JPH0640921A - Activated-form vitamin d3 composition - Google Patents

Abstract

(57) [Summary] [Purpose] Particle size distribution and active vitamin D₃Content of
Uniform and stable active vitamin D₃Provide similar compositions
To do. [Structure] Consists of excipients that are poorly soluble in organic solvents
Layer, active vitamin D ₃Easy to dissolve in compounds and organic solvents
Active Vitamin Formed by Forming an Outer Layer Consisting of Excipients
D₃Compositions.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel active vitamin D.
Class ₃ composition. More specifically, the present invention comprises an inner layer formed of an excipient that is poorly soluble in an organic solvent, and an outer layer formed of an excipient that is easily soluble in an active vitamin D ₃ and an organic solvent. It relates to an active vitamin D ₃ composition.

[0002]

2. Description of the Related Art 1α-hydroxycholecalciferol, 1α, 25-dihydroxycholecalciferol,
Active vitamin D ₃ such as 1α, 24-dihydroxycholecalciferol absorbs calcium in the small intestine,
It promotes transport, elutes bone calcium to increase serum calcium concentration, promotes reabsorption of inorganic phosphate in renal tubular cells to increase serum inorganic phosphate concentration, and feedback mechanism with parathyroid hormone secretion In connection with this, it is expected to have a great effect on rickets or osteomalacia caused by vitamin D ₃ metabolic system such as chronic kidney disease or parathyroid dysfunction.

However, all of these compounds are
Since it is unstable to light and is easily oxidized, it is necessary to take measures such as freezing, shading, and inert gas replacement during storage.

Therefore, this series of active vitamin D ₃
It is extremely useful to provide a compound in a stable form for formulation.

Conventionally, a method as a stabilizing method of these active vitamin D ₃ compounds, the method (JP 55-69562 JP) to form a clathrate compound with bile acids to form the cholesterols and complex (JP-A-57-4046
No. 1) is known.

[0006] In these methods, the solvent and active vitamin D ₃ compound and a bile acid or cholesterols, capable of dissolving both the active vitamin D ₃ compound and a bile acid or cholesterol, such as ethanol, methanol, Mix well in an alcohol solvent such as propanol, mix,
Then, the solvent is distilled off under reduced pressure to obtain a composition.

Activated vitamin D thus obtained
_If necessary, the composition of the _third class contains other components such as known excipients, binders, disintegrants, antioxidants and their synergists, colorants, flavoring agents, lubricants, emulsifiers, suspensions. A drug can be prepared by mixing an agent, a surfactant and the like.

However, the active vitamin D ₃ composition obtained by distilling off the solvent under reduced pressure as described above is partly resinified at the time of distilling off under reduced pressure, so that it is difficult to handle and it is taken out. However, there were drawbacks such as difficulty in obtaining uniform particle size when crushing by crushing. Thus, in this way after removal of the active vitamin D ₃ compounds composition, when the drug is mixed with other ingredients as described above, active vitamin D ₃
It also had a drawback that it was difficult to say that the homogeneity of the content of the class was sufficient.

On the other hand, as a method for making a poorly absorbable drug easily absorbable, Japanese Patent Laid-Open No. 85-85316 discloses that fine particles obtained by granulating a water-soluble pharmaceutical additive are nifedipine and polyvinylpyrrolidone. A method of coating with a solid solution consisting of

However, this method requires a step of previously granulating the water-soluble pharmaceutical additive into fine granules to produce a carrier, and is not a simple method.

On the other hand, JP-A-54-135218 discloses a prostaglandin E as a pharmaceutical stabilizing composition.
And a pharmaceutical excipient that is difficult to dissolve in an organic solvent, such as crystalline cellulose, are mixed in an organic solvent in the presence of a complex-forming compound that is soluble in an organic solvent such as polyvinylpyrrolidone, and then an organic solvent is added. Remove Prostaglandin E
Methods of obtaining a class of stabilized compositions are described.

However, there is no description about stabilization of active vitamin D ₃ such as 1α-hydroxycholecalciferol and 1α, 25-dihydroxycholecalciferol.

[0013]

An object of the present invention is an object of the invention, a simple and efficient manner, and active vitamin D ₃ which may be the particle size distribution to obtain a uniform active content of vitamin D ₃ compounds also homogeneous composition To provide a pharmaceutical composition of the same class.

[0014]

[Configuration and Advantages of the Invention] The present inventors have, together with the stabilized active vitamin D ₃ compounds, a uniform particle size distribution, pharmaceutical composition also uniform activity content of the active ingredient vitamin D ₃ compounds As a result of earnest research aimed at obtaining the active vitamin D ₃ and an organic solvent, an easily soluble excipient was dissolved in the organic solvent, and then an insoluble excipient was added. By a simple method of adding and mixing, and then distilling off the organic solvent, a shape that is easily soluble in the active vitamin D ₃ and the organic solvent is formed in the inner layer consisting of an excipient that is poorly soluble in the organic solvent. A composition having an outer layer formed of an agent is obtained, and the stability of the composition is remarkably improved as compared with the case of using a drug other than active vitamin D ₃ class such as prostaglandin. And achieve the purpose as described above. The inventors of the present invention have found that they can be achieved and reached the present invention.

