WO2019131712A1 - 増毛、頭皮若しくは皮膚の改質、創傷治癒、骨形成促進、または毛髪の改質に用いるための医薬組成物 - Google Patents
増毛、頭皮若しくは皮膚の改質、創傷治癒、骨形成促進、または毛髪の改質に用いるための医薬組成物 Download PDFInfo
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- A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
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Definitions
- the present invention relates to pharmaceutical compositions and methods for use in hair growth, scalp or skin modification, wound healing, bone formation promotion, or hair modification.
- Mammalian milk (especially colostrum) contains various things including nutrients such as immune substances and intracellular mediators, exosomes, mRNA, cytokines and the like. When taken by an infant, these substances are taken into the body and contribute to the infant's development.
- Non-patent Document 1 It has been reported that fat cell lineage cells contribute to the niche of skin stem cells to drive hair cycling by comparative examination in the presence or absence of fat lineage cells (Non-patent Document 1).
- Non-Patent Document 1 suggests that the appearance of CD34 positive cells, the increase of PPAR ⁇ positive fat cells, and the maturation of adipocytes are associated with the growth of hair during growth.
- Non-Patent Document 2 reports that an increase in tissue resident M2-like macrophages is observed when tissue regeneration occurs in tissues.
- the present invention provides a pharmaceutical composition for topical administration for use in modifying the scalp or skin.
- the present invention also provides a pharmaceutical composition for topical administration for use in treating wounds, the present invention further provides a pharmaceutical composition for topical administration for use in promoting hair growth or modifying hair. Provide the goods.
- the inventors of the present invention have found that milk, a centrifugal supernatant component of milk, and soybean oil, and a composition containing fatty acids such as major fatty acids contained therein modify the scalp or skin and heal wounds. Have been found to be useful in promoting bone formation, and in modifying hair. The present invention is based on these findings.
- a pharmaceutical composition for topical administration for use in modifying the scalp or skin (ii) a pharmaceutical composition for topical administration for use in treating a wound, or (iii) hair growth
- a pharmaceutical composition for topical administration for use in promoting or a pharmaceutical composition for topical administration for use in modifying hair comprising a therapeutically effective amount of a saturated fatty acid or a pharmaceutically acceptable salt thereof
- Pharmaceutical composition containing (2) The pharmaceutical composition according to (1) above, for use in modifying scalp or skin.
- the present invention it is advantageous in that it can be used for the above-mentioned various medical applications and also provides a pharmaceutical composition or a therapeutic method which can exert effects continuously even after the end of treatment.
- FIG. 1 is a photograph showing the effect of milk administration on the hair cuticle.
- FIG. 2A is a picture of a local area showing the effect of reducing milk by administration of milk.
- FIG. 2B is a photograph of the side of the head showing the effect of reducing milk upon administration of milk.
- FIG. 3 is a view showing the relationship between milk administration and the thickness of the fat layer of the skin. # 1 to # 6 indicate that it is after 1 to 6 months of treatment, respectively.
- FIG. 4A shows tissue staining of type I collagen and type III collagen in skin tissue before and after treatment.
- FIG. 4B shows tissue staining of type I collagen and type III collagen in skin tissue before and after treatment.
- FIG. 5 shows the effect of milk administration on adipocyte size.
- FIG. 6A shows the effect of milk administration on wound healing.
- FIG. 6B shows the effect of lactoferrin administration on wound healing.
- FIG. 6C shows the effect of saturated or unsaturated fatty acid administration on wound healing.
- FIG. 6D shows the effect of soy oil administration on wound healing.
- FIG. 7 shows the results of immunohistological staining (staining of Ki67 positive adipocytes and staining of CD68 positive macrophages) of Wistar rat back subcutaneous adipose layer tissue by milk administration.
- FIG. 8A shows the results of immunohistological staining (CD31 staining and CD34 staining) of scalp fat layer tissue by milk administration.
- FIG. 8B shows the results of immunohistological staining (staining of CD68-positive macrophages, staining of CD163-positive tissue-resident M2-like macrophages and staining of PPAR ⁇ -positive cells) of milk of the scalp fat layer tissue.
- FIG. 9 shows the results of immunohistological staining (staining of CD68 and PPAR ⁇ -positive cells) of rat back subcutaneous fat tissue by oral administration of lactoferrin.
- FIG. 10A shows the staining results of CD68 and PPAR ⁇ positive cells in tissues 4 weeks and 8 weeks after saline administration. Arrowheads in the figure indicate locations where positive cells are present, and numbers in parentheses at the lower right of each stained image indicate the number of positive cells in the field of view.
- FIG. 10A shows the staining results of CD68 and PPAR ⁇ positive cells in tissues 4 weeks and 8 weeks after saline administration. Arrowheads in the figure indicate locations where positive cells are present, and numbers in parentheses at the
- FIG. 10B shows the staining results of CD68 and PPAR ⁇ positive cells in tissues 4 and 8 weeks after palmitic acid administration. Arrowheads in the figure indicate locations where positive cells are present, and numbers in parentheses at the lower right of each stained image indicate the number of positive cells in the field of view.
- FIG. 10C shows the staining results of CD68 and PPAR ⁇ positive cells in tissues 4 and 8 weeks after stearic acid administration. Arrowheads in the figure indicate locations where positive cells are present, and numbers in parentheses at the lower right of each stained image indicate the number of positive cells in the field of view.
- FIG. 10D shows the staining results of CD68 and PPAR ⁇ positive cells in tissues 4 and 8 weeks after administration of myristic acid.
- FIG. 10E shows the staining results of CD68 and PPAR ⁇ positive cells in tissues 4 and 8 weeks after oleic acid administration. Arrowheads in the figure indicate locations where positive cells are present, and numbers in parentheses at the lower right of each stained image indicate the number of positive cells in the field of view.
- FIG. 10F shows the staining results of CD68 and PPAR ⁇ positive cells in tissues 4 weeks and 8 weeks after ⁇ -linolenic acid administration.
- FIG. 10G shows the staining results of CD68 and PPAR ⁇ positive cells in tissues 4 and 8 weeks after linoleic acid administration. Arrowheads in the figure indicate locations where positive cells are present, and numbers in parentheses at the lower right of each stained image indicate the number of positive cells in the field of view.
- FIG. 11A shows the sum of length ⁇ number of hairs by length of hair by milk administration.
- FIG. 11B illustrates the results of FIG. 11A in bar graph format.
- Fig. 12 is obtained by placing a palmitic acid-coated biocompatible membrane or non-coated biocompatible membrane on a bone excision site (diameter 8.8 mm) and observing the subsequent bone formation by 3D-CT. Image. Some artificially 3 mm diameter holes are made for tissue sampling of bone after bone formation.
- FIG. 13 shows hematoxylin-eosin stained images of sections of bone sampled tissue after bone formation. The dashed oval shows the newly formed bone at the osteotomy site.
- FIG. 14 shows changes in gene expression of bone morphogenetic protein-4 (Bmp4) and bone morphogenetic protein-7 (Bmp7) in subjects who received palmitin or milk.
- FIG. 15 shows the change of gene expression by palmitic acid administration or milk administration to control.
- subject means a mammal. Mammals include, for example, humans (male and female).
- milk means milk of mammalian origin. Mammals include, for example, humans and cows.
- Whey refers to an aqueous solution obtained by removing milk fat, casein, and the like from milk. Whey may be obtained, for example, by subjecting milk to an operation such as centrifugation to remove precipitates.
- scalp refers to the area of the skin of the head, including the top of the head, other than the face, chin, and neck (including the ears).
- skin is used to include skin and skin other than scalp.
- the human scalp has an area of about 700 mm 2 to about 800 mm 2 .
- hair means hair that grows on the skin.
- hair refers to hair that grows on the scalp.
- white hair refers to hair that is white, in particular from the hair, lacking pigments such as eumelanin (or true melanin) and / or pheomelanin.
- black hair refers to hair that contains eumelanin and exhibits a black color.
- a "cuticle” is a structure that covers the surface of the hair and is a structure that is present in the outermost layer of the hair.
- the cuticle plays a role of protecting the hair from external stimuli and a role of preventing the outward loss of water or ingredients from the inner cortex.
- the cuticle coats the hair from the root to the hair tip in a scaly manner.
- wound means physical damage to tissue.
- the wounds include wounds on the body surface.
- a pharmaceutical composition for topical administration, for use in modifying scalp or skin comprising a therapeutically effective amount of a fatty acid (especially saturated fatty acid) or a pharmaceutically acceptable salt thereof;
- B a pharmaceutical composition for topical administration for use in treating wounds, comprising a therapeutically effective amount of a fatty acid (especially saturated fatty acid) or a pharmaceutically acceptable salt thereof;
- C a therapeutically effective amount of Pharmaceutical composition for topical administration for use in promoting hair growth, or pharmaceutical composition for topical administration for use in modifying hair, comprising a fatty acid (especially saturated fatty acid) or a pharmaceutically acceptable salt thereof
- D a pharmaceutical composition for use in promoting bone formation, comprising a therapeutically effective amount of a fatty acid (especially saturated fatty acid) or a pharmaceutically acceptable salt thereof (hereinafter referred to as (A) ) To (D) may be collectively referred to as "the pharmaceutical composition of the present invention".
- the therapeutically effective amount of saturated fatty acids or pharmaceutically acceptable salts thereof includes milk, milk extract (eg whey) and milk products (eg milk products) Cheese whey, yogurt whey, etc.) and mixtures thereof.
- the milk, milk extract or milk product may be sterilized, for example, may be pasteurized (for example, heat sterilization at 62 ° C. to 68 ° C.) or high temperature sterilization (heat sterilization at 120 ° C. or more) .
- Milk sterilization is usually performed by low-temperature sterilization performed at 62 ° C. to 68 ° C. for about 30 minutes (eg, 30 minutes at 65 ° C.) and 1 second to 4 seconds at 120 ° C. to 150 ° C. (eg, 120 ° C. to 130 ° C. It is divided roughly into high temperature sterilization performed for 2 seconds-3 seconds.
