JP2012158538A - Gel preparation for external use - Google Patents

Abstract

Disclosed is an external preparation containing myproxyfen phosphate, having an excellent skin permeability and a mild skin irritation.
A (A) myproxyfen phosphate and (B) an inorganic salt are contained, and the molar ratio (A: B) of the component (A) to the component (B) is from 1: 0.1 to 1: 0. Gel external preparation characterized by being .5.
[Selection figure] None

Description

  The present invention relates to a gel external preparation having good skin permeability and reduced skin irritation.

  Tamoxifen has a potent anti-estrogenic effect and is useful as a hormone-dependent breast cancer therapeutic agent. As a 1,1,2-triaryl-1-butene derivative having a stronger breast cancer therapeutic action than tamoxifen and high safety, miproxyfen phosphate (4- [1- [4- [2- (Dimethylamino) ethoxy] phenyl] -2- (4-isopropylphenyl) -1-butenyl] -phenol phosphate) is known (Patent Document 1).

  As preparations containing myproxyfen phosphate, preparations for oral administration such as tablets and capsules and injectable preparations are known (Examples of Patent Document 1). Will arise. On the other hand, since breast cancer is a cancer that occurs in the breast duct and mammary gland tissue, it is considered that the drug only needs to reach the breast duct and mammary gland tissue, and systemic administration such as oral administration and injection is not necessary. From this point of view, an attempt has been made to externally use breast cancer treatment, that is, to perform local administration through the skin.

  In addition to transdermal administration, iontophoresis preparations that administer drugs locally from the nipple to the ducts and mammary tissues by electrification are reported as local therapy for breast cancer treatment. (Patent Documents 2 and 3).

Japanese Patent Publication No. 05-57277 International Publication No. 2007/043580 International Publication No. 2009/128273

However, no attempt has been made to use myproxyfen phosphate as an external preparation, and no skin permeability or skin irritation when blended with an external preparation base is known.
Accordingly, an object of the present invention is to provide an external preparation containing myproxyfen phosphate, which has good skin permeability and has reduced skin irritation.

  Therefore, the present inventor conducted various studies to make myproxyfen phosphate into a gel-like external preparation, and the balance between skin permeability and skin irritation of myproxyfen phosphate is adjusted by the amount of inorganic salt added. It is possible to find that a gel external preparation with good skin permeability and reduced skin irritation can be obtained by blending myproxyfen phosphate and inorganic salt in a certain molar ratio. The present invention has been completed.

  That is, this invention contains (A) myproxyfen phosphate and (B) inorganic salt, and the molar ratio (A: B) of component (A) and component (B) is 1: 0.1-1. : It provides a gel-form external preparation characterized by being 0.5.

  The gel external preparation of the present invention has good skin permeability of miproxyfen phosphate and mild skin irritation, so that miproxyfen phosphate quickly migrates from the nipple or breast to the affected area. In addition, it has little effect on breasts that are sensitive to stimulation. Furthermore, the gel-form external preparation of this invention does not change a viscosity with time, and its stability and usability are also good.

  The (A) miproxyfen phosphate used in the gel external preparation of the present invention has an excellent antiestrogenic activity and antitumor activity, and is safer than tamoxifen, and thus is useful as a breast cancer therapeutic agent. The myproxyfen phosphate ester which is the active ingredient of the medicament of the present invention can be produced, for example, by the method described in Patent Document 1.

  The content of myproxyfen phosphate in the gel external preparation of the present invention is not particularly limited, but is 0.01 to 10% by mass from the viewpoint of skin irritation, solubility in gel base, and stability. Is preferable, and 0.05-5 mass% is more preferable.

  The inorganic salt (B) used in the gel external preparation of the present invention is important in terms of the balance of skin permeability and skin irritation of the miproxyfen phosphate, but the gel external preparation of the present invention is used for breast cancer. When used as an agent for a donor part or a teat in a therapeutic iontophoresis preparation, the electrical resistance when miproxfen phosphate is transferred from the teat to the milk duct and mammary tissue is reduced, It also acts as an accelerator for improving migration. The inorganic salt is preferably a halogenated salt, more preferably an alkali metal halide or an alkaline earth metal halide, and particularly preferably an alkali metal halide. Specific examples include sodium chloride, sodium bromide, sodium iodide, potassium chloride, potassium bromide, calcium chloride, calcium bromide, and the like. Sodium chloride, sodium bromide, sodium iodide are more preferred, especially chloride. Sodium is preferred in terms of safety and handling.

