WO2021213485A1 - 蒲公英及其单体化合物在杀螨中的应用 - Google Patents

蒲公英及其单体化合物在杀螨中的应用 Download PDF

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Publication number
WO2021213485A1
WO2021213485A1 PCT/CN2021/089110 CN2021089110W WO2021213485A1 WO 2021213485 A1 WO2021213485 A1 WO 2021213485A1 CN 2021089110 W CN2021089110 W CN 2021089110W WO 2021213485 A1 WO2021213485 A1 WO 2021213485A1
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dandelion
mites
eye
preparation
demodex
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PCT/CN2021/089110
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English (en)
French (fr)
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张岩
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珠海岐微生物科技有限公司
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Priority to JP2022564790A priority Critical patent/JP2023522772A/ja
Priority to US17/920,734 priority patent/US20230165921A1/en
Priority to EP21791867.1A priority patent/EP4129314A4/en
Publication of WO2021213485A1 publication Critical patent/WO2021213485A1/zh

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A61K36/288—Taraxacum (dandelion)
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N31/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic oxygen or sulfur compounds
    • A01N31/06—Oxygen or sulfur directly attached to a cycloaliphatic ring system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N35/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical
    • A01N35/06—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical containing keto or thioketo groups as part of a ring, e.g. cyclohexanone, quinone; Derivatives thereof, e.g. ketals
    • A—HUMAN NECESSITIES
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    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/02—Saturated carboxylic acids or thio analogues thereof; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/36—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids
    • A01N37/38—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids having at least one oxygen or sulfur atom attached to an aromatic ring system
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/14—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings
    • A01N43/16—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings with oxygen as the ring hetero atom
    • A—HUMAN NECESSITIES
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    • A01N45/00—Biocides, pest repellants or attractants, or plant growth regulators, containing compounds having three or more carbocyclic rings condensed among themselves, at least one ring not being a six-membered ring
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    • A—HUMAN NECESSITIES
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    • A01N65/00—Biocides, pest repellants or attractants, or plant growth regulators containing material from algae, lichens, bryophyta, multi-cellular fungi or plants, or extracts thereof
    • A01N65/08—Magnoliopsida [dicotyledons]
    • A01N65/12—Asteraceae or Compositae [Aster or Sunflower family], e.g. daisy, pyrethrum, artichoke, lettuce, sunflower, wormwood or tarragon
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P7/00—Arthropodicides
    • A01P7/02—Acaricides
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
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    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
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    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
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Definitions

  • the present invention relates to the technical field of medicine and daily care, in particular to the application of dandelion and its monomer compounds, especially taraxacum acerol, geraniol, and dandelion sterol acetate, in killing mites.
  • Mites belong to a class of tiny animals in the Arthropod phylum Arachnida.
  • the body size is generally about 0.5 mm, some as small as 0.1 mm, and most species are less than 1 mm. It has been found that the mites have a very close relationship with the health of humans and animals (such as dogs, cats and other pets), such as gamma mites, chiggers, scabies, demodex mites, acaroid mites, dust mites and tarsal mites can suck blood and damage the skin. Cause "rosacea" or demodex, allergies, urinary tract mites, lung mites, intestinal mites and scabies, etc., seriously endangering the health of humans and animals.
  • Demodex mites (belonging to Arachnid and Acarina) are microscopic ectoparasites that usually infect the sebaceous gland units of the skin hair follicles.
  • Demodex folliculorum and Demodex sebaceous have been found on human body surfaces, and they mainly reside in hair follicles, sebaceous glands, and meibomian glands.
  • Demodex can swallow epithelial cells of hair follicles, cause hair follicle expansion and hair loss, manifested as clinical blepharitis, meibomian gland dysfunction, eyelash loss, abnormal eyelash alignment, conjunctivitis and blepharoconjunctivitis, pterygoid Pterygium, keratitis, basal cell carcinoma of the eyelid, etc.
  • Demodex can also swallow lipids and cause dry eyes.
  • demodex mites can also cause obstruction of the meibomian gland discharge duct through mechanical obstruction, causing difficulty in lipid discharge and excessive secretion retention, leading to the formation of chalazion.
  • demodex infection of eye disease mainly include: recurrent red and itchy eye edges; dry eyes, eye burning sensation, eye foreign body sensation, photophobia, increased secretion; may be accompanied by repeated eyelash loss; severe cases involving cornea There may be blurred vision and decreased vision.
