CN116874638A - Diamino pyrimidine oxide and cationic zinc hyaluronate coupling derivative and preparation method and application thereof - Google Patents
Diamino pyrimidine oxide and cationic zinc hyaluronate coupling derivative and preparation method and application thereof Download PDFInfo
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- CN116874638A CN116874638A CN202310661064.5A CN202310661064A CN116874638A CN 116874638 A CN116874638 A CN 116874638A CN 202310661064 A CN202310661064 A CN 202310661064A CN 116874638 A CN116874638 A CN 116874638A
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- VJVOFLWZDWLHNR-MRCUWXFGSA-N icosan-9-yl (z)-docos-13-enoate Chemical compound CCCCCCCCCCCC(CCCCCCCC)OC(=O)CCCCCCCCCCC\C=C/CCCCCCCC VJVOFLWZDWLHNR-MRCUWXFGSA-N 0.000 title abstract description 30
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Classifications
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- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
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- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/58—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing atoms other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur or phosphorus
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- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
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- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
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Abstract
The application provides a diaminopyrimidine oxide and low-molecular cationic zinc hyaluronate coupling derivative, and a preparation method and application thereof. The structure of the coupling derivative is shown in a formula I:wherein R is 1 、R 2 、R 3 Each independently selected from the group consisting of hydroxypropyl trimethylammonium chloride and hydrogen, and R 1 、R 2 、R 3 Are not hydrogen at the same time; r is R 4 Is pyrrolidinyl or hydrogen; m is greater than or equal to 1, and n is greater than or equal to 0. The conjugate has good water solubility and slow release transdermal effect, has excellent anti-hair loss and hair growth functions, and solves the defects of poor solubility and poor permeability of diaminopyrimidine oxide hair growth agents in the prior art, and strong irritation caused by high-dose and high-frequency use.
Description
Technical Field
The application relates to the fields of medicines and cosmetics, in particular to a diaminopyrimidine oxide and cationic zinc hyaluronate coupling derivative, and a preparation method and application thereof.
Background
Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.
In recent years, the occurrence ratio of hair loss has been on the rise, and the trend of younger age has become more and more remarkable. Alopecia can occur at any age, and currently available effective components for alopecia are extremely limited, and mainly comprise traditional Chinese medicine components and hair-dissolving agents for students. At present, although a plurality of traditional Chinese medicine components have the effect of preventing alopecia, such as angelica sinensis, ginseng, ginkgo leaves, eucommia ulmoides and the like, the traditional Chinese medicine hair-growing product produced by taking plant extracts as raw materials is difficult to ensure stable curative effect due to the fact that the stability of the extract components is poor, the effective substances and the content are uncertain, and the action mechanism is ambiguous. The common chemical germinal agents for treating alopecia are minoxidil, finasteride and the like, but the side effects of the substances are obvious, the minoxidil can cause scalp dryness, dandruff, scalp erythema, inflammation, irritation and the like, and can influence blood pressure, and the finasteride has a male hormone activity inhibition effect.
The molecular structures of diaminopyrimidine oxides, such as diaminopyrimidine oxide and pyrrolidinyl diaminopyrimidine oxide, are similar to minoxidil, but they are not pharmaceutical products, but raw materials for cosmetic approval. Wherein the diaminopyrimidine oxide inhibits lysine hydroxylase activity, thereby slowing down follicular sclerosis and contraction, and inhibits 5α -reductase activity, reducing testosterone conversion to dihydrotestosterone, and simultaneously dilating blood vessels around hair follicles, and promoting hair transition from telogen to anagen. The pyrrolidinyl diaminopyrimidine oxide can promote proliferation of epidermal papilla cells, improve scalp microcirculation and provide nutrition for hair growth by affecting potassium ion channels. However, because of the poor water solubility of diaminopyrimidine oxides, it is often necessary to add large amounts of alcohols to increase solubility when used in the preparation of hair growth agents. In addition, when using such products, it is desirable to keep the hair dry, preventing the liquid from entering the face and neck through the hair, resulting in abnormal hair growth in these areas. During the use, discomfort such as itching, dryness and the like can be generated, and all the discomfort needs to be paid attention. Meanwhile, because of the barrier effect of the skin, the transdermal absorption effect of the hair tonic is poor, and the hair tonic needs to be repeatedly used for many times in a large dosage and high concentration.
In order to improve the shortcomings of such a hair tonic, for example, inclusion of a pyrrolidinyl diaminopyrimidine oxide with a β -cyclodextrin-based derivative to increase the solubility of the pyrrolidinyl diaminopyrimidine oxide in water has been disclosed, but the inclusion compound thus obtained has a larger particle size and cannot penetrate deeply into the hair follicle structure. For example, nano-drug targeting carrier preparation technology is used for preparing nano-compositions containing diaminopyrimidine oxide and pyrrolidinyl diaminopyrimidine oxide to improve transdermal property and bioavailability, but the production process of the nano-preparation is complicated and the application is inconvenient.
It is an object of the present application to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative. Throughout the specification and claims, the words "comprise," "include," and the like are to be construed in an inclusive sense, rather than an exclusive or exhaustive sense, unless the context clearly requires otherwise; that is, it is interpreted in the light of "including, but not limited to".
Disclosure of Invention
The application provides a diaminopyrimidine oxide and low-molecular cationic zinc hyaluronate coupling derivative, and a preparation method and application thereof. The derivative provided by the application has good water solubility and slow release transdermal effect, has functions of fixing hair, preventing hair loss and growing hair, solves the defects of poor solubility, poor permeability, short action time, high-frequency use with large dosage, strong irritation and the like of diaminopyrimidine oxide pilatory in the prior art, and also has the advantages of moisture retention, good adsorptivity and affinity to skin and hair; meanwhile, the method is simple and feasible, accords with the green chemical concept and is environment-friendly.
Specifically, the present application provides the following technical features, and one or more of the following technical features are combined to form the technical scheme of the present application.
