JPS6187619A - Activated vitamin d3 for external use - Google Patents

Abstract

PURPOSE:To provide the titled agent for external use, capable of increasing the concentration of activated vitamin D3 in the local tissue when administered to the local part of the human body, and expected to be effective as a remedy for arthrorheumatism, cancer, etc., by using an activated vitamin D3 as an active component. CONSTITUTION:An agent for external use, containing an activated vitamin D3 (e.g. 1alpha,25-dihydroxycholecalciferol, 1alpha-hydroxycholecalciferol, etc.) as an active component. The amount of the activated vitamin D3 is preferably 1ng-2 mg/g, especially 5ng-0.5mg/g. It can be used in the form of ointment, cream, solution, aerosol, etc. The concentration of the activated vitamin D3 can be increased remarkably at the administered part or its neighborhood when applied to the skin, mucous membrane, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a novel external preparation. More particularly, the present invention relates to an external preparation containing active vitamin D as an active ingredient.

<Conventional Techniques> α,25-Dihydroquine Calciferol, ] α
, 24-dihydro a-? Calcifer d-ol, lα-
Human ailments - Active vitamin D, such as cicholecalciferol, promotes absorption and transport of calcium in the small intestine,
Regulates bone resorption and bone formation in bones, l1lIIj l in the thyroid gland
It is a hormone that has the effect of suppressing the secretion of ll11 thyroid hormone. Therefore, active vitamin D,
Kidney failure due to deficiency of calcium and decreased absorption of calcium,
Activated vitamins D and 'iA are used to treat osteomalacia, osteoporosis, which is an abnormal disease in the anterior fascia, and rickets, which is a deficiency of active vitamins 01 and the like.

However, in recent years, it has been suggested that the active form of vitamin D, #f, may be applied not only to the various diseases associated with abnormal calcium metabolism, but also to rheumatoid arthritis, cancer, and the like. In other words, in rheumatoid arthritis, active vitamin D
, etc. have been shown to normalize the balance between bone resorption and bone formation locally in the bone, thereby promoting bone formation and improving osteopenia. Furthermore, in cancer, it has been suggested that active vitamin Ds* has the effect of promoting differentiation induction of cancer cells locally in cancer cells and suppressing cancer cell proliferation.

Therefore, there is a need for a method for effectively administering active vitamin D to treat these diseases.

<Problems to be Solved by the Invention> Conventionally, active vitamin DseA has been orally administered as an oily solution or an oily bath (in capsules filled with gelatin). Type vitamin D is absorbed from the urinary tract, enters the bloodstream, and is widely distributed throughout the body.However, it is metabolized by the liver or kidneys, becomes inactive, and is eventually excreted.

Therefore, when it is desired to maintain a high concentration of active vitamin D in local areas of the human body such as joints or skin, oral administration is disadvantageous.

It is also possible to increase the amount of oral administration in order to increase local 4 degrees, but in that case, the placement in other tissues that are not needed will increase, such as in the intestine. There is a risk that undesirable side effects such as increased absorption of carunium from the air and hypercalcemia may occur.

Therefore, we have developed an administration method that allows active vitamin D3 to be present in the necessary amount for the necessary time only in the areas of the human body that require active vitamin D3, and to prevent it from being distributed to areas where it is not needed as much as possible. is desired.

<Means for Solving the Problems> The present inventors locally administered active vitamin D5gJ4 to improve active vitamin D in local tissues.

As a result of intensive research into ways to increase the concentration of active vitamin D, we have developed ointments and creams containing active vitamin D.

When administered to the skin or mucous membranes as an external preparation such as a solution, film, poultice, or spray, it is expected that active vitamin SD and congeners will increase significantly at the site of administration and its vicinity. This discovery led to the present invention.

Therefore, the present invention is an external preparation containing active vitamin D and the like as an active ingredient.

The active vitamin D of the present invention, 5A, is 1-D,
), 1α,25-dihydroxycholerol (1α+25(Oli)t-L)s)
.