According to the present invention, however, an outer layer comprising an active vitamin D ₃ and an easily soluble excipient is formed on an inner layer comprising an excipient which is poorly soluble in an organic solvent. It is an active vitamin D ₃ composition.

Excipients that are sparingly soluble in the organic solvent used in the present invention include, for example, crystalline cellulose, starch, casein, cyclodextrin, lactose (including anhydrous lactose), hydroxypropyl starch, dextrin,
Examples include gelatin. These excipients, on the other hand, are water-soluble or water-insoluble but water-absorbable. Among these, crystalline cellulose, starch,
Casein, lactose anhydrous, and cyclodextrin are particularly preferable.

The active vitamin D ₃ is represented by the following formula [I]

[0018]

[Chemical 3]

(In the formula, R ₁ represents a hydrogen atom or a hydroxyl group. R ₂ represents

[0020]

[Chemical 4]

Represents (where r₁, R₂Are the same
Represents a hydrogen atom or a hydroxyl group. However, R₁Is hydrogen
R for an atom₁, R₂At least one of them is a hydroxyl group
It r ₃Represents a hydrogen atom or a hydroxyl group). )
Activated Vitamin D₃The kind is mentioned.

These active vitamin D ₃ compounds include the following compounds.

That is, the following formula [I-1]

[0024]

[Chemical 5]

[0025] (In the formula, R ₁ .r _1, r ₂ represents the same or different hydrogen atom or a hydroxyl group. Provided that at least one r _1, r ₂ when the R ₁ is a hydrogen atom represent a hydrogen atom or a hydroxyl group Is a hydroxyl group.) Active vitamin D ₃ represented by the following formula [I-2]

[0026]

[Chemical 6]

(Wherein R ₁ represents a hydrogen atom or a hydroxyl group, r ₃ represents a hydrogen atom or a hydroxyl group), an active vitamin D ₃ represented by the following formula [I-3]:

[0028]

[Chemical 7]

(Wherein R ₁ represents a hydrogen atom or a hydroxyl group), an active vitamin D ₃ represented by the following formula [I-4]

[0030]

[Chemical 8]

(In the formula, R ₁ represents a hydrogen atom or a hydroxyl group) and is an active vitamin D ₃ class.

Specific examples of these active vitamin D3s include the following.

Active vitamin D of the above formula [I-1]₃Kind
As, for example, 1α-hydroxycholecalciferol
(1α-OHD₃), 25-hydroxycholecalcife
Roll (25-OHD₃), 24-hydroxycholecal
Ciferol (24-OHD ₃) 1α, 25-dihydr
Roxycholecalciferol (1α, 25- (OH) ₂
D₃) 1α, 24-dihydroxycholecalcifero
Le (1α, 24- (OH)₂D₃) 1α, 24, 25
-Trihydroxycholecalciferol (1α, 24,
25- (OH)₃D₃) Etc .; the activity of the above formula [I-2]
Type vitamin D₃Examples of the class include 24-oxocorea
Luciferol, 1α-hydroxy-24-oxocore
Calciferol, 25-hydroxy-24-oxoco
Lecalciferol, 1α, 25-dihydroxy-24
-Oxocholecalciferol and the like; the above formula [I-3]
Active Vitamin D₃For example, 25-hydroxy
Sicolecalciferol-26,23-lactone, 1
α, 25-dihydroxycholecalciferol-26,
23-lactone and the like; activated vitamin of the above formula [I-4]
D₃Examples of the class include 25-hydroxycholecalci
Ferrol-26,23-peroxylactone, 1α,
25-dihydroxycholecalciferol-26,23
-Peroxy lactone etc. are mentioned.

Even among these active vitamin D ₃ compounds, the compound represented by the above formula [I-1], for example, 1αOHD ₃ ,
25-OHD ₃ , 24-OHD ₃ , 1α, 25- (O
H) ₂ D ₃ , 1α, 24- (OH) ₂ D ₃ , 1α, 2
4,25- (OH) ₃ D ₃ is preferred.

Examples of the easily soluble excipient for the organic solvent used in the composition of the present invention include polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, deoxycholic acid and the like. Among these, polyvinylpyrrolidone is particularly preferable.

Polyvinylpyrrolidone has a molecular weight of 250 to
Polyvinylpyrrolidone in the range of 1,000,000 is preferable, and more preferably, the molecular weight is 1,000 to 700,
000 polyvinylpyrrolidone.

