JPS6251948B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel active vitamin _D3 derivative compositions. For more information, see Active Vitamin D ₃
Active vitamin consisting of derivatives and sterols
The present invention relates to a novel active vitamin D ₃ derivative composition with improved chemical stability of the D ₃ derivative. Vitamin D ₃ is hydroxylated at the 25th carbon position in the liver to form 25-hydroxy cholecalciferol (hereinafter abbreviated as 25-OHD _3. The above formula [1]
R ₁ = H, R ₂ = OH, R ₃ = H), and when the serum calcium concentration decreases or the serum phosphate concentration decreases, the 1-hydroxyl oxygen localized in the mitochondria of renal tubular cells causes 1,25-dihydroxycholecalciferol (hereinafter referred to as 1,25-
It is abbreviated as (OH) ₂ D ₃ . In the above formula [1], R ₁
= H, R ₂ = OH, R ₃ = OH) and is said to exhibit physiological activity. This 1,25-(OH) ₂ D ₃ is a metabolite with the highest physiological activity known at present, and it promotes absorption and transport of calcium in the small intestine, elutes bone calcium, and lowers serum calcium concentration. It also promotes the reabsorption of inorganic phosphate in renal tubular cells, increasing serum inorganic phosphate concentration, and is associated with the feed and back function of parathyroid hormone secretion, leading to chronic kidney disease and parathyroid dysfunction. It is expected to be highly effective against rickets and osteomalacia caused by the vitamin _D3 metabolism system. In addition, as similar compounds to this 1,25-(OH) ₂ D ₃ , compounds having a hydroxyl group at the 1α position, such as 1α
-Hydroxycholecalciferol (hereinafter referred to as 1α)
-Abbreviated as OHD ₃ . In the above formula [1], R ₁ =
H, R ₂ = H, R ₃ = OH) 1,24-dihydroxycholecalciferol (hereinafter 1,24-(OH) ₂ D ₃
It is abbreviated as. In the above formula [1], R ₁ =OH,
R ₂ = H, R ₃ = OH], 1,24,25-trihydroxy-cholecarferol (hereinafter referred to as 1,24,25-
(OH) Abbreviated _{as 3D3} . In the above formula [1], R ₁
=OH, R ₂ = OH, R ₃ = OH), etc. are synthesized,
1,25-(OH) ₂ D ₃ is being used clinically as a substance with similar physiological activity. However, these compounds are all sensitive to heat, light,
Because it is unstable and easily oxidized,
During storage, it is necessary to take measures such as freezing, shielding from light, and replacing with inert gas, and considering that during actual preparation operations, the effects of heat, light, and oxidation cannot be avoided, and the storage stability of the preparation may deteriorate. Significant impact. Therefore, it is extremely useful to provide a series of active vitamin _D3 compounds in a stable form. Conventionally, methods for stabilizing active vitamin D ₃ in a solid state include, for example, the method of forming an inclusion compound with cyclodextrin (Japanese Patent Application Laid-Open No. 128417/1989) proposed by the present applicant. Are known. Further, German Patent No. 713235 describes a method for stabilizing non-active vitamin D ₃ with cholesterol. However, active vitamins
Until now, it has been completely unknown whether or not a reaction product is formed with D ₃ cholesterol, or even if a reaction product is formed, what properties it exhibits. We have developed a series of these activated Vitan _D3
As a result of intensive research aimed at stabilizing compounds, we found that when these active vitamin _D3 compounds are reacted with sterols, they are stable against heat, light, oxidation, etc. The inventors have discovered that similarly stable preparations can be produced using the same methods, and have arrived at the present invention. That is, the present invention provides a novel active vitamin comprising at least one active vitamin D ₃ derivative selected from hydroxycholecalciferols represented by the above formula [1] and sterols. A D ₃ derivative composition and a formulation containing the composition. Active vitamin D ₃ used in the present invention
The derivative is represented by the above formula [1], for example, 1α-hydroxycholecalciferol, 24-hydroxycholecalciferol, 25
―Hydroxycholecalciferol, 1α, 24―
Dihydroxycholecalciferol, 1α, 25-
Dihydroxycholecalciferol, 24,25-dihydroxycholecalciferol, 1α, 24,25
-trihydroxycholecalciferol, etc., and at least one of R ₁ , R ₂ and R ₃ in the above formula [1] is a hydroxyl group. In addition, sterols that can be used in the present invention include cholesterol, β-sitosterol, campesterol, stigmasterol, △
⁷ - Cholesterol, △ ⁷ - Coprostenol,
△ ⁷ - ergostenol, ergostatetraenol, △ ⁷ - stigmastenol clionasterol, 7-dehydroclionasterol, parisol, 22α-hydroquine cholesterol, cerebrosterol, 7β-hydroxycholesterol, penicerol, 3α, 7α,22α-trihydroxystigmast-5-ene, lophenol,
Macdogalin, cholestanol, coprostanol, thymosterol, desmosterol, 22-dehydrocholesterol, coudehydrocholesterol, neospongosterol, aptostanol, brassicasterol, ergosterol,
5,6-dihydroergosterol, 22,23-dihydroergosterol, 14-dehydroergosterol, 24-methylenechoretenol, episterol, fuecosterol, ascosterol,
Ergostatetraenol, pyrocalciferol, α-spinasterol, corbisterol,
△ ⁵ , ²⁵ - Stigmastadiene-3β-ol, △
⁷ , ²⁵ -stigmastadiene-3β-ol, △ ⁷ , ^2
2 , ²⁵ -stigmastaen-3β-ol, polyferasterol, chondrillasterol, fucosterol, isofucosterol, △ ⁷ -apenasterol, epicoprostanol, cerebisterol, salingosterol, 24-methylenelophenol, citro Examples include stadienol, α-sitosterol, and their esters.
