JPS5944375A - Stable aqueous solution of alpha-tocopherol phosphoric ester - Google Patents

Abstract

PURPOSE:The titled aqueous solution improving clouding, useful for improving peripheral circulation, etc., obtained by adding a nonionic surface active agent to a solution having a specific pH, wherein an alpha-tocopherol phosphoric ester is dissolved as a pharmaceutically acceptable water-soluble salt. CONSTITUTION:A stable aqueous solution of alpha-tocopherol phosphoric ester, wherein an alpha-tocopherol phosphoric ester is dissolved as a pharmaceutically acceptable water-soluble salt (e.g., alkali metal salt), having 3-9pH, preferably 5-8pH, containing a nonionic surface active agent. The nonionic surface active agent has preferably 11-20HLB. The amount of it used is >=15(W/W), preferably >=100(W/W) based on alpha-tocopherol phosphoric ester. Defects such as clouding, etc. with respect to pharmaceutical manufacturing, obstacles in the preparation of an aqueous solution of hydrophilic alpha-tocopherol, caused by the adjustment of concentration or pH, can be improved.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a stable water-17-fk of tocopherol phosphate ester.

α-l/Coferol improves peripheral blood circulation17, and relieves numbness and coldness in the hands and feet, and υJ1 history published by Till (rj″i,
II'1. It has been shown to be effective in single treatment with I and T. In recent years, it has also been effective for oral treatment with 1: 1' and 1' and has been long-awaited.

α-Tocopherol is an oily substance that is abundantly contained in wheat germ, and its calcium salts r'l and lotus are found in acetate, nicotii, -1, and sacunate.
The old one has 1 volume of water and 7 cups. .

In order to obtain an aqueous solution of ty-'p copherol, we added the phosphoric acid ester [-'l L,ta1,α-
Tocopherol phosphate ester is soluble in water in the form of Yukai! J game, TLF & squid, that nonodium IS
Since A dissolves in ice, it is unreasonably salted out by salts such as sodium chloride from water's action, and has a degree of flux of (1.5 (W/◇)%). When dissolved in water, 1) I-I is about 105, which is not suitable for use as injections or eye drops. In addition, in order to approach the physiological 1)I], add an acid to the aqueous solution to make it close to I)l-17('', and leave it at room temperature or let it dissolve on its own after freezing, and the viscosity increases. .l L and becomes cloudy, so the formulation is unfavorable.

As a result of extensive research to overcome these drawbacks, Tetsu and his colleagues completed the present invention.

Wood 5Q Clear: , α-tocopherol phosphate ester is dissolved as a pharmaceutically acceptable water-soluble salt, and its I)I-I or') to 9, preferably 5 to 8, and non- Ion (41 world divination agent added IJ1
4゜(pharmaceutical solution of tocopherol phosphate ester;
(The water-soluble salt to be mixed is a water-soluble salt formed from α-gawa-copherol phosphate and a synergistically harmless base, such as an alkali metal salt, preferably a sodium phosphate salt. Examples include 1-lium salt and potassium salt.

If desired, other alkali metal salts, such as lithium salts, may be used.The water-soluble salts mentioned above may be dissolved in water by adding them to water in the form of a salt. or α-tocopherol phosphate ester and salt J, (
The aqueous solution of the salt obtained by reacting with and in water may be used as is. The preferred concentration of α-1 cosoerol phosphate in water soluble percentage is (1, tl 1-5
(~V/'V).

I) II of the aqueous solution is selected in the range of 3 to 0, preferably 5 to 8. To this end, as necessary,
1) Adjust IT using an acid such as hydrochloric acid, acetic acid, hydroxide, or an alkali such as sodium carbonate. Reacting α-tocophero-luphosphate ester with a base in water to dissolve water-soluble j'i1Y? When obtaining Ik, use thorium as a base, for example, to obtain α-tocopherol phosphorus having the pH within the range of 7. An aqueous solution of acid ester 1 to 1 obtained from aqueous solution of O.-
Tocopherol phosphate ester (N-J-1-') When lamb salt is dissolved in water, an aqueous solution with a relatively high pH is obtained as described above, and an acid, for example hydrochloric acid, is added to this to adjust the desired pH. (You may adjust it to

The non-ionic field 1fl n agent is currently available in various types or can be done by hand, in the present invention I Tagawa 31
It is preferable to use one of 1 or 2 (). Non-ionic 1-1 interface? Preferred types of i'r IYI agents include:
Examples include polyoxy lower alkylene ester type such as polyoxyethylene higher fatty acid ester, polyoxy lower alkylene ether type such as highly treated alcohol polyoxoethylene ether and alkylphenol polyoxyethylene ether, sorbitol or sorbitan. Some of the hydroxyl groups of polyhydric alcohols or their dehydrates form polyoxyethylene ether, and other hydroxyl groups form esters with higher fatty acids, and ether ester types such as Himashiura's polyoxyethylene derivatives. 3. The nonionic surfactant is 15% (\~'/~\゛% or more than 1-200% of α-tocopherol phosphate).
(W/W)%, preferably ■1 (W/'W%
J:11 (l O(W/W) %JTJia+0:)Kayoi,,'/l" 1rll lh 'lIf the number of opening kites for cow medicine is too small, the stabilizing effect tends to decrease1, α -Tocopherol phosphate ester -4 which can be derived from tocopherol, the mode of its synthesis is shown below.

