CN113712968A - Application of minoxidil-containing pharmaceutical composition in preventing and treating alopecia - Google Patents

Application of minoxidil-containing pharmaceutical composition in preventing and treating alopecia Download PDF

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CN113712968A
CN113712968A CN202111135629.3A CN202111135629A CN113712968A CN 113712968 A CN113712968 A CN 113712968A CN 202111135629 A CN202111135629 A CN 202111135629A CN 113712968 A CN113712968 A CN 113712968A
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minoxidil
chinese medicine
pharmaceutically acceptable
alopecia
pharmaceutical composition
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冯年平
何泽慧
刘珍达
吴奕涵
郭腾
张永太
钟延强
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Shanghai University of Traditional Chinese Medicine
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Shanghai University of Traditional Chinese Medicine
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/08—Antiseborrheics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Abstract

The invention discloses a pharmaceutical composition for preventing and/or treating alopecia, which comprises minoxidil or a pharmaceutically acceptable non-covalent derivative thereof and a traditional Chinese medicine active ingredient, wherein the molar ratio of the minoxidil or the pharmaceutically acceptable non-covalent derivative thereof to the traditional Chinese medicine active ingredient is (1-3) to (1-3). The pharmaceutical composition combines the traditional Chinese medicine active ingredients with different onset mechanisms and the minoxidil in a quantitative compatibility manner, can synergistically enhance the hair regeneration promoting capability, achieves a better alopecia prevention and treatment effect, and simultaneously reduces the dosage of the minoxidil, thereby avoiding adverse reactions accompanied by high-dosage minoxidil and improving the curative effect and the medication safety.

Description

Application of minoxidil-containing pharmaceutical composition in preventing and treating alopecia
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to an application of a minoxidil-containing pharmaceutical composition in preparation of a medicine or a preparation for treating alopecia.
Background
In recent years, the population of hair loss is gradually increasing due to increased social stress, environmental pollution, unhealthy diet, frequent perms and dyeing, wrong scalp care, bacterial and viral infections, sex hormone disorders, vitamin and mineral deficiencies.
Alopecia is mainly classified into anagen phase alopecia, acute and chronic telogen phase alopecia, alopecia areata, cicatricial alopecia, male pattern alopecia (MPHL), and female pattern alopecia (FPHL). Any link affecting the hair growth process can lead to hair loss. Although alopecia has no subjective symptoms, the psychological influence on a person suffering from alopecia is large, and the psychological influence often has adverse effects on daily life. With the improvement of living standard, people pay more attention to the treatment of alopecia, and the market demand of products for preventing and treating alopecia is increasing.
Minoxidil (MXD), a topical drug currently approved by the united states Food and Drug Administration (FDA) for the treatment of alopecia, has adverse effects including dry scalp, itching, erythema, irritation, and allergic contact dermatitis. Clinical recommendations suggest that local minoxidil concentrations are primarily 2% and 5%, and although studies have shown that 5% minoxidil is more effective than 2%, patients using 5% dosage forms reported more cases of local irritative reactions and allergic dermatitis than 2% dosage forms, indicating that the adverse effects of minoxidil are dose-dependent.
Compared with western medicines, the traditional Chinese medicine has small side effect and high safety, and the traditional Chinese medicine is concerned by people to treat alopecia. The traditional Chinese medicine components can play a role in treating alopecia through mechanisms of regulating cell growth factors, regulating signal pathways, inhibiting inflammation and the like, and have great development potential. Cedrol (CED) is a natural sesquiterpene alcohol, and is derived from volatile oil of plants of Cupressaceae, Cunninghamiae Lanceolatae and Pinaceae including Chinese medicinal material arborvitae. Baicalin (baicailin) is a flavonoid compound extracted and separated from dried root of Scutellaria baicalensis Georgi (Scutellaria baicalensis Georgi) belonging to family Labiatae. The literature demonstrates that cedrol and baicalin can promote hair growth. The traditional Chinese medicine active ingredients such as cedrol and baicalin have wide sources, mature process, low price, good skin compatibility, definite drug effect, low toxicity and small skin irritation, and have good clinical application prospect and commodity development value. Therefore, the invention adopts the scheme that the active ingredients of the traditional Chinese medicine such as the cedrol or the baicalin and the minoxidil are jointly used so as to improve the effect of preventing and treating the alopecia and reduce the adverse reaction of the skin.
Disclosure of Invention
The invention mainly aims to provide a natural and safe pharmaceutical composition for preventing and treating alopecia, which has definite curative effect and few side effects, so as to solve the problems that common medicines in the prior art are easy to generate allergic dermatitis and have local irritation reaction.
