JP2020111572A - Skin therapeutic agent and medical device - Google Patents

Abstract

To provide a skin therapeutic agent having improved therapeutic effect.SOLUTION: A skin therapeutic agent contains zinc chloride hydroxide containing Simonkolleite, the zinc chloride hydroxide being spherical one.SELECTED DRAWING: None

Description

The present invention relates to a skin treatment agent and a medical device.

Conventionally, a skin treatment agent containing zinc chloride hydroxide containing Simon Corlite is known (see Patent Document 1).

International Publication No. 2016/199905

It is an object of the present invention to provide a skin treatment agent that has a superior therapeutic effect.

As a result of intensive studies, the present inventors have found that the above object can be achieved by adopting the following configuration, and have completed the present invention.
That is, the present invention provides the following [1] to [6].
[1] A skin treatment agent containing zinc chloride hydroxide containing Simon Corlite, wherein the zinc chloride hydroxide is spherical.
[2] The skin treatment agent according to claim 1, wherein the approximate circle difference value of the zinc chloride hydroxide is 10 or less.
[3] The zinc chloride hydroxide has a Zn ²⁺ ion elution amount of 5 to 120 ppm after the elution test, and a pH after the elution test of 7.0 or more and less than 8.3. Skin treatment agent.
[4] The skin treatment agent according to any one of claims 1 to 3, which is applied to pressure ulcer consisting of necrosis extending just above the periosteum.
[5] The skin treatment agent according to any one of claims 1 to 4, which is applied to a skin wound or rough skin that extends through the epidermis to the dermis.
[6] A medical device comprising the skin treatment agent according to any one of claims 1 to 5 and a coating material that covers a part of the skin.

ADVANTAGE OF THE INVENTION According to this invention, the skin treatment agent which is more excellent in a therapeutic effect can be provided.

2 is a graph showing an XRD pattern of zinc chloride hydroxide containing Simon Corlite of Example 1. FIG.

[Skin treatment]
The skin treatment agent of the present invention (hereinafter, simply referred to as “the treatment agent of the present invention”) contains zinc chloride hydroxide containing Simon Corlite (hereinafter also simply referred to as “zinc chloride hydroxide”). Zinc hydroxide is a spherical skin treatment agent.

The therapeutic agent of the present invention is superior in therapeutic effect. More specifically, it is excellent not only in the therapeutic effect on skin wounds and rough skin, but also on the pressure sores (so-called bed sores).

Zinc chloride hydroxide contained in the therapeutic agent of the present invention, to skin wounds, skin roughness or pressure ulcers, by appropriately supplying zinc ions and the like, promote cell migration, increase collagen accumulation, skin wounds, It is believed to be able to promote healing of rough skin or pressure ulcers.

When the particles are transplanted or attached to the skin (living tissue), the living body recognizes the particles as foreign matter regardless of the shape of the particle surface.
At this time, when particles having an uneven surface or a sharply pointed surface are rubbed against normal skin, thickening of the epidermis occurs. This is one of the skin's protective responses to excessive irritation.
In contrast, particles with a round and smooth surface (ie, spherical) are hypoallergenic and less prone to thickening. It is less prone to chronic inflammation and less prone to inflammatory infiltration, making it easier to repair tissue. It is considered to have excellent therapeutic effects not only on skin wounds and skin roughness but also on pressure ulcers.

The spherical shape means that the approximate circle difference value described below is 10 or less. As will be described later, the approximate circle difference value is a numerical value representing the difference between a particle and its approximate circle. Therefore, the closer the approximate circle difference value is to 0, the more spherical it means.

<Zinc chloride hydroxide containing Simon Corite>
Simon call _{lights, Zn 5 (OH) 8 Cl} 2, _or represented by _{Zn 5 (OH) 8 Cl 2} · 5H 2 O).
The zinc chloride hydroxide containing such Simon Corlite is preferably zinc chloride hydroxide represented by the following formula (1). At this time, the molar ratio of Zn and Cl (Zn/Cl) is preferably 2.0 to 4.0.
_{Zn 4~6 Cl 1~3 (OH) 7~8} · nH 2 O (1)
However, in the formula (1), n is 0 to 6, and preferably 1 to 6.

