JPS58206533A - Active type vitamin d3 derivative composition and drug comprising it as active ingredient - Google Patents

Abstract

PURPOSE:The titled composition having improved chemical safety, comprising an active type vitamin D3 derivative and polyvinyl pyrrolidone. CONSTITUTION:A compound shown by the formula I [R1 is H or OH; R2 is group shown by the formula II (gamma1 and gamma2 are H or OH with the proviso that gamma1=gamma2not equal to H when R1=H), group shown by the formula III (gamma3 is H or OH), group shown by the formula VI, or group shown by the formula V] is blended with polyvinyl pyrrolidone in an amount to give 1-100,000 times, preferably 10-1,000 times as heavy as the compound shown by the formula I , and stirred in a solvent such as methanol, etc. The solvent is distilled a way under reduced pressure, or the solution is cooled, or water, a solution of salt is added to it, and precipitate occurs, to give an active type vitamin D3 derivative composition. The compound shown by the formula I has an action on the regulation of calcium level in an organism, and effective for osteoporosis, etc., to give a calcium adjustor containing the composition as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel active form of Vita-7D, a derivative composition and a drug containing it as a 'h'itl component of iJ4q-4. In order to further evaluate the novel active form of vitamin D, an intoxicant composition containing active form of hitamine D, a chemical composition of +6i 11 m vitamin DsM4 consisting of a spindle and polyvinylpyridone, and its composition. The present invention relates to a drug containing as a viscous component.

Vitamin D3 is converted to water 1 at position 25 in the liver and converted to 25-hydroxycholecalciferol (hereinafter referred to as
It is abbreviated as 25-0HD. ), and when the serum calcium concentration decreases or the serum phosphate concentration decreases, 1.25-dihydroxycholecalciferol (1.25-dihydroxycholecalciferol (
Hereinafter, it will be abbreviated as 1.26-(oH)tDm. ) and is said to exhibit physiological activity.

This 1.25-(OH)tDm is a known WS*- that has high physiological activity, and promotes absorption and transport of calcium in a small role. It elutes calcium to lower the serum calcium concentration, and promotes the reabsorption of inorganic phosphate in renal tubular cells.
It is highly effective against rickets or osteoporosis caused by vitamin D1-systems, such as chronic 14-dermatitis or parathyroid dysfunction, which is related to feedback disorders with parathyroid hormone secretion. There's a pot of things and Lou waiting.

In addition, as similar compounds to this 1.25- (OH)2D3, compounds having a hydroxyl group at the 1α position, such as 1α-hyI
-Roxychole force Lucifer ρ-(hereinafter, 1α-0kLD
, is abbreviated as . ), ■, 24-dihydro-luciferol (hereinafter abbreviated as 1.24-(OH)tDs), 1,24.25-)lihydro-? Cicolecalciferol (hereinafter referred to as 1,24゜25- (O
il) 3D, and g@distributeζ. ) etc. are synthesized, 1.
25- (OH), which has physiological properties similar to D, is being applied clinically.

i.

However, [1. All of these □ compounds W+ are insensitive to heat, light, etc., and are easily oxidized. There is a parody song, and if you think about the fact that the drug preparation is being manipulated, this is the one.
The parable due to the 2 yuan and -1 shi is unavoidable, and the production ^ 11
There is also a noticeable decline in the later preservation and enshrinement.

Therefore, these series of active vitamins 0. It is extremely useful to formulate a compound in a stable form.

Conventionally, methods for stabilizing these active vitamin 93M4 bodies include a method of forming an clathrate compound with cyclotextrin (Japanese Unexamined Patent Publication No. 128417/1982), a method of forming an clathrate compound with bile acids ( Japanese Unexamined Patent Publication 1986-1969
562 Publication @) or a method of forming a complex with cholesterol (Japanese Unexamined Patent Publication No. 67-40461) 1 is known.

On the other hand, as a method for stabilizing unstable pharmaceuticals,
Publication No. 46837 describes dimethyl 1.
A method for fractionating 4-dihydro-2,6-dimethy,4-(2-nitrophenyl)-3,5-pyridine (noedivin) into polyvinylhydrolidone is described. ing.

However, since 1.25- (OH)2D, , 1α
Hitherto, nothing has been known regarding a method for stabilizing viscous type 8 hitamine D and its derivatives using viscous vitamin D3M4 forms such as -0HD3 together with polyvinylpyridone.

Soko, Honkai, Akiban and others are active vitamin D.

As a result of intensive research to stabilize &4mV+, this
When the active vitamin osg conductor of I et al. is mixed with polyvinylpyridone, the active vitamin DSM substance is extremely stable against heat, light, oxidation, etc., and this can be used in preparations. The present invention was achieved by discovering that a stable preparation can be produced by

Therefore, the present invention provides a novel active vitamin D, i4 conductor composition characterized by comprising the first active vitamin DsM complex represented by the following formula (1) and polyvinylpyrrolidone, and a composition using the same as an active ingredient. Contains a calcium regulator.