In order to achieve the above objects, according to one aspect of the present invention, there is provided a pharmaceutical composition for preventing and/or treating alopecia, comprising minoxidil or a pharmaceutically acceptable non-covalent derivative thereof and a traditional Chinese medicine active ingredient or a pharmaceutically acceptable non-covalent derivative thereof, wherein a molar ratio of the minoxidil or the pharmaceutically acceptable non-covalent derivative thereof to the traditional Chinese medicine active ingredient or the pharmaceutically acceptable non-covalent derivative thereof is (1-3): (1-3).
Further, the molar ratio of the minoxidil or the pharmaceutically acceptable non-covalent derivatives thereof to the traditional Chinese medicine active ingredients or the pharmaceutically acceptable non-covalent derivatives thereof is (1-3): 1.
Further, the molar ratio of the minoxidil or the pharmaceutically acceptable non-covalent derivatives thereof to the traditional Chinese medicine active ingredient or the pharmaceutically acceptable non-covalent derivatives thereof is 1: 1.
Further, the molar ratio of the minoxidil or pharmaceutically acceptable non-covalent derivative thereof to the active ingredient of the traditional Chinese medicine or pharmaceutically acceptable non-covalent derivative thereof is about 1.
Further, the pharmaceutically acceptable non-covalent derivative is a salt, solvate, co-crystal or a mixture thereof.
Furthermore, the active ingredients of the traditional Chinese medicine are terpenoids and/or flavonoids.
Further, the terpenoid is a sesquiterpene alcohol compound and/or a triterpenoid saponin compound.
Further, the sesquiterpene alcohol compound is cedrol.
Further, the triterpenoid saponin compound is ginsenoside Rb1Ginsenoside Rg1And/or ginsenoside Re.
Further, the flavonoid compound is baicalin.
Further, the pharmaceutical composition further comprises one or more hair growth promoting substances.
Further, the substance for promoting hair growth is 5 alpha-reductase inhibitor, androgen receptor antagonist, prostaglandin analogue, autologous platelet rich plasma, compound growth factor, Chinese medicinal compound preparation, Chinese medicinal extract, or Chinese medicinal monomer compound and its derivative, wherein the Chinese medicinal monomer compound and its derivative are not the terpenoid compound and the flavonoid compound.
Further, the 5 alpha-reductase inhibitor is finasteride, dutasteride, epristeride, azelaic acid, beta-sitosterol, zinc and/or vitamin B6.
Further, the androgen receptor antagonist is spironolactone, cyproterone acetate, ketoconazole, nilutamide, bicalutamide and/or flutamide.
Further, the prostaglandin analogue is bimatoprost, travoprost and/or latanoprost.
Further, the Chinese medicinal materials include Chinese arborvitae, Polygoni Multiflori radix, herba Achilleae, herba et Gemma Agrimoniae, Chinese arborvitae, Carthami flos, radix Sophorae Flavescentis, herba Urticae Cannabinae, herba Equiseti hiemalis, radix Angelicae sinensis, folium fici and/or Scutellariae radix.
Further, the traditional Chinese medicine monomer compound and the derivative thereof are myristic acid, capsaicin and/or curcumin.
According to another aspect of the present invention, there is provided a pharmaceutical formulation comprising the above pharmaceutical composition, the pharmaceutical formulation comprising one or more pharmaceutically acceptable carriers, diluents or excipients.
Further, the carrier is selected from one or more of the following: nanospheres, nanocapsules, dendrimers, nanofibers, nanosponges, micelles, nanogels, nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers, liposomes, niosomes, transfersomes, ethosomes, mesoporous silica nanoparticles, metal organic frameworks, metal nanoparticles and nanocrystals.
Further, the diluent is selected from one or more of the following: water, ethanol, propylene glycol and glycerol.
Further, the diluent is a mixed solution of ethanol and propylene glycol in a volume ratio of 7: 3.
Further, the excipient is selected from one or more of the following: lactose, starch, cellulose and sodium citrate.
Furthermore, the dosage form of the pharmaceutical preparation is injection, freeze-dried powder injection, tincture, solution, lotion, rinse, liniment, patch, ointment, emulsion, aerosol, drop, gel, microneedle, controlled release agent or sustained release agent.
Further, the pharmaceutical preparation is administered transdermally or intradermally.
According to another aspect of the present invention, there is provided a use of the above pharmaceutical composition or the above pharmaceutical preparation for the preparation of a medicine, health product and/or food for preventing and/or treating alopecia, and/or improving hair follicle and/or hair health, and/or promoting hair regeneration and/or growth.