The amount of Simon Corlite contained in zinc chloride hydroxide is preferably 60% by mass or more, more preferably 80% by mass or more, and further preferably 95% by mass or more.

《Approximate circle difference value》
The approximate circle difference value of zinc chloride hydroxide contained in the therapeutic agent of the present invention is preferably 10 or less, and more preferably 7 or less because the therapeutic effect is further excellent.

The approximate circle difference value is obtained as follows. First, the sample is observed with a scanning electron microscope at a magnification of 1000 times to obtain an image. About particles in the obtained image, an approximate circle is measured using image analysis software WinROOF2015 (manufactured by Mitani Corporation). The difference between the approximate circle and the original particle is compared on a radial line of 360 degrees, and the total value of the absolute value on the concave side and the absolute value on the convex side is calculated. The average value of the total values of 100 arbitrary particles is set as the approximate circle difference value.

<Characteristics after dissolution test>
Zinc chloride hydroxide containing Simon Corite preferably has a Zn ²⁺ ion elution amount of 0.5 to 120 ppm after the elution test and a pH of 7.0 or more and less than 8.3 after the elution test. preferable. In addition, "ppm" means "mass ppm" unless otherwise specified.
The elution amount of Zn ²⁺ ions after the elution test is more preferably 10 ppm or more, further preferably 20 ppm or more, while more preferably 80 ppm or less, further preferably 50 ppm or less.
The pH after the dissolution test is more preferably 7.1 or more, further preferably 7.2 or more, while more preferably 8.0 or less, further preferably 7.8 or less.

The characteristics after the dissolution test are determined as follows.
First, zinc chloride hydroxide containing Simon Corite is stirred at 37° C. in physiological saline for 3 hours at 500 rpm using a rotor. The concentration of zinc chloride hydroxide containing Simon Corlite in physiological saline is 20 g/L. This is the dissolution test.
After the dissolution test (that is, after stirring for 3 hours), the amount of Zn ²⁺ ions (unit: ppm) dissolved in physiological saline is measured using an ICP emission spectrometer (ICPE-9000, manufactured by Shimadzu Corporation). The value obtained by the measurement is the Zn ²⁺ ion elution amount after the elution test of zinc chloride hydroxide containing Simon Corlite.
Further, the pH of the physiological saline solution after the dissolution test is measured, and the obtained value is taken as the pH after the dissolution test of zinc chloride hydroxide containing Simon Corlite.

<Other ingredients>
The therapeutic agent of the present invention may further contain a pharmaceutically acceptable carrier (hereinafter simply referred to as “carrier”), if necessary.
Examples of the carrier include solvents such as organic solvents and inorganic solvents, and specific examples thereof include water, physiological saline, alcohols, polyhydric alcohols, and mixtures thereof.
When the therapeutic agent of the present invention contains a solvent as a carrier, a thickener or the like is further added to the therapeutic agent of the present invention to improve the handleability by processing the therapeutic agent of the present invention into a gel or paste. Good.
In addition, as the carrier, for example, the carriers described in paragraphs [0020] to [0023] of Patent Document 1 can be used.

The therapeutic agent of the present invention may contain other additives depending on the actual use.
Other additives are not particularly limited, and examples thereof include moisturizers, antioxidants, antiseptics, antiphlogistics, whitening agents, blood circulation promoters, antiseborrheic agents, thickeners, and pH adjusters. Specific examples thereof include the components described in paragraphs [0024] to [0027] of Patent Document 1.

<Use>
The therapeutic agent of the present invention can be applied to skin wounds or rough skin (skin wounds or rough skin that reaches the dermis through the epidermis). The therapeutic agent of the present invention can also be applied to pressure ulcers (pressure ulcers consisting of necrosis extending just above the periosteum).
At this time, the therapeutic agent of the present invention may be directly applied to the skin wound, rough skin or pressure sore, or may be applied to the skin around the skin wound, rough skin or pressure sore.
The form of the therapeutic agent of the present invention may be a liquid form containing a carrier such as physiological saline as a solvent, or may be a powder form containing no solvent (carrier). When the skin wound or the like is moistened with the exudate, it can be used in the form of powder. Further, it may have a thickened form or a gelled form which is intermediate between the two.
The therapeutic agent of the present invention can also be used, for example, as an additive for pharmaceutical compositions and an additive for cosmetics.