The composition of the present invention comprises an inner layer composed of an excipient which is hardly soluble in the organic solvent as described above, and an outer layer composed of an excipient which is easily soluble in the active vitamin D ₃ and the organic solvent. Is formed. That is, the inner layer is particles or fine particles composed of an excipient that is poorly soluble in an organic solvent,
On the surface of the inner layer, active vitamin D ₃ and an easily soluble excipient for an organic solvent are adhered or coated to form an outer layer. In the outer layer, it is preferable that the active vitamin D ₃ is uniformly dispersed in an excipient that is easily soluble in an organic solvent.

The amount of the excipient which is poorly soluble in the organic solvent is
It is preferably 1 to 5,000,000 times by weight, based on the excipient that is easily soluble in the organic solvent that is one component that forms the outer layer,
Particularly preferably 1 to 10,000, more preferably 1 to
It is 100 times the weight. The amount of easily soluble excipient in an organic solvent, the active vitamin D ₃ compounds, preferably 1～5,000,000 times by weight, particularly preferably 1 to
1,000,000, more preferably 10-100,0
It is 00 times the weight.

In the composition of the present invention, the stability of the active vitamin D ₃ is improved by using the active vitamin D ₃ as a drug to prepare a composition having the above-mentioned form.
This is a marked improvement over the use of other drugs such as prostaglandins.

In such a composition, an active vitamin D ₃ and an excipient which is easily soluble in an organic solvent are dissolved in an organic solvent, and then an excipient which is hardly soluble in the organic solvent is added and mixed. , Then the organic solvent is distilled off. Alternatively, an excipient that is sparingly soluble in an organic solvent is used as a nucleating agent, and an active vitamin D ₃ and an excipient that is easily soluble in an organic solvent are dissolved in an organic solvent and then coated. , Then the organic solvent is distilled off.

Examples of the organic solvent used here include alcohol solvents such as methanol, ethanol and propanol; halogenated hydrocarbons such as dichloromethane and chloroform; ether solvents such as diethyl ether. Among these, especially methanol,
Alcoholic solvents such as ethanol are preferred. Two or more kinds of organic solvents may be mixed and used. In such an organic solvent, an active vitamin D ₃ and an easily soluble excipient for the organic solvent are dissolved. The amount of the organic solvent used is usually 1 to 1,000 for the excipient that is easily soluble in the organic solvent.
It is 0 times by weight, preferably 1 to 100 times by weight.

Next, an excipient which is hardly soluble in the organic solvent is added. At this time, the excipient is made to exist uniformly in a suspended state in the organic solvent. After stirring well, the organic solvent is removed by an appropriate method such as heating under reduced pressure or atmospheric pressure, or spray drying.

By doing so, an outer layer composed of an active vitamin D ₃ and an easily soluble excipient is formed on an inner layer composed of an excipient which is hardly soluble in an organic solvent. A composition is obtained.

According to the method as described above, a composition having a uniform particle size distribution and a uniform drug content can be obtained, and the composition does not become a resin in the production process, and the composition of interest is extremely efficient. Is obtained.

The composition thus obtained may be used as it is, or may be mixed with other components as necessary, for example, known excipients, lubricants, binders, colorants, antioxidants, flavoring agents, and the like. , Can be a drug. Examples of the excipient include starch, crystalline cellulose, dextrin, lactose, mannitol, sorbitol, anhydrous calcium phosphate and the like. Examples of the lubricant include talc, stearic acid, a salt of stearic acid, wax and the like. Examples of the binder include starch, dextrin,
Examples include tragacanth, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, polyvinyl alcohol and the like. Examples of the colorant include tar dyes such as Sunset Yellow. Examples of antioxidants include butylhydroxytoluene (BHT), propyl gallate, and butylhydroxyanisole (BH).
A), lecithin, α-tocopherol, hydroquinone,
Ascorbic acid, octyl gallate, dodecyl gallate and the like can be mentioned. Examples of the flavoring agents include citric acid, fumaric acid, menthol and citrus flavors. The form of the preparation includes tablets, powders, granules, capsules and the like.

Hereinafter, the present invention will be described in more detail with reference to Examples.

[0047]

Example 1 1 mg of 1α-OHD ₃ was dissolved in 1 ml of ethanol to prepare a solution, and 10 g of polyvinylpyrrolidone (molecular weight of about 40,000) was dissolved in this ethanol solution 10
It was added to 0 ml and mixed with stirring for 10 minutes. Further, 30 g of crystalline cellulose was added to this solution and mixed with stirring for 10 minutes. Next, ethanol was distilled off under reduced pressure and dried to obtain 38.8 g of a reaction product. 1α-OH in this reaction product
The content of D ₃ was 0.0025%.