Among these, one or more selected from the group consisting of cholesterol, β-sitosterol, campesterol, and esters thereof are particularly preferably used. The amount of sterols used in the present invention is in the range of 1 to 100,000 times (by weight) the amount of the active vitamin derivative, preferably 10 to 10,000 times (by weight), particularly preferably 10 to 10,000 times (by weight). ~1000 times the amount (by weight) is used. In an embodiment of the present invention, active vitamin
This reaction is preferably carried out by reacting the D ₃ derivative and the sterol in a solvent such as ethanol, and then adding water, saline, etc., or precipitating the reaction product by concentration, cooling, etc. The novel active vitamin D ₃ derivative composition, which is characterized by comprising the active vitamin D ₃ derivative obtained in this manner and sterols, may be prepared by adding other ingredients, such as known excipients and binders, as necessary. Tablets, capsules, granules, powders, and dry syrups are prepared by mixing agents, disintegrants, antioxidants and their conjugates, colorants, flavorings, lubricants, emulsifiers, suspending agents, surfactants, etc. The agent can be dissolved or suspended in an aqueous or non-aqueous solvent to form a liquid preparation or a soft capsule. Examples of excipients used as necessary include starch, crystalline cellulose, dextrin, lactose,
Mannitol, sorbitol, anhydrous calcium phosphate, white sugar, talc (natural hydrated magnesium silicate), kaolin, precipitated calcium carbonate, sodium chloride, titanium oxide, light anhydrous silicic acid, etc., and binders such as starch, dextrin, and tragacanth. , gelatin, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropylcellulose, crystalline cellulose, hydroxypropylmethylcellulose, ethylcellulose, carboxymethylcellulose, gum arabic, etc. Disintegrants include starch, crystalline cellulose, carboxymethylcellulose, calcium, agar powder, etc.
Examples of antioxidants include butylated hydroxytoluene (BHT), propyl gallate, butylated hydroxyanisole (BHA), lecithin, α-tocopherol, hydroquinone, ascorbic acid, octyl gallate, dodecyl gallate, isoamyl gallate, nordihydroguay. Aletic acid, guaiac butter, α-naphthylamine, ethyl protocatechuate (EPG), ascorbyl stearate, ascorbyl palmitate,
Thiodipropionic acid, thiodilaurylpropionic acid, sodium bisulfite, cysteine hydrochloride,
Isoascorbic acid, citric acid, sodium ascorbate stearate, sodium sulfite, sodium metasulfite, erythorbic acid, sodium erythorbate, thioglycerol, thioglycerol, thiosorbidol, thiolactic acid, etc.
Antioxidant synergists include, for example, maleic acid, malonic acid, pyruvic acid, aconitic acid, succinic acid,
Fumaric acid, tartaric acid, dihydroxyethylglycine, ethylenediaminetetraacetic acid, glycerin, phenylalanine, phosphoric acid, sorbitol, tryptophan, etc., and coloring agents include, for example, tar pigments that can be used in pharmaceuticals as specified by the Ministry of Health and Welfare ordinance. Flavoring agents include, for example, citric acid, fumaric acid, tartaric acid, menthol, citrus flavor, and lubricants include, for example, talc, starch, magnesium and calcium stearate, boric acid, paraffin, cocoa butter, macrogol,
Examples of emulsifiers and suspending agents include gum arabic, tragacanth, sodium carboxymethylcellulose, methylcellulose, and sodium alginate. Examples of surfactants include polysorbates, lauromacrogol, and monostearic acid. Examples include glycerin, sodium lauryl sulfate, and triethanolamine. EXAMPLES Hereinafter, in order to clarify the excellent effects of the present invention, an explanation will be given using Examples, but the present invention is of course not limited thereto. Example 1 1 mg of 1α-OHD ₃ was dissolved in 1 ml of ethanol to make a solution. This solution was added to 100 ml of an ethanol solution in which 1 g of cholesterol was dissolved, and the mixture was stirred and mixed for 10 minutes to react. Ethanol was distilled off under reduced pressure and the residue was dried to obtain 990 mg of the reaction product. The content of 1α-OHD ₃ in this reaction product was 0.1% by weight. This 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, corn starch with 1α-OHD ₃
A 1000x dispersion was used. This control is 1α-OHD ₃ 1
mg was dissolved in 10 ml of ethanol, 1 g of corn starch was added to the solution, the ethanol was distilled off under reduced pressure, and the product was dried. Table 1 shows the changes over time in the residual rate of 1α-OHD ₃ in the composition of the present invention and the control material. As is clear from Table 1, in the composition of the present invention, 1α-
It can be seen that while OHD ₃ hardly decreases over a long period of time, 1α-OHD ₃ decomposes rapidly in the control sample. The photostability of 1α-OHD ₃ in the composition of the present invention is also listed in Table 1. The composition and the above-mentioned control were placed separately in transparent glass bottles and left indoors near a window, and the residual rate of 1α-OHD ₃ was examined over time. It can be seen that the composition of the present invention is also much more stable against light. Table 1 also shows the stability of 1α-OHD ₃ in the composition of the present invention against oxygen. The composition and the control material were separately packed into gas tubes, both ends of which were closed with glass wool, through which oxygen gas was passed at a flow rate of 15 ml/min to examine the residual rate of 1α-OHD ₃ over time. It can be seen that the composition of the present invention is also more stable against oxygen.