- the pharmaceutical composition of the present invention comprises milk as an active ingredient.
- animal oils, vegetable oils, oil extracts or processed products thereof eg, soybean oil
- therapeutically effective amounts of saturated fatty acids or pharmaceutically acceptable salts thereof, Soybean oil extract or soybean oil processed product or a mixture of these.
- extract from milk or soy oil is the fraction extracted from milk or soy oil, sometimes referred to as milk extract or soy oil extract, respectively, each saturating a therapeutically effective amount It contains a fatty acid or a pharmaceutically acceptable salt thereof.
- milk or soy oil processing is a product obtained by processing milk or soybean oil, sometimes referred to as milk processing or soybean oil processing, respectively, and each has a therapeutically effective amount of It contains saturated fatty acid or its pharmaceutically acceptable salt.
- compositions comprising a therapeutically effective amount of saturated fatty acids or pharmaceutically acceptable salts thereof include solutions comprising milk and whey, and lyophilized formulations thereof.
- the fatty acid contained in the pharmaceutical composition for topical administration of the present invention may be a fatty acid contained as a component of milk.
- the saturated fatty acid contained in the pharmaceutical composition for topical administration of the present invention is one or more saturated fatty acids selected from the group consisting of palmitic acid, stearic acid and myristic acid.
- the fatty acid contained in the pharmaceutical composition for topical administration of the present invention may be a saturated fatty acid, for example, one or more fatty acids selected from the group consisting of palmitic acid, stearic acid and myristic acid It is.
- the saturated fatty acid contained in the pharmaceutical composition for topical administration of the present invention is palmitic acid. In one aspect of the present invention, the saturated fatty acid contained in the pharmaceutical composition for topical administration of the present invention is stearic acid. In one aspect of the present invention, the saturated fatty acid contained in the pharmaceutical composition for topical administration of the present invention is myristic acid.
- the pharmaceutical composition for topical administration of the present invention may further contain an unsaturated fatty acid, and as the unsaturated fatty acid, for example, a group consisting of oleic acid, alpha linolenic acid, and linoleic acid It may contain one or more unsaturated fatty acids selected from
- the fatty acid contained in the pharmaceutical composition for topical administration of the present invention is oleic acid.
- the fatty acid contained in the pharmaceutical composition for topical administration of the present invention is alpha linolenic acid.
- the fatty acid contained in the pharmaceutical composition for topical administration of the present invention is linoleic acid.
- the fatty acid contained in the pharmaceutical composition for topical administration of the present invention may be a mixture of at least one saturated fatty acid and at least one or more unsaturated fatty acids.
- the fatty acids contained in the pharmaceutical composition for topical administration of the present invention are palmitic acid and linoleic acid.
- the fatty acids included in the pharmaceutical composition for topical administration of the present invention are palmitic acid and oleic acid.
- the fatty acids included in the pharmaceutical composition for topical administration of the present invention are stearic acid and linoleic acid.
- the fatty acids included in the pharmaceutical composition for topical administration of the present invention are stearic acid and oleic acid.
- the fatty acids included in the pharmaceutical composition for topical administration of the present invention are palmitic acid and stearic acid and linoleic acid. In one aspect, the fatty acids included in the pharmaceutical composition for topical administration of the present invention are palmitic acid, stearic acid and oleic acid. In one embodiment, the fatty acid contained in the pharmaceutical composition for topical administration of the present invention is myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid and ⁇ -linolenic acid.
- the milk, milk extract or milk product or mixture thereof which may be used in the present invention may, for example, contain one or more fatty acids selected from saturated fatty acids, where it may be When it is naturally contained in and when it is added to milk ⁇ .
- the milk, milk extract or milk product or mixture thereof that may be used in the present invention may further comprise unsaturated fatty acids.
- the milk, milk extract or milk product or mixture thereof that may be used in the present invention may comprise, for example, one or more fatty acids selected from the group consisting of palmitic acid, stearic acid, and myristic acid. .
- the milk, the milk extract or the milk product or the mixture thereof which can be used in the present invention is, for example, one or more unsaturations selected from the group consisting of oleic acid, ⁇ -linolenic acid, and linoleic acid It may contain fatty acids.
- the milk, milk extract or milk product or mixture thereof that may be used in the present invention may, for example, comprise one or more saturated fatty acids and one or more unsaturated fatty acids.
- the milk, milk extract or milk product or mixture thereof that may be used in the present invention comprises oleic acid, one or more fatty acids selected from the group consisting of palmitic acid, stearic acid, and myristic acid, It may comprise ⁇ -linolenic acid, and one or more fatty acids selected from the group consisting of linoleic acid.
- the milk, milk extract or milk product or mixture thereof that may be used in the present invention may comprise myristic acid, palmitic acid, and oleic acid.
- the milk, milk extract or milk processed product or mixture thereof that may be used in the present invention may comprise myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, and ⁇ -linolenic acid.
- the one or more fatty acids may be added to the pharmaceutical composition in the form of milk, milk extract or milk processing or mixtures thereof.
- the milk, milk extract or milk product or mixture thereof may have an enhanced content of one or more fatty acids selected from saturated fatty acids and unsaturated fatty acids.
- the fatty acid content after enhancement may be higher than the fatty acid content in the milk, the milk extract or the processed milk product or the mixture thereof before the enhancement.
- the enhancement can be performed, for example, by the addition of one or more fatty acids selected from saturated fatty acids and unsaturated fatty acids to milk, milk extract or milk processing or mixtures thereof.
- the enhancement can be, for example, an enhancement of the content of one or more fatty acids selected from the group consisting of palmitic acid, stearic acid, and myristic acid.
- the enhancement can be, for example, an enhancement of the content of one or more fatty acids selected from the group consisting of oleic acid, ⁇ -linolenic acid, and linoleic acid.
- the enhancement can be, for example, an enhancement of the content of one or more saturated fatty acids and one or more unsaturated fatty acids.
- the enhancement is selected from the group consisting of oleic acid, ⁇ -linolenic acid, and linoleic acid, for example, the content of one or more fatty acids selected from the group consisting of palmitic acid, stearic acid, and myristic acid May be an increase in the content of one or more fatty acids.
- the enhancement may be an increase in the content of each of myristic acid, palmitic acid, and oleic acid. In one aspect, it may be an increase in the content of myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, and ⁇ -linolenic acid, respectively.
- the milk, milk extract or milk product or mixture thereof may have a reduced lactoferrin content.
- the reduction of the lactoferrin content may be carried out by a method such as high temperature sterilization.
- the milk, milk extract or processed milk product or mixture thereof may be enhanced in fatty acid content and reduced in lactoferrin content.
- the animal oil, vegetable oil, oil extract or processed product thereof, or a mixture thereof may comprise one or more fatty acids selected from saturated fatty acids. In one aspect, the animal oil, vegetable oil, oil extracts or processed products thereof, or a mixture thereof may further contain unsaturated fatty acids. In one aspect, the animal oil, vegetable oil, oil extract or processed product thereof or mixture thereof which may be used in the present invention is selected from the group consisting of palmitic acid, stearic acid and myristic acid, for example. It may contain one or more fatty acids.
- the animal oil, vegetable oil, oil extract or processed product thereof or mixture thereof which may be used in the present invention is selected from, for example, the group consisting of oleic acid, ⁇ -linolenic acid, and linoleic acid. May contain one or more unsaturated fatty acids. In one aspect, the animal oil, vegetable oil, oil extract or processed product thereof or mixture thereof which may be used in the present invention contains, for example, one or more saturated fatty acids and one or more unsaturated fatty acids. obtain.
- the animal oil, vegetable oil, oil extract or processed product thereof or mixture thereof which may be used in the present invention is one or more selected from the group consisting of palmitic acid, stearic acid and myristic acid And one or more fatty acids selected from the group consisting of oleic acid, ⁇ -linolenic acid, and linoleic acid.
- animal oils, vegetable oils, oil extracts or processed products thereof, or mixtures thereof that may be used in the present invention may comprise myristic acid, palmitic acid, and oleic acid.
- animal oils, vegetable oils, oil extracts or processed products thereof, or mixtures thereof which may be used in the present invention are myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, and ⁇ - It may contain linolenic acid.
- the animal oil, the vegetable oil, their oil extract or processed product, or a mixture thereof has an enhanced content of one or more fatty acids selected from saturated fatty acids and unsaturated fatty acids. It is also good.
- the fatty acid content after enhancement may be increased over the fatty acid content in the animal oil, vegetable oil, oil extract or processed product thereof or their mixture before enhancement.
- the enhancement can be performed, for example, by the addition of one or more fatty acids selected from saturated fatty acids and unsaturated fatty acids to animal oils, vegetable oils, their oil extracts or processed products, or mixtures thereof.
- the enhancement can be, for example, an enhancement of the content of one or more fatty acids selected from the group consisting of palmitic acid, stearic acid, and myristic acid.
- the enhancement can be, for example, an enhancement of the content of one or more fatty acids selected from the group consisting of oleic acid, ⁇ -linolenic acid, and linoleic acid.
- the enhancement can be, for example, an enhancement of the content of one or more saturated fatty acids and one or more unsaturated fatty acids.
- the enhancement is selected from the group consisting of oleic acid, ⁇ -linolenic acid, and linoleic acid, for example, the content of one or more fatty acids selected from the group consisting of palmitic acid, stearic acid, and myristic acid May be an increase in the content of one or more fatty acids.
- the enhancement may be an increase in the content of each of myristic acid, palmitic acid, and oleic acid. In one aspect, it may be an increase in the content of myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, and ⁇ -linolenic acid, respectively.
- the pharmaceutical composition for topical administration of the present invention comprises fatty acids in a solubilised form. In one aspect, the pharmaceutical composition for topical administration of the present invention comprises a fatty acid as a pharmaceutically acceptable salt. In one aspect, the pharmaceutical composition for topical administration of the present invention comprises a fatty acid in the form of an emulsion. In one aspect, in the pharmaceutical composition for topical administration of the present invention, the fatty acid is not in ester form and glyceride form.