  In the present invention, the molar ratio (A: B) of the component (A) and the component (B) is 1: 0.1 to 1: 0.5, more preferably 1: 0.15 to 1. : 0.5, and more preferably 1: 0.15 to 1: 0.4. When this content molar ratio is in this range, the skin permeability of myproxyfen phosphate is good and the skin irritation is low. Moreover, when the content molar ratio is within this range, the viscosity of the gel does not change for a long time, the formulation stability is good and the usability is also good.

  The concentration of the inorganic salt (B) in the gel external preparation of the present invention is not particularly limited, but is preferably 0.50 to 6.00 mM from the viewpoint of skin permeability, skin irritation and stability, 0.75 to 5.00 mM is more preferable, and 1.00 to 4.00 mM is particularly preferable.

  In the gel external preparation of the present invention, the content of the component (A) is preferably 0.01 to 10% by mass, and the concentration of the component (B) is preferably 0.50 to 6.00 mM, and the component (A) More preferably, the content of 0.05 to 5% by mass and the concentration of component (B) is 0.75 to 5.00 mM, and the content of component (A) is 0.05 to 5% by mass. More preferably, the concentration of (B) is 1.00 to 4.00 mM.

  The gel external preparation of the present invention has good applicability to the nipple and breast and is excellent in usability. Moreover, when using for the agent for donor parts of the said iontophoresis formulation, you may apply to a donor part previously and may apply | coat to a teat part at the time of a treatment. In order to obtain such a good coating property, the viscosity (25 ° C.) of the gel-like external preparation of the present invention is preferably 230 to 280 dPa · s as measured with a rotating cylindrical viscometer, and preferably 230 to 260 dPa · s. More preferably, it is s.

The gel-type external preparation of the present invention preferably contains a gel base, alcohol and water in addition to the above components, and may further contain a pH adjuster, polyhydric alcohol, preservative, stabilizer and the like. Good. Here, as the gel base, sodium alginate, ethyl cellulose, carrageenan, carmellose sodium, agar, xanthan gum, gelatin, kaolin, bentonite, montmorillonite, zinc oxide, titanium oxide, anhydrous silicic acid, D-sorbitol, talc, terbene resin, Examples thereof include hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, urea, polyvinyl alcohol, and sodium metaphosphate.
Examples of the alcohol include lower alcohols such as ethanol and isopropanol. Polyhydric alcohols include ethylene glycol, diethylene glycol, triethylene glycol, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diethylene glycol monomethyl ether, polyethylene glycol, propylene glycol, dipropylene glycol, 1,3-butylene glycol, dipropylene glycol Examples include polyethylene glycol, 2-ethyl-1,3-hexanediol, polypropylene glycol 2000, polypropylene glycol, (concentrated) glycerin, butyl alcohol, pentaerythritol, and D-sorbitol. Examples of the pH adjuster include alkanolamines such as monoethanolamine, diethanolamine, diisopropanolamine and triethanolamine, and alkylamines such as triethylamine. Preservatives include phenolic substances such as methyl paraoxybenzoate, phenol and cresol, neutral substances such as chlorobutanol, phenoxyethanol and phenylethyl alcohol, reverse soaps such as benzalkonium chloride and benzethonium chloride, benzoic acid and sorbine Acidic substances such as acid, dehydroacid and salicylic acid can be mentioned. Stabilizers include antioxidants such as vitamin E and butylhydroxyanisole, reducing agents such as ascorbic acid, sodium bisulfite and sodium thiosulfate, and synergists such as sodium citrate, sodium tartrate, lecithin and EDTA. Can be mentioned.

  The gel-form external preparation of the present invention is preferably an aqueous gel in terms of usability, skin irritation and skin permeability, and the water content is preferably 75 to 98% by mass, and 80 to 95% by mass. More preferred. Moreover, pH 7.0-10.5 is preferable, as for the range of pH of the gel-form external preparation of this invention, pH 7.5-10.0 is more preferable, and pH 8.0-9.5 is especially preferable.

  The gel-form external preparation of this invention can be manufactured by mixing the said component and adjusting pH.

