JP5761597B2 - Allergic dermatitis treatment - Google Patents

Description

  The present invention relates to a novel allergic dermatitis therapeutic agent utilizing the bactericidal action and blood flow promoting action of nanodiamond having semiconductor characteristics (hereinafter referred to as semiconductor diamond or nanodiamond).

In recent years, with changes in the living environment or lifestyle, it has been exposed to various external substances, and in order to protect the body from such external substances, antigens in the living body of pet animals (pets) are not limited to humans. Antibody reactions are frequently occurring, which has caused many various allergic diseases.
The cause is air pollution caused by waste gas from factories and automobiles, generation of irritating gas oxidants due to sunlight of contaminated air, body stress due to noise, and effects due to combined effects with various food additives. Can be considered. Particularly in the case of pets, it is considered that the deterioration of physical immunity due to the influence of long life resulting from the improvement of the breeding environment and food is also large.

  Conventionally, as a method for treating allergic dermatitis, contact dermatitis, and atopic dermatitis among allergic diseases, in the case of humans and pets, oral corticosteroids, commonly referred to as steroidal drugs and application, In addition, although dietary therapy is performed in parallel, side effects are often seen if the treatment period is long and proper use is mistaken. There are skin disorders that develop as a result of the base or combination of steroids being the antigen or source of stimulation, but the side effects of topical drugs include skin atrophy, delayed wound repair, capillary dilation, steroid purpura, and steroid flush There are other systemic side effects due to transdermal absorption. As side effects of internal medicines, infectious disease induction enhancement and peptic ulcers often appear after long-term use.

Although there is a therapy that expects a symptom-reducing effect by improving the constitution, there is a cost because a special allergen-removed food is used. Moreover, since skin allergic symptoms are accompanied by itching, there is concern about exudate due to scratching and promotion of the pathology due to staphylococcal infection.
Especially in the case of pets, this tendency is large, and steroidal drugs and dietary therapy are used in parallel for the treatment, so that the healing period is often prolonged and the cost burden is large.

Atopic dermatitis by Kazuya Yamamoto Gyosei Corporation 1995 Atopic dermatitis Yasuyuki Igarashi Co., Ltd.

  In view of the above circumstances, an object of the present invention is to provide a therapeutic agent for allergic dermatitis having an action of removing skin disorders caused by allergic diseases without using steroidal drugs or reducing the amount of use. is there.

Nanodiamonds may have semiconductor characteristics in which thermally excited carriers are generated at a temperature of about room temperature having an activation energy level of 0.1-1.0 eV due to additives or impurities during manufacture. For the first time, the present inventors have found that when nanodiamonds having such semiconductor characteristics are brought into contact with a living body, a large amount of charged particles are generated, so that a strong bactericidal effect can be obtained by oxidation reaction or reduction reaction by charged particles. It was issued. It has been found that the bactericidal effect by the oxidation reaction or reduction reaction by the charged particles can be expected to protect against exudate due to scratching based on the allergic dermatitis itch and the bacterial infection caused by staphylococci.
The inventors pay attention to the fact that nanodiamond has a moisturizing effect due to its special structure, a bactericidal effect, a biological function promoting effect on the skin surface by promoting blood flow, and an ultraviolet protective effect by ultraviolet-infrared conversion at a wavelength of 400 nm or less. As a result, the inventors have found that the effect of removing skin disorders due to these effects is effective in treating allergic dermatitis, and have completed the present invention.

  The anti-allergic action of charged particles generated from nanodiamonds, exudate due to scratching based on the itch of allergic dermatitis, and the protective action against bacterial infections caused by staphylococci, etc. were first discovered by the present inventors. The anti-allergic action of such charged particles has not been reported so far.

One aspect of the present invention that achieves the above object is that 0.0005-3.0 wt% of nanodiamond having an activation energy level of 0.1-1.0 eV and a particle size of 5-300 nm is dispersed and mixed in a solution or oil. It is characterized by being an allergic dermatitis treatment agent (claim 1).
In another aspect of the present invention, nano-diamonds having an activation energy level of 0.1-1.0 eV and a particle size of 5-300 nm are dispersed and mixed in a solution at 0.0005-3.0 wt%. It is a therapeutic agent for allergic dermatitis, which is adhered to a fiber cloth by a method, a textile printing method or a melt spinning method (claim 2).