- Fatty acids are dissolved in dimethyl sulfoxide, ethanol, chloroform, diethyl ether. Fatty acids are improved in water solubility when used as pharmaceutically acceptable salts, such as sodium salts.
- the fatty acid salt may form micelles and be dissolved in water.
- the pharmaceutical composition for topical administration of the present invention may, in one aspect, be a formulation for injection.
- the pharmaceutical composition for topical administration of the present invention can be provided in the form of a kit comprising a lyophilized preparation of a solution containing fatty acid and water for injection, wherein the lyophilizing agent is water for injection It can be prepared from time to time. The water for injection may be used by heating.
- the pharmaceutical composition for use in promoting bone formation of the present invention may be provided as applied on a biocompatible membrane.
- the present invention can provide a medicament comprising a therapeutically effective amount of a saturated fatty acid or a pharmaceutically acceptable salt thereof coated on a biocompatible membrane.
- a thin film having a calcium phosphate surface for example, a calcium phosphate thin film
- a thin film having a polylactic acid surface for example, a polylactic acid thin film
- a thin film having a polyglycolic acid surface for example, A thin film of polyglycolic acid, a thin film having a surface of a copolymer or block copolymer of lactic acid and polyglycolic acid (for example, a thin film of a copolymer or block copolymer of lactic acid and polyglycolic acid), and hydroxy
- a thin film having a surface of apatite for example, a thin film of hydroxyapatite
- Application of the active ingredient onto a biocompatible membrane can be performed, for example, by dropping a solution in which the active ingredient is dissolved onto the biocompatible membrane and drying it.
- a solution in which the active ingredient is dissolved onto the biocompatible membrane For example, about 10 to 50 ⁇ g of a pharmaceutically active ingredient can be applied to a biocompatible membrane and used.
- a pharmaceutical composition for topical administration for use in modifying the scalp or skin comprising a therapeutically effective amount of a saturated fatty acid or a pharmaceutically acceptable salt thereof, after administration, the scalp improves from near the administration site
- the effect spreads gradually to the surroundings over time. Therefore, the effect of the present invention can be transmitted to the surroundings over time by being scattered on the scalp or the skin, or can be concentrated to shorten the time required for the transmission.
- the pharmaceutical composition of the present invention is not particularly limited, and for example, 1 cm 2 to 10 cm 2 , 1 cm 2 to 5 cm 2 , 1 cm 2 to 4 cm 2 , 1 cm 2 to 3 cm 2 , 1 cm 2 to 2 cm 2 , 0.5cm 2 ⁇ 2cm 2, it may be one place relative to 0.7cm 2 ⁇ 1.5cm 2.
- the pharmaceutical compositions of the present invention for example, following one place 0.5 cm 2, less one place 0.6 cm 2, less one place 0.7 cm 2, to 0.8 cm 2 1 It can be administered at a dose density of 1 site or less in 0.9 cm 2 or 1 site or less in 1 cm 2 .
- the pharmaceutical composition of the present invention can be topically administered, for example, directly under the skin, or from the dermal layer to the upper fat layer. Administration can be performed, for example, by injection.
- a therapeutically effective amount of a saturated fatty acid or a pharmaceutically acceptable salt thereof can be administered, for example, 10 ⁇ L to 50 ⁇ L, 15 ⁇ L to 30 ⁇ L, 15 ⁇ L to 25 ⁇ L, or about 20 ⁇ L of solution per site.
- the site of administration can be selected as appropriate, but can be administered, for example, to the entire scalp, or to an inferior part of the entire scalp as compared to the other.
- the present inventors have found that the effect is likely to be transmitted to the environment when administered to a relatively good part of the entire scalp.
- the good part is highly responsive to the pharmaceutical composition of the present invention, and the effect is transmitted to extend around the administration site.
- the ameliorating effect of transmission appears strongly near the administration site, but ranges from several centimeters from the administration site (eg, 1 cm to 4 cm). Therefore, it can be administered to a relatively good site of the scalp.
- the improvement effect is transmitted from the good site to the relatively poor site, the therapeutic effect to the bad site can be obtained even when administered to the relatively good site. Therefore, it may be administered to a relatively good site of the scalp, and the effect of transmission may be used to try to improve the poor part.
- the pharmaceutical composition of the present invention is administered to the poor part after that. It is also good.
- tissue stimulation, macrophage activity and juvenile adipocyte activity increase at the administration site and repair function increases. It is desirable to check and administer the patient's symptoms (conditions) and the degree of improvement.
- the topical administration can be from 150 to 250 (eg, about 200) or 250 to 800 per scalp of an adult, the number of administration being determined as needed be able to.
- the term "about” is meant to include the numerical range of ⁇ 10% or ⁇ 5% of the numerical value following the term.
- the pharmaceutical composition of the present invention is not particularly limited, for example, twice a month to once a month in June, twice a month in a month to once a month in May, twice a month in a month to a month in a month, 2 times in January to 1 time in March, 2 times in January to 1 time in February, 1.5 times in January to 1 time in 1.5 months, or 1.2 times in January It can be administered once every two months, for example, about once every month.
- the pharmaceutical composition of the present invention has a scalp and skin modifying effect by a single administration, and this effect can be sustained. Therefore, administration may be performed once or plural times.
- the pharmaceutical composition of the present invention can also be administered continuously until the treatment is completed or until the patient is satisfied.
- the modifying effect of the scalp and the skin appears from the good part of the condition and appears late in the bad part of the condition. Therefore, the treatment period and treatment interval may vary depending on the condition of the scalp and skin.
- the treatment period with the pharmaceutical composition of the present invention may be, for example, a minimum of one treatment to three years, a minimum of one treatment to two years, a minimum of one treatment to 1.5 years, a minimum of one.
- the treatment can be from 1 treatment to 1 month, from 1 treatment to 8 months, from 1 treatment to 6 months, or from 1 treatment to 4 months.
- the pharmaceutical composition of the present invention may also be administered before, when or after observed changes in hair, scalp, skin due to aging.
- the pharmaceutical composition of the present invention was also or as observed in the subject after treatment by administration of the pharmaceutical composition, before age-related changes in the hair, scalp, skin are observed Administration may be resumed later.
- the pharmaceutical composition described in the above (A) may be a pharmaceutical composition for promoting rejuvenation or rejuvenation of the scalp or skin. In one aspect of the present invention, the pharmaceutical composition described in the above (A) may be a pharmaceutical composition for promoting regeneration of the scalp or skin. In one aspect of the present invention, the pharmaceutical composition described in the above (A) may be a pharmaceutical composition for activation of the scalp or skin. In one embodiment of the present invention, the pharmaceutical composition described in the above (A) can be used in combination with a hair growth agent or a hair growth agent.
- the pharmaceutical composition described in (B) above can be used to treat a wound.
- treatment of a wound may be wound healing, promoting wound healing, or accelerating wound healing.
- the hair improving effects include reduction of white hair, reduction of weight of white hair part, and reduction of ratio of white hair, reduction of ratio of white hair, improvement of cuticle roughness. Improvements in hair thickness and extension speed can be mentioned. Therefore, in one aspect of the present invention, the pharmaceutical composition described in the above (C) may be a pharmaceutical composition for use in reducing gray hair.
- the reduction in white hair includes a reduction in the number of white hair, a reduction in weight of the white hair portion, and a reduction in the proportion of white hair.
- the loss of gray hair can be accompanied by an increase in the number of hairs colored with various melanins, an increase in the weight of such hair parts, and an increase in the proportion of such hair.
- the pharmaceutical composition described in the above (C) may be a pharmaceutical composition for use in improving hair cuticle roughness. Improving the cuticle roughness of the hair includes increasing the degree of cuticle alignment and reducing the disordered area of the cuticle.
- the pharmaceutical composition described in the above (C) may be a pharmaceutical composition for use in improving hair thickness or elongation rate. Hair thickness improvements include thickening hair, increasing the number of thick hair, and increasing the proportion of thick hair.
- a method for modifying the scalp or skin in a subject in need thereof (or a site where the scalp is needed), wherein a therapeutically effective amount of a saturated fatty acid or a pharmaceutically acceptable salt thereof is topically applied to the scalp or skin A method comprising administering;
- C A method of promoting hair growth in a subject in need thereof, or a method of modifying hair in a subject in need thereof, which comprises a therapeutically effective amount of a saturated fatty acid or a pharmaceutically acceptable salt thereof in the scalp or A method comprising topically administering to the skin; and
- ⁇ Use of a therapeutically effective amount of a saturated fatty acid or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical preparation for topical administration for use in modifying the scalp or skin;
- ⁇ Use of a therapeutically effective amount of a saturated fatty acid or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical preparation for topical administration for use in treating a wound;
- the pharmaceutical preparation may be provided that a therapeutically effective amount of fatty acid (especially saturated fatty acid) or pharmaceutically acceptable salt thereof is applied to the biocompatible membrane ⁇ Is provided.
- the pharmaceutical composition comprises an excipient (eg, solvent, cosolvent, solubilizer, wetting agent, suspension agent) in addition to a therapeutically effective amount of a fatty acid or a pharmaceutically acceptable salt thereof.
- an excipient eg, solvent, cosolvent, solubilizer, wetting agent, suspension agent
- the pharmaceutical composition may be in the form of an injection.
- the pharmaceutical composition may be administered topically, for example, intradermally or subcutaneously.
- Example 1 Preparation and administration of milk
- Milk was prepared as follows. As milk for administration to humans, so-called colostrum (milk collected within 3 weeks after delivery) was obtained from breasts of females 34 and 40 using a breast pump. As milk for administration to rats, bovine colostrum obtained by hand squeezing or commercially available milk was used as milk.
- Milk was administered as follows. Milk was injected into the right or left half of the human scalp or the back skin of rats in an amount of 20 ⁇ l per site. In the case of a human, a total of 2 mL of colostrum (ie, 100 per one patient) was injected per patient for each patient.
- the 12-week-old Wister rat male has 3 areas from head to tail on the back, and each area is further divided into 2 areas on the left and right of the spine. I set the area. Two 20 ⁇ l / one milk injections were made near the center of each area. The distance between the two points was 1 cm.