In a first aspect of the application, the application provides a substance which is a diaminopyrimidine oxide and a low molecular cationic zinc hyaluronate coupled derivative, the structure of which is shown in formula I:
wherein R is 1 、R 2 、R 3 Each independently selected from hydroxypropyl trimethyl ammonium chlorideAnd hydrogen, and R 1 、R 2 、R 3 The three are not hydrogen at the same time;
R 4 is pyrrolidinyl or hydrogen;
m≥1，n≥0。
in some embodiments of the application, the cationic hyaluronic acid is a low molecular cationic hyaluronic acid having a molecular weight of between 2kDa and 100kDa, preferably between 5kDa and 10kDa.
In some embodiments of the application, the average molecular weight of the substance of formula I is less than 100kDa, preferably from 2kDa to 20kDa.
In some embodiments of the application, the hydroxypropyl trimethylammonium chloride content of the compounds of formula I is 15-35%.
In some embodiments of the application, the zinc content of the compound of formula I is not less than 5%.
In some embodiments of the application, the degree of substitution of the diaminopyrimidine oxide in the compounds of formula I is 0.01 to 0.7; preferably 0.1 to 0.5.
In a second aspect of the present application, there is provided a process for preparing a substance of formula I as set out in the first aspect above, comprising: coupling reaction is carried out on the diaminopyrimidine oxide and cationic hyaluronic acid; zinc acetate is added for salt conversion;
wherein the diaminopyrimidine oxide is shown in a formula II, and the cationic hyaluronic acid is shown in a formula III:
wherein R is 1 、R 2 、R 3 Each independently selected from hydroxypropyl trimethyl ammonium chlorideAnd hydrogen, and R 1 、R 2 、R 3 The three are not hydrogen at the same time;
R 4 is pyrrolidinyl or hydrogen;
m≥1，n≥0。
in some embodiments of the application, the method comprises: the diaminopyrimidine oxide, the cationic hyaluronic acid and the coupling reagent are subjected to coupling reaction in water, ultrafiltration and washing are carried out after the reaction is finished, the reactant is obtained through alcohol precipitation, and zinc acetate is added for salt conversion.
In some embodiments of the application, the salt conversion may be accomplished by lyophilization or by alcohol precipitation followed by drying.
In a third aspect of the present application there is provided a composition comprising a substance of formula I as described in the first aspect above.
In some embodiments of the application, the composition is a pharmaceutical composition or a cosmetic composition.
In a fourth aspect of the present application, there is provided a formulation comprising a substance of formula I as described in the first aspect above, and at least one necessary adjuvant.
In some embodiments of the application, the formulation is a pharmaceutical formulation or a cosmetic formulation.
In some embodiments of the application, the composition or formulation is generally a topically applicable formulation. "topical application" in the sense of the present application means that the formulation is topical, i.e. the formulation must be suitable for scalp and/or hair (especially hair) and the like.
In some embodiments of the application, a carrier may also be included in the composition or formulation to further enhance permeability and therapeutic efficacy. The carrier may be in the form of an emulsion, gel, powder, solution or other suitable application. The pH of the formulation can be adjusted by introducing an acid or alkaline substance at the appropriate location to ensure stability and high efficiency of the composition and formulation.
In some embodiments of the application, other hair nutrients or bioactive substances may also be included in the composition or formulation, and mild cleansing ingredients may also be included. For example, natural plant ingredients such as ginger, peppermint, licorice, onion, etc., which are capable of promoting scalp blood circulation, regulating scalp grease secretion, and increasing hair elasticity; for example, nutritional ingredients such as vitamins, minerals, amino acids, etc., which provide the necessary nutrition to nourish the hair and scalp; such as proteins, e.g., serine, collagen, ergotamine, etc.; for example, essential oils such as rosemary, lavender, tea tree essential oil, jojoba oil, etc., to promote scalp blood circulation, reduce inflammation and itching of the scalp; for example, herbal extracts such as extracts of sappan wood, cypress bark, black sesame, mulberry and the like.
Specifically, the formulation of the present application may be in a form acceptable in cosmetics, particularly hair-care products, such as liquids (dew, liquid, water, oil-water separation, etc.), gels (jelly, gum, etc.), cream emulsions (cream, honey, fat, milk liquid, etc.), powders (loose powders, granules, etc.), nuggets (cake powders, bulk solids, etc.), purees (muddy solids, etc.), sprays (without propellant), aerosols (with propellant), freeze-drying (lyophilized powders, lyophilized sheets, etc.), wax-based (with wax as a major base), patches, films, substrates (patches, films, substrates with use with cosmetics), etc.; specifically, examples of these forms of products include, but are not limited to, shampoos, conditioners, hair essences, rinse-off hair films, leave-on products, scalp lotions, shampoos soaps, sprays, and the like.
In some embodiments of the present application, the present application provides a gel formulation comprising a substance of formula I described in the first aspect above and sodium acetylalginate, wherein sodium acetylalginate is used as an encapsulation carrier. In one embodiment of the present application, there is provided a method for preparing the gel formulation, comprising: the substance shown in the formula I is added into an acetyl sodium alginate solution, and then calcium chloride solution is added.
In one specific embodiment, the method for preparing the gel formulation comprises: dissolving acetyl sodium alginate in deionized water to prepare a solution; adding a substance shown in a formula I into an acetyl sodium alginate solution under the stirring condition; adding calcium chloride solution, stirring, and standing.
The acetyl sodium alginate can be obtained by purchasing or modifying sodium alginate by acetic anhydride, wherein the substitution degree of acetyl in the acetyl sodium alginate is 10-25%.
The composition and the preparation for scalp and hair provided by the application can promote metabolism of hair follicles and improve scalp environment, improve growth speed and quality of hair, and reduce hair loss, so that effects of improving health and beauty of hair are achieved.