1α,24-dihydroxycholectoluciferol (1α
, 24-(OH), -D, ), 1α+24+25-trihydroxycholecalciferal (1·α.

24 t 25 < o H) s os ), l
a-human akin-24-oxocholelic acid lucifer,
lα.

25-dihydro axy-24-oxocholecarnph:r-
al, 1α, 25-dihydroxycholerol-26,23-lactone.

1α, 25-dihydroxy choleric lucifera-26
．． 23-Peroxylactone, 26°26.26. ″2
Activated vitamins having a hydroxyl group at the 1α position such as 7+27127-hexafluora-1α, 25-dihydroxycholecalciferol (I), or 25-hydroxycholecalciferol (25-OH-L),
24-human oxycholecalcif ICyl (24-OH
-D,).

24-oxocholecalciferol, 24゜25-dioxycholecalciferol (24,25(OH)t
Da), 25' doroquine-24-oxocholecalcifer, 25-human cI xicholecalcifer O
Active vitamins that do not have a hydroxyl group at the 1α position, such as -26°23-lactone and 25-hydroxylicolyllucifera-26123-74-okynelactone, may be mentioned. Among these active forms of vitamin D, 1α-0)f-D, 1α, 25(OH)*Ds
, 1α124-(O)(), -D,, 1α.

24, 25-(OH), -D8.25-(OH)-D
,,24-(OH)-D,,24,25-(lJ
li), -D, and O are preferred.The form of the external preparation of the present invention is a laxative.

Examples include gel softeners, creams, 0-noyone preparations, bath preparations, suspensions, film preparations, liquid preparations, and spray preparations. That shape! If a different dosage form is to be molded, other ingredients may be added to the active vitamin D depending on the dosage form, and the product may be molded according to the conventional method.

For example, when molding is performed using a softening agent, vaseline, alcohol, miso oil, petroleum oil, polyethylene glycol, etc. are added.

When formed as a gel softener, carphobol,
Hydrophilic acid σ Hirsel O-su.

Fulgin 11'1 etc. are added. When molded as a cream, oils and fats, acetic acid, cylindrical fatty acids, higher alcohols, etc. are added. When molded as an a-joon agent, ethanol, glycerin, propylene glycol, etc. are added to the I/C. When molding as a f74 K agent, ethanol, turmeric water, glycol, etc. are added to the pressure. When formed as a suspension agent, tracanth, gum arabic, sodium alginate, seratino, methylcellulose, CMC, etc. are used. Adhesives made from acrylic varnish, acrylic varnish, acrylic varnish, etc., which are molded as films, natural rubber thread adhesives,
)17 molecule-based patch etc. are used. Kaolin when molded with a bump agent.

Glycerin is used.

In addition to these ingredients, pufffin, squalane, phosphorus, cholesterol ester, higher fat ester, colloidal silica, bentonite, montmorillonite, etc. may be used as required.

As antioxidants, BHA, B)iT, propyl gallate, h'eff galol, human mixiquinone.

Human ayan coumarin, tocopheres, etc. may also be used.

Preservatives include phenol, cresol, parabens, benzyl alcohol, and rubin.

A quaternary ammonium compound or the like may also be used.

Absorption enhancers include alcohol, pyrene glycol, oleic acid, and various surfactants.

Urine accumulation, DMSO, DMA, DMF, sugar esters,
Fatty acid esters, pyrrolidone, etc. may also be used.

In addition, as a coloring agent, 9-71-rutocarbothinophenyl-6-hydroquine-2,,1,5,7-titrayotho:3-inxanthone disodium salt, 1-para-sulfophenylazo-2-naphthol-6 -Sulfonic acid disodium salt.

4-i(4-(N-enal-metersulfobendi, luminone-phenyl)-(2-sulfoniumphenyl)-
methylene)-(1-(N-ethyl-, mekusulfobenzyl)-Δ1--ink).