- Example 2 Change in Hair Quality
- the human colostrum described in Example 1 was used as milk.
- the average hair extension rate is about 10 mm in January.
- the hair of the test site was adhesively fixed to the fixing plate with a resin on the hair collection day or the next day.
- the carbon was fixed on the next day or the next day, and the state of the hair cuticle was observed by a scanning electron microscope in the usual way on the same day.
- As a negative subject the hair of an untreated part (non-administration site) of the same patient was used.
- a comparison was made between the newly stretched part of the hair (root side) and the existing part (tip side).
- FIG. 1 is an electron microscope image of the hair of the same patient.
- Example 3 Change in Hair Quality
- attention was paid to the color of hair (white hair) was examined before and after treatment.
- 20 ⁇ L of human colostrum described in Example 1 was injected into 100 portions at 2 points per head, and observed after 1 month.
- the trichogram is taken each time with a focus on marking (Canon Power Shot A520, Tokyo, Japan), and the hair in a circle of 11 mm in diameter (area 95 mm 2 ) centered on a tattoo included in the imaging range is photographed, It measured by visual observation.
- FIG. 2A A representative example of the hair of a patient (a 48-year-old female) half a year old after shaving and a single injection of colostrum is shown in FIG. 2A.
- the non-administration site there was no reduction in gray hair, but at the administration site, gray hair was clearly reduced.
- the number of gray hair was 49 before the treatment increased to 63 after 6 months, whereas at the administration site, it was 85 before the treatment. Decreased to 66 bottles.
- milk human colostrum described in the examples was used. Milk was injected in 100 spots of 20 ⁇ L per scalp into the patient's scalp (6 injections, 4 injections once in January).
- the change in thickness of the fat layer of the subcutaneous tissue of the scalp after a single administration was observed by echography using a 10 Mz probe. In this examination, the area from the sebaceous gland area to the lower part is measured, and it is considered that the thickness of the area to the dermis layer is generally measured (although the dermis layer is not included in the measurement value).
- the results were as shown in FIG. In FIG. 3, “# 1 to # 6” indicate that the data were obtained 1 to 6 months after the treatment, respectively. As shown in FIG. 3, at 6 months after the start of the treatment, a slight increase in the thickness of the fat layer was observed but no significant change was observed.
- Example 5 Histological Image of the Scalp
- the effects of the improvement of the cuticle and the reduction of the gray hair were confirmed.
- collagen amount of the scalp was examined.
- FIG. 4A shows a scalp sample of a female patient (49 years old) who is 5 months after single administration
- FIG. 4B is a male patient who received 15 monthly administrations once a month and 15 months after the initial treatment ( 50 shows a scalp sample of 50 years old).
- the number of greenish pixels (corresponding to the amount of type III collagen), the number of yellowish pixels (corresponding to the amount of type I collagen), and reddish yellow (corresponding to the total amount of collagens other than type III) are tabulated. Summarized.
- the number of greenish pixels (corresponding to the amount of type III collagen), the number of yellowish pixels (corresponding to the amount of type I collagen) and reddish yellow (corresponding to the total amount of collagens other than type III) are tabulated. Summarized.
- type III collagen significantly decreased from 26.3% to 2.8% in comparison between untreated side and treated side, and type I collagen was 24.7% to 56.3%.
- An increase to% was observed (see FIG. 4B).
- the total amount of total collagen other than type III is also found to increase from 73.7% to 97.2% as well, but this increase is considered to be mainly due to an increase in type I collagen.
- Cells having a diameter of 51 ⁇ m or less were designated as “S”, cells having a diameter of more than 51 ⁇ m and not more than 63 ⁇ m as “M”, and cells exceeding 63 ⁇ m as “L”.
- the patient receives 6 months after a single dose (hereinafter referred to as “patient 1”) and the patient who administers once a month 4 times and 15 months after the start of treatment (hereinafter referred to as “patient 2”) Went at The results were as shown in FIG.
- Example 6 Effect on Wound Healing So, in this Example, it was confirmed whether the administration of milk had the effect of accelerating wound healing on the skin.
- Preparation of Wounds The backs of 12-week-old Wister rats were shaved with a hair clipper, and circular skin full-thickness defects with a diameter of 8 mm were created on each of the head and tail sides. The skin full-thickness defects were created at four points per body.
- Administration of milk 20 ⁇ L of milk was injected subcutaneously at four locations up, down, left, and right, at a distance of 4 mm from the wound edge.
- As milk commercially available milk which has been heat-killed (130 degrees, 2 seconds and 65 degrees and 30 minutes) described in Example 1 was used.
- fatty acid Sterile purified water (administration solution) containing palmitic acid, stearic acid, myristic acid, linolenic acid, alpha linolenic acid, and oleic acid as fatty acids contained in milk is heated by the saturated fatty acid by heating. Saturated fatty acids were administered at room temperature. As for administration, 20 ⁇ L of the administration solution (containing 1 mg of fatty acid) was subcutaneously administered to 4 mm from top, bottom, left, and right from the wound edge.
- the results were expressed as the ratio of the above score divided by the saline score. As shown in FIG. 6A, a promoting effect on wound healing was observed in the group to which milk was administered.
- centrifuge 2600 g ⁇ 6 minutes 2 x 8 mL of commercially available pasteurized milk (65 degrees, 30 minutes) with a centrifuge and collect 2 mL each corresponding to 1 ⁇ 4 of the supernatant from which the whipped part has been removed, Were made into 4 mL, this 4 mL was stirred and it used for experiment (Hereafter, the obtained sample is called "spin sample”).
- the resulting centrifuged samples were administered at the wound site at a dose of 20 ⁇ L per site as described above. The results were as shown in the "centrifugal sample" of FIG. 6A.
- the centrifugal sample exhibited the same or higher wound healing improvement effect as milk. From this, it was suggested that the wound healing effect by milk is mainly an effect by the component contained in the component which is not precipitated by centrifugation. In addition, natural healing of the wound occurs after saline administration, but it was shown that healing was promoted more than natural healing after saline administration by either milk administration or centrifugal sample administration (Fig. 6A). .
- Lactoferrin was purchased from Lion (product name: nyslim essence 62971), and 20 ⁇ g or 60 ⁇ g was administered at one site in the same manner as described above. Specifically, lactoferrin was sufficiently dissolved in purified water after grinding. The lactoferrin concentration was adjusted so that the above amount was included in the injection volume of 20 ⁇ L. The results were obtained by dividing the scores after 7 days and 10 days by the scores of the saline administration group. The results were as shown in FIG. 6B. As shown in FIG. 6B, lactoferrin did not show a significant promoting effect on wound healing. This suggests that components other than lactoferrin have an effect of promoting wound healing.
- lactoferrin In normal raw milk, about 3 mg of lactoferrin (also referred to as “LF”) is contained in 1 L. 20 ⁇ L of raw milk will contain about 0.06 ⁇ g of lactoferrin.
- lactoferrin is weak to heating, and almost disappears from the milk heat-sterilized at high temperature used in the above example (see Noro et al., Electrophoresis 59: 21-24, 2015). Therefore, while the effect of promoting wound healing was observed in the administration of heat-sterilized milk, the effect of promoting wound healing was observed even with centrifugal sample administration, while the effect of promoting wound healing was hardly observed with administration of lactoferrin. There was a consistent result in the conclusion that lactoferrin is not an active ingredient.
- each fatty acid contained in milk was administered to the wound as described above, and the presence or absence of a wound healing promoting effect was examined.
- the results were as shown in FIG. 6C.
- palmitic acid, stearic acid and myristic acid were found to have a high promoting effect on wound healing. From this, it became clear that these fatty acids may contribute to the wound healing promoting effect in milk administration.
- oleic acid, alpha linolenic acid and linoleic acid had a weak promoting effect on wound healing.
- soybean oil (Riken Agrochemicals Co., Ltd., Fukuoka Factory made) known to be rich in palmitic acid, stearic acid, linoleic acid and ⁇ -linolenic acid is administered to the wound area to promote wound healing. I checked the existence. The results were as shown in FIG. 6D. As shown in FIG. 6D, soybean oil showed a high promoting effect on wound healing.
- Example 7 Detection of tissue-resident M2-like macrophages and PPAR ⁇ -positive adipocytes in scalp tissue after milk administration
- tissue regeneration occurs in peripheral tissues (particularly adipose tissue)
- increase of tissue-resident M2-like macrophages Satoh T. et al., Nature, 495: 524-528, 2013
- appearance of CD34 positive cells or increase of PPAR ⁇ positive adipocytes it has been reported that appearance of CD34 positive cells or increase of PPAR ⁇ positive adipocytes occurs (Festa E et al., Cell, 146: 761-71, 2011). Therefore, in this example, it was examined whether an increase in tissue-resident M2-like macrophages or an increase in PPAR ⁇ -positive cells occurred in scalp tissue after administration of 20 ⁇ L of milk.
- Ki67 positive cells occurred as an activation marker of cell proliferation in 12-week-old Wister rat back skin.
- Tissue resident M2-like macrophages were detected as CD68 positive cells or CD163 positive cells.
- human milk was administered to human colostrum in human and rat colostrum to rat.
- Tissue sections of the back skin of a plurality of rat milk administration groups were fixed in a conventional manner and subjected to immunohistological staining.
- the sample was sampled at 5 weeks and 8 weeks after administration at the administration site and at 10 sites away from the administration site (distal) at 5 weeks and 8 weeks, respectively.
- the patient treated half of the head and the other half was untreated.
- Sections of 3 mm diameter punch were fixed, including from the patient's scalp surface to the skull periosteum or on the temporal fascia.
- the primary and secondary antibodies used for staining in this example were as follows.
- the number of Ki67 positive fat cells and the number of macrophages decreased after 8 weeks of administration.
- the number of Ki67 positive adipocytes and the number of CD68 positive macrophages were observed both distally and later than the administration site. This suggests that the effect of milk administration is to transmit tissue.
- FIG. 8A also shows CD31 and CD34 staining.
- CD31 positive cells were observed only on the vascular endothelium.