  • Demodex infection is related to a variety of common skin diseases, including seborrheic dermatitis, acne, rosacea, pityriasis follicularis, perioral dermatitis, demodex, and basal cells. Cancer etc.
  • Demodex mites are often located in the sebaceous glands and meibomian glands. It occupies the human eyelash follicles and can cause eye disease when it infects the skin of the face.
  • Ocular Demodicosis as a Potential Cause of Ocular Surface Inflammation (Cornea 36 Suppl 1(Suppl 1): s9-s14) proves that Demodex short and Demodex folliculorum are two kinds of Demodex that cause ocular mitosis in humans. There is a positive correlation between human age and the risk of disease, and there is a strong positive correlation between eye mite disease and ocular surface inflammation.
  • Demodex species in human ocular disease new clinical pathological aspects (International ophthalmology 37(1): 303-312) Studies have shown that Demodex short mites and Demodex folliculorum are related to the pathogenesis of external eye diseases, and ocular acariasis can cause extraocular diseases. The ecological environment is out of balance.
  • Ocular Demodex a systematic review of the clinical literature (Ophthalmic&physiological optics:the journal of the British College of Ophthalmic Opticians(Optometrists)40(4):389-432) describes the potential cause of demodex infection as a potential cause of ocular surface diseases. Demodex parasites on the front structures of the eyes, such as the eyelids, eyelashes and ocular surface, will cause eye mites in humans and the incidence is positively correlated with age.
  • demodex The relationship between demodex and ocular discomfort (Investigative ophthalmology & visual science 51(6): 2906-2911) proposed that the number of demodex mites is positively correlated with the severity of eye disease and the age of the patient.
  • Demodex mites (Clinics in dermatology 32(6):739-743) proposed that Demodex infection can cause chronic blepharitis, and the prevalence of chronic blepharitis is positively correlated with the number of mites and the age of the patient.
  • Demodex is a carrier of Bacillus, which can play a role in the pathogenesis of blepharitis as a co-pathogen.
  • Bacillus oleronius and Demodex mite infection in patients with chronic blepharitis (Clinical microbiology and infection: the official publication of the European Society of Clinical Microbiology and Infectious Diseases 1020-1025) Occurrence, and it is a carrier of Bacillus, which can act as a co-pathogen in the development of blepharitis.
  • the first aspect of the present invention provides an application of dandelion in the preparation of acaricidal products.
  • the above-mentioned dandelion can be used as the only acaricidal active component, and can also be combined with other components with the same or different activities to kill acaricides.
  • the second aspect of the present invention provides an application of dandelion extract in the preparation of acaricide products.
  • the above-mentioned dandelion extract can be obtained by an appropriate traditional Chinese medicine extraction method known in the art, such as one of decoction, dipping, soaking, refluxing, steam distillation, ultrasonic extraction, etc. Multiple combinations.
  • the above-mentioned dandelion extract can be obtained by decoction.
  • the above-mentioned dandelion extract is prepared by a method including the following steps:
  • step (2) Heat the mixture of step (1) to boiling, then decoct and filter.
  • the aforementioned extraction solvent is water.
  • the soaking time is 1-24 hours (specifically, 1, 2, 3, 4, 5, 6, 12, 18, 24 hours).
  • the decoction time is 10-60 minutes (specifically, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 minutes).
  • the above method may further include:
  • step (3) The filter residue obtained in step (2) and the extraction solvent are heated to boiling, then decocted and filtered; the filtrate obtained in steps (2) and (3) are combined.
  • the above method may further include one or more of processing steps such as mixing, concentrating, quantifying, and sterilizing the obtained filtrate.
  • the above-mentioned dandelion extract contains one or more of dandelion sterol, taraxacilol, taraxazone, geraniol, taraxerol acetate, caffeic acid, acetyl taraxacum terpene alcohol, and lupeenone.
  • the above-mentioned dandelion extract contains one or more of taraxerol, geraniol, and taraxerol acetate.
  • the third aspect of the present invention provides an application of a dandelion monomer compound or its salt, isomer, solvate, or derivative in the preparation of acaricidal products.
  • the salts, isomers, solvates, and derivatives of the aforementioned dandelion monomer compound are pharmaceutically acceptable corresponding salts, isomers, solvates, and derivatives.
  • the above-mentioned monomer compound is selected from one or more of dandelion sterol, taraxerol, taraxerone, geraniol, taraxerol acetate, caffeic acid, acetyl taraxerol, and lupenone.