According to the first aspect of the invention, since semiconductor nanodiamonds having no cytotoxicity are used, there are no side effects depending on the amount used and the period of use, and there are no restrictions on the usage compared to steroids. In addition, unlike general electrically insulating diamond, since semiconductor nanodiamond having an activation energy level of 0.1 to 1.0 eV, in which many carriers excited by body temperature heating are generated, the bactericidal effect by charged particles, Water retention effect on skin contact surface due to biological effects and spontaneous charge is great. Furthermore, since nanodiamond having a particle size of 5-300 nm is used, dispersion in a solution or ointment base is facilitated. The basic size of explosive nanodiamonds is in the vicinity of 5 nm, but when the aggregate exceeds 300 nm, the excitation charge from the individual particles is trapped, and the charged particle emission effect is reduced. Furthermore, since the semiconductor nanodiamond powder is used by being mixed in a solution or an oil base, it is less scattered into the air and can be efficiently attached to the affected area. Moreover, solutions, ointments and 0.0005 blending amount of the fabric - because 3.0 wt% is selected, with the number of excitation charged particles is appropriate, the desired biological effect is obtained, allergic property The production efficiency of the dermatitis therapeutic agent is also good. If it is 0.0005 wt% or less, the number of nanodiamonds itself decreases, the number of excited charged particles decreases, and the biological effect decreases. If the content exceeds 3.0 wt%, the number of nanodiamond particles increases, so that the affected area and the dyed cloth are likely to adhere to each other, resulting in poor efficiency. Also, in the melt spinning method and more than 3.0 wt%, the wear of the nozzle matter what the, the production efficiency drops.
According to the invention which concerns on Claim 2, since semiconductor nanodiamond can be used in the state disperse | distributed and adhered to the fiber cloth, a required amount can be contacted stably to an affected part. A higher therapeutic effect can be obtained by the combined use of the solution mixed with the oil or fat base and the material dispersed and adhered to the fiber cloth.

It is a drawing substitute photograph showing the surface tension evaluation by the contact angle of nano diamond compound liquid and pure water It is a figure which shows the sunlight ray wavelength conversion effect by a 400 nm wavelength cut. It is a figure which shows the charging effect by the body temperature excitation carrier of a nano diamond compounding fiber cloth. It is a figure which shows the blood flow promotion effect of a nano diamond compounding fiber cloth. It is a figure which shows the nanodiamond mixing | blending fiber antimicrobial effect. It is a drawing-substituting enlarged photograph which copied the part of the fluffy human foot showing the therapeutic effect of the therapeutic agent for allergic dermatitis according to the present invention. It is the drawing substitute enlarged photograph which copied the part of the larva of the human foot which shows the therapeutic effect of the steroid drug which is the conventional dermatitis treatment drug. Similarly, it is a drawing substitute enlarged photo showing the other parts of Fukurahagi. It is the drawing substitute enlarged photograph which copied the erythema part of the dog. It is a drawing-substituting photograph showing a state in which the rash of the same site has been settled. It is a drawing-substituting photo showing the state of hair growth at the site where the erythema has settled.

Next, embodiments of the present invention will be described.
The therapeutic agent for allergic dermatitis according to the present invention has a skin surface protective action and water retention action by a semiconductor nanodiamond crystal surface and a UV protection effect, and a bactericidal action and blood flow promoting action using charged particle radiation effect by body temperature excitation. It is what you use.

[Production method]
There are two methods for producing nanodiamond: a method in which carbon powder is converted to nanodiamond using the explosive compressive force of carbon powder, and C carbon in the molecule constituting the explosive by exploding CB explosive in a non-oxidizing atmosphere There is a method of converting to nanodiamond, but in any case, semiconductor characteristics in which thermally excited carriers are generated at a temperature of about room temperature having an activation energy level of 0.1 to 1.0 eV due to additives or impurities during manufacture. What you have is obtained.