[Synthesis of α-1-copherol phosphate ester] Phosphorus oxytrichloride (POC/!'3) 6.127 was dissolved in henocene 5011zc and cooled.
) L-α-tocopherol 3. ('+ 9 and Hirin 13, 52 were transferred to Benson 50 me. 711 buttocks are 1 piece!', 1 piece) (After mixing this product F,
Bring to room temperature: Stir for 3 hours. Next, add 1. of water while cooling. After stirring for 2 minutes, the pyrinone hydrochloride released was separated, the henocene was distilled off, and the residual oil was extracted with ethyl C'ii acid.
After washing with % hydrochloric acid and water and drying over dry sodium sulfate, ethyl acetate is distilled off. Hydroxide 1 to 2 pieces of the remaining limestone (1-2 times) Dissolve in IJium, filter any insoluble matter using Celite, and chloride it in R solution) - White precipitate that precipitates by adding Lium. Remove σi from the object, wash it thoroughly with posetone to remove 1:j2 dirt, ? After that, dissolve it in water 1
-C filtered at -7, added hydrochloric acid for θ, extracted with ethyl acetate (7, washed with water, dried with sulfuric acid,
Z After the operation, 1-' When the ethyl acid is distilled off, a pale yellow oil substance (crystals if left unattended) is obtained. 4. [Production of α-tocopherol phosphate ester nina l-!Jum!'j72] Add 5 g of the above α-1-copherol phosphate ester to water]
, and place it in the suspension, add 1()% thorium hydroxide 11M in L':1 and dissolve 1) 11 is 1-
(Adjust to 1.5, add about 407 grams of sulfur and lithium chloride, collect the precipitated white precipitate, wash thoroughly with acetone and then ether, and dry. About 4.
.

5. The effect qL of the present invention is sensible. As a column, the aqueous solution of α-tocopherol sodium phosphate according to Test Formulation Example 1-2? Ogawa 3, Test Formulation Example 1 α-Tocopherol Phosphate Ni, sodium (1,:+ (W/”V) Φ mannitol !'i, Ort nonionic interfacial dli (1,1u acetic acid (pi talk, IJ tidying agent) tLj decrease j, 1 Blue water production fully closed;
] il +l l11) 11 7 Table J, Appearance test formulation example 2 in test formulation example 1 α-tocopherol phosphate disodium each concentration V/V) % Mannitol 5
nPOE20? / Rubitan Monoole 1・
Each concentration 〃Acetic acid (pH adjuster)
Appropriate amount of sterile purified water Total amount 100
ttTable 2. Table 3. pH of test formulation example 2 at pH 7 and P at 06 (w/v)% sodium α-tocopherol phosphate
Q E: 20) Effect of sorbitan monooleate 1' O
I' stands for polyoxyethylene, and the number within 0 is I.
The degree of turbidity becomes mild in the order of 1, which indicates the number of moles added, + and 10, and - indicates transparency.

The bottom of Table 1 shows each 1Φ nonionic interface llb property agent (1,]-(W
, /' S・) Addition of tomono showed an effect on white cloudiness 11-.
j: Sorbikun Monosteare - 1. with 1 degree of agriculture:! '
α-1-cohuelo-ruphosphate disodium (non-ionic field ir for heavy + v)
The effect of the I activator was more than 3 (1(w/νv) L)6, and Table 3 shows the relationship between the weakening caused by I)H and the surfactant. thing, zunawara, 1) II ], t, l
Tehakai iii active ill J! + (Transparency can be maintained even with addition, but injection 1111, point) 11 (It is not preferable in terms of irritation with shavings.Also, α-1-copherol phosphate Nisdel same score,!PL- with pear) T9.8
．． The ratio of 7 to 1 bite is 1. ) I (Ka: Mr. Naru Hotokai 1F
11. (It was found that a large amount of FL agent was required. 1. The present invention will now be described with reference to Examples. 2. Examples). 1~1j
, 057 fructose
50 no lr' OE), :o: Solhitan monooleka (+
, :EI acetic acid(+)H regulator)
i (1: Distilled water for injection (1)
11 old) 7 no, (1 (+) 1-17.0 key 4% Q -
The above mixture was passed through a sterile filter and
m('II!!!', fill each color ampoule with 2 m(') and make it a fusible Schiff, muscle day and month Jfll, goods 1.