  • the above-mentioned monomer compound is selected from one or more of taraxerol, geraniol, and taraxerol acetate.
  • the fourth aspect of the present invention provides an application of taraxarol in the preparation of acaricidal products.
  • the fifth aspect of the present invention provides an application of geraniol in the preparation of acaricidal products.
  • the sixth aspect of the present invention provides an application of dandelion sterol acetate in the preparation of acaricidal products.
  • the above-mentioned acaricidal products of the present invention can be used for therapeutic/or preventive purposes, and can also be used for non-therapeutic/or preventive purposes.
  • the aforementioned mites of the present invention may be one or more of Demodex mites, dust mites, and scabies mites.
  • the above-mentioned mites of the present invention are Demodex mites, such as Demodex folliculorum and Demodex sebaceous.
  • the above-mentioned acaricidal product of the present invention is a pharmaceutical composition.
  • the above-mentioned pharmaceutical composition further comprises pharmaceutically acceptable excipients.
  • the above-mentioned pharmaceutical composition of the present invention is used to prevent and/or treat diseases caused by mite infection.
  • the aforementioned diseases may be eye diseases, skin diseases, allergic diseases, and the like.
  • the above-mentioned eye diseases may be blepharitis, meibomian gland dysfunction, meibomitis, eyelash loss, abnormal eyelash alignment, glaucoma, cataracts, ocular folliculitis, conjunctivitis, blepharoconjunctivitis, pterygium, One or more of keratitis, eyelid sagging and ectropion, basal cell carcinoma of the eyelid, dry eye, chalazion, etc.; it may have one or more symptoms selected from the following: red and itchy eyes, dry eyes , Eye burning, foreign body sensation, photophobia, increased ocular secretions, eyelash loss, blurred vision, decreased vision, etc.
  • the aforementioned skin disease may be one or more of seborrheic dermatitis, acne, rosacea, pityriasis follicularis, perioral dermatitis, demodicosis, scabies, basal cell carcinoma, and the like.
  • the above-mentioned allergic disease may be one or more of allergic asthma, allergic rhinitis, allergic dermatitis, and the like.
  • the above-mentioned pharmaceutical composition may be in any dosage form suitable for administration, such as an external preparation, especially an ophthalmic preparation, an external preparation for the skin, and the like.
  • the above-mentioned ophthalmic preparations may be eye drops, eye ointments, ophthalmic gels, ophthalmic emulsions, ophthalmic suspensions, ophthalmic membranes, eye washes, intraocular injections, and the like.
  • the ophthalmic preparations may include pharmaceutically acceptable excipients, such as pH regulators, solubilizers, osmotic pressure regulators, viscosity regulators, antioxidants, bacteriostatic preservatives, buffers, suspending agents, Local anesthetics, surfactants, solubilizers, wetting agents, emulsifiers, stabilizers, fillers, protective agents, solvents, etc.
  • pharmaceutically acceptable excipients such as pH regulators, solubilizers, osmotic pressure regulators, viscosity regulators, antioxidants, bacteriostatic preservatives, buffers, suspending agents, Local anesthetics, surfactants, solubilizers, wetting agents, emulsifiers, stabilizers, fillers, protective agents, solvents, etc.
  • the above-mentioned external preparations for skin may be aerosols, powders, lotions, tinctures, liniments, coatings, ointments, gels, pastes, emulsions, and the like.
  • the various dosage forms of the above-mentioned pharmaceutical composition of the present invention can be prepared according to conventional production methods in the pharmaceutical field.
  • the ophthalmic preparation technology can use “Ophthalmology Medicine and Pharmacy” (China Light Industry Press, 2010), “Development and Production of Eye Drops” (Chemical Industry Press, 2009), etc.
  • the above-mentioned pharmaceutical composition of the present invention may contain 0.01-99.5% by weight (specifically, 0.01%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7 %, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5%) active ingredients.
  • the above-mentioned pharmaceutical composition can be used for humans, and can also be used as a veterinary medicine for non-human animals, such as non-human mammals, such as pet animals (such as dogs, cats, rabbits, rats, etc.), livestock animals (such as, Horses, cows, sheep, pigs, dogs, rabbits, etc.) and other animals.
  • non-human mammals such as pet animals (such as dogs, cats, rabbits, rats, etc.), livestock animals (such as, Horses, cows, sheep, pigs, dogs, rabbits, etc.) and other animals.
  • the above-mentioned acaricide products of the present invention are cosmetics.
  • the aforementioned cosmetics also include auxiliary materials acceptable in the cosmetics field.