Further, the alopecia is androgenetic alopecia, alopecia areata, female pattern alopecia, acute and chronic telogen effluvium, chemotherapy and radiotherapy induced alopecia, seborrheic alopecia and/or scarring alopecia.
Further, the pharmaceutical composition or pharmaceutical preparation promotes proliferation of human hair follicle papilla cells, promotes differentiation of mammalian hair follicles, and induces transformation of resting-phase hair follicles to anagen phase.
Further, the mass concentration of the minoxidil or the pharmaceutically acceptable non-covalent derivative thereof and the traditional Chinese medicine active ingredients in the medicine, health care product and/or food is about 2%.
The invention has the beneficial effects that:
the research of the invention finds that the quantitative compatibility and combined administration of the traditional Chinese medicine active ingredients with different effect mechanisms, such as cedrol and/or baicalin and minoxidil, can synergistically enhance the hair regeneration promoting capability, achieve better alopecia prevention and treatment effect, and reduce the dosage of minoxidil, thereby avoiding adverse reaction accompanied by high-dosage minoxidil, improving the drug efficacy and medication safety, and being applicable to clinical treatment, auxiliary treatment and prognosis recurrence prevention related treatment of alopecia. Therefore, the combined medication scheme of the cedrol and the minoxidil has important significance and wide application prospect in the aspects of preventing and treating alopecia and researching.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings needed to be used in the description of the embodiments are briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present application, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without exceeding the protection scope of the present application.
FIG. 1 is a graphical representation of the results of the effect of different active substances (baicalin, cedrol, shikimic acid, minoxidil) on cell proliferation of hDPC after 24 hours of administration alone.
FIG. 2 is a graph showing the effect of different active substances (baicalin, cedrol, shikimic acid) on hDPC cell proliferation (5. mu.M) after 24 hours (5. mu.M) combined with minoxidil at different ratios (1:3, 1:1, 3: 1).
FIG. 3 shows the effect of baicalin, cedrol and minoxidil, respectively, on hDPC cell proliferation 24 hours after single administration, baicalin-minoxidil 1:1 combination, and cedrol-minoxidil 1:1 combination (P <0.05, P < 0.01).
Figure 4 is a graph of the effect of different active ingredients on testosterone induced androgenic alopecia mouse hair regrowth: photographs of the skin of the back of mice taken at 0, 5, 10, 15, 21, 28 days after administration (a); dorsal dermal tissue was taken at day 18 post-dose for H&E dyeing (B); mean mouse regenerated hair length (C) (n ═ 9); the number ratio of hair follicles in the skin growth phase to hair follicles in the telogen phase (D) (n-3); (#P<0.05，##P<0.01, compared to the testosterone treated model group; p<0.05，**P<0.01)。
Detailed Description
The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application, and it is obvious that the described embodiments are some, but not all, embodiments of the present application. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.
As used in this specification and the claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.
As described in the background section, the existing common drugs for preventing and treating alopecia are prone to allergic dermatitis and have problems of local irritative reactions. In order to solve the above problems, the present invention provides a pharmaceutical composition for preventing and/or treating alopecia, which comprises minoxidil or a pharmaceutically acceptable non-covalent derivative thereof and a traditional Chinese medicine active ingredient, wherein the molar ratio of the minoxidil or the pharmaceutically acceptable non-covalent derivative thereof to the traditional Chinese medicine active ingredient or the pharmaceutically acceptable non-covalent derivative thereof is (1-3): (1-3).
The pharmaceutical composition has the advantages of high efficiency, low toxicity, small skin irritation, less adverse reaction, hair growth promotion and good alopecia prevention effect. Specifically, the pharmaceutical composition and the related proportion thereof show a synergistic effect in promoting the proliferation of human hair follicle papilla cells and a curative effect in resisting androgenetic alopecia in vivo.
The term "hair" or "hair" as used herein refers to hair, fur, facial hair and/or body hair, which broadly includes, but is not limited to, hair, eyelashes, eyebrows, moustaches, beards, earhairs, nasal hairs, chest hairs, pubic hairs, and the like.
In order to utilize the remarkable synergistic effect between the minoxidil or the pharmaceutically acceptable non-covalent derivative thereof and the traditional Chinese medicine active ingredient to promote hair regeneration, in a preferred embodiment, the molar ratio of the minoxidil or the pharmaceutically acceptable non-covalent derivative thereof to the traditional Chinese medicine active ingredient or the pharmaceutically acceptable non-covalent derivative thereof is (1-3): 1.