The active type Hitami D used in the present invention.

The derivative is represented by the above formula CI).

Such active vitamin D derivatives are R7 of the above formula (1).
Based on the definition, it is classified into the following compounds.

That is, active vitamin D represented by the following formula (1-1), derivatives, and the following formula (1-1)
2) Active vitamin D, U conductor, expressed by the following m1 formula (1
) [In the formula, R represents a hydrogen atom or a hydroxyl group. 8. Type vitamin Dsfl! conductor, and the following formula (
1-4) [In the formula, R1 represents a hydrogen atom or a hydroxyl group. ] is an active vitamin Dsu conductor.

Specific examples of these active 8: type hitamine D and conductor include the following.

The active vitamin Ds@conductor of the above formula (1-t) is, for example, 1 a-OHDl, 25-0HD3.24
-Human p-xycholecalciferum (hereinafter referred to as z4-OH
D, approximately 1se), 1.2 5- (OR)
, D, , 1.24-(OH), Ds, 1,24.2
6- (OR), D, etc.; Examples of active vitamin D derivatives of the above formula (1-2) are 24-'A xocholecalciferol, la-hydroxy-24-oxocholecalciferol, 25 -Hydroxy-24-oxocholecalciferol, lα, 25-dihydroxy-24-oxocholecalciferol, etc.; the above formula (1
-3) active vitamin D, as a derivative, for example 25
-Hydroxycholecalciferol-26,23-lactone, 1α,25-dihydrocholecalciferol-26,23-lactone, etc.; active vitamin D of the above formula (1-4), derivatives include, for example, 25-human Examples include g-xycholecalciferol-26,23-peroxylactone, lα, 25-dihydroxycholecalciferol-26,23-peroxylactone, and the like.

The polyvinylvinyl pyrrolidone used in the present invention is preferably polyvinylpyrrolidone with a molecular weight of 250 to t, o o o, o o o, and more preferably polyvinylpyrrolidone with a molecular weight of 1,000 to 700,000.

The amount of polyvinylbilidone used in the present invention is 1 to 100,000 of the active vitamin Dsnn form.
The range of double violet (311 lids) is preferable, and more preferably 1
It is in the range of 0 to o, o o o times it (weight),
Particularly preferred is a range of 10 to 1,000 times the amount (by weight).

Active vitamin Dsi of the present invention! The conductor composition can be manufactured as follows.

The activated vitamin D of formula (1), the brocade conductor, and polyvinylpyrrolidone are dissolved in a 4416 solvent such as methanol, ethanol, and polyvinylpyrrolidone. 77 record m'1 Stir and mix well in dried tanol solvent, remove the edges and melt peaks under reduced pressure, cool, or add water, 9 salt solution, etc. to precipitate. The m-drink of the present invention is swallowed by pressing.

The active vitamin D, d4 and polyvinylpyrrolidone obtained in this manner may contain other ingredients, such as known excipients, binders, etc., depending on the parody. A disintegrating agent, an antioxidant and its #, a coloring agent, a flavoring agent, a lubricant, an emulsifier, a suspending agent, an interfacial viscosity agent, etc. can be mixed to form a "C" agent. Formula (I
)'s active form of vitamin Ds N# conductor has the effect of regulating the calcium level in the body, and is self-effective for osteoporosis, osteomalacia, etc. (V, s, Patent A
4.022゜syx; Vitamin D
nD) :Basic Research 7 Node Germans Clinical Application (Ba5ic Re5ear)
ch and its clinic
aLlon) (1979) 1099-1106)
Therefore, according to Kien ψ1, active vitamin Dsmi 4' body composition, which is represented by the above formula CI)::71), and consists of caster 4 body and holi-vinylpyrrolidone, is contained as active ingredient 1. A calcium regulator is provided.

Such preparations are, for example, tablets, capsules, -granules.

It can be dissolved or suspended in a flux, dry syrup, pond water, or non-aqueous solvent to form a liquid preparation, or a soft capsule.

Examples of excipients that are used as necessary in the production of these preparations include starch, crystalline cellulose, texturin, lactose, mannitol, sorbitol, anhydrous phosphorus, calcium monosucrose, and talc (natural hydrated silicic acid). magnesium).

Kaolin, precipitated calcium carbonate, sodium chloride, fermented titanium, light anhydrous silica, acids, etc., and examples of binders include Te/Pun, Desaki Strine, Tragacanth, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropylene. Cellulose, crystalline cellulose, hydroxypropylene methylcellulose, ethylcellulose, carboxymethylcellulose, gum arabic, etc. 1. Examples of disintegrants include TEMP/ and Krystal Nana+・μm.