INDUSTRIAL APPLICABILITY The therapeutic agent of the present invention has a therapeutic effect not only on pressure ulcers and serious wounds or rough skin, but also on various kinds of large and small wounds or rough skin, and can be widely used as a wound medicine.
From the mechanism of wound healing, it is presumed that the therapeutic agent of the present invention can be applied to the following diseases. In other words, pemphigus, epidermolysis bullosa, pustular infection, Stevens-Johnson syndrome, toxic epidermal necrosis, systemic sclerosis, congenital ichthyosis, pemphigus vulgaris, Crohn's disease, etc. To be done. Furthermore, it is considered to be effective for protection and cure against dermatitis due to various allergic reactions.
Further, application to various intractable ulcers is also considered. For example, skin ulcer due to trauma, diabetes, irradiation, arteriosclerosis, collagen disease and the like can be mentioned.

[Method for producing skin treatment agent]
In the method for producing the therapeutic agent of the present invention, for example, spherical zinc chloride hydroxide is obtained, and if necessary, a carrier and the like may be combined therewith.
As described below, spherical zinc chloride hydroxide is obtained by first obtaining zinc chloride hydroxide containing Simon Corlite by a precipitation-forming reaction, and then using the obtained zinc chloride hydroxide on a spherical medium. It is preferably obtained by a method of spheroidizing by crushing used.

<Precipitate formation reaction>
Zinc chlorhydroxide containing Simon Corite is preferably obtained by a precipitate forming reaction (alkali precipitation method) using a zinc source, a chlorine source and an alkali.
Examples of the zinc source include zinc sulfate (ZnSO ₄ ), zinc chloride (ZnCl ₂ ), zinc acetate (Zn(CH ₃ COO) ₂ ), zinc nitrate (Zn(NO ₃ ) ₂ ), and zinc chloride. Is preferred.
Examples of the chlorine source include hydrochloric acid (HCl), sodium chloride (NaCl), ammonium chloride (NH ₄ Cl), and ammonium chloride is preferable.
Examples of the alkali include ammonia (NH ₃ ) and sodium hydroxide (NaOH), and sodium hydroxide is preferable.
The zinc source, chlorine source and alkali are preferably used in the form of an aqueous solution.

In the precipitation generating reaction, specifically, for example, an aqueous solution of a zinc source (an acidic aqueous solution) is dropped into an aqueous solution of a chlorine source, and during this dropping, an aqueous solution of an alkali is sent to the aqueous solution of the chlorine source to supply chlorine. It is preferable that the pH of the aqueous solution of the source is maintained in a certain range, and after the dropping of the aqueous solution of the zinc source is completed, stirring (curing with stirring) is performed for 10 to 30 hours to obtain a reaction solution containing a precipitate.
The pH is preferably 6.0 or more and 8.5 or less, more preferably 6.0 or more and less than 7.5. That is, although a precipitate is obtained by the reaction of Zn ²⁺ ion, Cl ⁻ ion and OH ⁻ ion, it is preferable to use the precipitate obtained in the reaction field whose pH is controlled within the above range.
The molar ratio of zinc to chlorine in the zinc source and the chlorine source (zinc:chlorine) is preferably 5:2.
The concentration of the aqueous zinc source solution is preferably 0.05 mol/L or more, and more preferably 0.1 mol/L or more. On the other hand, 10 mol/L or less is preferable, 5 mol/L or less is more preferable, and 3 mol/L or less is further preferable.
The concentration of the chlorine source aqueous solution is preferably 0.05 mol/L or more, more preferably 0.1 mol/L or more. On the other hand, 10 mol/L or less is preferable, 5 mol/L or less is more preferable, and 3 mol/L or less is further preferable.
The reaction temperature is preferably 5 to 40°C, preferably 10 to 30°C.

After the precipitate-forming reaction, for example, the reaction liquid containing the precipitate is subjected to solid-liquid separation by suction filtration or centrifugation, and the obtained precipitate is washed with pure water or distilled water, and then vacuum dried. As a result, zinc chloride hydroxide is obtained.
The obtained zinc chloride hydroxide may contain unreacted substances (raw materials), reaction by-products, impurities mixed from the raw materials, and the like.

