Oral preparations containing forskolin derivatives and...

Details Oral preparations containing forskolin derivatives and... Oral preparations containing forskolin derivatives and...

2000-10-16

2002-11-05

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S400000, C424S439000, C424S451000, C424S464000, C424S490000

Reexamination Certificate

active

06475525

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a pharmaceutical preparation with good storage stability comprising a salt of a forskolin derivative which is useful for the treatment of chronic heart failure, etc., and a process for producing the pharmaceutical preparation.
BACKGROUND ART
It is known from JP-A-63-10783, etc., that the forskolin derivatives and their salts have a positive inotropic action, a vascular smooth muscle relaxing action and an adenylate cyclase activating action, etc. It is also known from JP-B-6-102625 that the forskolin derivatives and their salts are unstable to water. Further, JP-A-4-342526 discloses the granules and tablets in which lactose, crystalline cellulose, etc., have been compounded.
Since the forskolin derivatives and their salts, such as colforsin dapropate hydrochloride etc., are unstable to water, their preparations obtained from an ordinary wet granulation method using water have the defects that they are bad in storage stability and the degradation products increase with time. The preparations obtained from a dry granulation method using no water or a direct powder compaction method are relatively good in storage stability but have the problem in uniformity of content. In the preparations comprising a salt of a forskolin derivative, the content of the salt per preparation is small, so that a wet granulation method which hardly causes classification etc. is suited for ensuring content uniformity of the preparations. However, as mentioned above, it is impossible with an ordinary wet granulation method to obtain the preparations with good storage stability.
An object of the present invention is to provide an oral preparation containing a salt of a forskolin derivative, which preparation is cleared of the above defects and has excellent storage stability.
Another object of the present invention is to provide a process for producing the pharmaceutical preparation with excellent storage stability.
DISCLOSURE OF THE INVENTION
As a result of extensive studies for attaining the above-said objects, the present inventors found that by using an alkali metal halide, it is possible to obtain an oral preparation containing a salt of a forskolin derivative with excellent stability and to obtain a pharmaceutical preparation with excellent stability by a wet granulation method, and completed the present invention.
Thus, the present invention pertains to the following inventions 1) to 20):
1) An oral preparation characterized by comprising a salt of a forskolin derivative as a pharmaceutically active ingredient and an alkali metal halide;
2) An oral preparation according to 1) above, wherein the salt of a forskolin derivative is a salt of a forskolin derivative represented by the following formula (1):
 wherein R
1
is a hydrogen atom; R
4
is a vinyl group, an ethyl group or a cyclopropyl group; and one of R
2
and R
3
represents a partial structural formula —CO(CH
2
)mNR
5
R
6
wherein R
5
and R
6
are a hydrogen atom or a lower alkyl group or they are combined together to represent a lower alkylene group which may contain an oxygen atom or a nitrogen atom in the bonding chain, and m is an integer of 1 to 5 and the other represents a hydrogen atom or a partial structural formula —CO(CH
2
)nX wherein X is a hydrogen atom or a group represented by the formula —NR
7
R
8
wherein R
7
and R
8
are a hydrogen atom or a lower alkyl group or they are combined to represent a lower alkylene group which may contain an oxygen atom or a nitrogen atom in the bonding chain, and n is an integer of 1 to 5;
3) An oral preparation according to 1) or 2) above, wherein the salt of a forskolin derivative is colforsin dapropate hydrochloride (a hydrochloride of 6-(3-dimethylaminopropionyl)forskolin);
4) An oral preparation according to 1), 2) or 3) above, wherein the alkali metal halide is sodium chloride or potassium chloride;