- CD34 positive cells were observed in the area excluding blood vessels. This suggested that milk administration increased CD31 negative CD34 positive cells at the administration site.
- CD34 positive cells increased per unit area before treatment and at 5 months after single treatment (female, 49 years old).
- An increase in CD34 positive cells was observed on the treatment side in all patients.
- CD34 positive cells are known as fat stem cell markers, and the increase in CD34 positive cells suggests an increase in fat stem cells. Therefore, it became clear from this result that adipose tissue at the milk administration site was modified to generate adipose stem cells.
- Example 9 Tissue change by representative fatty acids contained in milk and PPAR ⁇ activity
- the representative fatty acid contained in milk was administered to the back of 12-week-old Wistar rats as described in Example 1 (2) above. It was administered to multiple locations on the skin, and tissue changes due to administration were observed by immunohistological staining. More specifically, changes in CD68 positive macrophage staining image and PPAR ⁇ positive cell image were observed by administration of 20 ⁇ L of physiological saline / 1 site and administration of 20 ⁇ L of 1% fatty acid / 1 site of fatty acid. Wistar rat samples were sampled at each administration site (4 weeks after administration and 8 weeks after administration). The results were as shown in FIGS. 10A-10G.
- FIG. 10A shows the results in the group to which saline was administered (negative control).
- FIGS. 10B to 10D respectively, with palmitic acid, stearic acid or myristic acid administration, an increase in PPAR ⁇ positive cells and CD68 positive cells was observed at the administration site 4 weeks after administration. In addition, 8 weeks after administration of any of the above-mentioned fatty acids, the increase in PPAR ⁇ positive cells and CD68 positive cells at the administration site was maintained. At the site of saturated fatty acid injection, infiltration of many CD68 positive cells was observed, and fibrosis of normal tissue was observed. Therefore, in FIGS. 10B to 10D, changes in adipose tissue were observed at a site (non-fibrotic site) where the normal tissue closest to the administration site was maintained. As shown in FIGS.
- Palmitic acid, stearic acid or myristic acid is a saturated fatty acid
- oleic acid, ⁇ -linolenic acid or linoleic acid is an unsaturated fatty acid.
- saturated fatty acids have an effect of inducing expression of PPAR ⁇ positive cells (including juvenile adipocytes) at an early stage to tissues, and unsaturated fatty acids are later than that. It had the effect of inducing the expression (juvenile adipocytes) of PPAR ⁇ positive cells.
- saturated fatty acid induces strong tissue inflammation to accumulate macrophages, but at the same time accumulation of macrophages in tissues increases PPAR ⁇ positive cells and suppresses the induced inflammation.
- unsaturated fatty acids are considered to be weakly accumulated in the tissues of macrophages, and the suppression effect of inflammation by PPAR ⁇ was dominant.
- Fatty acids are known to stimulate the secretion of inflammatory cytokines (see Hotamisligil GS, Nature, 542: 177-185, 2017).
- saturated fatty acid induced a strong inflammatory response, but on the other hand, it attenuated inflammation through the increase of PPAR ⁇ positive cells and promoted tissue regeneration.
- PPAR ⁇ -positive cells increased in tissues by saturated fatty acid administration may induce adipose stem cells and juvenile adipocytes and induce M2 macrophages to cause wound healing response and tissue regeneration. .
- Example 10 Relationship between the improvement of scalp and the improvement effect of hair quality and the hair raising effect
- milk administration causes regeneration and modification of the scalp and skin, thereby improving the quality of hair It became clear that the effect was produced.
- the effect of milk administration was evaluated, focusing on the fast-growing hair. Specifically, hair extending 0.9 mm or more in 3 days was extracted from the scalp image, and the total length of extension was calculated. In addition, it is known that in adult hair, it is extended at a rate of about 10 mm in one month (that is, a rate of about 1 mm in 3 days).
- a portion of the scalp of multiple adults (6 patients treated with 1 dose only and 1 patient treated with 4 months once a month) who received 20 ⁇ L of milk per site was shaved for 3 days
- the image of the site shaved later was taken and image analysis was performed.
- one year after administration the same site was shaved again, and after 3 days, an image of the shaved site was taken and analyzed.
- the hair had an average length of 0.4 mm.
- the sum total of the extended length was computed about the hair which has a length of 1.4 mm or more three days after shaving.
- FIGS. 11A and 11B The results of the counting of the patient for which the length of the hair portion was counted by image analysis software are shown in FIGS. 11A and 11B.
- the treatment progress comparison result of patient A 50 years / male, treatment once a month for 4 months, 1 year after treatment start
- patient A patient
- patient A patient
- FIG. 11B The result of the comparative measurement of the non-treatment side and the treatment side of B (47 years old / female, treatment of only one dose, 1 year after treatment)
- FIG. 11A measurement results of patient A before treatment and one year after the start of treatment are compared.
- FIG. 10A the sum of the lengths of hair having a length of 1.4 mm or more (1.4 mm or more) after 3 days of shaving and all hair including 0.9 mm or more and less than 1.4 mm of hair after 3 days of shaving The total (total) of the hair length of each is shown.
- patient A the sum of lengths for hair having a length of 1.4 mm or more after 3 days was 311.9 before the treatment, but was 337.9 at 1 year after the initiation of the treatment.
- the total of the total hair length three days after shaving was 405.7 before the treatment, showing 419.2 at one year after the initiation of the treatment.
- FIG. 11B the measurement results of the untreated side and the treated side of patient A and B at 1 year of treatment start are compared.
- FIG. 10B all of the total length of hair having a length of 1.4 mm or more (1.4 mm or more) after 3 days of shaving and all hair including 0.9 mm or more and less than 1.4 mm after 3 days of shaving The total (total) of the hair length of each is shown.
- patient A the total length of hair having a length of 1.4 mm or more after shaving for 3 days was 337.9 on the treatment side, as it was 199.4 on the untreated side.
- the total length of hair having a length of 1.4 mm or more was 114.3 on the non-treated side, whereas it was 300.7 on the treated side.
- the total of the hair length of 0.9 mm or more three days after shaving was 357.8 on the non-treatment side, and 419.2 on the treatment side.
- the total of the total hair length three days after shaving was 261.5 on the non-treated side and 378.1 on the treated side.
- Saline was injected into one half of the head as a negative control.
- the change in hair due to saline injection (the number of hairs of 1.4 mm or more) was observed on one side of the head monthly for 6 months, but the change rate before treatment and 6 months after treatment was -0.84% to + 1.24%, The average was 1.03%.
- milk (20 ⁇ L / one-site administration) administration shows scalp modification and thus an improvement in the rate of hair extension.
- Example A11 Bone formation promoting action
- palmitic acid administration on bone formation was confirmed.
- 3D-CT images of the skull were acquired using the following system.
- Device name Comscan ScanXmate-E090 Shooting conditions X-ray tube voltage 88 kV X-ray tube current 89 ⁇ A Resolution 30.649 ⁇ m / pixel
- Three-dimensional construction was performed using VGSTUDIO MAX (VOLUME GRAPHICS).
- the hematoxylin-eosin stained section was as shown in FIG. As shown in FIG. 13, when a thin film coated with palmitic acid is placed, many bones stained with red (see broken line) are formed, whereas when a thin film is placed, Less red stained bone (see dashed line) was formed.
- the palmitic acid coating film When comparing the respective stained area of bone formation portion in tissue sections (the number of pixels and mm 2), the palmitic acid coating film, whereas was 12,132 pixels (0.984mm 2), in the control, 1 , 025 pixels (0.083 mm 2 ). The bone formed was significantly thicker than the control film with palmitic acid coated film.
- palmitic acid has a bone formation promoting action.
- Bone tissue pieces (3 mm in diameter) were collected at the time of sacrifice. After rearing for 8 weeks, tissues were collected and fixed by perfusion. The bone tissue is collected using tref bars (3 mm in diameter) when bone formation is sufficient, and in the case of insufficient specimens (rats), existing bones in the open bone edge area with osteotomy (Luwell forceps) And regenerated bones were collected.
- RNA Stabilization Solution (Thermo Fisher Scientific, Lithuania), frozen with liquid nitrogen and stored at -80 ° C.
- 25 mg of tissue fragments are enclosed in a sample tube with 5 stainless steel beads (3 mm in diameter), and RNeasy Mini Kit (QIAGEN GmbH, Hilden, Germany) and Tissue sections were homogenized using TissueLyser II (QIAGEN GmbH, Hilden, Germany), and then performed using a spin column according to the protocol attached to the kit.
- Ribosomal protein lateral stalk subunit P0 (RplP0), Rattus norvegicus: mRNA, 1,093 bp, NM_0222402.2, GI: 310616731 6-FAM / CCT GTC TTC / ZEN / CCT GGG CAT CAC G / IABkFQ CAA TCC CTG ACG CAC CG TGT CTG CTC CCA CAA TGA AG 2.
- CXC motif chemokine ligand 12 (Cxcl12), transcript variant 1, Rattus norvegicus: mRNA 1,880 bp NM_022177.3 GI: 7649650 56-FAM / TCA ACA CTC / ZEN / CAA ACT GTG CCC TTC A / 3IABkFQ GAG CCA ACG TCA AAC ATC TG GGC TTT GTC CAG GTA CTC TTG 3.) CXC motif chemokine receptor 4 (Cxcr4), Rat
- Ribosomal protein lateral stalk subunit P0 Ribosomal protein lateral stalk subunit P0 (RplP0), which is a Housekeeping Genes
- RplP0 Ribosomal protein lateral stalk subunit P0
- target gene mRNA average of duplicate test, 12 weeks old and 18 weeks old each
- the difference between the expression levels of RplPO and mRNA of the target gene in the case of age, no palmitic acid administration), the difference between them is converted to the gene expression ratio (magnification), the (See FIG. 14).
- Example A12 Changes in gene expression in tissues after subcutaneous administration Next, changes in gene expression in tissues were confirmed. A total of 6 areas were set up on the back by setting 3 areas from head to tail on the back of a 12-week-old Wister rat (male) and further dividing each area into 2 areas on the left and right of the spine . Two injections of 20 ⁇ L / one milk or palmitic acid were injected near the center of each area. The distance between the two points was 1 cm. The collected tissue pieces were frozen in liquid nitrogen and stored at -80.degree.