[Crystal structure of nanodiamond]
The nanodiamond crystal structure is composed of SP3 diamond structure at the center, SP2 + X intermediate layer and SP2 graphite layer as the outermost layer. (100) plane is positive and (111) plane is negative. It has a special structure with charge. A hydration layer is formed by this strong electrostatic potential, and a strong water retention capability is formed. This strong water retention ability penetrates the skin surface, enhances the skin barrier ability, protects the skin from bacterial infection and reduces itching.

[Unknown attributes of nanodiamonds: pharmacological action]
When such nanodiamonds are brought into contact with a living body, many charged particles are generated. A bactericidal effect is obtained by the oxidation or reduction reaction by the charged particles. Therefore, exudate due to scratches caused by itching of allergic dermatitis, and a protective action against bacterial infection caused by staphylococci and the like can be expected.

  When nanodiamonds with spontaneous charge are applied as a spray solution or ointment to the skin diseased part or attached to the fiber cloth by melt spinning or dyeing method, the nanodiamonds are electromagnetically separated from each other on the diseased part and the fiber surface by the spontaneous charge. It is easy to arrange with anisotropy due to the interaction, and charged particles generated from individual nanoparticles by body temperature heating in the vicinity of the affected part are integrated to generate a large electromotive force and generate a bioelectric current. The current of 3-20 μA resulting from this biological battery phenomenon widens the blood vessels directly under the affected skin, promotes blood flow, enhances the therapeutic effect, and reduces allergic dermatitis skin atrophy, skin streak, purple spots, telangiectasia To prevent.

Ultraviolet rays have an immunosuppressive effect, and it is said that a treatment method (PUVA therapy) that irradiates long-wave ultraviolet rays after taking or taking a drug that increases sensitivity to ultraviolet rays (oxoralen) is also effective for atopic dermatitis, It is used for treatment. However, the sun rays include many short wavelength ultraviolet rays of 40 nm or less which are harmful to the human body, and it is necessary to remove harmful ultraviolet rays in this wavelength band. The band gap width of diamond having an activation energy level of 0.1-1.0 eV is 5-4.5 eV depending on the particle size, absorbs ultraviolet rays with a wavelength of 400 nm or less well, and is said to be a biological infrared ray effective for living organisms. It converts to 3-15 μm and contributes effectively to blood circulation promotion and skin regeneration in the affected area.

[Toxicity evaluation]
The present invention appropriately applies the water retention, bactericidal effect, short wavelength ultraviolet ray removal, and blood circulation promoting effect by electromotive force of the semiconductor nanodiamond described above to allergic dermatitis, and exhibits a therapeutic effect by its synergistic effect. . In addition, nanodiamonds are substantially spherical, have no carcinogenicity as seen in acicular CNTs, and diamond itself is chemically inert, so there is no biotoxicity and there is no restriction on the amount used. Cytotoxicity evaluation of various fine powder carbon materials, nanodiamond (ND), carbon black (CB), and carbon nanotubes (MWCNT & SWCNT) has been made in References 3 and 4 below, but ND is reported to be the safest Has been.
References 1) Now of explosive nanodiamonds Eiji Osawa Science and Industry 83 (4) 2009 2) Crystallnity and Suraface electrostatics of diamond nanocrystals
Amanda S Barnard etal J. Mater. Chem 2007 17
3) Differential Biocompatibility of Carbon nanotubes and nanodiamonds
Amnda N Schrand etal Univ. Of Dayton Diamond and Related Material
2007 (16)
4) Cytotoxiety and genotoxity of carbon nanomaterials Medical
application Webster 2008 Chapter 8 New York

[Usage / Dosage Form]
The method of administering the allergic dermatitis therapeutic agent is limited to external applications such as application, and the dosage form is not particularly limited, but examples include those usually used on the skin, such as sprays, ointments, lotions, creams, gels, and emulsions. Can do. It is also possible to use a fiber cloth adhered by melt spinning or dyeing.