Active Higmine D, type F, which is incorporated into external preparations
% ft J'd =? 7s Ka1 target/' M
~211197,! +' It is preferable to mix -. ! j! K 5 n,! $/ & ~f+, 5m9
/'+'7゛car more preferable.

<U (: +4) 4 2 + 4 > Depending on Akira Hongen's external preparation, 1α-OH-D.

la, 2 D (OH)t -DA, etc., t-occupation-type hitamino 1] class 3e, human body functions IIi'1, etc.
It is effective to administer l) Jiihihi,
Fugenmei is of great significance as the person who provided fj+tanal old form of vitamin D and Asahi's ill form.

Kuno 4 Weaving Shun 〉 This will be explained in more detail in 8-f by dividing Honwaakii below.

Example 1: Ointment A hydrophilic ointment was manufactured according to method A of the Japanese Pharmacopoeia, and this was
．． 51, this has 1α-OH-L) 3 (1 is la
, 25 (□I()t Ds u, 5m9 dissolved m
Mix the propylene glycol ly well to form a soft 1
I made ↑. The hydrophilic ointment contains six colors of vaseline 25y, stearyl alcohol 22y, propylene crystal 2y, and sodium lauryl sulfate 1,5JI'.

Ethyl and propyl roseoxybenzoate each tt 0
0025.9, O, t) 13 #Kl [Use the product prepared by adding purified water to make a total of 100 J/bin.

Example 2 1α, 25 (OH)t Ds cream Glycerin monostearate 20 & polyquinone glycerin palmitate 4I were taken and heated on a water bath at 60°C.
Stir while maintaining the temperature, add 1α, 25-(OH),
-D, t), 5■ and butyl human a-oxytoluene 0.2y
(Mixed. 1^ Methyl paraoxen benzoate + 1.15.9% was added to about 61 ml of spring water, and 7y of glycerin was added.

Add the oil layer created earlier to this water layer little by little and mix well.4≧r
μ and a small amount of purified water was added to make the total mass 1110 &.

! l! Application 11: ( 1a + 25 (OH)t Us O, 5rf
9! Evening/-L 40M and Bu-a pyrene glycol 1
uJ/[gM. And 1y Hebiswako-1 ()
Add 20p of purified N water to 4 and stir. Next, diimp O panolamine t, 1&fJtnH water 1
(1, 5' with the addition of the popular interpretation, all jj nails 1
The gel ointment was complimented by adding purified water until it reached 00&.

Example 4 The thighs of j male Vistar pigs with body N 220 to 23011 were removed, and each was treated with
Rub in 100 dabs of blow blue. After 2 hours, kill the rat, carefully remove the skin 14 of the area where the cartilage was administered, and take out the internal muscle.
(OH)*-υ, or 1α-OH-D, amount lα,
25-(OH)t-υ was determined by the binding protein assay, and lα-human mixicholecalciferol was determined by the radioimmunoassay method.

Simultaneously, as a control, rat VC1α, 25-(OH)
, -D, alloy is 1 a-OH-D, 0.5 p
It was orally administered. (1α+25 (
01()t ”s or 1α-U HD, is 5
0 μy/− of 0.2% Tritonex-1009 [
40 ual of this was administered. ) The rats in the control group were also sacrificed 2 hours after administration, and injections were administered into the thigh muscles in the same manner.

25- (OH), -D, JPJ a) or 1α-OH
-D, a large number of measurements were taken.

lα in the major muscle of the soft * administration group and the control group.

The amounts of 25-(OH), -1-, or 1α-OH-D are shown in Table 1.

Claims (1)

[Claims] 1. An external preparation containing active vitamin D_3 as an active ingredient. 2. Active vitamin D_3 types 1ng/g to 2mg/g
An external preparation according to claim 1, which contains: 3. The external preparation according to claim 1 or 2, which is in the form of an ointment, cream, solution, film, spray, or poultice.