<Crushing using spherical media>
Next, the obtained zinc chloride hydroxide is pulverized into a spherical shape. At this time, for example, spherical media (balls, beads, etc.) can be used for grinding. That is, it can be crushed by a crusher using a spherical medium (ball mill, bead mill, etc.).
The zinc chloride hydroxide as it is (before pulverization) obtained by the above-mentioned reaction for producing precipitates is, for example, plate-shaped (plate-shaped crystals), but not only the plate-shaped crystals are cracked by pulverization using a spherical medium. It is considered that the plate-shaped crystals are worn down and aggregated to obtain spherical particles.

The preferable conditions for pulverization using a spherical medium are as follows. The following conditions are, for example, conditions when a ball mill is used as the crusher.
The material of the spherical media is not particularly limited, and examples thereof include ceramics such as zirconia.
The diameter of the spherical medium is preferably 1 to 10 mm, more preferably 1 to 5 mm.
The amount of zinc chloride hydroxide to be crushed is preferably 1 to 60 parts by mass, and more preferably 5 to 50 parts by mass with respect to 100 parts by mass of the spherical medium.
In the case of batch processing, the crushing time is preferably 1 to 72 hours, more preferably 10 to 40 hours.

As long as a desired spherical shape is obtained, the conditions for pulverization using a spherical medium are not limited to the above conditions. Examples of the pulverizer that uses the spherical medium include a ball mill and a bead mill. In addition, a pulverizer that pulverizes by using the rocking, vibration, stirring, rotation, etc. of the spherical medium can be appropriately used.

[Medical equipment]
The medical device of the present invention has the above-described therapeutic agent of the present invention and a coating material that covers a part of the skin.
Skin wounds, skin roughness or pressure ulcers may be healed in a dry environment or in a moist environment.
When healing in a dry environment, skin wounds, rough skin or pressure ulcers are usually covered and protected by a breathable dressing such as a gauze, bandage, breathable film.
On the other hand, when healing is performed in a moist environment, an appropriate moist environment can be maintained by using a covering material that keeps skin wounds, skin roughness or pressure sores in a closed environment.

The covering material for keeping skin wound, skin roughness or pressure ulcer in a closed environment is not particularly limited, and examples thereof include polyurethane film dressing material, hydrocolloid dressing material, polyurethane foam dressing material, alginate coating material, and hydrogel. At least one coating material selected from the group consisting of dressing materials, hydropolymers, cellulose films, and silk films can be mentioned. Specific examples of these coating materials include the coating materials described in paragraphs [0031] to [0037] of Patent Document 1.

When the therapeutic agent of the present invention and the covering material are integrated, for example, the therapeutic agent of the present invention is applied to, contained in, or attached to the covering material.
On the other hand, the therapeutic agent of the present invention and the covering material may not be integrated. In this case, the medical device of the present invention can be said to be a medical set in which the therapeutic agent of the present invention and a covering material are combined.

Hereinafter, the present invention will be specifically described with reference to examples. However, the present invention is not limited to the following examples.

<Example 1>
A 0.08 mol/L ammonium chloride aqueous solution (500 mL) was prepared in the reaction vessel. Separately, a 0.1 mol/L zinc chloride aqueous solution (1000 mL) was prepared. Further, a 30 mass% sodium hydroxide aqueous solution was prepared as a pH adjusting liquid.
While stirring the ammonium chloride aqueous solution in the reaction vessel with the rotor, the ammonium chloride aqueous solution was charged with a pH controller. The zinc chloride aqueous solution and the sodium hydroxide aqueous solution were added dropwise to the ammonium chloride aqueous solution using a pump whose on/off control was performed by this pH controller. The aqueous ammonium chloride solution was maintained at pH 6.5 during the dropwise addition. After all the zinc chloride aqueous solution was dropped, the mixture was stirred for 16 hours for curing. The reaction temperature (environmental temperature during dropping and curing) was 25°C. Thus, a reaction liquid containing a precipitate was obtained.
The obtained reaction liquid was subjected to solid-liquid separation by centrifugation. The obtained solid (precipitate) was washed by repeating washing with water and centrifugation 3 times. The washed precipitate was vacuum dried to obtain zinc chloride hydroxide powder.
The obtained zinc chloride hydroxide powder was pulverized using a ball mill (table-top ball mill "V-1ML" manufactured by Irie Shosha Co., Ltd.). More specifically, a zirconia ball having a diameter of 5 mm was used as a spherical medium. 50 g of zinc chloride hydroxide powder was used for 500 g of spherical media, and the powder was pulverized for 30 hours to obtain a pulverized powder.