- RNA from stored tissue fragments 25 mg are enclosed in a sample tube with 5 stainless steel beads (3 mm in diameter), and RNeasy Mini Kit (QIAGEN GmbH, Hilden, Germany) and Tissue sections were homogenized using TissueLyser II (QIAGEN GmbH, Hilden, Germany), and then performed using a spin column according to the protocol attached to the kit.
- Cxcl12, Cxcr4 and Itga4 are markers found in bone marrow cells, and their expression in tissues indicates that bone marrow-derived cells have been recruited into tissues. Since Cxcl12 is expressed in tissues, it also indicates that the system for receiving these bone marrow-derived cells has been simultaneously established. Furthermore, as shown in FIG. 15, an increase in CD34 was also observed simultaneously. Adipocytes may be induced in the presence of bone marrow progenitor cells and macrophages.
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Abstract
Description
(1)(i)頭皮または皮膚を改質することに用いるための局所投与用医薬組成物、(ii)創傷を治療することに用いるための局所投与用医薬組成物、または、(iii) 増毛を促進させることに用いるための局所投与用医薬組成物または毛髪を改質することに用いるための局所投与用医薬組成物であって、治療上有効量の飽和脂肪酸またはその医薬上許容可能な塩を含む、医薬組成物。
(2)頭皮または皮膚を改質することに用いるための、上記(1)に記載の医薬組成物。
(3)創傷を治療することに用いるための、上記(1)に記載の医薬組成物。
(4)増毛を促進させることまたは毛髪を改質することに用いるための、上記(1)に記載の医薬組成物。
(5)骨形成を促進させることに用いるための、上記(1)に記載の医薬組成物。
(6)飽和脂肪酸が生体適合性膜に塗布された形態である、上記(6)に記載の医薬組成物。
(7)前記飽和脂肪酸が、パルミチン酸、ステアリン酸、およびミリスチン酸からなる群から選択される1以上の脂肪酸である、上記(1)~(6)のいずれかに記載の医薬組成物。
(8)不飽和脂肪酸をさらに含む、上記(1)~(7)のいずれかに記載の医薬組成物。
(9)治療上有効量の飽和脂肪酸またはその医薬上許容可能な塩を含む、大豆油若しくはミルクまたはこれらの抽出物若しくは加工物を含むものである、上記(1)~(6)のいずれかに記載の医薬組成物。
(10)ミルクが、滅菌されている、上記(9)に記載の医薬組成物。
(11)ミルクが、高温滅菌されている、上記(10)に記載の医薬組成物。
(A)治療上有効量の脂肪酸(特に飽和脂肪酸)またはその医薬上許容可能な塩を含む、頭皮または皮膚を改質することに用いるための局所投与用医薬組成物;
(B)治療上有効量の脂肪酸(特に飽和脂肪酸)またはその医薬上許容可能な塩を含む、創傷を治療することに用いるための局所投与用医薬組成物;および
(C)治療上有効量の脂肪酸(特に飽和脂肪酸)またはその医薬上許容可能な塩を含む、増毛を促進させることに用いるための局所投与用医薬組成物、または毛髪を改質することに用いるための局所投与用医薬組成物;並びに
(D)治療上有効量の脂肪酸(特に飽和脂肪酸)またはその医薬上許容可能な塩を含む、骨形成を促進させることに用いるための医薬組成物
が提供される(以下、上記(A)~(D)に記載の医薬組成物を「本発明の医薬組成物」と総称することがある)。
本発明のある態様では、本発明の局所投与用医薬組成物に含まれる飽和脂肪酸は、ステアリン酸である。
本発明のある態様では、本発明の局所投与用医薬組成物に含まれる飽和脂肪酸は、ミリスチン酸である。
本発明のある態様では、本発明の局所投与用医薬組成物に含まれる脂肪酸は、オレイン酸である。
本発明の局所投与用医薬組成物に含まれる脂肪酸は、αリノレン酸である。
本発明の局所投与用医薬組成物に含まれる脂肪酸は、リノール酸である。
本発明のある態様では、ミルク、ミルク抽出物若しくはミルク加工物またはこれらの混合物は、脂肪酸含量の増強とラクトフェリン含量の低減がなされていてもよい。
本発明の骨の形成を促進させることに用いるための医薬組成物は、生体適合性膜上に塗布された状態で提供されていてもよい。従って、本発明では、生体適合性膜上に塗布された治療上有効量の飽和脂肪酸またはその医薬上許容可能な塩を含む、医薬が提供され得る。生体適合性膜としては、例えば、リン酸カルシウムの表面を有する薄膜(例えば、リン酸カルシウムの薄膜)、ポリ乳酸の表面を有する薄膜(例えば、ポリ乳酸の薄膜)、ポリグリコール酸の表面を有する薄膜(例えば、ポリグリコール酸の薄膜)、乳酸とポリグリコール酸の共重合体またはブロック共重合体の表面を有する薄膜(例えば、、乳酸とポリグリコール酸の共重合体またはブロック共重合体の薄膜)、およびヒドロキシアパタイトの表面を有する薄膜(例えば、ヒドロキシアパタイトの薄膜)が挙げられる。生体適合性膜上への有効成分の塗布は、例えば、有効成分を溶解した溶液を生体適合性膜上に滴下し、これを乾燥させることによって行うことができる。例えば、生体適合性膜に10~50μg程度の医薬有効成分を塗布して用いることができる。
従って、頭皮のうち、比較的良好な部位に対して投与し、伝播の効果により不良な部分の改善を試みてもよい。また、比較的不良な部位において改善が得られると本発明の医薬組成物に対する応答性が高まる。従って、頭皮のうち、比較的良好な部位に対して投与し、伝播の効果により不良な部分の改善が進んできたら、その後で当該不良であった部分に本発明の医薬組成物を投与してもよい。
本発明の医薬組成物を投与する毎に、投与部位における、組織刺激、マクロファージの活性や幼若脂肪細胞の活性があがり修復機能が上昇すると考えられる。患者の症状(状況)と改善度合いを診て投与することが望まれる。
(a)頭皮または皮膚をその必要のある対象(またはその必要のある部位)において改質する方法であって、治療上有効量の飽和脂肪酸またはその医薬上許容可能な塩を頭皮または皮膚に局所投与することを含む、方法;
(b)創傷をその必要のある対象において治療する方法であって、治療上有効量の飽和脂肪酸またはその医薬上許容可能な塩を頭皮または皮膚に局所投与することを含む、方法;
(c)増毛をその必要のある対象において促進させる方法、または毛髪をその必要のある対象において改質する方法であって、治療上有効量の飽和脂肪酸またはその医薬上許容可能な塩を頭皮または皮膚に局所投与することを含む、方法;並びに
(d)骨形成をその必要のある対象において促進させる方法であって、治療上有効量の脂肪酸(特に飽和脂肪酸)またはその医薬上許容可能な塩を骨形成の必要な部位(例えば、骨の損傷部位)に投与することを含む、方法{ここで、治療上有効量の脂肪酸(特に飽和脂肪酸)またはその医薬上許容可能な塩は生体適合性膜に塗布された状態で投与されてもよい}
が提供される。
(α)頭皮または皮膚を改質することに用いるための局所投与用医薬製剤の製造における、治療上有効量の飽和脂肪酸またはその医薬上許容可能な塩の使用;
(β)創傷を治療することに用いるための局所投与用医薬製剤の製造における、治療上有効量の飽和脂肪酸またはその医薬上許容可能な塩の使用;
(γ)増毛を促進することに用いるための局所投与用医薬製剤または毛髪を改質することに用いるための局所投与用医薬製剤の製造における、治療上有効量の飽和脂肪酸またはその医薬上許容可能な塩の使用;および
(δ)骨形成を促進することに用いるための医薬組成物または医薬製剤の製造における、治療上有効量の飽和脂肪酸またはその医薬上許容可能な塩の使用{ここで、医薬製剤は、治療上有効量の脂肪酸(特に飽和脂肪酸)またはその医薬上許容可能な塩は生体適合性膜に塗布された状態で提供され得る}
が提供される。
(1)ミルクは、以下のように調製した。
ヒトに投与するためのミルクとして、女性34才と40才の***から搾乳器を用いて、いわゆる初乳(出産後3週間以内に採取される乳)を得た。
ラットに投与するためのミルクとして、牛乳としては、手搾りで得たウシの初乳または市販の牛乳を用いた。
(2)ミルクは以下のように投与した。
ミルクは、1箇所当り20μLの量でヒトの頭皮の右半分若しくは左半分またはラットの背部皮膚に注射した。ヒトの場合は患者1名につきその患者の頭半分に対して合計2mLの初乳(すなわち、1名につき100箇所)を注射した。ラットの場合は12週齢ウイスターラット(雄)背部に頭部から尾部に対して3つの領域を設定し、さらに各領域を背骨の左右で2つの領域に分けることで、背部に計6個の領域を設定した。各領域の中央付近に2箇所ずつ20μL/1箇所のミルクを注射した。なお、前記2箇所間の距離は1cmとした。
本実施例では、髪のキューティクルについて処置前後で改善がみられたかを調べた。
5点:キューティクルが整っており、荒れが見当たらない
4点:平均よりもキューティクルが整っているが、多少の荒れが認められる
3点:キューティクルの整い方が平均的である
2点:平均よりもキューティクルが荒れており、多少の剥がれが認められる
1点:キューティクルが全体的に荒れており、全体的に剥がれが認められる
本実施例では、髪の色(白髪)に着目し、処置前後でその改善効果を調べた。
具体的には、患者の両側の目尻を頭側に延長し、両耳と頭頂を結ぶ線と交差する2点に墨汁で刺青をし、マーキングを中心に2cmの範囲を剃毛した。剃毛3日後に頭皮1箇所に対して実施例1に記載の20μLのヒトの初乳を頭部半分に対して2mL、100箇所に注射し、1月後に観察した。トリコグラムは、毎回マーキングを中心に撮影(Canon Power Shot A520, Tokyo, Japan)し、撮影範囲に含まれる入れ墨を中心とした直径11mmの円(面積95mm2)内の毛髪を、写真撮影し、目視で計量した。