Example 2 Nisdernib I Rium α-cocopherol phosphate for injection
202 glucose
5Al17POE (()0) Hydrogenated castor oil 1. (1#
Acetic acid (pT-1 regulator)
b) le (pI (adjust to 7, o)) Filter the tail liquid from step 1 without using t'l'; Close up, muscle Yamakawa upper body 1, I'ill 1, ability color spacing 3 points l Current use α-) Cohueloru phosphate ester
017 Mannitrile
5.0ltPOE (2()) Solhitane monooleto fl, 05n ethorium ethate (], o I
I+5/')0 thorium hydroxide (pl+ tone, jβ cutting)
j:1d'l'1 version/→Norconium (1(l F+
7 r + L) large (1?, 1 i'-i 2r ma 1 water
All i7i;
J (1(1+++f(,I) [finish to 17, 2) 1°, 5"M 71!< without fT'4 ?j" j
W'i L, sterile (1. li mC each point) IL
,! Fill the bottle, seal it, and score 1111! rlK and Zuro.

Real I'' [J Example・1・、Kakekisui (1 Tokofue V''-Ruphosphoric acid ester)
05yPOE ((i 0 :) Ii historic pine) mountain 0.5u glycerin 1・(]n citric acid ()1γ
Paraoquin benzoin: methyl acid f
l, lI + II Nord
] f') Jlrnor (5% potassium hydroxide 1,
(1) II tone・ji%I'l'I), j 1i sterile viscous water gold'l'I D
tlnon((+) II (i, I) ji'
(do) the following 1-1K of our bank is sterilized, 9.
(l)n (Fill into a container for chemical transfer, seal it, and use it as Kawabetsu water. Example 5 Copherol phosphate ester for drink α-Kawa
0] no L-ascorbic acid
(1,511 citric acid
0.211 Taurine
1. t) ++ Inosit (15n nicotinic acid amino 1- 〇, (] ,'(n honey゛)
fi, 0flPOE (4
0) Monostearley good 0.
]#5/:)0 thorium hydroxide (-I preparation agent)
Appropriately, the mixture of -1- is sterilized (no passing,
Fill a 1.00 rr+e drink hing without placing it in place, seal it, and use it as a drink preparation.) Example 0. N V Co-Top (1・-Tokofuet, 1-ruphosphate disodium ester 307P (monthly luck 40) monostearyl-
11,,+l rrTsuruhito-111'1 acid (1 tonic), 1 is 11 Medyl Balaoquin benzoate (1. 2 8 7 Pyropyl Balaoquin benzoate 0. + 2
7. Slimy water made from bacteria, total j-, l;
] 0(1+)d'(+)II i3. 5) Adjust to 3) 1 liter (k) of I- aseptically, filter through sterilization, fill in a sterile container of 0.50 ml, and seal tightly (↑) to use as a tablet.

July 11, 2011 〢L Procedural Amendment (Tumor) December 13, 1980 Dear Commissioner of the Japan Patent Office 1, Indication of the case 1982'f, 1o! 'lllAj 1st! l J
(T 3 7 'J2, Title of the invention ('IIl, II-): J:IJ--Alin N?: l-
,:',rノL'/i. -i/i:/l(d,:?I
'! 3. Relationship with the case of the person making the amendment Q, '11t'l appearance, I11's work 1su' Osaka Burning Osaka City Higashi 1×:'1'-!IJ'll
li: (I'tl 6 city 11j1, σ) 1 name
Chikaru 11, 41, join? 1 Representative, '7 Ill 'r't'' 6, Number of inventions increased by Sleeve IY'. O:;'.
? 1. Appearance test formulation example 2 for heki formulation example 1 α-tocopherol phosphorus l'l! Esteruni sodium 6p. '． Wu (1V/',') ”!Mannitol 5I/Ifu OE2
1+) Sorbitan monoole 1.
Appropriately annihilated j'+'4shi1"■Sasu water
Total amount 100 ttshiq'2.
Test formulation example 2 at pH 7) a) 1.1.

Claims (1)

[Scope of Claims] ] α-tocopherol phosphate or pharmaceutically; i
'l' dissolves as a water-soluble salt in 'fJl, Part 1) [
■ is ) to 1), preferably 5 to 8,
A stable aqueous solution of tosul α-1-copherol phosphate is characterized by the addition of a nonionic surfactant. 2 Pharmaceutically acceptable aqueous solution i: ;7F1 is an alkali metal salt; , 3 nonionic surfactants from 11 to 20 tll
, 13. The solution according to claim 1, having:・l tv-tocopherol phosphate ester non-ionic 1r ilj + active agent 15 (W/W)
% or more 1, θf or 3()(8~'/'~■)/)
,,,That's all for the poem I:Request Jl:ll Listening 1)
1 Top side! Aqueous solution of 戊. 5 At least one sugar or alcohol is added as an isotonic agent q! Industrial License Claims No. 1r (+ Aqueous solution 1.6 α-tocopherol phosphate 10,000 yen is dissolved in water, and the lll is:) to 0
113 and added a nonionic surfactant (
-〇First addition to the scope of patent claims. Watermelon 7'1
Sh.