In order to obtain a stronger synergistic effect to promote hair regrowth, in a preferred embodiment, the molar ratio of the minoxidil or pharmaceutically acceptable non-covalent derivative thereof to the active ingredient of the traditional Chinese medicine or pharmaceutically acceptable non-covalent derivative thereof is 1: 1.
In a preferred embodiment, the molar ratio of the minoxidil or pharmaceutically acceptable non-covalent derivative thereof to the active ingredient of the traditional Chinese medicine or pharmaceutically acceptable non-covalent derivative thereof is about 1.
The term "about" as used herein is used herein to modify a numerical value and indicates a defined range around that value. If "X" is the value, "about X" is generally a value indicating from 0.90X to 1.10X. Whenever "about X" is mentioned, at least these values of X, 0.90X, 0.91X, 0.92X, 0.93X, 0.94X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, 1.05X, 1.06X, 1.07X, 1.08X, 1.09X, and 1.10X are indicated. Thus, "about X" is intended to disclose, for example, "0.98X". "about" may also include variations in the amount that a regulatory agency for a drug (e.g., NMPA, FDA, or EMEA) would consider bioequivalent to the required amount.
In a preferred embodiment, the pharmaceutically acceptable non-covalent derivative is a salt, solvate, co-crystal or mixture thereof.
The term "salt" as used herein refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al describe in detail the pharmaceutically acceptable salts in J.pharmaceutical Sciences (1977)66: 1-19. Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases.
The term "solvate" as used herein refers to a physical association of a compound of the invention and one or more solvent molecules. The physical association includes varying degrees of ionic and covalent bonding, including hydrogen bonding. In some examples, the solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "solvates" includes both solution phases and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. A "hydrate" is a solvate, wherein the solvent molecule is H2O。
The term "co-crystal" as used herein refers to a unique chemical composition between a drug and a coformer and generally has unique crystallographic and spectroscopic properties when compared to the drug and coformer alone. "cocrystals" are composed of multicomponent, stoichiometric, and neutral molecular species, each of which exists in solid form under ambient conditions. The co-crystals exhibit different properties than the free drug or salt. Solid forms can affect relevant physicochemical parameters such as solubility, dissolution rate of the drug, chemical stability, melting point, and hygroscopicity, which can result in the production of solids with superior properties.
In a preferred embodiment, the Chinese medicinal active ingredient is terpenoid and/or flavonoid.
In a preferred embodiment, the terpenoid is a sesquiterpene alcohol compound and/or a triterpenoid saponin compound.
In a preferred embodiment, the sesquiterpene alcohol compound is cedrol.
The natural component of the cedrol used in the invention has low toxicity and small skin irritation, and the combined administration can reduce the dosage of minoxidil, achieve the same curative effect and simultaneously avoid adverse reactions in the treatment process; and the cedrol has wide source and low cost, and can effectively reduce the treatment cost.
In a preferred embodiment, the triterpenoid saponin compound is ginsenoside Rb1Ginsenoside Rg1And/or ginsenoside Re.
In a preferred embodiment, the flavonoid is baicalin.
The natural component baicalin used in the invention has the functions of antioxidation, anti-aging, anti-tumor and antivirus, and has the function of inducing the secretion of vascular endothelial growth factors to promote the growth of hair follicles.
The above mentioned terpenoids and flavonoids are only exemplified by the present invention, and other terpenoids and flavonoids known in the art to be useful for preventing and treating alopecia should be included.
In a preferred embodiment, the pharmaceutical composition further comprises one or more hair growth promoting substances.
In a preferred embodiment, the hair growth substance is a 5 α -reductase inhibitor, an androgen receptor antagonist, a prostaglandin analog, autologous platelet rich plasma, a complex growth factor, a herbal compound, a herbal extract, or a herbal monomer compound and its derivatives, wherein the herbal monomer compound and its derivatives are not the terpenoid and the flavonoid.
In a preferred embodiment, the 5 α -reductase inhibitor is finasteride, dutasteride, epristeride, azelaic acid, β -sitosterol, zinc and/or vitamin B6.
In a preferred embodiment, the androgen receptor antagonist is spironolactone, cyproterone acetate, ketoconazole, nilutamide, bicalutamide and/or flutamide.
In a preferred embodiment, the prostaglandin analogue is bimatoprost, travoprost and/or latanoprost.
In a preferred embodiment, the Chinese medicine is arborvitae, polygonum multiflorum, shikimic acid, agrimony, cypress, safflower, sophora flavescens, nettle, ramose scouring rush, angelica, fig leaves and/or scutellaria baicalensis.