5) An oral preparation according to 1), 2), 3) or 4) above, wherein an alkali metal halide is contained in an amount of 0.01 to 26 parts by weight per one part by weight of a salt of a forskolin derivative;
6) An oral preparation according to 1), 2), 3) or 4) above, wherein an alkali metal halide is contained in an amount of 0.25 to 10 parts by weight per one part by weight of a salt of a forskolin derivative;
7) An oral preparation according to 1), 2), 3), 4), 5) or 6) above, wherein a pharmaceutical adjuvant or adjuvants are contained in an amount of 10 to 500 parts by weight per one part by weight of a salt of a forskolin derivative;
8) An oral preparation comprising:
a salt of a forskolin derivative as a pharmaceutically active ingredient: 0.01-26 wt % an alkali metal halide: 0.05-22 wt %
a pharmaceutical adjuvant or adjuvants: 52-99.9 wt %
based on the whole preparation;
9) An oral preparation comprising:
a salt of a forskolin derivative as a pharmaceutically active ingredient: 0.03-13 wt %
sodium chloride or potassium chloride: 0.25-11 wt %
a pharmaceutical adjuvant or adjuvants: 76-99.7 wt %
based on the whole preparation;
10) An oral preparation according to 8) or 9) above, wherein the salt of a forskolin derivative is colforsin dapropate hydrochloride;
11) A process for producing a pharmaceutical preparation characterized by using an aqueous solution of an alkali metal halide in wet-granulating a mixture of a pharmaceutically active ingredient and a pharmaceutical adjuvant or adjuvants;
12) A process for producing a pharmaceutical preparation characterized by mixing a pharmaceutically active ingredient, a solid alkali metal halide and a pharmaceutical adjuvant or adjuvants, and wet-granulating the mixture;
13) The process according to 11) or 12) above, wherein the pharmaceutically active ingredient is a salt of a forskolin derivative;
14) The process according to 11) or 12) above, wherein the pharmaceutically active ingredient is colforsin dapropate hydrochloride;
15) The process according to I11), 12), 13) or 14) above, wherein the alkali metal halide is sodium chloride or potassium chloride;
16) The process according to 11), 12), 13), 14) or 15) above, wherein a pharmaceutical adjuvant or adjuvants and an alkali metal halide are used in amounts of 10 to 500 parts by weight and 0.01 to 26 parts by weight, respectively, per one part by weight of the pharmaceutically active
17) The process according to 11), 12), 13), 14) or 15) above, wherein a pharmaceutical adjuvant or adjuvants and an alkali metal halide are used in amounts of 10 to 500 parts by weight and 0.25 to 10 parts by weight, respectively, per one part by weight of the pharmaceutically active
18) The process according to any one of 11) and 13) to 17) above, wherein the concentration of the alkali metal halide in its aqueous solution is from 1% by weight to the concentration of saturated solution;
19) The process according to any one or 11) and 13) to 17) above, wherein the concentration of the alkali metal halide in its aqueous solution is from 5% by weight to the concentration of saturated solution;
20) The process according to any one of 12) to 17) above, wherein the solid alkali metal halide is powder type.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention will be described in detail below.
As a salt of a forskolin derivative, it is possible to use any of those which can serve as a pharmaceutically active ingredient, but preferably the forskolin derivatives represented by the above-shown formula (1) are used. As the lower alkyl group in the formula (1), the alkyl groups having 1 to 4 carbon atoms such as methyl group, ethyl group, propyl group, butyl group, etc. may be exemplified. As the lower alkylene group which may contain an oxygen atom or a nitrogen atom in the chain, those of 3 to 5 carbon atoms such as —(CH
2
)
3
—, —(CH
2
)
4
—, —(CH
2
)
5
—, —(CH
2
)
2
—NH—(CH
2
)
2
—, —(CH
2
)
2
—O—(CH
2
)
2
—, etc. may be exemplified.
As the groups of —CO(CH
2
)mNR
5
R
6
, for example, dimethylaminoacetyl group, diethylaminoacetyl group, diethylaminopropionyl group, butylaminoacetyl group, dimethylaminopropionyl group, dimethylaminobutylyl group, pyrrolidino

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