The composition of the present invention was stored at 40 ° C., and the residual rate of 1α-OHD ₃ was examined with the lapse of time. As a control, 1α-OHD ₃ corn starch 1,
000 times dispersion was used. This control is 1α-OHD ₃ 1mg
Was dissolved in 10 ml of ethanol, 1 g of corn starch was added, ethanol was distilled off under reduced pressure, and the residue was dried. The time course of the residual ratio of 1α-OHD ₃ in the composition of the present invention and the control product is shown in Table 1. As is clear from Table 1, in the composition of the present invention, 1α-OHD ₃ was present over a long period of time. Almost no decrease, whereas the control product drastically decreases 1α-OH.
It can be seen that decomposition of D ₃ occurs.

[0049]

[Table 1]

[0050]

Example 2 1 mg of 1α, 24- (OH) ₂ D ₃ was dissolved in 1 ml of ethanol to give a solution, which was added to 100 ml of an ethanol solution dissolved in 10 g of polyvinylpyrrolidone (molecular weight of about 40,000) and mixed with stirring for 10 minutes. I'm sorry. Further, 30 g of crystalline cellulose was added to this solution and mixed with stirring for 10 minutes. Next, ethanol was distilled off under reduced pressure and dried to obtain 38.8 g of a reaction product. 1α of this reaction product,
The content of 24- (OH) ₂ D ₃ was 0.0025%.

This composition of the present invention was stored at 40 ° C.
1α, 24- (OH) as the time passes₂D₃Survival rate
I checked. 1α, 24- (OH) as a control₂D₃
The corn starch of 1,000 times was used. This pair
Illumination is 1α, 24- (OH) ₂D₃1 mg ethanol 1
Add 1 g of corn starch to the solution dissolved in 0 ml and
The tanol was distilled off under reduced pressure and dried. A composition of the invention and
1α, 24- (OH) in the control₂D₃Of the remaining rate of
The changes are described in Table 2, and as is clear from Table 2, the present invention
In the composition of 1α, 24- (OH)₂D₃Is a long time
Almost no decrease over time, whereas the control sharply
1α, 24- (OH)₂D₃I know that the decomposition of
It

[0052]

[Table 2]

[0053]

Example 3 1 mg of 24-OHD ₃ was dissolved in 1 ml of ethanol to prepare a solution, and 10 g of polyvinylpyrrolidone (molecular weight: about 40,000) was dissolved in this ethanol solution 10
It was added to 0 ml and mixed with stirring for 10 minutes. Further, 30 g of crystalline cellulose was added to this solution and mixed with stirring for 10 minutes. Next, ethanol was distilled off under reduced pressure and dried to obtain 38.8 g of a reaction product. 24-OHD in this reaction product
The content of ₃ was 0.0025%.

The composition of the present invention was stored at 40 ° C., and the residual rate of 24-OHD ₃ was examined over time. As a control, 24-OHD ₃ corn starch 1,
000 times dispersion was used. This control is 24-OHD ₃ 1 mg
Was dissolved in 10 ml of ethanol, 1 g of corn starch was added, ethanol was distilled off under reduced pressure, and the residue was dried. The changes over time in the residual ratio of 24-OHD ₃ in the composition of the present invention and the control product are shown in Table 3. As is clear from Table 3, in the composition of the present invention, 24-OHD ₃ was present over a long period of time. Almost no decrease, whereas the control product drastically decreases 24-OH.
It can be seen that decomposition of D ₃ occurs.

[0055]

[Table 3]

[0056]

Example 4 1 mg of 1α-OHD ₃ was dissolved in 1 ml of ethanol to prepare a solution, and 10 g of polyvinylpyrrolidone (molecular weight of about 40,000) was dissolved in this ethanol solution 10
It was added to 0 ml and mixed with stirring for 10 minutes. Further, 30 g of corn starch was added to this solution and mixed with stirring for 10 minutes. Next, ethanol was distilled off under reduced pressure and dried to obtain 38.8 g of a reaction product. 1α-OH in this reaction product
The content of D ₃ was 0.0025%.

The composition of the present invention was stored at 40 ° C., and the residual rate of 1α-OHD ₃ was examined with the passage of time. As a control, 1α-OHD ₃ corn starch 1,
000 times dispersion was used. This control is 1α-OHD ₃ 1mg
Was dissolved in 10 ml of ethanol, 1 g of corn starch was added, ethanol was distilled off under reduced pressure, and the residue was dried. The time course of the residual ratio of 1α-OHD ₃ in the composition of the present invention and the control product is shown in Table 4. As is clear from Table 4, 1α-OHD ₃ was present in the composition of the present invention for a long time. Almost no decrease, whereas the control product drastically decreases 1α-OH.
It can be seen that decomposition of D ₃ occurs.

[0058]

[Table 4]

[0059]

Example 5 1 mg of 1α, 24- (OH) ₂ D ₃ was dissolved in 1 ml of ethanol to give a solution, which was added to 100 ml of an ethanol solution dissolved in 10 g of polyvinylpyrrolidone (molecular weight: about 40,000) and stirred for 10 minutes. I'm sorry. Further, 30 g of corn starch was added to this solution and mixed with stirring for 10 minutes. Next, ethanol was distilled off under reduced pressure and dried to obtain 38.8 g of a reaction product. The content of 1α, 24- (OH) ₂ D ₃ in this reaction product was 0.0025.
%Met.