In a preferred embodiment, the monomeric compound of traditional Chinese medicine and its derivatives are myristic acid, capsaicin and/or curcumin.
According to another aspect of the present invention, there is provided a pharmaceutical formulation comprising the above pharmaceutical composition, the pharmaceutical formulation comprising one or more pharmaceutically acceptable carriers, diluents or excipients.
In a preferred embodiment, the carrier is selected from one or more of the following: nanospheres, nanocapsules, dendrimers, nanofibers, nanosponges, micelles, nanogels, nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers, liposomes, niosomes, transfersomes, ethosomes, mesoporous silica nanoparticles, metal organic frameworks, metal nanoparticles and nanocrystals.
In a preferred embodiment, the diluent is selected from one or more of the following: water, ethanol, propylene glycol and glycerol.
In a preferred embodiment, the diluent is a mixed solution of ethanol and propylene glycol in a volume ratio of 7: 3.
In a preferred embodiment, the excipient is selected from one or more of the following: lactose, starch, cellulose and sodium citrate.
In a preferred embodiment, the pharmaceutical formulation further comprises one or more cosmetically/dermatologically acceptable carriers, diluents, or excipients known to the skilled person.
In a preferred embodiment, the pharmaceutical preparation is in the form of injection, lyophilized powder for injection, tincture, solution, lotion, rinse, liniment, patch, ointment, emulsion, aerosol, drop, gel, microneedle, controlled release agent or sustained release agent.
In a preferred embodiment, the pharmaceutical preparation is administered transdermally or intradermally.
In a preferred embodiment, the pharmaceutical preparation can be applied to the skin (any area of the skin of the body), the hair or mucous membranes.
According to another aspect of the present invention, there is provided a use of the above pharmaceutical composition or the above pharmaceutical preparation for the preparation of a medicine, health product and/or food for preventing and/or treating alopecia, and/or improving hair follicle and/or hair health, and/or promoting hair regeneration and/or growth.
The terms "prevention" and "treatment" as used herein refer to: (1) preventing or delaying the onset of clinical symptoms of the state, disorder, or condition developing in a mammal that is suffering from or susceptible to the state, disorder, or condition but has not experienced or exhibited clinical or subclinical symptoms of the state, disorder, or condition, (2) inhibiting the state, disorder, or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof, or (3) ameliorating the disease, i.e., resolving the state, disorder, or condition or at least one clinical or subclinical symptom thereof.
The pharmaceutical composition or pharmaceutical preparation of the present invention can be prepared in the form of tea, juice and drink as it is, and can be ingested in the form of granules, capsules and powders as health products or foods. In addition, the health care product or food of the present invention can be prepared in the form of a composition by mixing with known substances or active ingredients known to have an effect of promoting hair growth or preventing or improving hair loss.
In a preferred embodiment, the alopecia is androgenetic alopecia, alopecia areata, female pattern alopecia, acute and chronic telogen effluvium, chemotherapy and radiotherapy induced alopecia, seborrheic alopecia and/or scarring alopecia.
In a preferred embodiment, the pharmaceutical composition or pharmaceutical formulation promotes proliferation of human hair follicle papilla cells, promotes differentiation of mammalian hair follicles, and induces a transition of resting-phase hair follicles to anagen phase.
In a preferred embodiment, the mass concentration of minoxidil or a pharmaceutically acceptable non-covalent derivative thereof and the active ingredient of a traditional Chinese medicine in the medicine, health product and/or food is about 2%.
In a preferred embodiment, the drugs for the individual administration of the different active ingredients (baicalin, cedrol, shikimic acid, minoxidil) are present in the culture medium at a final concentration of: 0.5, 5, 50, 100, 250. mu.M.
In a preferred embodiment, baicalin, cedrol and shikimic acid are co-administered with minoxidil at different molar ratios (1:1, 1:3, 3:1) respectively, with the drug at a final concentration of 5 μ M in the culture medium.
In a preferred embodiment, baicalin, cedrol and minoxidil are administered separately and baicalin and cedrol are administered in combination with minoxidil at a ratio of 1:1, respectively, to a final concentration of 5 μ M in the culture medium.
According to another aspect of the present invention, there is provided a method for preventing and/or treating hair loss, and/or improving hair follicles and/or maintaining hair health, and/or promoting hair regrowth and/or growth, which comprises administering to a subject in need thereof an effective amount of the above-described pharmaceutical composition or pharmaceutical preparation.