[Dosage and administration example 1]
Nanodiamond (hereinafter sometimes referred to as “nanodiamond”) is dispersed in an aqueous solution containing pure water or an organic solvent such as glycerin and sprayed onto the affected area. Since nanodiamonds strongly adsorb water molecules due to electrostatic potential, the repulsive force acts between particles in the solution due to the polar potential of water molecules and does not aggregate. The effective dispersion concentration in the aqueous solution is 0.0005 wt% to 3.0 wt%, but most preferably 0.001-0.1 wt%. It is also effective to apply nanodiamond to a diseased part by kneading it into a base material such as petrolatum, but direct application to the affected part in an aqueous solution state is more effective for water retention effect.

Since the dispersion concentration exhibits its effect at a lower concentration as the size of the nanodiamond becomes smaller, 5 nm single crystal nanodiamond (trademark NanoAmando) is most effective. Beyond 300 nm, the diamond generally has an aggregate structure, and charged particles emitted from individual nanodiamonds excited at about body temperature are easily trapped during diffusion to the surface, and the number of particles penetrating into the human body decreases. Because. If it is 0.0005 wt% or less, the concentration attached to the affected area is insufficient, and if the effectiveness decreases and exceeds 3 wt%, the nanodiamond tends to aggregate on the affected area, and the effectiveness of individual particles decreases, which is not preferable. The activation energy level of the nanodiamond used is preferably 0.1-1.0 eV. A particularly effective activation energy level is 0.3-0.7 eV. Below 0.1 eV, carriers are excited at a temperature of 20 ° C. or less, and the number of radiated light near the body temperature is reduced. This is not preferable, and when it exceeds 1.0 eV, it is difficult to be excited at body temperature. Decreases and the medicinal effect decreases.

[Usage / capacity example 2]
It is also effective to attach the nanodiamond to natural fiber cotton or the like that is less irritating to the skin allergic diseased area by the spray method, or to cover the affected area by dyeing or adhering by a dipping or printing dyeing method. The adhesion concentration is preferably 0.001 wt% to 0.1 wt%. If it is 0.001 wt% or less, the number of charged particles is reduced, and the effectiveness as a medicine is reduced. Dyeing or spraying at a concentration of 0.1 wt% or more increases the degree of nanodiamond aggregation on the fiber surface, reducing the effectiveness of the individual particles and making them less economical. Covering with nano-diamond fiber cloth after applying nano-diamond to the affected area by spraying further enhances its medicinal effect.

[Dosage and administration example 3]
It is also effective to mix nanodiamonds into a predetermined polymer fiber material, make fibers by melt spinning, and process them into fiber cloths, or directly into non-woven fabrics to cover the affected area. As the polymer fiber material, two or more types of incompatible composite polymer materials that do not dissolve each other are used, and the distribution of the nanodiamond is determined by the difference between the surface energy of the blended nanodiamond and the surface energy of the composite polymer material. It is preferable to use a double percolation phenomenon concentrated on one of the polymers to bring out the nano diamond on the fiber surface. This is because the excited charged particles from the nanodiamond inside the fiber are easily trapped during the permeation process to the surface and the effect is reduced.

As a blending amount, 0.001 wt% to 3.0 wt% is effective. If it is 0.001 wt% or less, the effect of the excited charged particles is reduced, and the effectiveness as a medicine is reduced. If it is 3.0 wt% or more, it becomes difficult to produce fibers by the melt spinning method due to the mechanical polishing action of the nanodiamond and the decrease in fiber strength.
Reference 5) Dispersion of Fillers and the Electrical conductivity of Polymer
blends filled with Carbon black M． Sumita et al Polymer Bulletin
25. 1991

[Example]
Next, water retention, antibacterial properties, UV protection properties, and basic properties that contribute to blood flow promotion related to the skin allergy medical effect of Nanodiamond will be described, and the results of the affected area application test will be shown.