This composition of the present invention was stored at 40 ° C.
1α, 24- (OH) as the time passes₂D₃Survival rate
I checked. 1α, 24- (OH) as a control₂D₃
The corn starch of 1,000 times was used. This pair
Illumination is 1α, 24- (OH) ₂D₃1 mg ethanol 1
Add 1 g of corn starch to the solution dissolved in 0 ml and
The tanol was distilled off under reduced pressure and dried. A composition of the invention and
1α, 24- (OH) in the control₂D₃Of the remaining rate of
The changes are shown in Table 5, and as is clear from Table 5, the present invention
In the composition of 1α, 24- (OH)₂D₃Is a long time
Almost no decrease over time, whereas the control sharply
1α, 24- (OH)₂D₃I know that the decomposition of
It

[0061]

[Table 5]

[0062]

Example 6 1 mg of 24-OHD ₃ was dissolved in 1 ml of ethanol to give a solution, and 10 g of polyvinylpyrrolidone (molecular weight of about 40,000) was dissolved in ethanol solution 10
It was added to 0 ml and mixed with stirring for 10 minutes. Further, 30 g of corn starch was added to this solution and mixed with stirring for 10 minutes. Next, ethanol was distilled off under reduced pressure and dried to obtain 38.8 g of a reaction product. 24-O in this reaction product
The content of HD ₃ was 0.0025%.

The composition of the present invention was stored at 40 ° C., and the residual rate of 24-OHD ₃ was examined over time. As a control, 24-OHD ₃ corn starch 1,
000 times dispersion was used. This control is 24-OHD ₃ 1 mg
Was dissolved in 10 ml of ethanol, 1 g of corn starch was added, ethanol was distilled off under reduced pressure, and the residue was dried. The changes over time in the residual ratio of 24-OHD ₃ in the composition of the present invention and the control product are shown in Table 6. As is clear from Table 6, in the composition of the present invention, 24-OHD ₃ was present over a long period of time. Almost no decrease, whereas the control product drastically decreases 24-OH.
It can be seen that decomposition of D ₃ occurs.

[0064]

[Table 6]

[0065]

Example 7 1 mg of 1α-OHD ₃ was dissolved in 1 ml of ethanol to prepare a solution, and 10 g of polyvinylpyrrolidone (molecular weight of about 40,000) was dissolved in this ethanol solution 10
It was added to 0 ml and mixed with stirring for 10 minutes. Further, 30 g of casein was added to this solution and mixed with stirring for 10 minutes. Then, ethanol was distilled off under reduced pressure and dried to obtain a reaction product 3
8.8 g was obtained. The content of 1α-OHD ₃ in this reaction product was 0.0025%.

The composition of the present invention was stored at 40 ° C., and the residual rate of 1α-OHD ₃ was examined over time. As a control, 1α-OHD ₃ corn starch 1,
000 times dispersion was used. This control is 1α-OHD ₃ 1mg
Was dissolved in 10 ml of ethanol, 1 g of corn starch was added, ethanol was distilled off under reduced pressure, and the residue was dried. The changes over time in the residual ratio of 1α-OHD ₃ in the composition of the present invention and the control are shown in Table 7. As is clear from Table 7, in the composition of the present invention, 1α-OHD ₃ was present over a long period of time. Almost no decrease, whereas the control product drastically decreases 1α-OH.
It can be seen that decomposition of D ₃ occurs.

[0067]

[Table 7]

[0068]

Example 8 1 mg of 1α, 24- (OH) ₂ D ₃ was dissolved in 1 ml of ethanol to give a solution, which was added to 100 ml of an ethanol solution dissolved in 10 g of polyvinylpyrrolidone (molecular weight: about 40,000) and mixed by stirring for 10 minutes. I'm sorry. Further, 30 g of casein was added to this solution and mixed with stirring for 10 minutes. Next, ethanol was distilled off under reduced pressure and dried to obtain 38.8 g of a reaction product. 1α in this reaction product,
The content of 24- (OH) ₂ D ₃ was 0.0025%.