  • the aforementioned cosmetics of the present invention may be cosmetics for the face, such as facial cleansers, soaps, softeners, toners, skin care lotions, gels, creams, sunscreens, essences, facial masks, gels, liquid foundations, scrubs paste.
  • cosmetics for the face such as facial cleansers, soaps, softeners, toners, skin care lotions, gels, creams, sunscreens, essences, facial masks, gels, liquid foundations, scrubs paste.
  • the aforementioned cosmetics of the present invention may be cosmetics for other parts of the face, such as neck cream, shampoo, shower gel, soap, conditioner, body lotion, scrub and the like.
  • the aforementioned cosmetics of the present invention may also be cosmetics for the eyes and around the eyes, such as eye cream, mascara, eyeliner powder, eyeliner, eyeliner, eye shadow powder, eye shadow cream, eyebrow pencil, eyebrow powder and the like.
  • the various forms of the aforementioned cosmetics of the present invention can be prepared according to conventional production methods in the cosmetics field.
  • the aforementioned cosmetics of the present invention may contain 0.01-99.5% by weight (specifically, 0.01%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5%) active ingredients.
  • the above-mentioned acaricide products of the present invention are acaricides, which can be used to kill and inhibit items in the living environment (eg, pillowcases, pillow cores, bed sheets, bedding, mattresses, clothing, carpets). , Cushions, sofas, summer mats, plush toys, air conditioners, etc.) may live in mites.
  • acaricides which can be used to kill and inhibit items in the living environment (eg, pillowcases, pillow cores, bed sheets, bedding, mattresses, clothing, carpets).
  • Cushions, sofas, summer mats, plush toys, air conditioners, etc.) may live in mites.
  • the above-mentioned acaricide may contain any suitable auxiliary materials that can achieve the desired performance.
  • the above-mentioned acaricide may be in the form of sprays, lotions, patches, small packages, and the like.
  • the various forms of the above-mentioned acaricides of the present invention can be prepared according to conventional production methods in the field of daily care products.
  • the above-mentioned acaricide of the present invention may contain 0.01-99.5% by weight (specifically, 0.01%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7 %, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5%) active ingredients.
  • the present invention also provides a method for preventing and/or treating diseases caused by mite infections, which comprises administering dandelion, or extracts thereof, monomer compounds (especially taraxacilol, geraniol) to a subject in need thereof And dandelion sterol acetate) or the above-mentioned pharmaceutical composition of the present invention.
  • the aforementioned diseases may be eye diseases, skin diseases, allergic diseases, and the like.
  • the above-mentioned eye diseases may be blepharitis, meibomian gland dysfunction, meibomitis, eyelash loss, abnormal eyelash alignment, glaucoma, cataracts, ocular folliculitis, conjunctivitis, blepharoconjunctivitis, pterygium, One or more of keratitis, eyelid sagging and ectropion, basal cell carcinoma of the eyelid, dry eye, chalazion, etc.; it may have one or more symptoms selected from the following: red and itchy eyes, dry eyes , Eye burning, foreign body sensation, photophobia, increased ocular secretions, eyelash loss, blurred vision, decreased vision, etc.
  • the aforementioned skin disease may be one or more of seborrheic dermatitis, acne, rosacea, pityriasis follicularis, perioral dermatitis, demodicosis, scabies, basal cell carcinoma, and the like.
  • the above-mentioned allergic disease may be one or more of allergic asthma, allergic rhinitis, allergic dermatitis, and the like.
  • the aforementioned subject may be any animal receiving the prevention and/or treatment, particularly mammals, such as humans, cats, dogs, rabbits, mice, horses, cattle, sheep, pigs, and the like.
  • the above-mentioned subject is a human; in another embodiment of the present invention, the above-mentioned subject is a non-human animal.
  • the dosage of the above-mentioned dandelion, its extracts, its monomeric compounds (especially taraxarol, geraniol, and dandelion sterol acetate) or the above-mentioned pharmaceutical composition of the present invention can be based on the route of administration and the subject’s Changes in age, weight, type and severity of the disease to be treated, etc., can be administered one or more times.
  • the seventh aspect of the present invention provides the application of dandelion, dandelion extract, dandelion monomer compound or salt, isomer, solvate, and derivative thereof in the preparation of medicines for treating and/or preventing eye diseases caused by mites.