[Water retention test]
FIG. 1 shows the measurement results of the surface tension of the solution related to nanodiameter penetration into the skin.
The contact angle of 0.1 g water droplets on a 20 ° C. Cu plate of pure water and a nanodiamond 0.1 wt% aqueous solution was measured. Although the contact angle of pure water is 20 degrees, the contact angle of the water mixed with nanodiamond is 10 degrees, which indicates that the adsorption power of water molecules is reduced by the spontaneous charge of the nanodiamond and the surface tension is lowered. By reducing the surface tension, nanodiamonds that are easy to penetrate the skin and remain non-cytotoxic remain on the skin surface, replenish the skin with water, activate the skin, and improve the barrier function of the skin, thereby healing. It is thought that he contributed.

[UV protective properties]
Fig. 2 shows a comparison of the temperature rise of an aggregate of 0.001 wt% blended fibers and additive-free fibers when left at room temperature, irradiated with UV-cut sunlight of 400 nm or less, and sunlight, using a thermocouple placed at the bottom. The results are shown as temperature difference. Sun rays are composed of short-wavelength ultraviolet rays having a wavelength of 250 nm to long-wavelength infrared rays having a wavelength of 25000 nm. Within this wavelength band, short-wavelength ultraviolet rays of 400 nm or less are harmful ultraviolet rays that damage the skin. Infrared rays of 3-20 μm are called biological infrared rays. When irradiated to the skin, blood circulation is promoted by a heating effect. It is also used for treatment because it activates the skin. The temperature difference at room temperature is 0.1 ° C., 0.5 ° C. for 400 nm cut glass transmitted sunlight, and 1.6 ° C. for outdoor illumination light.

  Since the semiconductor nanodiamond has a bandwidth of 5-4.5 eV and an activation energy level by doping of 0.1-1.0 eV, it efficiently absorbs short wavelength harmful ultraviolet rays of 400 nm or less, and has a heat of 3-20 μm. It is shown that the nanodiameter attached to the skin protects the skin from short wavelength ultraviolet rays and contributes to the improvement of the circulatory system by heating because it converts to infrared rays and the heating effect increases.

[Blood flow promoting effect]
FIG. 3 and FIG. 4 show the generated voltage and blood flow measurement when nanodiamond 0.001 and 0.005 wt% blended fiber cloth is wound around the arm. The voltage was measured with an electrostatic potentiometer, and the blood flow was measured with a Doppler flow meter. The fabric blended with the semiconductor nanodiamond generates a voltage of 300V-500V because the blended diamond is excited at body temperature, the individual particles have potentials, and the potentials of the individual particles are integrated. With this potential, a bioelectric current of 3-20 μA flows, and blood flow is promoted by 10% at a nanodiagram mixing ratio of 0.001 wt% and by about 30% at 0.01%. This promotion of blood flow contributes to the activation of the skin, and is particularly effective for treating skin allergies. It is effective as a therapeutic agent for other skin diseases and inflammations such as wounds, burns, insect bites and athlete's foot, and is also effective as an old keratin peeling agent and hair growth / hair growth agent. Depending on the fiber manufacturing method, the arrangement of nanodiamonds overlaps and deviates from the percolation arrangement, so the relationship between the generated potential and the blending amount may be reversed.

[Antimicrobial effect]
Polyester fiber material was blended with 0.001 wt% of nanodiamond, fiber was prepared by melt spinning, and the antibacterial properties were measured after surface weight loss processing. The measurement was carried out using the JIS L1902 bacterial solution absorption method and using Staphylococcus aureus ATCC 6538P. A bacteriostatic activity value of 4.1 was obtained, and antibacterial properties due to the charged particle radiation effect from the single crystal nanodiamond semiconductor particles were observed. The bacteriostatic activity value is 5.4 when the nano diamond content is 0.005 wt%. In allergic skin diseases, a rash occurs and itchy, so scratching often damages the skin and causes staphylococci to adhere to the pus, thus prolonging the treatment period. The antibacterial activity of nanodiamond excited carrier is about 4 orders of magnitude higher than that of Ag ion antibacterial fiber 0.2 wt % , antibacterial value 2.4, and is effective in preventing itching and suppuration. In the dyeing method, nanodiamonds are concentrated on the fiber surface, so that the antibacterial properties are expected to be further improved.