This composition of the present invention was stored at 40 ° C.
1α, 24- (OH) as the time passes₂D₃Survival rate
I checked. 1α, 24- (OH) as a control₂D₃
The corn starch of 1,000 times was used. This pair
Illumination is 1α, 24- (OH) ₂D₃1 mg ethanol 1
Add 1 g of corn starch to the solution dissolved in 0 ml and
The tanol was distilled off under reduced pressure and dried. A composition of the invention and
1α, 24- (OH) in the control₂D₃Of the remaining rate of
The changes are described in Table 8, and as is clear from Table 8, the present invention
In the composition of 1α, 24- (OH)₂D₃Is a long time
Almost no decrease over time, whereas the control sharply
1α, 24- (OH)₂D₃I know that the decomposition of
It

[0070]

[Table 8]

[0071]

Example 9 1 mg of 24-OHD ₃ was dissolved in 1 ml of ethanol to give a solution, and 10 g of polyvinylpyrrolidone (molecular weight about 40,000) was dissolved in this ethanol solution 10
It was added to 0 ml and mixed with stirring for 10 minutes. Further, 30 g of casein was added to this solution and mixed with stirring for 10 minutes. Then, ethanol was distilled off under reduced pressure and dried to obtain a reaction product 3
8.8 g was obtained. The content of 24-OHD ₃ in this reaction product was 0.0025%.

The composition of the present invention was stored at 40 ° C., and the residual rate of 24-OHD ₃ was examined with the passage of time. As a control, 24-OHD ₃ corn starch 1,
000 times dispersion was used. This control is 24-OHD ₃ 1 mg
Was dissolved in 10 ml of ethanol, 1 g of corn starch was added, ethanol was distilled off under reduced pressure, and the residue was dried. The changes with time of the residual rate of 24-OHD ₃ in the composition of the present invention and the control are shown in Table 9. As is clear from Table 9, in the composition of the present invention, 24-OHD ₃ was used for a long time. Almost no decrease, whereas the control product drastically decreases 24-OH.
It can be seen that decomposition of D ₃ occurs.

[0073]

[Table 9]

[0074]

EXAMPLE 10-24 were prepared composition comprising active vitamin D ₃ 1 mg and various polyvinylpyrrolidone 10g and various inner material 30g in the same manner as in Example 1. This composition was stored at 40 ° C., and the residual rate of active vitamin D ₃ was measured after 1 month and 2 months. The results are shown in Table 10.

[0075]

[Table 10]

[0076]

Example 25 In the same manner as in Example 1, ₁ mg of prostaglandin E ₁ was dissolved in 1 ml of ethanol to give a solution, and 10 g of polyvinylpyrrolidone (molecular weight about 40,000) was obtained.
Was dissolved in 100 ml of an ethanol solution and stirred and mixed for 10 minutes, 30 g of crystalline cellulose was added to this solution and mixed by stirring for 10 minutes, and then ethanol was distilled off under reduced pressure and dried to obtain 38.7 g of a reaction product. The thermal stability of prostaglandin E _{1 in} this reaction product was determined according to Example 1 of the present invention.
The results are shown in Table 11 in comparison with the thermal stability of 1α-OHD ₃ in the reaction product of. As is clear from Table 11, 1α-OHD ₃ in the composition of the present invention is stabilized, whereas prostaglandin E ₁ produced by the same method is used.
Proves to be poorly stabilized.

[0077]

[Table 11]

[0078]

Example 26 1 mg of 1α-OHD ₃ was dissolved in 1 ml of ethanol to give a solution, and 1 g of polyvinylpyrrolidone (molecular weight about 40,000) was dissolved in ethanol solution 10
It was added to the mixture and mixed with stirring for 10 minutes. Further, 2 g of lactose (Japanese Pharmacopoeia lactose) was added to this solution and mixed with stirring for 10 minutes. Then, ethanol was distilled off under reduced pressure and the residue was dried to obtain 2.95 g of a reaction product. 1α-O in this reaction product
The content of HD ₃ was 0.033%.

This composition of the present invention was treated at room temperature (20 ° C. ± 2 ° C.
1) -OHD over time.
The survival rate of ₃ was investigated. As a control, 13,000 α-OHD ₃ corn starch 3,000 times was used. This control product was obtained by adding 3 g of corn starch to a solution prepared by dissolving 1 mg of 1α-OHD ₃ in 10 ml of ethanol, distilling off ethanol under reduced pressure and drying. 1α in compositions of the invention and controls
Table 12 shows the change with time of the residual rate of —OHD ₃ .
As is clear from Table 12, in the composition of the present invention, 1α-
While OHD ₃ hardly decreases for a long time,
It can be seen that the control product rapidly decomposes 1α-OHD ₃ .