In a preferred embodiment, the above pharmaceutical composition or pharmaceutical preparation can be used in combination with non-pharmaceutical treatment means in the treatment of alopecia, including (but not limited to): hair Transplantation (HT), autologous Platelet Rich Plasma (PRP), low energy laser therapy (LLLT), stem cell therapy, and the like. Combination therapy of the pharmaceutical composition with other non-pharmaceutical therapeutic means is also within the scope of the present invention.
The term "administration" as used herein refers to the act of administering a drug, prodrug, or other active agent, or therapeutic treatment (e.g., a pharmaceutical composition or pharmaceutical formulation of the invention) to a subject. An exemplary route of administration to the human body may be on the skin, e.g., on the scalp. Administration may be one or more administrations, administrations or servings and is not intended to be limited to a particular period of time. "administration" and "administering" are behaviors used to describe "administration" and are used synonymously.
The term "effective amount" as used herein refers to an amount representing an ameliorating, therapeutic or prophylactic effect of alopecia and an effect of promoting hair growth when administered to an individual, and the term "subject" includes animals, preferably mammals, and particularly animals that may include humans, cells, tissues, organs, etc. of animal origin.
The invention is further illustrated by the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The reagents, equipment, cells, animals and experimental methods used in the following examples are conventional and standard in the art.
Examples
Example 1: effect of active ingredients on human Hair follicle papilla cell proliferation
1.1 Experimental cell lines
Human hair follicle papilla cells (hDPC cells) were purchased from Shanghai, New Biotech, Inc. (Shanghai, China).
1.2 instruments and materials
Agilent 1260Infinity high performance liquid chromatograph (Agilent, USA); agilent 7890A gas chromatograph (Agilent corporation, usa); synergy HT multifunctional microplate reader (Bio-Tek, USA); HP-5 gas chromatography column (Agilent, USA); diamonsil Plus C18 chromatography column (dimales technologies ltd); CP 225D micro electron analytical balance (Sartorius, germany); SB-5200D ultrasonic cleaning machine (Ningbo Xinzhi Biotech Co., Ltd.); SMZ168-TLED stereomicroscope (Motic Corp.); Milli-Q water purifier (Millipore, USA).
Minoxidil (batch No. 38304-91-5, Shanghai-sourced leaf Biotech Co., Ltd.); baicalin (batch No. 21967-41-9, Dalian Meiren Biotechnology Co., Ltd.); cedrol (batch No. 77-53-2, Shanghai Aladdin Biotechnology Ltd.); shikimic acid (batch 138-59-0, Shanghai Aladdin Biotechnology Ltd.); finasteride (batch No. 98319-26-7, Shanghai-derived leaf Biotech Co., Ltd.).
1.3 cell culture
Inoculating human hair follicle papilla cells into culture flask at appropriate concentration, adding DMEM high-sugar incomplete culture medium containing 10% fetal calf serum, 1% penicillin and streptomycin, placing at 37 deg.C and 5% CO2Culturing in an incubator, and allowing cells to grow adherently. Cells in logarithmic growth phase were taken for experiments.
1.4 cell proliferation assay
hDPC cells were cultured at 2X 104Density per well was plated in parallel to 96 well plates and incubators were incubated for 12 h. Adding a drug-containing culture medium, adding a culture medium containing 0.3% DMSO into a control group, continuously incubating for 24h, removing the culture medium by aspiration, washing with PBS for 2 times, adding 90 mu L of culture medium and 10 mu L of CCK-8, incubating for 2.5h in the dark, measuring OD value at 450nm, and calculating the cell survival rate according to formula 1.
Wherein, the final concentration of the drug which is independently administrated by different active ingredients (baicalin, cedrol, shikimic acid and minoxidil) in the culture medium is as follows: 0.5, 5, 50, 100, 250 μ M;
respectively co-administering baicalin, cedrol and shikimic acid with minoxidil at different molar ratios (1:1, 1:3 and 3:1) to obtain a final concentration of 5 μ M in culture medium;
baicalin, cedrol and minoxidil are respectively and independently administered, and baicalin and cedrol are respectively and jointly administered with minoxidil according to the proportion of 1:1, and the final concentration of the medicine in a culture medium is 5 mu M.
Figure BDA0003282276760000111
ODAdministration of drugsIs the absorbance value of the cells of the administration group; ODControlThe absorbance value of the control group cells; ODBlank spaceThe absorbance value of the cell-free group was obtained.
1.5 results of the experiment
As shown in figure 1, baicalin, cedrol and shikimic acid have no cytotoxicity to hDPC cells within the concentration range of 0.5-250 μ M, and can play a role in promoting cell proliferation under a certain concentration. In addition, the minoxidil has no cytotoxicity to hDPC cells within the concentration range of 0.5-250 mu M.