In a fifth aspect of the application, the application provides the use of a substance of formula I as set out in the first aspect above or a composition as set out in the third aspect above or a formulation as set out in the fourth aspect above for the preparation of a medicament (such as a hair tonic) or cosmetic (such as a hair care product) for treating a hair and/or scalp condition. Wherein the hair is hair or body hair, especially hair.
In some embodiments of the application, treating hair and/or scalp conditions is preventing and/or improving hair loss and/or stimulating hair growth.
In the present application, "preventing and/or improving hair loss" means reducing, reversing, slowing or preventing the symptoms of alopecia including, but not limited to, alopecia, thin hair, uneven thickness of hair, etc., which may be hereditary alopecia, alopecia areata, seborrheic alopecia, hair breakage and loss due to trichomonas infection, seasonal alopecia, stress alopecia, and dystrophic alopecia, etc., and also includes.
In the present application, "stimulating hair growth" refers to promoting hair growth, regrowth or increasing the number of hairs, such as stimulating hair follicle regrowth, promoting natural thin or sparse hair thickening (increasing the amount of hair), optimizing the hair growth cycle to give the hair a longer growing period, promoting hair growth at bald or alopecia sites, and accelerating the rate of new hair growth, etc.
In some embodiments of the application, the cosmetic is primarily a hair-growing product, the dosage form of which includes liquids (dew, liquid, water, oil-water separation, etc.), gels (jelly, gum, etc.), cream emulsions (cream, honey, fat, milk, emulsion, milk-liquid, etc.), powders (loose powders, granules, etc.), nuggets (nugget powders, bulk solids, etc.), purees (muddy solids, etc.), sprays (without propellants), aerosols (with propellants), lyophilization (freeze-dried powders, freeze-dried flakes, etc.), wax-based (with waxes as the primary base), patches, films, substrates (patches, films, substrates for use with cosmetics), and the like; specifically, examples of these forms of products include, but are not limited to, shampoos, conditioners, hair essences, rinse-off hair films, leave-on products, scalp lotions, shampoos soaps, sprays, and the like.
In a sixth aspect of the present application there is provided a method of treating hair and/or scalp conditions comprising topically applying to the scalp and/or hair a substance of formula I as described in the first aspect above, or a composition or formulation comprising a substance of formula I, in an amount effective to prevent and/or ameliorate hair loss and/or stimulate hair growth.
In the present application, "preventing and/or improving hair loss" means reducing, reversing, slowing or preventing the symptoms of alopecia including, but not limited to, alopecia, thin hair, uneven thickness of hair, etc., which may be hereditary alopecia, alopecia areata, seborrheic alopecia, broken and shed hair caused by trichomonas infection, seasonal alopecia, stress alopecia, and dystrophic alopecia, etc.
In the present application, "stimulating hair growth" refers to promoting hair growth, regrowth and/or increasing the number of hairs, such as stimulating hair follicle regrowth, promoting natural thin or sparse hair thickening (increasing the amount of hair), optimizing the hair growth cycle to give the hair a longer growing period, promoting hair growth in bald or hair loss areas, and accelerating the rate of new hair growth, etc.
An effective amount according to the present application means an amount of a substance or composition or formulation that can significantly induce a positive effect on the scalp and/or hair during treatment (e.g., during use). Such as appearance and/or sensory benefits, such as, in one embodiment, appearance of new hair growth, thinning of hair thickening, reduced hair loss, etc. In some cases, an effective amount may be displayed using ex vivo and/or in vitro methods.
Topical application in the sense of the present application refers to contacting the component or formulation to be applied to the scalp and/or hair by means including, but not limited to, painting, dripping, spraying, massaging, and the like.
In an embodiment of the application, administration of a substance of formula I or a composition or formulation comprising it according to the application enables at least one of the following effects to be achieved in order to achieve a hair-fixing, hair-loss-preventing and/or hair-growing effect: prevent hair follicle blockage, nourish hair follicle, strengthen hair root to hair tip; promoting keratin fiber generation composition, increasing hair concentration; prolonging hair growth cycle and accelerating hair growth; healthy growth of fine and young hair and strengthening of hair; softening the collagen fiber net to prevent alopecia; and deep structures acting on the roots induce new hair and accelerate new hair growth.
Advantages of the present application compared to the prior art include:
in the technical scheme of the application, the diaminopyrimidine oxide and the low-molecular cationic zinc hyaluronate coupling derivative have good water solubility, slow-release transdermal effect and excellent functions of fixing hair, preventing hair loss and/or growing hair, and the defects of poor permeability, short acting time, high-dose high-frequency use, strong irritation and the like of the diaminopyrimidine oxide in the prior art are overcome, and the diaminopyrimidine oxide has the advantages of moisture retention, good adsorptivity and affinity to skin and hair and the like.
The derivative has a unique transdermal absorption mechanism, and under the action of amidohydrolase in body fluid, an amide bond is opened, so that diaminopyrimidine oxide and zinc hyaluronate are stably transferred to the dermis of the skin. An aqueous hyaluronic acid film is formed on the surface, and together with endogenous hyaluronic acid, a sandwich structure is formed on both sides of the stratum corneum. The water content of the horny layer is rapidly increased to become a semipermeable membrane, and the diaminopyrimidine oxide and ionic zinc can easily pass through the semipermeable membrane by utilizing the osmotic pressure principle, so that the diaminopyrimidine oxide can be slowly released, and the effects of preventing hair loss and growing hair are achieved. Besides the function of the diaminopyrimidine oxide is completely maintained, the product also has the effect of low-molecular cationic zinc hyaluronate. Meanwhile, zinc and diaminopyrimidine oxide have synergistic anti-hair loss and hair growth effects.
For the derivatization reaction of hyaluronic acid, the traditional salt conversion and organic solvent are avoided, water is directly used as the solvent for coupling, and for the operation of zinc salt conversion, the operation of ion exchange resin and the like are avoided, so that the method accords with the green chemical concept and is environment-friendly.