[0080]

[Table 12]

[0081]

Example 27 1α-OHD₃1 mg to 1 ml ethanol
Dissolve it into a solution and add it to polyvinylpyrrolidone (minute
Ethanol solution 1 in which 1 g (approximately 40,000)
It was added to 0 ml and mixed with stirring for 10 minutes. In addition to this solution
Add 2 g of anhydrous lactose (standard for pharmaceutical ingredients outside the Japanese Pharmacopoeia) to 1
Stir and mix for 0 minutes. Then ethanol under reduced pressure
It was distilled off and dried to obtain 2.96 g of a reaction product. This reaction
1α-OHD in the product ₃The content of 0.033%
It was

The composition of the present invention was treated at room temperature (20 ° C. ± 2 ° C.).
1) -OHD over time.
The survival rate of ₃ was investigated. As a control, 13,000 α-OHD ₃ corn starch 3,000 times was used. This control product was obtained by adding 3 g of corn starch to a solution prepared by dissolving 1 mg of 1α-OHD ₃ in 10 ml of ethanol, distilling off ethanol under reduced pressure and drying. 1α in compositions of the invention and controls
Table 13 shows the change over time in the residual rate of —OHD ₃ .
As is clear from Table 13, in the composition of the present invention, 1α-
While OHD ₃ hardly decreases for a long time,
It can be seen that the control product rapidly decomposes 1α-OHD ₃ .

[0083]

[Table 13]

[0084]

Example 28 100 mg of 1α-OHD _{3 was} added to ethanol 1
This was dissolved in 00 ml to give a solution, and this was added to 10 liters of an ethanol solution in which 1000 g of polyvinylpyrrolidone (molecular weight about 40,000) was dissolved, and the mixture was stirred and mixed for 10 minutes. Further, 3 kg of anhydrous lactose was added to this solution and mixed by stirring for 10 minutes. Next, this slurry was spray-dried with a spray dryer DL-41 type to obtain 3930 g of a product. The content of 1α-OHD ₃ in this product is 0.00
It was 25%.

[0085]

Example 29 100 mg of 1α-OHD _{3 was} added to ethanol 1
This was dissolved in 00 ml to give a solution, and this was added to 10 liters of an ethanol solution in which 1000 g of polyvinylpyrrolidone (molecular weight about 40,000) was dissolved, and the mixture was stirred and mixed for 10 minutes. Anhydrous lactose (3 kg) was taken and fluidized in a fluidized granulation coating apparatus (FLO-1 type: manufactured by Freund Sangyo Co., Ltd.), and the ethanol solution was sprayed onto the fluidized product. 1α-O in this product
The content of HD ₃ was 0.0025%.

[0086]

Example 30 1α-OHD₃100 mg of ethanol 1
Dissolve it in 00 ml to make a solution, and use this as polyvinylpyrrolid
Ethane dissolved in 1000 g (molecular weight of about 40,000)
Add 10 liters of the nol solution and stir and mix for 10 minutes.
It was Take 3 kg of anhydrous lactose and stir in a V-dryer.
The above ethanol solution was added dropwise to the place where it was stirred and rotated,
The product was stirred, rotated and dried to obtain 3900 g of a product. this
1α-OHD in the product ₃Content of 0.0025%
It was.

[0087]

Example 31 In Example 27, 1α-OHD ₃ ,
Polyvinylpyrrolidone (PVP, molecular weight about 40,000
0), except that the amount of lactose is as described in Table 14.
A sample composition was obtained in substantially the same manner as in Example 27.

The residual ratio of 1α-OHD ₃ when these compositions were stored at 40 ° C. was examined, and the results are summarized in Table 15.

[0089]

[Table 14]

[0090]

[Table 15]

[0091] From Table 15, the amount of readily soluble excipient in an organic solvent, the active vitamin D ₃ compounds 500 to 1
It can be seen that particularly excellent storage stabilization was achieved in the range of 0,000 times by weight.

[0092]

Example 32 Example 31 was repeated except that hydroxypropylmethylcellulose (HPMC, molecular weight about 15,000) was used instead of polyvinylpyrrolidone (PVP) or crystalline cellulose was used instead of lactose. A sample composition was obtained with the same composition as that shown in Table 14 in Table 1.

The residual ratio of 1α-OHD ₃ when these compositions were stored at 60 ° C. or 40 ° C. was examined, and the results are summarized in Table 16 for the case and Table 17 for the case.

[0094] From Table 16 and Table 17, the amount of readily soluble excipient in an organic solvent, in the range of 500 to 100,000 times by weight the active vitamin D _3, in particular excellent storage stability It can be seen that this has been achieved.

[0095]

[Table 16]

[0096]

[Table 17]

[0097]

Example 33 In Example 31, 1α-OHD ₃ ,
Polyvinylpyrrolidone (PVP, molecular weight about 40,000
0), except that the amount of lactose is as described in Table 18.
A sample composition was obtained in substantially the same manner as in Example 31.

The residual ratio of 1α-OHD ₃ when these compositions were stored at 40 ° C. was examined, and the results are summarized in Table 19.

From Table 19, the amount of the poorly soluble excipient in the organic solvent was particularly excellent in the range of 1 to 10,000 times by weight the easily soluble excipient in the organic solvent. It can be seen that storage was stabilized.

[0100]

[Table 18]

[0101]

[Table 19]

[0102]

Example 34 In Example 33, except that hydroxypropylmethyl cellulose (HPMC, molecular weight about 15,000) was used instead of polyvinylpyrrolidone,
A sample composition was obtained in exactly the same manner as the composition described in Table 18 of Example 33.