[Skin allergy application test]
Subsequently, the results of a clinical test using the therapeutic agent for allergic dermatitis of the present invention in humans and an animal test used in dogs will be described.

《Clinical trial》
(1) A follow-up test for allergic illness in 70-year-old female on both legs with diaper ointment and moisturizer as a comparative example The results are shown.
(2) Each drug was applied once a day after bathing. Only the nanodiamond formulation liquid according to the present invention was applied to the left foot, and a mixed solution of a steroid drug and a humectant was applied to the right foot for testing.
The nano diamond compounded liquid was prepared by mixing 0.01 wt% of nano diamond in pure water and applying the compounded liquid to the affected area in the form of a mist. As the steroid drug, a 0.5 mg / 1 g base of diblebrednate as a steroid and a hirudoid 0.3 wt% ointment as a humectant were used.
(3) Itching due to skin disease was settled 5 days after application in the case of the nanodiamond 0.01% compounding solution, and 2 days after application in the case of the steroid drug.
(4) About the rash by a skin disease, the result after 30 days is shown below.
FIG. 6 is a photograph of a 70-year-old woman's left foot larvae 30 days after the application of 0.01% nanodiamond solution, and FIG. 7 is a steroidal drug dibulbrednate 0.5 mg / 1 g base material + moisturizing agent hirudoid 0.3. FIG. 8 is a photograph of a large portion of a red rash on the right foot of a 70-year-old woman 30 days after application of the% ointment, and FIG. It is a photograph of the red rash small part of the part of the right foot fuculahie of a 70-year-old woman 30 days after application.
[Number of rashes]
In the case of the nanodiamond 0.01% mixture, the rash disappeared completely as shown in FIG. In the case of a steroid drug, as shown in FIG. 7, 1-2 red 5 mm diameter rashes (7 × 6 cm ² ) remain, and as shown in FIG. 8, a thin red 1-2 mm diameter rash (7 × 6 cm ² ). 10-30 pieces of 6 cm ² ) remained.
Thus, in the case of a steroid drug, a red rash that seems to be recurrent and telangiectasia tends to remain. In addition, the skin function was not sufficiently recovered, and many recurrences of rash and itching, which were probably caused by friction of clothes, etc. were observed.

《Animal testing》
(1) For dogs with a rash (five years old Shiba Inu female) diagnosed with food allergies, use 1 tablet of Investane as a steroid internal medicine (after dinner) and a nanodia 0.01% combination solution as an external medicine Was sprayed on the rash site.
(2) Result As shown in FIG. 10, the red rash shown in FIG. 9 was settled after 2 days, and the action of scratching the affected part for itching was stopped. As shown in FIG. 11, after 30 days, hair grew on the site where the rash disappeared. An early therapeutic effect was recognized by the synergistic action of the therapeutic agent for allergic dermatitis of the present invention and the steroid drug.

  From the above results, the therapeutic agent for allergic dermatitis of the present invention has antiallergic activity in humans or animals without using a steroid drug or even when the amount used is reduced, and contact dermatitis, atopic It is clear that it is an effective therapeutic agent for allergic dermatitis such as dermatitis. Furthermore, since the skin treatment agent of the present invention has no cytotoxicity, it has no side effects as compared with steroids, and there are no particular restrictions on the method of use and the period for the combined use.

Claims (2)

A therapeutic agent for allergic dermatitis in which nanodiamonds having an activation energy level of 0.1 to 1.0 eV and a particle size of 5 to 300 nm are dispersed and mixed in a solution or oil and fat in an amount of 0.0005 to 3.0 wt%. A nano-diamond having an activation energy level of 0.1-1.0 eV and a particle size of 5-300 nm dispersed and mixed in a solution by 0.0005-3.0 wt% is sprayed , printed, dyed or melt-spun. A therapeutic agent for allergic dermatitis that is attached to a textile cloth by the law .