  The gel external preparation of the present invention is applied to the nipple or breast part because the active ingredient is miproxyfen phosphate which is a therapeutic agent for breast cancer, and is absorbed from the nipple part or breast part and transferred to the affected part. Is preferred. Further, a donor part or nipple of an iontophoretic preparation for breast cancer treatment in which a donor is attached to the nipple as in Patent Documents 2 and 3, and an active ingredient is locally administered from the nipple to the breast duct and mammary gland tissue by electrification It can also be applied to partial preparations. More preferably, in an iontophoresis preparation for breast cancer treatment in which a donor having an electrode on the nipple is attached, a receptor is attached to the breast, and an active ingredient is locally administered from the nipple to the duct and mammary tissue by energization, Alternatively, the gel external preparation of the present invention can be applied to the nipple.

  EXAMPLES Next, although an Example is given and this invention is demonstrated in detail, this invention is not limited to this at all.

Example 1
Hydroxypropyl methylcellulose (Metroze 60SH-4000) dispersed in 10 g of ethanol (anhydrous) was added to 50 g of purified water (60 ° C.) preliminarily heated with stirring and dispersed uniformly (aqueous phase 1). After cooling the aqueous phase 1 to room temperature, a dispersion (aqueous phase 2) in which 0.01 g of sodium chloride and 0.3 g of carboxyvinyl polymer (Ultretz 10) were added to 20 g of purified water was added. K. Using a Hibismix stirrer (model; 2P-1 type, Primics Co., Ltd.), the mixture was stirred for 10 minutes at a rotation speed of 40 rpm under reduced pressure (−0.08 MPa). Separately, a solution (aqueous phase 3) prepared by dissolving 0.9 g of diisopropanolamine and 0.5 g of miproxyfen phosphate in 15 g of purified water was added to the mixture of the aqueous phase 1 and the aqueous phase 2, and the T.P. K. Using a Hibismix stirrer, the mixture was stirred for 15 minutes at a rotation speed of 40 rpm under reduced pressure (−0.08 MPa). After completion of the stirring, purified water was added so that the total amount was 100 g to prepare a gel preparation (pH is 9.0).

Example 2
A gel formulation (pH: 9.0) was prepared in the same manner as in Example 1 except that the amount of sodium chloride in Example 1 was changed from 0.01 g to 0.02 g.

Example 3
A gel preparation (pH: 9.0) was prepared in the same manner as in Example 1 except that sodium chloride was changed to sodium bromide in Example 1 and the blending amount was changed from 0.01 g to 0.033 g.

Example 4
A gel preparation (pH: 9.0) was prepared in the same manner as in Example 1 except that sodium chloride in Example 1 was changed to sodium iodide and the blending amount was changed from 0.01 g to 0.049 g.

Comparative Example 1
A gel preparation (pH: 9.0) was prepared in the same manner as in Example 1 except that sodium chloride in Example 1 was omitted.

Comparative Example 2
A gel formulation (pH: 9.0) was prepared in the same manner as in Example 1 except that the amount of sodium chloride in Example 1 was changed from 0.01 g to 0.04 g.

Comparative Example 3
A gel formulation (pH 9.0) was prepared in the same manner as in Example 1 except that the amount of sodium chloride in Example 1 was changed from 0.01 g to 0.08 g.

Comparative Example 4
A gel preparation (pH: 9.0) was prepared in the same manner as in Example 1 except that the amount of sodium chloride in Example 1 was changed from 0.01 g to 0.16 g.

Comparative Example 5
A gel preparation (pH is 9.0) was prepared in the same manner as in Example 1 except that the amount of sodium chloride in Example 1 was changed from 0.01 g to 0.32 g.

Comparative Example 6
A gel formulation (pH: 9.0) was prepared in the same manner as in Example 1 except that sodium bromide in Example 1 was changed to sodium bromide and the blending amount was changed from 0.01 g to 0.07 g.

Comparative Example 7
A gel preparation (pH: 8.9) was prepared in the same manner as in Example 1 except that sodium chloride in Example 1 was changed to sodium iodide and the blending amount was changed from 0.01 g to 0.1 g.