The powder of zinc chloride hydroxide obtained in Example 1 was subjected to XRD measurement using an XRD device (D8ADVANCE, manufactured by Bruker) before and after pulverization. The result of this XRD measurement is shown in FIG.
When the XRD pattern of FIG. 1 is seen, the peak showing Simon Corlite is recognized before pulverization. It is recognized that the peak representing Simon Corlite is maintained even after pulverization.

<Example 2>
First, in the same manner as in Example 1, zinc chloride hydroxide powder was obtained.
Then, the obtained zinc chloride hydroxide powder was crushed using a bead mill (Drystar SDA1 manufactured by Ashizawa Finetech Co., Ltd.) instead of the ball mill. More specifically, zirconia beads having a diameter of 3 mm were used as the grinding media. The filling rate of the grinding media was set to 50%, and zinc chloride hydroxide was supplied to the bead mill at a supply rate of 1.0 kg/h and ground to obtain ground powder.

<Comparative Example 1>
First, in the same manner as in Example 1, zinc chloride hydroxide powder was obtained.
Then, the obtained zinc chloride hydroxide powder was crushed using an AO-JET type jet mill (manufactured by Seishin Enterprise Co., Ltd.) instead of the ball mill. More specifically, 10 g of the obtained zinc chloride hydroxide powder was supplied to a jet mill at a supply rate of 12 g/h and pulverized at a pressure of 0.7 MPa to obtain a pulverized powder. The number of passes was once.

<Comparative example 2>
Powder of zinc chloride hydroxide was crushed using a jet mill under the same conditions as in Comparative Example 1 except that the number of passes was twice, to obtain crushed powder.

<Comparative example 3>
In the same manner as in Example 1, zinc chloride hydroxide powder was obtained. In Comparative Example 3, the obtained powder was used as it was without being crushed.
Comparative Example 3 corresponds to Production Example 1 described in paragraph [0039] of Patent Document 1.

<Characteristics after dissolution test>
Regarding the zinc chloride hydroxide powders of Examples 1 and 2 and Comparative Examples 1 to 3 (Examples 1 and 2 and Comparative Examples 1 and 2 before and after crushing), Zn after the dissolution test was performed by the method described above. ^{The 2+} ion elution amount and pH were determined. The results are shown in Table 1 below.

<Approximate circle difference value>
With respect to the zinc chloride hydroxide powders of Examples 1 and 2 and Comparative Examples 1 to 3 (Examples 1 and 2 and Comparative Examples 1 and 2 were powders after crushing), the approximate circle difference value was measured by the method described above. .. The results are shown in Table 1 below.

As seen from Table 1 above, the grinding reduced the pH after the dissolution test and increased the amount of Zn ²⁺ ion dissolution after the dissolution test. No significant difference was observed due to the difference in the grinding method.

Regarding the approximate circle difference value, the data of Comparative Example 3 corresponds to the data before grinding of Examples 1 and 2 and Comparative Examples 1 and 2.
From Table 1 above, it was found that, in Examples 1 and 2, the approximate circle difference value was significantly reduced by the pulverization using the spherical medium.

<Evaluation>
Approximately 500 g of SD rats were administered 2% cederac (xylazine) by intramuscular injection at 0.2 mL/500 g to sedate the rats. Rats were general anesthetized with sevoflurane inhalation anesthetic at 2%. Xylocaine (lidocaine+2% adrenaline) was administered to the ventral region of the rat for local anesthesia, and then a full-thickness defect wound with a diameter of 10 mm from the epidermis to the subcutaneous tissue was formed.

0.01 g of each of the powders of Examples 1 and 2 and Comparative Examples 1 to 3 was applied to the formed all-layer defect wound. Further, the application site was covered with a hydrocolloid dressing material (Duoactive) as a coating material. Here, the coating amount was adjusted to 0.01 g because the volume of the powder occupying the volume of all-layer defect wound was made uniform and the space condition in new tissue formation was prioritized rather than the Zn ²⁺ ion elution amount in the lab preliminary evaluation. Is.