As shown in figure 2, the combination of baicalin-minoxidil 1:1 and cedrol-minoxidil 1:1 can synergistically improve the activity of hDPC cells, and the synergistic effect is the best. In addition, the combination of the cedrol and the minoxidil 1:3 can also synergistically improve the activity of hDPC cells, and the effect is slightly weaker than that of the combination of 1:1, but is obviously better than that of the combination of the cedrol and the minoxidil 3: 1.
As shown in figure 3, the synergistic effect of baicalin and minoxidil, and cedrol and minoxidil in promoting hDPC cell proliferation is further verified, and is remarkably superior to that of single administration.
The invention provides a combined administration mode of matching the traditional Chinese medicine active ingredients with different action mechanisms with minoxidil, and provides the condition of promoting the proliferation of cells under a specific proportion.
Example 2: in vivo pharmacodynamic examination of active substances
2.1 animals
Seven week old, SPF grade C57BL/6 mice were purchased from the laboratory animal center of Shanghai university of medicine and were bred under standard conditions of 23 + -2 deg.C temperature and 55 + -10% relative humidity using a license SYXK (Shanghai) 20200009, all animal experiments were performed according to the provisions of the ethical Committee for laboratory animals of Shanghai university of medicine (review number: PZSHHUTCM 200731006).
2.2 in vivo pharmacodynamic examination of antiandrogen alopecia
C57BL/6 mice were anesthetized with 1g/kg of ulinase and 6cm with thioglycolic acid2The area of skin was depilated and the thioglycolic acid was washed off with clear water and the next day the dose was started. The preparation method comprises preparing 0.5% Testosterone (TES) solution with 50% ethanol solution, and preparing each drug with 2% concentration in ethanol-propylene glycol (70:30), smearing 200 μ L each time, and continuously administering for 28 days.
Grouping:
1. a normal group;
2. model group (testosterone treatment group);
3. minoxidil + testosterone group;
4. cedrol + testosterone group;
5. minoxidil-cedrol + testosterone group (wherein the molar ratio of minoxidil to cedrol is 1: 1).
The testosterone-containing groups were each applied to the skin with 0.5% testosterone 1h prior to dosing. Daily photographs were taken, from the beginning of the day of depilation, mice were sacrificed on day 18 after the administration, H & E sections were taken from their back skin, hair follicle analysis was performed to calculate the ratio of the number of hair follicles in anagen phase/telogen phase, and after the end of administration, a total of 9 hairs were plucked from 3 different sites of the shaved area, and the length of the hairs was measured.
2.3 results of the experiment
As shown in fig. 4, compared with the minoxidil group and the cedrol group, each of the indices (the coverage of the contemporary hair, the length of the regenerated hair, and the proportion of the anagen/telogen hair follicles) of the cedrol-minoxidil combination group was improved and had statistical differences. The combination of cedrol and minoxidil is proved to be capable of synergistically enhancing the capacity of promoting hair regeneration by resisting the interference of androgen on hair follicles and inducing the hair follicles in the resting stage to be converted to the growth stage by promoting the differentiation of the hair follicles, thereby effectively preventing and treating alopecia with the curative effect superior to that of single administration and no obvious adverse reaction of skin occurs in the treatment process.
The foregoing detailed description of the embodiments of the present application has been presented to illustrate the principles and implementations of the present application, and the description of the embodiments is only intended to facilitate the understanding of the methods and their core concepts of the present application. Also, variations, combinations, and equivalents of the specific embodiments, methods, and examples herein will be understood and appreciated by those of ordinary skill in the art. Thus, the compounds, uses and methods provided herein should not be limited by the above-described embodiments, methods or examples, but rather should encompass all embodiments and methods within the scope and spirit of the compounds, uses and methods provided herein. In view of the above, the description should not be taken as limiting the application.

Claims (10)

1. A pharmaceutical composition for preventing and/or treating alopecia, which comprises minoxidil or a pharmaceutically acceptable non-covalent derivative thereof and a traditional Chinese medicine active ingredient or a pharmaceutically acceptable non-covalent derivative thereof, wherein the molar ratio of the minoxidil or the pharmaceutically acceptable non-covalent derivative thereof to the traditional Chinese medicine active ingredient or the pharmaceutically acceptable non-covalent derivative thereof is (1-3): 1-3.
2. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable non-covalent derivative is a salt, solvate, co-crystal, or mixture thereof.
