound (I) or its pharmacologically acceptable salt can be produced by various methods, for example, by the method described in Japanese Laid-Open (Kokai) No. 173,889/1991.
Specific examples of Compound (I) are shown in Table 1.
TABLE 1

Compound Number
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
Compound No. 1 in the above Table 1 is 8-(3-noradamantyl)-1,3-dipropylxanthine (KW-3902).
The fat emulsion of the present invention contains Compound (I) represented by the formula (I) as an active ingredient, a fatty oil, a surfactant and a pharmaceutically acceptable carrier.
More specifically, the fat emulsion of the present invention contains the fatty oil in an amount of from 0.5 to 30% (w/v) of fat emulsion, the surfactant in an amount of from 0.1 to 2 times by weight based on the fatty oil, and the pharmaceutically acceptable carrier.
With respect to the fat emulsion of the present invention, the particle diameter is between 0.005 and 0.3 &mgr;m, preferably between 0.02 and 0.15 &mgr;m.
The fat component used in the fat emulsion of the present invention is not particularly limited so long as it is parenterally administrable. Preferable examples thereof include vegetable oils such as soybean oil, sesame oil, olive oil and coconut oil. More preferable is soybean oil.
With respect to the surfactant to be used in the fat emulsion of the present invention, any surfactant can be used so long as an O/W emulsion can be formed, and the surfactant can be administered parenterally. Preferable examples thereof include egg yoke lecithin, soybean lecithin, highly purified phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl glycerol, phosphatidic acid, lysolecithin, polyoxyethylenesorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyeth

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