Two weeks and four weeks after the powder was applied, the coating material was peeled off, and the application site was observed using a microscope as follows.
First, the application site was trimmed (excised) from a rat and used as a sample. The sample was then fixed with formalin, degreased (soaked in xylene for 24 hours) and then dehydrated. Dehydration was performed as follows. First, the sample was immersed in 70% ethanol for 12 hours, and then ethanol was removed by evaporation. Then, dehydration was performed for 30 minutes each using 80% ethanol, 90% ethanol and 95.5% ethanol. Then, the sample was washed twice with xylene.
After dehydration, the sample was embedded in paraffin to prepare a section for microscopic observation. The prepared sections were stained with hematoxylin-eosin (HE) and Masson trichrome (MT). HE stain is a stain for observing cell types. The MT stain is a stain for observing collagen fibers. The stained section was enclosed in a slide and observed using a microscope.

The state of wound healing after 2 weeks and after 4 weeks was evaluated by the following items by observation with a microscope. The evaluation results are shown in Table 2 below. The following evaluations are relative evaluations.

<Wound healing stage>
Evaluation of the progress of wound healing. The wound healing stage proceeds in the order of “hemostasis stage”→“inflammatory stage”→“proliferation stage”→“maturation stage”. The wound healing stage was determined from the observed cell types and the increasing tendency of the number of new blood vessels, and the results are shown in Table 2 below.

<Collagen thickness>
When the thickness of the collagen fiber is comparable to that of healthy skin cells, "◎" is given, "○" is given if it is a little thin, "△" is given if it is thin, and " “X” is shown in Table 2 below. "◎○" was described between "◎" and "○".

<Collagen orientation>
It was observed that the thick collagen fibers extended in one direction. When the orientation of collagen fibers is comparable to that in healthy skin cells, "◎" is given, "○" is given if it is slightly inferior, "△" is given if it is considerably inferior, and it is random. “X” is shown in Table 2 below. "◎○" was described between "◎" and "○".

《Hairball》
In Table 2 below, “⊚” indicates that the formation of hair bulbs was marked, “◯” indicates that the formation of hair bulbs was observed, and “x” indicates that the formation of hair bulbs was not observed. did. "◎○" was described between "◎" and "○".

<<Granulation>>
In Table 2, below, "⊚" is shown when the formation of granulation is noticeable, "○" is shown when the formation of granulation is observed, and "○△" is shown when the formation of granulation is slight. "◎○" was described between "◎" and "○".

<Summary of evaluation results>
As is clear from the results shown in Table 2 above, it was found that the wound healing of Examples 1 and 2 was earlier than that of Comparative Examples 1 to 3.
In Examples 1 and 2, after 4 weeks, collagen fibers were regenerated to the same extent as healthy skin cells, and hair bulbs and granulations were remarkably formed.
It is considered that the zinc chloride hydroxide powders of Examples 1 and 2 have a small approximate circle difference value (that is, close to a spherical shape), and therefore, there is little irritation to the living body.
Such an effect was more remarkably recognized in Example 1 in which the approximate circle difference value of zinc chloride hydroxide was smaller than in Example 2.

Claims (6)

A skin treatment agent containing zinc chloride hydroxide containing Simon Corite, wherein the zinc chloride hydroxide is spherical. The skin treatment agent according to claim 1, wherein the approximate circle difference value of the zinc chloride hydroxide is 10 or less. The skin treatment according to claim 1 or 2, wherein the zinc chloride hydroxide has an elution amount of Zn ²⁺ ions of 5 to 120 ppm after the dissolution test and a pH of 7.0 or more and less than 8.3 after the dissolution test. Agent. The skin treatment agent according to any one of claims 1 to 3, which is applied to pressure ulcer consisting of necrosis extending just above the periosteum. The skin treatment agent according to any one of claims 1 to 4, which is applied to a skin wound or rough skin that extends through the epidermis to the dermis. A medical device comprising the skin treatment agent according to any one of claims 1 to 5 and a coating material that covers a part of the skin.