  • the eighth aspect of the present invention provides a method of treating and/or preventing ocular diseases caused by mites, the method comprising administering dandelion, dandelion extract, dandelion monomer compound or the ophthalmic administration to a subject in need thereof Steps of salts, isomers, solvates, derivatives.
  • the aforementioned subject may be any animal receiving the prevention and/or treatment, particularly mammals, such as humans, cats, dogs, rabbits, mice, horses, cattle, sheep, pigs, and the like.
  • the above-mentioned subject is a human; in another embodiment of the present invention, the above-mentioned subject is a non-human animal.
  • the ocular administration is in the form of eye drops, eye ointments, eye gels, eye emulsions, eye suspensions, eye membranes, eye washes, and intraocular injections.
  • the above-mentioned eye diseases may be blepharitis, meibomian gland dysfunction, meibomitis, eyelash loss, abnormal eyelash alignment, glaucoma, cataracts, ocular folliculitis, conjunctivitis, blepharoconjunctivitis, pterygium, One or more of keratitis, eyelid sagging and ectropion, basal cell carcinoma of the eyelid, dry eye, chalazion, etc.; it may have one or more symptoms selected from the following: red and itchy eyes, dry eyes , Eye burning, foreign body sensation, photophobia, increased ocular secretions, eyelash loss, blurred vision, decreased vision, etc.
  • the relationship between mites and eye diseases has been proven by the following documents:
  • Ophthalmic&physiological optics the journal of the British College of Ophthalmic Opticians (Optometrists) 40(4): 389-432.
  • Herpes virus keratitis, recurrent keratitis, herpes keratitis, dry eye disease, blepharitis, meibomitis, meibomian gland cyst, basal cell carcinoma, glaucoma, cataract, ocular folliculitis, chronic and recurrent eyelids Limb inflammation, keratitis, eyelid inflammation, eyelash disorders, and relaxation Meibomian gland dysfunction, blepharoconjunctivitis, meibomian conjunctivitis , Herpes virus keratitis, recurrent keratitis, herpes keratitis, dry eye disease, blepharitis, meibomitis, meibomian gland cyst, basal cell carcinoma, glaucoma, cataract, ocular folliculitis, chronic and re
  • dandelion By comparing the killing effects of multi-flavored Chinese medicinal materials on mites, it was found that dandelion can effectively reduce the survival time of mites, and a variety of dandelion monomer compounds were further screened to carry out mites killing experiments. Through comparison, it was found that compared with the control group, these Monomer compounds can reduce the survival time of mites.
  • taraxarol, geraniol and taraxerol acetate can significantly shorten the survival time of mites, and can be used in mites killing and inhibiting products (such as medicines, cosmetics, daily necessities, etc.).
  • the application provided by the invention can effectively utilize natural resources and improve the utilization value and commercial value of dandelion.
  • dandelion refers to the traditional Chinese medicinal dandelion, which is the dried whole plant of the Compositae plant Taraxacum officinale, Taraxacum officinale or several plants of the same genus, processed:, remove impurities, wash, cut into sections, and dry ; Cold in nature, bitter in taste, sweet; in the liver and stomach meridian; Efficacy: clearing away heat and toxins, reducing swelling and dispelling lumps, diuresis and leaching.
  • Chinese medicine monomer refers to a compound obtained from a single Chinese medicine (for example, obtained by extraction), especially a compound having therapeutic or health benefits.
  • the dandelion monomer compound described in the present invention refers to the compound obtained from dandelion
  • the monomeric compounds such as, but not limited to, dandelion sterol (CAS: 1059-14-9), taraxerinol (CAS: 127-22-0), taraxacum acetophenone (CAS: 514-07-8), Leaf lignin (CAS: 520-34-3), dandelion sterol acetate (CAS: 6426-43-3), caffeic acid (CAS: 331-39-5), acetyl dandelion alcohol (CAS: 2189-80-2) ), Lupenone (CAS: 1617-70-5).
  • the term "animal” generally refers to vertebrates, especially mammals, including humans.
  • the term “non-human animal” refers to any vertebrate other than humans, especially mammals.
  • the non-human animal in the present invention is a domestic animal, that is, an animal that is raised and domesticated by humans and whose reproduction can be artificially controlled for functions such as food, labor, fur, pets, experiments, etc. , Such as economic animals, pet animals, laboratory animals, etc.
  • Pet animals such as dogs, cats, rabbits, rats (such as guinea pigs, hamsters, gerbils, chinchillas, squirrels, etc.).
  • Experimental animals such as monkeys, dogs, rabbits, cats, mice (such as rats, mice), etc.