【table】

[Table] Example 2 1 mg of 1,24-(OH) ₂ D ₃ was dissolved in 1 ml of ethanol to make a solution, which was added to 100 ml of an enol solution in which 1 g of cholesterol was dissolved, and stirred and mixed for 10 minutes to react. Ethanol is distilled off under reduced pressure,
After drying, 990 mg of the reaction product was obtained. The content of 1,24-(OH) ₂ D ₃ in this reaction product was 0.1% by weight. This composition of the present invention was stored at 40°C, and the residual rate of 1,24-(OH) ₂ D ₃ was examined over time. As a control, 1,24-(OH) ₂ D ₃ corn starch powder 1000 times was used. This contrast is 24
1 g of corn starch was added to a solution of 1 mg of -(OH) ₂ -D ₃ dissolved in 10 ml of ethanol, the ethanol was distilled off under reduced pressure, and the solution was dried. Table 2 shows the changes over time in the residual rate of 1,24-(OH) ₂ -D ₃ in the composition of the present invention and the control sample. , 24-(OH) ₂ D ₃ hardly decreases over a long period of time, whereas in contrast, 1,24-(OH) ₂ D ₃ rapidly decomposes. Furthermore, 1,24-(OH) ₂ D ₃ in the composition of the present invention
The photostability of the compounds is listed in Table 2. The composition and the control described above are each placed separately in transparent glass bottles;
Leave it indoors near the window and over time it will become 1,24-
The residual rate of (OH) ₂ -D ₃ was investigated. It can be seen that the composition of the present invention is also much more stable against light. Furthermore, 1,24-(OH) ₂ - in the composition of the present invention
The stability of D ₃ towards oxygen is listed in Table 2.
The composition and the control material were placed in each glass tube, both ends of which were closed with glass wool, and 15 ml of oxygen gas was poured into the tube.
At a flow rate of min, as time passes, 1,24
The residual rate of (OH) ₂ -D ₃ was investigated. It can be seen that the composition of the present invention is also more stable against oxygen.

[Table] Examples 3 to 12 Compositions consisting of 1 mg of active vitamin D ₃ and 1 g of various sterols were prepared 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 one month and two months later. The results are shown in the third display.

[Table] Example 13 A powder having the following composition containing the composition of the present invention obtained in Example 1 was prepared and made into tablets using a single-shot tablet press made by Elueca, with a diameter of 7 mm and a thickness of approx. It was made into a 2 mm tablet. Composition of the present invention 1.02 parts by weight Lactose 1500 parts by weight Corn starch 27.5 parts by weight Magnesium stearate 1.0 parts by weight Talc 0.5 parts by weight This tablet contains approximately _1.0μ of 1α-OH-D3 in each tablet.
It contains g. Example 14 The composition of the present invention obtained in Example 1 was mixed with refined white sugar, and then granulated using a mesh granulator using corn starch as a binder to obtain granules for dry syrup having the following composition. Composition of the present invention 1.02 parts by weight Corn starch 2.0 parts by weight Refined white sugar 997.0 parts by weight This dry syrup granule contains 1α-
It contains approximately 1.0μg of OH- _D3 .

Claims (1)

[Claims] 1. The following formula [1] [In the formula, R ₁ , R ₂ , R ₃ are the same or different,
Hydrogen atom or hydroxyl group, provided that R ₁ , R ₂ , R ₃
At least one of them represents a hydroxyl group. ] At least one type of active vitamin D selected from hydroxycholecalciferols represented by ₃
A novel active vitamin _D3 derivative composition comprising a derivative and a sterol. 2. The active vitamin D ₃ derivative composition according to claim 1, wherein the sterol is one or more selected from the group consisting of cholesterol, β-sitosterol, campesterol, and esters thereof. thing. 3. The active vitamin D ₃ derivative composition according to claim 1, wherein the amount of sterols is in the range of 1 to 100,000 times the amount (weight) of the active vitamin D ₃ derivative.