Drawings
The accompanying drawings, which are included to provide a further understanding of the application and are incorporated in and constitute a part of this specification, illustrate embodiments of the application and together with the description serve to explain the application. Embodiments of the present application are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1 shows a nuclear magnetic resonance hydrogen spectrum of a compound of formula I1 prepared in preparation example 1 of the present application.
FIG. 2 shows a hydrogen nuclear magnetic resonance spectrum of the compound of formula I2 prepared in preparation example 2 of the present application.
FIG. 3 is a graph showing the comparative results of the water-solubility test of experimental example 1 according to the present application.
FIG. 4 shows a graph of cumulative permeation of samples from different experimental groups of experimental example 2 according to the present application.
FIG. 5 shows a graph of retention of samples from different groups of experiments according to the application.
FIG. 6 shows the comparison of the apparent efficiency of the test samples of the different experimental groups of the experimental example 2.
Detailed Description
The application will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application. The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions or under conditions recommended by the manufacturer.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The reagents or materials used in the present application may be purchased in conventional manners, and unless otherwise indicated, they may be used in conventional manners in the art or according to the product specifications. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present application. The preferred methods and materials described herein are presented for illustrative purposes only.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The reagents or materials used in the present application may be purchased in conventional manners, and unless otherwise indicated, they may be used in conventional manners in the art or according to the product specifications. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present application. The preferred methods and materials described herein are presented for illustrative purposes only.
The application provides a diaminopyrimidine oxide and low-molecular cationic zinc hyaluronate coupled derivative, the structure of which is shown in formulas I1 and I2:
R 1 、R 2 、R 3 each independently selected from hydroxypropyl trimethyl ammonium chlorideAnd hydrogen, and R 1 、R 2 、R 3 The three are not hydrogen at the same time; m is greater than or equal to 1, and n is greater than or equal to 0. The average molecular weight of the substance of formula I is less than 100kDa, preferably 2kDa-20kDa; the content of hydroxypropyl trimethyl ammonium chloride in the compound of the formula I is 15-35%, and the zinc content is not less than 5%.
The compound of the application can be prepared by the following reaction route:
R 1 、R 2 、R 3 each independently selected from hydroxypropyl trimethyl ammonium chlorideAnd hydrogen, and R 1 、R 2 、R 3 The three are not hydrogen at the same time; r is R 4 Is pyrrolidinyl or hydrogen; m is greater than or equal to 1, and n is greater than or equal to 0. The average molecular weight of the substance of formula I is less than 100kDa, preferably 2kDa-20kDa; the content of hydroxypropyl trimethyl ammonium chloride in the compound of the formula I is 15-35%, and the zinc content is not less than 5%.
Specifically, the preparation and properties of the conjugates of the present application will be schematically illustrated in the following examples, and it should be understood that the examples are merely illustrative and not exhaustive, and that the skilled person can easily prepare derivatives having the structure of the present application or other derivatives similar to the structure of the present application according to the present application and perform structural verification through nuclear magnetic resonance spectroscopy.
The low molecular cationic sodium hyaluronate is obtained by modifying low molecular hyaluronic acid by using glycidol trimethyl ammonium chloride, for example, the low molecular cationic sodium hyaluronate in the following embodiment of the application is prepared by the following method: adding low molecular sodium hyaluronate into deionized water with the volume of 4 times, uniformly stirring, adding 2.5 equivalents of glycidol trimethyl ammonium chloride and 0.1 equivalent of tetrabutylammonium hydroxide, dropwise adding 3.0 equivalents of 3mol/L sodium hydroxide solution, stirring for 4-5 hours at the temperature of 20-30 ℃, after the reaction is finished, pouring the reaction solution into 95 ethanol for precipitation, pouring out supernatant, carrying out solid phase precipitation by absolute ethanol, washing the precipitate by 95 ethanol for 2-3 times, and drying the precipitate to obtain the low molecular cationic sodium hyaluronate.
Preparation examples, preparation of Compounds of formula I
Preparation example 1 preparation of Compounds of formula I1
100g of low molecular weight cationic sodium hyaluronate (18.6% cationic substitution) with a molecular weight of 5kDa to 10kDa is added to 2000g of purified water and stirred until dissolved. Adding 100g O-benzotriazol-tetramethylurea hexafluorophosphate, adjusting pH to 6-7 with sodium hydroxide, and adding 3g of the compound of formula II (R 4 H), stirring for 16 hours at 20-30 ℃; adding 50g O-benzotriazole-tetramethylurea hexafluorophosphate and 3g of compound III, adjusting the pH to 6-7 with sodium hydroxide, and stirring for 24 hours at 20-30 ℃; adding 50g O-benzotriazole-tetramethylurea hexafluorophosphate and 3g of compound III, adjusting the pH to 6-7 with sodium hydroxide, and stirring for 16 hours at 20-30 ℃. After the reaction was completed, the mixture was added to 2000g of purified water. Ultrafiltering with nanofiltration membrane (molecular weight cut-off 1000 Da), washing, concentrating, and precipitating with ethanol to obtain white solid.
Adding the solid into 1L of 95 ethanol containing 6% zinc acetate, stirring for 16 hours, standing, pouring supernatant, repeating the steps for 6 times, dehydrating with absolute ethanol for 2 times, filtering and drying to obtain 110g of a compound shown as the formula I1, wherein the molecular weight is 8kDa, the substitution degree of diaminopyrimidine oxide is 0.27, the content of hydroxypropyl trimethyl ammonium chloride is 17.1%, and the content of zinc is 6.0%. The nuclear magnetic resonance hydrogen spectrum of the compound of formula I1 (also referred to as diaminopyrimidine oxide and low molecular cationic zinc hyaluronate coupled derivative in the present application) is shown in FIG. 1.