その結果、上記剃毛部において、治療前に白髪のある3人の患者のうち単回注射後治療後6ヶ月で3人全ての白髪が減少し、上記撮影範囲当り平均7.7本/95mm2の白髪が減少した(n=3)。また、治療側の治療前後では白髪本数が92.9%に減少した。未治療側の治療開始前を100としたときの白髪減少率は、治療側の治療開始前を100とした時と比べて28.2%も低く治療側で大きく白髪が減少した(n=3)。
毛髪の改質が上記により示されたが、頭皮のどのような改質に基づくものであるのかを検証した。
上記実施例では、キューティクルの改善や白髪の減少の効果が確認された。本実施例ではこれらの効果が頭皮の改善によるものかどうかを調べるため、頭皮のコラーゲン量を調べた。
まず、I型コラーゲンおよびIII型コラーゲンの増減を観察した。具体的には、頭皮の組織(表皮から頭蓋骨に向かう面)の切片を作製し、Picrosirius Red Stain Kit試薬(Polysciences, Inc., Cat#: 24901-250)を用いて製造者による説明書に従ってI型コラーゲンおよびIII型コラーゲンを染色した。I型コラーゲンは、黄色系に染色され、III型コラーゲンは緑色系に染色された。この系では、III型以外のコラーゲンは、赤黄色系に染色された。
III型コラーゲンの減少とI型コラーゲンの増加は、組織修復、特に創傷治癒において生じる現象である。本実施例の結果から、ミルクの投与は、頭皮および皮膚の組織修復を誘発させていることが示唆される。
そこで、脂肪細胞の若返りを観察した。
脂肪細胞は成長すると共に細胞質のほとんどが脂肪滴となって細胞質に脂肪滴を蓄え、肥大化する。従って、大きな細胞は成熟した古い細胞を意味し、小さな細胞は幼若な新しい細胞(すなわち、幼弱な脂肪細胞)であるとされている。本実施例では、ミルク投与により小さく幼若な細胞が増加するかを確認した。より具体的には、ミルク20μLを投与した人頭皮組織切片を観察して脂肪層における脂肪細胞の大きさの変化を確認した。脂肪細胞の画像を円に近似し、その直径に基づいてS、M、またはLに分類した。その直径が51μm以下の細胞を「S」とし、51μmを超え63μm以下の細胞を「M」とし、63μmを超える細胞を「L」として集計した。患者は、単回投与後6ヶ月経過した患者(以下、「患者1」という)と、月1回の投与を4回行い、治療開始から15ヶ月経過した患者(以下、「患者2」という)において行った。結果は、図5に示される通りであった。
そこで、本実施例では、ミルクの投与が皮膚に対する創傷の治癒を早める効果があるか否かを確認した。
ミルクの投与:創部辺縁から4mm離れた場所に上下左右4箇所にミルク20μLを皮下注入した。ミルクとしては、実施例1記載の加熱殺菌(130度、2秒および65度30分)されている市販の牛乳を用いた。
脂肪酸の投与:ミルクに含まれる脂肪酸として、パルミチン酸、ステアリン酸、ミリスチン酸、リノレン酸、αリノレン酸、およびオレイン酸をそれぞれ含む滅菌性精製水(投与液)を飽和脂肪酸は加熱して、不飽和脂肪酸は室温の状態で投与した。投与は、創傷辺縁から4mm上下左右4箇所に投与液20μL(1mg脂肪酸含有)を皮下投与した。
5点:治癒
4点:創傷部位の面積の縮小率が70%以上
3点:創傷部位の面積の縮小率が50%以上70%未満
2点:創傷部位の面積の縮小率が20%以上50%未満
1点:創傷部位の面積の縮小率が20%未満
末梢組織(特に脂肪組織)において組織再生が生じる際には組織常在型M2様マクロファージの増加(Satoh T. et al., Nature, 495: 524-528, 2013)、CD34陽性細胞の出現、またはPPARγ陽性脂肪細胞の増加が生じることが報告されている(Festa E et al., Cell, 146: 761-71, 2011)。そこで、本実施例では、ミルク20μL投与後の頭皮組織において、組織常在型M2様マクロファージの増加、またはPPARγ陽性細胞の増加が生じているかを調べた。また、12週齢ウイスターラット背部皮膚における細胞増殖の活性化マーカーとしてKi67陽性細胞の増加が生じているかを確認した。組織常在型M2様マクロファージは、CD68陽性細胞またはCD163陽性細胞として検出した。本実施例ではミルクとしてはヒトにはヒトの初乳、ラットには牛の初乳を投与した。
このことから、ミルクの投与により、Ki67陽性脂肪細胞が増加すること、すなわち、脂肪細胞が活性化して***を活発化させること、および、組織内のマクロファージが増加することが明らかになった。顕微鏡像からは、Ki67陽性脂肪細胞は主に脂肪細胞と脂肪幹細胞であると考えられた。しかし、投与8週後にはKi67陽性脂肪細胞数とマクロファージ数は減少した。一方で、驚くべきことに遠位においても投与部位よりも遅れてKi67陽性脂肪細胞数およびCD68陽性マクロファージ数の増加が観察された。このことは、ミルク投与による効果は、組織を伝播することを示唆する。
このように、ミルク投与部位では、組織常在型M2様マクロファージが増加し、PPARγ陽性細胞である幼若な脂肪細胞の関与が示された。
なお、図8Aおよび8Bでは、記号「H」は毛包を表し、記号「V」は血管を表し、記号「S」は皮脂腺を表す。
比較試験として、ミルクに代えてラクトフェリン投与し、CD68陽性細胞およびPPARγ陽性細胞の増加が生じるか否かを確認した。ラクトフェリンは、ナイスリムエッセンス(ライオン製、62971)3錠、有効ラクトフェリン300mg(人の1日摂取量)を12週齢のウイスターラットに経口投与した(n=3)。投与は1日1回行い、経口ゾンデを用いて胃内に注入(強制摂取)させ、投与8週後に常法にて背部皮膚のパラフィン包埋切片を作製して免疫組織学的染色に供した。結果は、図9に示される通りであった。
次に、ミルクに含まれる代表的な脂肪酸を投与箇所は上記実施例1(2)のとおり12週齢のウイスターラットの背部皮膚の複数箇所に投与して、投与による組織変化を免疫組織学的染色により観察した。より具体的には、生理食塩水20μL/1箇所の投与、脂肪酸1mgを含有する投与液20μL/1箇所の投与による、CD68陽性マクロファージ染色像、およびPPARγ陽性細胞像の変化を観察した。ウイスターラットのサンプルは、投与部位(投与4週後および投与8週後)をそれぞれにサンプリングした。結果は、図10A~10Gに示される通りであった。図10Aは、生理食塩水を投与した群(陰性対照)における結果を示す。
なお、飽和脂肪酸注入部位では多数のCD68陽性細胞の浸潤が認められ、正常組織の線維化が認められた。従って、図10B~10Dでは、投与部位に最も近い正常組織が維持されている箇所(非線維化箇所)の脂肪組織の変化を観察した。
図10E~10Gにそれぞれ示されるように、オレイン酸、α-リノレン酸またはリノール酸投与では、投与4週後には対照と比較してPPARγ陽性細胞やCD68陽性細胞の顕著な増加は認められなかったが、投与8週後にPPARγ陽性細胞の増加が認められた。一方、オレイン酸、α-リノレン酸またはリノール酸投与では、CD68陽性細胞の大きな増加は認められなかった(全体的には弱い効果が認められた)。CD68陽性細胞は、PPARγにより組織常在型M2様マクロファージに分化し、組織の恒常性維持を促進する。パルミチン酸、ステアリン酸またはミリスチン酸などの飽和脂肪酸投与では、CD68陽性細胞の増加とPPARγ陽性細胞の増加が生じたことから、脂肪酸が投与された組織内では、組織常在型M2様マクロファージが増加したと考えられる。一方で、不飽和脂肪酸では、PPARγ陽性細胞は増加したが、CD68陽性細胞の大きな増加は認められず、組織常在型M2様マクロファージの誘導の効果は限られていると考えられた。また、この結果は、上記実施例6において、飽和脂肪酸は高い創傷治癒促進効果を奏したのに対して、不飽和脂肪酸の創傷治癒促進効果は限定的であったことと一致する結果であった。マクロファージのPPARγ活性が脂肪細胞の機能に対して大きく関与していることが報告されている(Odegaard J I, et al., Nature, 447:1116-1121, 2007参照)ことからも、飽和脂肪酸投与による脂肪組織内でのCD68陽性細胞の増加とPPARγ陽性細胞の増加は、飽和脂肪酸投与により皮膚の改質がおきているとの考察を支持する結果であった。なお、脂肪滴を細胞内に有するPPARγ陽性細胞の増加から、PPARγ陽性脂肪細胞の増加が確認され、この結果から、飽和脂肪酸投与によるPPARγ陽性の脂肪幹細胞の活性化が示唆された。
上記実施例1~9によれば、ミルク投与により頭皮や皮膚の再生と改質が生じ、これにより髪質が向上する効果を生じたことが明らかとなった。
本実施例では、上記実施例の結果から、伸びる速度の速い髪の毛に着目し、ミルク投与の効果を評価した。具体的には、3日で0.9mm以上伸びる毛髪を頭皮画像から抽出し、伸びた長さの総和を算出した。なお、成人の毛髪では1ヶ月で約10mmの割合(すなわち、3日で約1mmの割合)で伸びることが知られている。
この目的のために、ミルク20μL/1箇所を投与した複数の成人(1回投与のみの治療が6名、月1回4ヶ月治療が1名)の頭皮の一部を剃毛し、3日後に剃毛した部位の画像を撮影し、画像解析した。また、投与1年後に再び同一箇所を剃毛し、3日後に剃毛した部位の画像を撮影し、画像解析した。剃毛後、毛髪は平均的に0.4mmの長さを有していた。以下では、剃毛3日後に1.4mm以上の長さを有する毛髪について、伸びた長さの総和を算出した。
同様に、患者Aでは、剃毛3日後の0.9mm以上の毛髪の長さの総和が、未治療側で357.8であったのが、治療側では419.2を示した。患者Bでは、剃毛3日後の全毛髪の長さの総和が、未治療側で261.5であったのが、治療側では378.1を示した。
この結果から、ミルク(20μL/1箇所投与)投与により、伸長速度が速く、太い毛髪が増加することが明らかとなった。
ミルク投与では、毛髪のハリやコシの改善が観察された(毛髪のハリやコシが向上し、毛髪のボリューム増が観察された)が、このことと太い毛髪が増加することとは一貫する結果であった。
このように、ミルクを投与した対象では増毛が見られた上に、ミルク投与による頭皮の改質は、毛髪の伸長速度の改善と、太くコシとハリのある良質な毛髪の増加に繋がっていた。
本実施例では、骨形成に対するパルミチン酸投与の効果を確認した。
骨形成の観察:ヒドロキシアパタイト薄膜を骨欠損部の大きさに合わせて作成したものを骨欠損部に載せた。この時にシートにパルミチン酸0.02mg(20μg)を塗布した。具体的には、1mLに1mgを溶かし込んだものを0.02mL(20μL)薄膜に垂らし乾燥させて骨欠損部に載せた。