Carboxymethyl cellulose calcium, agar powder, and as antioxidants for dogs, heptanal hydroxytoluene (BHT), gallic acid boupy/l.

7 chirhi l'q xyl nisole (BHA),
Lecithin, α-tocopherol, hydroquinone/l
Ascolhin #, gallic octyl, gallic acid dodenyl, gallic acid iso7 mil, nordihydroguphiarenainic acid, guaiac butter, α-su7 tyl (amine, protocatechudiethyl (EPG), 77:Iruhin stearin) Acid Nisder, 7 scolhino-catalyzed palmitic ester, thiodipropionic acid, thiodylauryl dipropionic acid, sodium bisulfite, cysteine IIA salt,
Isoascor, citric acid, sodium ascorbic acid phosphate, sodium sulfite, sodium metametahite, erythorbine H1, storum erythorbate, thioglycerol, thioglycol, thione rubitol, thiolactic acid, etc. An example of a symtomer of the oxidizing agent is 7-leic acid.

Maronroku, pyruvic acid, /conitic acid, succinic acid, fumaric acid, tartar #, dihydroxyethylglycine, ethylenedidominetetraacetic acid, glycerin.

Phenyl 7-ranine, phosphoric acid, sorbitol, tryptophan, etc. are used as coloring agents and tar pigments, etc.
Examples of flavoring agents include citric acid, fumaric acid, Roishi m, menthol, and citrus flavor, and examples of lubricants include talc.

Starch, stearin, magnesium and calcium, horax, paraffin, cocoa butter.

Examples of emulsifiers and clouding agents include macrogol, piscine, sodium benzene, etc., examples of emulsifiers and clouding agents include gum 7rabi 7, tragacanth, sodium carboxymethyl cellulose, methyl cellulose, sodium alginate, etc., and examples of surfactants include polysorbates. , Raumac p-gol, glyceryl monostearate, lauryl@i[no)lium, triethanolamine, and the like.

Known methods can be used to produce tablets, capsules, and granules using these ingredients.

Thus, according to the present invention, stabilized active vitamin D
The s* conductor composition and its drug have been provided and are of great significance.

Ju, l. In order to clarify the outstanding effects of the present invention, an explanation will be given using examples, but the present invention is of course not limited by these examples.

Ika I example l.

Kou α-0HD, 1 ml of ethanol Ic
@Dissolve and make a solution of this polyvinyl pyridone (molecular cap approximately 40,000) 1,? The mixture was added to 100 Rt of my ethanol solution and stirred and mixed for 10 minutes. Ethanol was distilled off under reduced pressure) and dried to obtain reaction product 9909. lα-0HD in this reaction product.

Noki violet ↓0.1 heavy JIlchi)) ivy.

The composition of the present invention was stored at 40° C., and the residual rate of lα-0HD was examined over time.

As a control, 1α-0HD, corn starch 1
,00 o multiplication was used. This control is 1α-0) ID
, 111 & was dissolved in ethanol 1-1011/ To a solution of
11f was removed and dried. The changes over time in the residual rate of I & I [object and comparison lα knee OHD] are #p, 1
As described in the table, as is clear from Table 1, in the composition of the present invention, lα-011D hardly decreases over a long period of time, whereas in the control material, decomposition of lα-0HDs occurs rapidly. I understand.

Furthermore, the photostability of 1α-0HD in the composition of the present invention is listed in Table 1. The composition and the above-mentioned control were placed separately in transparent glass bottles and left to stand next to a guide window, and the residual rate of lα-0HD was measured over time. Against the light
It can also be seen that the composition of the present invention is much more stable.

Furthermore, the stability of 1α-0HD in the composition of the present invention against aS is described in Part 1. The composition and the above-mentioned control substance were each separately packed into a glass tube. Both ends were closed with a glass cooler and the gas was passed through the Hl tube at a flow rate of 15 mm/m to increase the concentration of α-0HD over time. The survival rate has been reduced.

It can be seen that the composition of the present invention is also more stable against wire elements.

Table 1 Example 2 1.24- (OH), -o, t~ in ethanol 1-
This was added to an ethanol-resistant liquid "100i+4" in which polyvinylpyridone (molecules - approximately 40.00,0)'l JF had been dissolved and stirred and mixed for 10 minutes.The ethanol was distilled off under reduced pressure. , and dried to obtain 990 inches of the reaction product.1.24-(
The content of OR) and -D was 0.1 ml.

This composition of the present invention was stored at 40°C, and the residual rate of 1.24-(Off)1-D was examined over time. As a control, 1,000 times reduced corn starch of 1.24-(OH), -D, was used. This control is 1.24-(OR)2-D, 1 Da in ethanol I
1 g of corn starch was added to 4-fuei dissolved in ON, ethanol was distilled off under reduced pressure, and the mixture was dried.