Experimental Example 1 (Skin permeability measurement)
Using the gel preparations prepared in Examples 1 to 4 and Comparative Examples 1 to 7, permeation experiments (in vitro) through the rat-extracted skin using vertical Franz cells were performed.
The rat-extracted skin was used after removing the hair of the abdomen of a rat (Slc: Wistar, male, 8 weeks old) and then extracting the skin. As the donor (donor application area; 3.14 cm ² ), the gel preparations prepared in Examples 1 to 4 and Comparative Examples 1 to 7 were used, and the receptor solution was physiological saline in which 1% diisopropanolamine was dissolved. A vertical Franz cell was attached with the surface of the excised skin facing the donor, and the donor was filled with 3 mL of gel and 30 mL of receptor solution in the receptor. A silver / carbon coated electrode (Shin-Etsu Polymer Co., Ltd .; 25 μm PET carbon coated electrode TRIAL-6) is inserted on both sides of the donor and receptor so that they are in sufficient contact with each other. 6144), a constant current of 1.57 mA (0.5 mA / cm ² ) was applied for 120 minutes. After 120 minutes from the start of energization, 1 mL of receptor fluid was collected from the sampling port on the receptor side, and 1 mL of new receptor fluid was replenished. The concentration of myproxyfen phosphate in the collected receptor fluid was measured by HPLC method (reference: Chem. Pharm. Bull. 141 (4) 720-724 (1993)), and the cumulative permeation amount per unit area Was calculated.

Experimental Example 2 (Skin resistance measurement)
In the skin permeability experiment of Experimental Example 1, a digital voltmeter (HIOKI; Memory HiCorder 8807) was inserted in parallel with the donor and receptor electrodes, and the voltage value immediately after energization was measured. In addition, it can be judged that there is little skin irritation (redness, erythema, etc.) if the voltage applied in the experimental system using rat-extracted skin is 4.5 V or less.

Experimental Example 3 (Physical property evaluation (sag))
1 g of the gel preparations prepared in Examples 1 to 4 and Comparative Examples 1 to 7 were placed on a silicon plate, and the inclination was tilted by about 45 degrees and visually evaluated.
Evaluation was performed according to the following criteria.
○: Almost no

Experimental Example 4 (Viscosity measurement)
Using a rotating cylindrical viscometer (Rion Co., Ltd., Viscotester VT-04F), 40 g of the gel preparations prepared in Examples 1 to 4 and Comparative Examples 1 to 7 were placed in a 50 mL beaker and kept at 25 ° C. for 1 hour After the surface was flattened by standing, the viscosity was measured. The rotor is No. 2 (measurement allowable range; 100 to 4000 dPa · s) was used.

The measurement results of Experimental Examples 1 to 4 are shown in Table 1.
The skin permeability was good in Examples 1 to 4, Comparative Example 1 and Comparative Example 7 in which the cumulative permeation amount after 120 minutes had elapsed after the start of energization was 4.5 μg / cm ² or more. The skin resistance value was 4.3 V or less except for Comparative Example 1, and was predicted to be less irritating. In the physical property evaluation (sag), Examples 1 to 4 and Comparative Example 1 were good. The viscosities were good in Examples 1 to 4 and Comparative Example 1 at 230 dPa · s or more, and correlated with physical property evaluation (sag).
Moreover, all the miproxyfen phosphate ester in the gel formulation prepared in Examples 1-4 and Comparative Examples 1-7 was stable.
From the above results, it was found that the gel preparations of Examples 1 to 4 suppressed sagging, had high skin permeability, and reduced skin irritation.

Claims (6)

  (A) contains miproxyfen phosphate and (B) inorganic salt, and the molar ratio (A: B) of component (A) to component (B) is 1: 0.1 to 1: 0.5. Gel-like external preparation characterized by the above-mentioned.   (B) The gel external preparation according to claim 1, wherein the inorganic salt is a halogenated salt.   (B) The gel external preparation according to claim 1, wherein the inorganic salt is an alkali metal halide.   Furthermore, the gel external preparation of any one of Claims 1-3 which contains a gel base, alcohol, and water.   The gel external preparation according to any one of claims 1 to 4, wherein the content of the component (A) is 0.01 to 10% by mass and the concentration of the component (B) is 0.50 to 6.00 mM.   The gel external preparation according to any one of claims 1 to 5, which is applied to an iontophoresis preparation for breast cancer treatment.