Preparation example 2 preparation of Compounds of formula I2
100g of low molecular weight cationic sodium hyaluronate (18.6% cationic substitution) with a molecular weight of 5kDa to 10kDa is added to 2000g of purified water and stirred until dissolved. Adding 100g O-benzotriazol-tetramethylurea hexafluorophosphate, adjusting pH to 6-7 with sodium hydroxide, and adding 4.5g of the compound of formula II (R 4 Pyrrolidinyl) at 20-30 ℃ for 16 hours; adding 50g O-benzotriazole-tetramethylurea hexafluorophosphate and 4.5g of compound VI, adjusting the pH to 6-7 with sodium hydroxide, and stirring for 24 hours at 20-30 ℃; 50g O-benzotriazol-tetramethylurea hexafluorophosphate and 4.5g of compound VI are added, the pH is regulated to 6-7 by sodium hydroxide, and the mixture is stirred for 16 hours at 20-30 ℃. After the reaction was completed, the mixture was added to 2000g of purified water. Ultrafiltering with nanofiltration membrane (molecular weight cut-off 1000 Da), washing, concentrating, and precipitating with ethanol to obtain white solid.
Adding into 1L of 95 ethanol containing 6% zinc acetate, stirring for 16 hours, standing, pouring out supernatant, repeating the above steps for 6 times, concentrating under reduced pressure to remove ethanol, adding the solid into 1L of deionized water, filtering with 0.22 μm, and lyophilizing to obtain 108g of the compound of formula I2 with molecular weight of 9kDa, pyrrolidinyl diaminopyrimidine oxide substitution degree of 0.30, hydroxypropyl trimethylammonium chloride content of 17.4%, and zinc content of 6.6%. The nuclear magnetic resonance hydrogen spectrum of the compound of formula I2 (also referred to herein as pyrrolidinyl diaminopyrimidine oxide and low molecular cationic zinc hyaluronate coupled derivative) is shown in fig. 2.
Experimental example 1: comparison of Water solubility test
The compound I1 and the compound I2 prepared in preparation example 1 and preparation example 2, respectively, were dissolved in purified water at a concentration of 0.1g/mL, respectively. At 0.1g/mL of diaminopyrimidine oxide (i.e., formula II, R 4 Is hydrogen) and pyrrolidinyl diaminopyrimidine oxide (i.e., formula II, R 4 Pyrrolidinyl) was used as a control. The results are shown in FIG. 3. From the results of the water-solubility experiments, it was confirmed that the diaminopyrimidine oxide and the pyrrolidinyl diaminopyrimidine oxide were almost insoluble in water at the same concentration and thus in an opaque state, whereas both compounds of the present application were completely soluble in water.
ExperimentExample 2
The experimental example is used for detecting 1) in-vitro cytotoxicity experiment, irritation experiment, 2) transdermal experiment and 3) hair growth activity test of a tested sample.
1. Experimental grouping and sample:
experiment group 1: dissolving acetyl sodium alginate in deionized water to prepare a solution with the concentration of 2 wt%; under the condition of mechanical stirring, adding low molecular cationic zinc hyaluronate into acetyl sodium alginate solution, wherein the addition amount is 0.08mol/L; adding 0.2wt% calcium chloride solution, stirring for 20min, and standing for 24 hr to obtain low molecular cationic zinc hyaluronate gel as the sample to be tested in experiment group 1.
Experiment group 2: dissolving acetyl sodium alginate in deionized water to prepare a solution with the concentration of 2 wt%; under the condition of mechanical stirring, zinc acetate is added into the acetyl sodium alginate solution, and the addition amount is 0.08mol/L; adding 0.2wt% calcium chloride solution, stirring for 20min, and standing for 24 hr to obtain zinc acetate gel as the tested sample of experiment group 2.
Experiment group 3: dissolving acetyl sodium alginate in deionized water to prepare a solution with the concentration of 2 wt%; under the condition of mechanical stirring, adding diaminopyrimidine oxide into acetyl sodium alginate solution with the addition amount of 0.08mol/L; adding 0.2wt% calcium chloride solution, stirring for 20min, and standing for 24 hr to obtain diaminopyrimidine oxide gel as the sample to be tested in experiment group 3.
Experiment group 4: dissolving acetyl sodium alginate in deionized water to prepare a solution with the concentration of 2 wt%; under the condition of mechanical stirring, adding diaminopyrimidine oxide and low-molecular cationic zinc hyaluronate into acetyl sodium alginate solution, wherein the addition amount is 0.08mol/L; adding 0.2wt% calcium chloride solution, stirring for 20min, and standing for 24 hr to obtain test sample of experiment group 4.
Experimental group 5: dissolving acetyl sodium alginate in deionized water to prepare a solution with the concentration of 2 wt%; under the condition of mechanical stirring, adding diaminopyrimidine oxide and zinc acetate into acetyl sodium alginate solution, wherein the addition amounts are 0.08mol/L; adding 0.2wt% calcium chloride solution, stirring for 20min, and standing for 24 hr to obtain test sample of experiment group 5.
Experiment group 6: dissolving acetyl sodium alginate in deionized water to prepare a solution with the concentration of 2 wt%; under the condition of mechanical stirring, zinc acetate and low molecular cationic zinc hyaluronate are added into an acetyl sodium alginate solution, wherein the addition amounts are 0.08mol/L; adding 0.2wt% calcium chloride solution, stirring for 20min, and standing for 24 hr to obtain test sample of experiment group 6.
Experiment group 7: dissolving acetyl sodium alginate in deionized water to prepare a solution with the concentration of 2 wt%; under the condition of mechanical stirring, adding diaminopyrimidine oxide, zinc acetate and low-molecular cationic zinc hyaluronate into acetyl sodium alginate solution, wherein the addition amounts are all 0.08mol/L; adding 0.2wt% calcium chloride solution, stirring for 20min, and standing for 24 hr to obtain test sample of experiment group 7.