The residual ratio of 1α-OHD ₃ when these compositions were stored at 60 ° C. was examined, and the results are summarized in Table 20.

From Table 20, the amount of the excipient which is hardly soluble in the organic solvent was in the range of 1 to 10,000 times by weight that of the excipient which was easily soluble in the organic solvent, which was particularly excellent. It can be seen that storage was stabilized.

[0105]

[Table 20]

[0106]

Example 35 In Example 27, 1α-OHD ₃ ,
Polyvinylpyrrolidone (PVP, molecular weight about 40,000
0) and the amounts of excipients that are poorly soluble in various organic solvents are shown in Table 2.
A sample composition was obtained in substantially the same manner as in Example 27 except that the procedure described in 1 was used.

The residual ratio of 1α-OHD ₃ when these compositions were stored at 40 ° C. was examined, and the results are summarized in Table 22.

From Table 22, it can be seen that the storage stability is excellent when lactose, anhydrous lactose or crystalline cellulose is used.

[0109]

[Table 21]

[0110]

[Table 22]

[0111]

Reference Example 1 A powder having the following composition containing the composition of the present invention obtained in Example 1 was prepared and tableted using an Elweka single punch tableting machine to obtain a diameter of 7 mm and a thickness of about 2 mm. As tablets.

Composition of the present invention 40.0 parts by weight crystalline cellulose 58.0 parts by weight magnesium stearate 1.0 part by weight Talc 1.0 part by weight This tablet contains about 1α-OHD _{3 in an amount} of about 1. It contains 0 μg.

[0113]

[Reference Example 2] The composition of the present invention obtained in Example 1 was mixed with purified sucrose and then granulated with a corn starch using a net granulator to obtain dry syrup granules having the following composition. .

Composition of the present invention 40.0 parts by weight Corn starch 2.0 parts by weight Purified sucrose 958.0 parts by weight This dry syrup granule contains 1α-OHD ₃ in 1 g.
Of about 1.0 μg.

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] February 4, 1992

[Procedure Amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0093

[Correction method] Change

[Correction content]

The residual ratio of 1α-OHD ₃ when these compositions were stored at 60 ° C. or 40 ° C. was examined, and the results are summarized in Table 16 for the case and Table 17 for the case. The solvent for HPMC is ethanol.
Dichloromethane (1: 1) was used.

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0099

[Correction method] Change

[Correction content]

From Table 19, the amount of the poorly soluble excipient in the organic solvent was particularly excellent in the range of 1 to 10,000 times by weight the easily soluble excipient in the organic solvent. It can be seen that storage was stabilized. On the other hand, for organic solvents
The amount of the poorly soluble excipient is easily soluble in organic solvents.
When the amount is 0.5 times the weight of the excipient, after distilling off the solvent,
The composition tends to be resinified, making it difficult to handle.
In case of 15,000 weight times, storage stability decreases
It tended to.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Reference number within the agency FI Technical display area A61K 47/32 J 7433-4C D 7433-4C 47/36 B 7433-4C 47/38 B 7433- 4C J 7433-4C D 7433-4C 47/40 B 7433-4C 47/42 B 7433-4C

Claims (6)

[Claims] 1. An active vitamin comprising an inner layer made of an excipient that is poorly soluble in an organic solvent and an outer layer made of an active vitamin D ₃ and an easily soluble excipient in an organic solvent. D ₃ type composition. 2. The active vitamin D _{3 according to} claim 1, wherein the excipient which is poorly soluble in an organic solvent is crystalline cellulose, starch, casein, cyclodextrin, lactose, hydroxypropyl starch, dextrin or gelatin.
Compositions. 3. The active vitamin D _{3 according to} claim 1, wherein the excipient which is easily soluble in an organic solvent is polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, or deoxycholic acid. Composition. 4. Active vitamin D₃The class is represented by the following formula [I](In the formula, R₁Represents a hydrogen atom or a hydroxyl group. R₂IsRepresents (where r₁, R₂Are the same or different hydrogen
Represents an atom or a hydroxyl group. However, R₁When is a hydrogen atom
r₁, R₂At least one of them is a hydroxyl group. r ₃Is water
Represents an elementary atom or a hydroxyl group). ) Active type
Tamin D₃4. The method according to any one of claims 1 to 3, which is a class.
Activated vitamin D₃Compositions. 5. Amount of an excipient that is easily soluble in an organic solvent
But active vitamin D ₃1 to 5,000,0 for class
It is 100 times weight, The activity of any one of Claims 1-4.
Sexual vitamin D₃Compositions. 6. The amount of the excipient which is poorly soluble in an organic solvent is 1 to 5 with respect to the excipient which is easily soluble in an organic solvent.
It is 1,000,000 times the weight, any one of Claims 1-5
Active vitamin D ₃ composition according to the item.