装置名 コムスキャン社製 ScanXmate-E090
撮影条件 X線管電圧 88 kV
X線管電流 89 μA
解像度 30.649 μm/pixel
3次元構築は、VGSTUDIO MAX (VOLUME GRAPHICS社)を用いて行った。
屠殺時に骨組織片(直径3 mm)を採取した。
8週飼育後、組織採取、灌流固定した。骨組織採取は骨形成が十分な時はトレフィンバー(直径3 mm)を用いて採取し、不十分な検体(ラット)に対しては骨鉗子(リュウエル鉗子)にて開放骨縁部分の既存骨と再生骨を採取した。
1.) Ribosomal protein lateral stalk subunit P0 (RplP0), Rattus norvegicus: mRNA, 1,093 bp, NM_022402.2, GI: 310616731
6-FAM/CCT GTC TTC /ZEN/CCT GGG CAT CAC G/IABkFQ
CAA TCC CTG ACG CAC CG
TGT CTG CTC CCA CAA TGA AG
2.) C-X-C motif chemokine ligand 12 (Cxcl12), transcript variant 1, Rattus norvegicus: mRNA 1,880 bp NM_022177.3 GI: 7649650
56-FAM/TCA ACA CTC /ZEN/CAA ACT GTG CCC TTC A/3IABkFQ
GAG CCA ACG TCA AAC ATC TG
GGC TTT GTC CAG GTA CTC TTG
3.) C-X-C motif chemokine receptor 4 (Cxcr4), Rattus norvegicus: mRNA 1,726 bp NM_022205.3 GI: 82617587
56-FAM/CAA TGC TCG /ZEN/CTC TCC AGC CCT /3IABkFQ
CGT TTG GTG CTC CGG TAG
TCT CCA GAC CCT ACT TCT TCG
4.) Integrin subunit alpha 4 (Itga4), Rattus norvegicus: mRNA 3,736 bp NM_001107737.1 GI: 157819948
56-FAM/CGA AGG ACG /ZEN/TCA AAT CAG CCA GTC A/3IABkFQ
GCA TCT CCT CTA CAT ACT CAC AG
CAC CAA CCG CTA CAT CAA CA
5.) CD34, Rattus norvegicus: CD34 molecule (Cd34), mRNA 1,161 bp NM_001107202.2 GI: 169790781
56-FAM/TCC CTG GAA /ZEN/GTA CCA GCC ACT ACT /3IABkFQ
GGA GTA TTT CCA CCA GTT CCT AC
GAT GGC TGG TGT GGT CTT ATT
6.) Bone morphogenetic protein-4 (BMP4), Rattus norvegicus: mRNA 1,559 bp NM_012827.2 GI: 148747215
56-FAM/CCT TGT TTT /ZEN/CTG TCA AGA CAC CAT GAT TCC /3IABkFQ
ATA AAA CGA CCA TCA GCA TTC G
GCC TTT CCA GCA AGT TTG TTC
7.) Bone morphogenetic protein-7 (BMP7), Rattus norvegicus: mRNA 2,448 bp NM_001191856.2 GI: 683523995
56-FAM/TGC GAT GAT /ZEN/CCA GTC CTG CCA G/3IABkFQ
CGT TCA TGT AGG AGT TCA GAG G
CTG TAT GTT AGC TTC CGA GAC C
次に、組織における遺伝子発現の変化を確認した。12週齢ウイスターラット(雄)背部に頭部から尾部に対して3つの領域を設定し、さらに各領域を背骨の左右で2つの領域に分けることで、背部に計6個の領域を設定した。各領域の中央付近に2箇所ずつ20μL/1箇所のミルクまたはパルミチン酸を注射した。なお、前記2箇所間の距離は1cmとした。
採取した組織片を液体窒素で凍結し、-80℃で保存した。保存された組織片からのtotal RNAの精製と抽出は、25 mgの組織片を5個のステンレスビーズ(直径3 mm)と共にサンプルチューブに封入し、RNeasy Mini Kit(QIAGEN GmbH, Hilden,Germany)およびTissueLyser II(QIAGEN GmbH, Hilden, Germany)を用いて組織片をホモゲナイズした後に、キットに付属のプロトコル通りにスピンカラムを利用して行った。定量PCRによる遺伝子発現解析は、Integrated DNA Technologies, Inc(Skokie, IL, USA)に遺伝子特異的プライマーおよびプローブの設計と合成を委託し、PrimeTime Gene Expression Master Mix試薬(Integrated DNA Technologies, Inc, Skokie, IL, USA)とRotor-Gene Q PCR装置(QIAGEN GmbH, Hilden, Germany)を利用して、1検体1遺伝子あたり2回のPCR解析を実施し、対象遺伝子の発現量を解析した。Housekeeping GenesであるRibosomal protein lateral stalk subunit P0 (RplP0)と目的遺伝子のmRNAの発現量(Ct値)の差 (各検体2回検査の3体平均)を、対照(パルミチン酸またはミルクの投与無し)の場合のRplP0と目的遺伝子のmRNAの発現量の差と比較し、それらの差を遺伝子発現比(倍率)に変換し、その倍率をさらにlog2変換してグラフ上に示した。
野呂未来他, 電気泳動, 59: 21-24, 2015
Satoh T. et al., Nature: 495, 524-528, 2013
Festa E et al., Cell, 146: 761-71, 2011
M. Yag, et al., Journal of Oral Science, 50: 419-425, 2008
Odegaard J I, et al., Nature, 447: 1116-1121, 2007
Hotamisligil G. S., Nature, 542: 177-185, 2017
Croadell A. et al., PPAR Research, ID 549691, 2015
Claims (11)
- (i)頭皮または皮膚を改質することに用いるための局所投与用医薬組成物、(ii)創傷を治療することに用いるための局所投与用医薬組成物、(iii) 増毛を促進させることに用いるための局所投与用医薬組成物または毛髪を改質することに用いるための局所投与用医薬組成物、または(iv)骨形成を促進させることに用いるための医薬組成物であって、治療上有効量の飽和脂肪酸またはその医薬上許容可能な塩を含む、医薬組成物。
- 頭皮または皮膚を改質することに用いるための、請求項1に記載の医薬組成物。
- 創傷を治療することに用いるための、請求項1に記載の医薬組成物。
- 増毛を促進させることまたは毛髪を改質することに用いるための、請求項1に記載の医薬組成物。
- 骨形成を促進させることに用いるための、請求項1に記載の医薬組成物。
- 飽和脂肪酸が生体適合性膜に塗布された形態である、請求項5に記載の医薬組成物。
- 前記飽和脂肪酸が、パルミチン酸、ステアリン酸、およびミリスチン酸からなる群から選択される1以上の脂肪酸である、請求項1~6のいずれか一項に記載の医薬組成物。
- 不飽和脂肪酸をさらに含む、請求項1~7に記載のいずれか一項に記載の医薬組成物。
- 治療上有効量の飽和脂肪酸またはその医薬上許容可能な塩を含む、大豆油若しくはミルクまたはこれらの抽出物若しくは加工物を含むものである、請求項1~6のいずれか一項に記載の医薬組成物。
- ミルクが、滅菌されている、請求項9に記載の医薬組成物。
- ミルクが、高温滅菌されている、請求項10に記載の医薬組成物。
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US20200246409A1 (en) | 2020-08-06 |
BR112020003022A2 (pt) | 2020-08-25 |
TWI787423B (zh) | 2022-12-21 |
JP6628946B2 (ja) | 2020-01-15 |
JP2020033370A (ja) | 2020-03-05 |
KR20200102978A (ko) | 2020-09-01 |
SG11202000906YA (en) | 2020-03-30 |
US20220409688A1 (en) | 2022-12-29 |
JP6731129B1 (ja) | 2020-07-29 |
MX2022013816A (es) | 2022-11-30 |
AU2018396512A1 (en) | 2020-02-13 |
EP3733173A1 (en) | 2020-11-04 |
AU2018396512B2 (en) | 2024-06-13 |
JP2020128400A (ja) | 2020-08-27 |
US11413321B2 (en) | 2022-08-16 |
EP3733173A4 (en) | 2021-10-27 |
JPWO2019131712A1 (ja) | 2019-12-26 |
JP6732088B2 (ja) | 2020-07-29 |
TW201929848A (zh) | 2019-08-01 |
JP2020128399A (ja) | 2020-08-27 |
MX2020001764A (es) | 2020-07-29 |
CA3070854A1 (en) | 2019-07-04 |
JP6765024B2 (ja) | 2020-10-07 |
CN111050763A (zh) | 2020-04-21 |
TW202308606A (zh) | 2023-03-01 |
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