Experiment group 8: dissolving acetyl sodium alginate in deionized water to prepare a solution with the concentration of 2 wt%; under the condition of mechanical stirring, adding the compound of the formula I1 prepared in the preparation example 1 into an acetyl sodium alginate solution, wherein the addition amount is 0.08mol/L; adding 0.2wt% calcium chloride solution, stirring for 20min, and standing for 24 hr to obtain test sample of experiment group 8.
Experiment group 9: dissolving acetyl sodium alginate in deionized water to prepare a solution with the concentration of 2 wt%; under the condition of mechanical stirring, adding pyrrolidinyl diaminopyrimidine oxide into acetyl sodium alginate solution with the addition amount of 0.08mol/L; adding 0.2wt% calcium chloride solution, stirring for 20min, and standing for 24 hr to obtain diaminopyrimidine oxide gel as the sample to be tested in experiment group 9.
Experimental group 10: dissolving acetyl sodium alginate in deionized water to prepare a solution with the concentration of 2 wt%; under the condition of mechanical stirring, adding pyrrolidinyl diaminopyrimidine oxide and low molecular cationic zinc hyaluronate into acetyl sodium alginate solution, wherein the addition amount is 0.08mol/L; adding 0.2wt% calcium chloride solution, stirring for 20min, and standing for 24 hr to obtain test sample of experiment group 10.
Experiment group 11: dissolving acetyl sodium alginate in deionized water to prepare a solution with the concentration of 2 wt%; under the condition of mechanical stirring, adding pyrrolidinyl diaminopyrimidine oxide and zinc acetate into acetyl sodium alginate solution, wherein the addition amounts are 0.08mol/L; adding 0.2wt% calcium chloride solution, stirring for 20min, and standing for 24 hr to obtain test sample of experiment group 11.
Experiment group 12: dissolving acetyl sodium alginate in deionized water to prepare a solution with the concentration of 2 wt%; under the condition of mechanical stirring, adding pyrrolidinyl diaminopyrimidine oxide, zinc acetate and low molecular cationic zinc hyaluronate into an acetyl sodium alginate solution, wherein the addition amounts are 0.08mol/L; adding 0.2wt% calcium chloride solution, stirring for 20min, and standing for 24 hr to obtain the test sample of experiment group 12.
Experiment group 13: dissolving acetyl sodium alginate in deionized water to prepare a solution with the concentration of 2 wt%; under the condition of mechanical stirring, adding the compound of the formula I2 prepared in the preparation example 2 into an acetyl sodium alginate solution, wherein the addition amount is 0.08mol/L; adding 0.2wt% calcium chloride solution, stirring for 20min, and standing for 24 hr to obtain test sample of experiment group 13.
Experimental group 14 (blank): dissolving acetyl sodium alginate in deionized water to prepare a solution with the concentration of 2 wt%; under the condition of mechanical stirring, adding a calcium chloride solution with the concentration of 0.2 weight percent, stirring for 20min, and then standing for 24h to obtain a tested sample with gel as a blank group 14.
Wherein, the sodium acetylalginate used in the application is obtained by modifying sodium alginate with acetic anhydride, and the preparation method of the sodium acetylalginate in the embodiment comprises the following steps: sodium alginate (mannuronic acid: guluronic acid=1.40-1.70) is placed in acetic acid/acetic anhydride/triethylamine (1:1:0.1) solution, the mass-volume ratio of the sodium alginate to the acetic anhydride/triethylamine is 1:10, the reaction is carried out under stirring at 80 ℃ for 10 hours, after the reaction is finished, reaction liquid is poured into ethanol for precipitation, supernatant is poured out, the precipitate is washed for 2-3 times by 95 ethanol, the precipitate is dried, water is added for dissolving and drying solids, then the solid is filtered, and then filtrate is frozen and dried into powder, so that acetyl sodium alginate with the acetyl substitution degree of 12% is obtained.
The preparation method of the low molecular cationic zinc hyaluronate in the embodiment comprises the following steps: 100g of low molecular cationic sodium hyaluronate with the molecular weight of 5 kDa-10 kDa (with the cationic substitution degree of 18.6%) is added into 1L of 95 ethanol containing 6% zinc acetate, the mixture is stirred for 16 hours, the mixture is stood still, the supernatant is poured away, the steps are repeated for 6 times, the absolute ethanol is dehydrated for 2 times, the low molecular cationic zinc hyaluronate with the molecular weight of 10kDa, the hydroxypropyl trimethyl ammonium chloride content of 17.6% and the zinc content of 6.7% are obtained after filtration and drying.
2. In vitro cytotoxicity and irritation assays
The fifth section of medical device biological evaluation according to GB T16886.5-2017/ISO 10993-5:2009: in vitro cytotoxicity experiments were performed on experimental group 8 and experimental group 13 to verify biocompatibility. Selecting MTT cytotoxicity test evaluation method, selecting L929 cells as cell line, using 10% DMSO solution as positive control group, using 3% calf serum culture medium as negative control group, using 3% calf serum culture medium extract added with tested sample as test group, shake culturing at 37deg.C for 24 hr.
The specific experimental steps are as follows: l929 cells subcultured for 48 hours were prepared into 1X 10 cells using the cell culture solution 5 Cell suspension of individual/mL for use; will be 1X 10 5 The individual/mL cell suspensions were inoculated into 96-well cell culture plates (100. Mu.L/well) and placed at 37℃in 5% CO 2 Culturing for 24 hours in an incubator to form a semi-confluent monolayer; after 24 hours, the original culture solution is discarded, 100 mu L of sample leaching solution, positive control solution and negative control solution are respectively added, each group of 5 holes are placed at 37 ℃ and 5 percent CO 2 Culturing in an incubator for 24 hours. mu.L of MTT solution was added to each well, followed by further addition of 5% CO at 37℃ 2 Incubating in the incubator for 2 hours;
the MTT solution was discarded, 100. Mu. LDMSO solution was added to each well, the plate was shaken, absorbance at 570nm was measured on a microtiter plate photometer, and the cell proliferation degree (RGR,%) was calculated, and cytotoxicity was evaluated according to the criteria in the following table.