Wood brother 111417) ffi 11t# To vs. M Monochu no 1.24- (OH), -D.

The change in residual rate over time is described in the second box, and as is clear from Table 2, 1.24-(OR) in the composition of the present invention,
It can be seen that -D hardly decreases over a long period of time, whereas decomposition of 1.24-(OR)*-O occurs rapidly in the control sample.

In addition, 1,24-(OHn, -D) in the composition of the present invention
.

The photostability of the compounds is shown in Table 2. The composition and the above-mentioned control substance were placed separately in transparent glass bottles and left near a window in the house.
The 'IITF rate of Ds was investigated. Book 9Q also for light
It can be seen that the light composition is much more stable.

In addition, 1.24- (OH), - in the composition of the present invention
I).

The stability against # element is listed in Table 2. The composition and the control substance were each placed in a glass tube, both ends of which were closed with glass wool, and oxygen gas was passed through the tube at a flow rate of 15 mt/m, with a residual rate of 1.24(01()t-Ds) over time. It can be seen that the composition of the present invention is more stable against oxygen.

Example 3 24-OHD, 1■ was dissolved in 1 ml of ethanol to make a solution.
000) s Etanopa dissolved in y, solution 100m
1 [The mixture was stirred and mixed for 10 minutes. Ethanol was removed under reduced pressure and dried to obtain a reaction product 9901v. 24-0HD in this reaction product.

Until then, it was 0.1 μch.

This composition of the present invention was stored for 4 ()''C1 hours until tiled.
The residual rate of 24-011D was investigated over time.

. λimqs, = 24-01 (D, σ) and 5 sorghum starch 1,000 times loss? j Terumono number↓24-0)10. s w ik xri/-/shi10*
Corn starch ty was added to a solution dissolved in J, and the ethanol was distilled off under reduced pressure and dried. 24-0110 in the composition and text of the present invention. Although the survival rate of the #chi time change is listed in the #43 table, it is clear from Table 3 that it is 12.24-0HD3)
There was almost no low 1 for one long time and one game.
K (accurately 24-0HI) 30 decomposition occurs.

-E, the photostability of 24-oua in the composition of the present invention is described in Section 36. The composition and the control sample were placed separately in transparent J-glass bottles and left near a window indoors, and as time passed, the amount of 24-0HD3 remaining was 4.

Even when exposed to light, the composition of the agent 1 of the present invention is much more stable.

Also in the composition of the present invention 17) 24-OHD, #
The stability against chemical substances is shown in the t443 table. The composition and the control substance were separately packed in glass tubes, both ends of which were closed with glass wool. Oxygen gas was passed through the tube at a flow rate of 15 txl/m, and the residual rate of 24-0 HD was determined as time passed. Peta. [It can be seen that the composition of the present invention is also more stable with respect to kK.

5143 Table implementation [furnace 1s 4-15 Same as Example 1, t6 type vitamin D, 11v? ! A composition consisting of r11 polyvinylpyrrolidone H11t was prepared. This composition was stored at 40° C., and the residual rate of vitamin D3 type 76 was measured after 1 month and 2 months. The results are listed in Table 4.

'511Lh Example 16 A powder having the following composition containing the composition of the present invention obtained in Example 1 was subjected to 1A test using an Elweka temperature blasting machine (・
The tablet was made into a tablet with a diameter of 7 mm and a thickness of approximately 2 mm.

Composition of the present invention 1.02 parts by weight Milk N
160.0 11 [ji parts and 5 parts sorghum starch 27.5 parts by weight Magnesium stearate 1.0 parts by weight Talc 0.5 1 part This tablet contains about 1.0 parts of 1a-OH-D in the IN. -Contains.

Example 17 The composition of the present invention obtained in Example 1 was mixed with refined white sugar, and then granulated using a mesh granulator using sorghum starch as a binder to obtain dry silt granules having the following composition: 1.
And so.

Composition of the present invention 1.02 parts by weight and 5 sorghum starch 2.0 lk Ayabe refined white sugar
997.0 Blood ms This fine granule for dry syrup contains about 1.0 μl of 1a-OH-D in Il.

Patent applicant: Yudai Co., Ltd.

Claims (1)

[Claims] II! Ds#A4 16 characterized by consisting of topolyhinyl pyrrolitonone
Type 1 vitamin D, spindle composition. 2. Polyvinylpyrrolidone has a molecule of 1i250 to 1.00
0,000 of polyvinylpyrrolidone). 3.K of polyvinylpyrrolidone is activated Big4F DaM
14 bodies 1~100,000@lid (l amount) -'s face 111
1. An active vitamin D3 spindle composition according to claim 1 or claim 2. 4. Active T+ type vitamin D3v expressed by the above formula (1)
44 and polyvinylpyrrolidone, m
A calcium arranging agent containing vitamin D and #ij conductor composition as active ingredients.