3. The pharmaceutical composition according to claim 1, wherein the molar ratio of minoxidil or a pharmaceutically acceptable non-covalent derivative thereof to the active ingredient of the traditional Chinese medicine or a pharmaceutically acceptable non-covalent derivative thereof is (1-3): 1;
preferably, the molar ratio of said minoxidil or pharmaceutically acceptable non-covalent derivative thereof to said traditional Chinese medicine active ingredient or pharmaceutically acceptable non-covalent derivative thereof is about 1;
preferably, the active ingredients of the traditional Chinese medicine are terpenoids and/or flavonoids;
more preferably, the terpenoids are sesquiterpene alcohols and/or triterpenoid saponins;
particularly preferably, the sesquiterpene alcohol compound is cedrol;
particularly preferably, the triterpenoid saponin compound is ginsenoside Rb1Ginsenoside Rg1And/or ginsenoside Re;
particularly preferably, the flavonoid compound is baicalin.
4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition further comprises one or more hair growth promoting substances;
preferably, the substance for promoting hair growth is a 5 alpha-reductase inhibitor, an androgen receptor antagonist, a prostaglandin analogue, autologous platelet rich plasma, a complex growth factor, a compound Chinese medicine preparation, a Chinese medicine extract, or a Chinese medicine monomer compound and a derivative thereof, wherein the Chinese medicine monomer compound and the derivative thereof are not the terpenoid compound and the flavonoid compound;
more preferably, the 5 α -reductase inhibitor is finasteride, dutasteride, epristeride, azelaic acid, β -sitosterol, zinc and/or vitamin B6;
more preferably, the androgen receptor antagonist is spironolactone, cyproterone acetate, ketoconazole, nilutamide, bicalutamide and/or flutamide;
more preferably, the prostaglandin analogue is bimatoprost, travoprost and/or latanoprost;
more preferably, the Chinese medicine is arborvitae, polygonum multiflorum, grass, agrimony, cypress, safflower, sophora flavescens, nettle, pipewort, angelica, fig leaves and/or scutellaria;
more preferably, the traditional Chinese medicine monomer compound and the derivative thereof are myristic acid, capsaicin and/or curcumin.
5. A pharmaceutical formulation comprising a pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical formulation comprises one or more pharmaceutically acceptable carriers, diluents or excipients.
6. The pharmaceutical formulation of claim 5, wherein the carrier is selected from one or more of the following: nanospheres, nanocapsules, dendrimers, nanofibers, nanosponges, micelles, nanogels, nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers, liposomes, niosomes, transfersomes, ethosomes, mesoporous silica nanoparticles, metal organic frameworks, metal nanoparticles and nanocrystals;
preferably, the diluent is selected from one or more of the following: water, ethanol, propylene glycol and glycerol;
preferably, the diluent is a mixed solution of ethanol and propylene glycol in a volume ratio of 7: 3;
preferably, the excipient is selected from one or more of the following: lactose, starch, cellulose and sodium citrate.
7. The pharmaceutical preparation according to claim 5 or 6, wherein the pharmaceutical preparation is in the form of injection, lyophilized powder for injection, tincture, solution, lotion, rinse, liniment, patch, ointment, emulsion, aerosol, drops, gel, microneedle, controlled release agent or sustained release agent;
preferably, the pharmaceutical formulation is administered transdermally or intradermally.
8. Use of the pharmaceutical composition of any one of claims 1 to 4 or the pharmaceutical formulation of any one of claims 5 to 7 for the preparation of a medicament, nutraceutical and/or food product for preventing and/or treating hair loss, and/or improving hair follicle and/or hair health, and/or promoting hair regeneration and/or growth.
9. Use according to claim 8, characterized in that the alopecia is androgenetic alopecia, alopecia areata, female pattern alopecia, acute and chronic telogen effluvium, chemotherapy and radiotherapy induced alopecia, seborrheic alopecia and/or cicatricial alopecia.
10. Use according to claim 8 or 9, wherein the pharmaceutical composition or pharmaceutical preparation promotes proliferation of human hair follicle papilla cells, promotes differentiation of mammalian hair follicles and induces a transition of hair follicles in the telogen phase to the anagen phase;
preferably, the mass concentration of the minoxidil or the pharmaceutically acceptable non-covalent derivative thereof and the traditional Chinese medicine active ingredients in the medicine, health care product and/or food is about 2%.
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WO2023101256A1 (en) * 2021-12-03 2023-06-08 주식회사 팜어스바이오사이언스 5-alpha-reductase inhibitor, pharmaceutically acceptable salt thereof, and use thereof
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