TABLE 1 in vitro cytotoxicity fractionation table
| Level of | 0 | 1 | 2 | 3 | 4 | 5 |
| Relative proliferation/% | ≥100 | 75-99 | 50-74 | 25-49 | 1-24 | 0 |
The experimental results are shown in table 2, and the in vitro cytotoxicity of the compound shown in the formula I1 and the compound shown in the formula I2 prepared by the application is 1 grade, which shows that the compound has good biocompatibility and can not generate toxicity and cause toxicity residues.
TABLE 2 in vitro cytotoxicity assay results
| Sample of | Toxicity grade |
| Experiment group 8 | 1 |
| Experiment group 13 | 1 |
| Positive control group | 5 |
Taking 15 healthy rabbits, wherein the weight is about 2kg, randomly dividing the rabbits into 3 groups, removing the hair on two sides of the skin on the back of the rabbits 24 hours before the experiment, detecting whether the skin on the hair removal area is injured or not 24 hours after the hair removal, and coating samples of the experiment group 8, the experiment group 13 and the experiment group 14 (blank group) for 3 times every day for continuous 7 days to observe the experimental results, wherein the experimental results are shown in table 3.
TABLE 3 skin irritation test results
Note that: the + "indicates red and swollen skin, inflammation and congestion of rabbit; "++" indicates that the rabbit has red and swollen skin and has inflammation and congestion, and the tendency of increasing; "-" indicates that the rabbit had no skin reddening and swelling, and inflammation and congestion.
As can be seen from the experimental results of table 3, the samples of experimental group 8 and experimental group 13 were not irritating to the skin.
3. Transdermal experiments
The transdermal experiments of the isolated murine skin were performed using the vertical Franz diffusion cell method. SD male rat belly skin is fixed between a receiving room and a supply room, and experimental group 3, experimental group 4, experimental group 5, experimental group 7, experimental group 8, experimental group 9, experimental group 10, experimental group 11, experimental group 12 and experimental group 13 are taken in the supply room, and are stirred and diffused at 300 rotating speed under 37 ℃ by taking physiological saline containing 2% sodium dodecyl sulfate and 20% ethanol as a receiving solution. Samples were taken at 0.5,1,2,4,6,8, 10, 12 and 24h and analyzed by uv-vis spectrophotometry to calculate the cumulative permeation of the skin diaminopyrimidine oxide, the compound of formula I1, the pyrrolidinyl diaminopyrimidine oxide and the compound of formula I2 for different unit areas. After 24 hours of in vitro transdermal test, the mouse skin with effective penetration area is sheared, a proper amount of receiving solution is added, homogenate is carried out, the homogenate is centrifuged for 30 minutes at 8 000r/min, supernatant is taken, a 0.22 mu m filter membrane is used for filtration, and analysis by ultraviolet-visible spectrophotometry is carried out, so as to calculate the retention of diaminopyrimidine oxide, the compound of formula I1, the pyrrolidinyl diaminopyrimidine oxide and the compound of formula I2 in unit area of skin. Experimental data are shown in figures 4 and 5.
FIG. 4 is a graph showing cumulative permeation amounts of different groups in a transdermal test; figure 5 shows the retention of different groups in the transdermal experiments. From FIGS. 4 and 5, it can be seen that the compounds I1 and I2 of the present application have good skin permeation and skin retention ability. The cumulative transmission per unit area of the compound I1 of the application in FIG. 4 is about 2.5 times that of diaminopyrimidine oxide, the transdermal effect is obviously improved, and the addition of zinc acetate and low molecular cationic zinc hyaluronate can increase the transdermal property of diaminopyrimidine oxide, but the physical mixture is inferior to that of the compound I1 of the application; the cumulative transmission rate of the I2 compound per unit area is about 3.5 times that of the pyrrolidinyl diaminopyrimidine oxide, the transdermal effect is obviously improved, and the addition of zinc acetate and low-molecular cationic zinc hyaluronate can increase the transdermal property of the pyrrolidinyl diaminopyrimidine oxide, but the physical mixture of the compound is inferior to that of the compound of the formula I2. FIG. 5 shows that the skin retention per unit area of the compound I1 of the present application is 11.5. Mu.g cm 24h after transdermal administration -2 While the diaminopyrimidine oxide is transdermal for 24 hours, the skin retention per unit area is only 3.6 mug cm -2 The method comprises the steps of carrying out a first treatment on the surface of the I2 of the applicationThe skin retention per unit area of the composition after 24h of transdermal treatment reaches 10.8 mug cm -2 While the pyrrolidinyl diaminopyrimidine oxide is transdermal for 24 hours, the unit area skin hold-up is only 2.8 mug cm -2 . The diaminopyrimidine oxide is difficult to penetrate through the stratum corneum of skin and cannot act on the deep structure of hair follicles, so that the bioavailability is low, and the diaminopyrimidine oxide and low-molecular cationic zinc hyaluronate coupling derivative can deeply penetrate into hair follicles to reach target spots, can stay in the hair follicles for a long time, is controlled in a sustained release manner, remarkably improves the bioavailability, and enhances the effects of preventing hair loss and promoting hair growth.
4. Hair growth Activity test
280 patients with grade III-V alopecia rated by Hamilton-Norwood scale aged 25-50 were selected, of which 200 men and 80 women. It was randomly divided into 14 groups.
Inclusion criteria: no hair loss treatment is carried out within half a year, follow-up is willing to be accepted, and the hair can be positively matched with the treatment, and the hair is not dyed by scalding during the treatment period. Exclusion criteria: patients with systemic diseases accompanied by impairment of heart, lung, liver or kidney function, endocrine or psychiatric diseases, scalp damage or other skin diseases.
The treatment method comprises the following steps: the sample gel of the test group 1-14 is packaged into a container with a metering pump head (the pump head can pump 1mL each time), the sample of the test group 1-14 is used twice daily in the morning and at night, 1mL of medicine is pumped each time for smearing treatment, the scalp and the hair are kept dry before use, and after use, the scalp is massaged by hands for 3-5min.
Treatment cycle: the treatment effect was observed after 4 weeks as a treatment course and 4 treatment courses.
Treatment effect judgment standard: 1) The effect is shown: stopping hair loss and regrowing hair in the hairless area; 2) The method is effective: the alopecia is obviously improved, and black hair grows again in part of the hairless area; 3) Invalidation: the alopecia is not improved or reduced, and no new hair grows in the hairless area. The test results are shown in Table 4, and the calculated efficiency is shown in FIG. 6. .
Table 4 comparative table of therapeutic effects
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As can be seen from the treatment effect of Table 4 and the data in the table, the experimental groups 1,2, 6 and 14 were ineffective, which indicates that the low molecular cationic zinc hyaluronate and zinc acetate have no effect of fixing hair and preventing hair loss, and also cannot promote hair growth. The treatment of alopecia in experimental groups 4, 5 and 7 is slightly better than that in experimental group 3, which shows that the low molecular cationic zinc hyaluronate and zinc acetate can slightly enhance the effect of diaminopyrimidine oxide in treating alopecia. The treatment effect of the experimental group 8 is obviously higher than that of the single diamino pyrimidine oxide gel of the experimental group 3, and is also obviously higher than that of the mixed gel of the diamino pyrimidine oxides of the experimental groups 4, 5 and 7 and the low molecular cationic zinc hyaluronate and zinc acetate respectively, and the treatment effect of the low molecular cationic zinc hyaluronate and zinc acetate for treating alopecia is slightly better than that of the experimental group 9, so that the treatment effect of the low molecular cationic zinc hyaluronate and zinc acetate can slightly enhance the effect of the pyrrolidinyl diamino pyrimidine oxide for treating alopecia, and the treatment effect of the experimental group 13 is obviously higher than that of the pyrrolidinyl diamino pyrimidine oxide gel of the single experimental group 9 and is also obviously higher than that of the mixed gel of the pyrrolidinyl diamino pyrimidine oxides of the experimental groups 10, 11 and 12 and the low molecular cationic zinc hyaluronate and zinc acetate respectively. The application fully proves that the compound of the formula I1 and the compound of the formula I2 prepared by the application have obviously improved alopecia treatment effect, and are not generated by simple combination of diaminopyrimidine oxide, low molecular cation zinc hyaluronate and zinc acetate, but fundamentally endowed with better characteristics by chemical modification.
In conclusion, the application solves the defects of the prior art that the diaminopyrimidine oxide germinal agent has poor solubility and permeability, short action time, strong irritation caused by high-dose high-frequency high-concentration use, has good water-solubility and slow-release transdermal effect, has excellent functions of fixing hair, preventing hair loss and germinal, has the advantages of moisturizing property, good adsorptivity and affinity to skin and hair, and the like, and also solves the technical problems that the hyaluronic acid component and the diaminopyrimidine oxide in the functional cosmetic need to be added respectively, the action time is short, and the like.
The foregoing description is only a preferred embodiment of the present application, and the present application is not limited thereto, but it is to be understood that modifications and equivalents of some of the technical features described in the foregoing embodiments may be made by those skilled in the art, although the present application has been described in detail with reference to the foregoing embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the protection scope of the present application.
Claims (10)
1. A substance having the structure shown in formula I:
wherein R is 1 、R 2 、R 3 Each independently selected from the group consisting of hydroxypropyl trimethylammonium chloride and hydrogen, and R 1 、R 2 、R 3 Are not hydrogen at the same time;
R 4 is pyrrolidinyl or hydrogen;
m≥1，n≥0。
2. substance according to claim 1, characterized in that the average molecular weight of the substance of formula I is less than 100kDa, preferably between 2kDa and 20kDa;
preferably, the content of hydroxypropyl trimethylammonium chloride in the compound of formula I is 15-35%;
preferably, the zinc content in the compound of formula I is not less than 5%;
preferably, the degree of substitution of the diaminopyrimidine oxide in the compounds of formula I is 0.01 to 0.7; preferably 0.1 to 0.5.
3. A process for preparing a substance of formula I in claim 1, comprising: coupling reaction is carried out on the diaminopyrimidine oxide and cationic hyaluronic acid; zinc acetate is added for salt conversion;
wherein the diaminopyrimidine oxide is shown in a formula II, and the cationic hyaluronic acid is shown in a formula III:
wherein R is 1 、R 2 、R 3 Each independently selected from the group consisting of hydroxypropyl trimethylammonium chloride and hydrogen, and not both hydrogen;
R 4 is pyrrolidinyl or hydrogen;
m≥1，n≥0。
4. a method according to claim 3, characterized in that the method comprises: performing coupling reaction on diaminopyrimidine oxide, cationic hyaluronic acid and a coupling reagent in water, ultrafiltering after the reaction is finished, washing, precipitating with alcohol to obtain a reactant, and adding zinc acetate to perform salt conversion;
preferably, the salt conversion is completed by freeze-drying or by alcohol precipitation followed by drying.
5. A composition comprising a substance of formula I as set forth in claim 1 or 2.
6. The composition of claim 5, wherein the composition is a pharmaceutical composition or a cosmetic composition.
7. A formulation comprising a substance of formula I as described in claim 1 or 2, and at least one necessary auxiliary material.
8. The formulation of claim 7, wherein the formulation is a pharmaceutical or cosmetic formulation;
preferably, the formulation is an external formulation.
9. Use of a substance of formula I as defined in claim 1 or 2 or of a composition as defined in claim 5 or 6 or of a formulation as defined in claim 7 or 8 for the preparation of a medicament or cosmetic for treating a hair and/or scalp condition.
10. The use according to claim 9, wherein the treatment of hair and/or scalp conditions is preventing and/or improving hair loss and/or stimulating hair growth.
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