  • the decoction pieces of Chinese medicine (honeysuckle, dandelion, white fresh peel, skullcap, houttuynia cordata, chrysanthemum) selected in this experiment were all purchased in the traditional Chinese pharmacy of Guangdong Provincial Hospital of Traditional Chinese Medicine.
  • honeysuckle, dandelion, skullcap, houttuynia cordata, and chrysanthemum come from Kangmei Pharmaceutical Co., Ltd.
  • white fresh peel and qin peel are from Lingnan Traditional Chinese Medicine Decoction Pieces Co., Ltd.
  • the experimental group was decoction of different traditional Chinese medicines prepared according to the above method, and the negative control group was sterilized water.
  • the positive control is tea tree essential oil and the main component of tea tree essential oil, 4-terpineol
  • Tea tree oil (TTO) and 4-terpineol (Terpinen-4-ol, T4O) were purchased from Milwaukee (WI, USA) and diluted in sterilized water to a final concentration of 10%.
  • Demodex mites were cultured in an environment with a humidity of 96% and a temperature of 20°C. The survival of Demodex mites was dynamically observed and the survival time was recorded. The experimental results are shown in Table 1. Compared with the negative control group, the in vitro survival time of Demodex mites in the dandelion group was significantly shorter (21.61 ⁇ 11.95 vs.50.81 ⁇ 19.90, P ⁇ 0.01), and the survival time was significantly shorter than that of TTO and T4O, which are currently believed to be effective in killing mites.
  • Table 1 The effect of Chinese herbal decoction on the survival time of Demodex folliculorum in vitro
  • P A denotes P ⁇ 0.05
  • P a represents P ⁇ 0.001
  • TTO compared with TTO
  • P B indicates P ⁇ 0.05
  • P b denotes P ⁇ 0.01
  • compared with T4O P C denotes P ⁇ 0.05
  • P c represents: P ⁇ 0.01
  • P c' represents P ⁇ 0.001.
  • Example 2 In vitro preliminary screening of traditional Chinese medicine monomers on the survival time of Demodex mites
  • Example 1 According to the experimental results of Example 1, dandelion can significantly shorten the survival time of Demodex mites in vitro, so the monomer of this traditional Chinese medicine is selected.
  • the Chinese and English names and molecular formulas of the monomers are shown in the following table:
  • the monomer was purchased from Chengdu Refines Biotechnology Co., Ltd. as a standard product.
  • the Chinese herbal medicine monomer reference product powder shown in Table 2 was dissolved in dimethyl sulfoxide (DMSO) first, and then diluted with sterilized double-distilled water to make the final concentration of DMSO 10%. After the control test, this concentration cannot be shortened. Demodex survival time.
  • the negative control is DMSO mixed with sterile water, and the final concentration is 10%.
  • Example 1 As in Example 1, 35 ⁇ l of different solutions were added to each glass slide, and the survival of the parasites was observed under an optical microscope every 2 hours. It is judged whether it is dead by observing whether the insect body is moving (body, limbs, etc.) under the microscope. During the experiment, two skilled demodex related experimenters will observe and judge separately. If the judgment results are not the same, please ask the third person Skilled experimenters make independent judgments.
  • the in vitro culture is carried out in a climate chamber with a temperature of 20°C and a humidity of 96%. The wet box transportation of the slides during observation has ensured a high humidity state.
  • Demodex mites were cultured in an environment with a humidity of 96% and a temperature of 20°C. The survival of Demodex mites was dynamically observed and the survival time was recorded. The results are shown in Table 3. Compared with the negative control 10% DMSO, the dandelion monomer compound can shorten the in vitro survival time of Demodex mites.
  • the in vitro survival time of Demodex in the dandelion sterol acetate group was significantly shorter than that in the control group ( 37.91 ⁇ 20.96 vs. 80.79 ⁇ 25.34, P ⁇ 0.001).
  • Example 3 Clinical study on the treatment of dry eyes caused by mite infection
  • the patients Before treatment and every week after treatment, the patients will receive ocular surface discomfort symptom score, general eye examination (visual acuity, intraocular pressure, slit lamp examination), dry eye (conjunctival hyperemia score, BUT test, Schirmer I test), and ocular surface disease index Scoring (OSDI), dry eye instrument and eye demodex examination.
  • general eye examination visual acuity, intraocular pressure, slit lamp examination
  • dry eye conjunctival hyperemia score, BUT test, Schirmer I test
  • OSDI ocular surface disease index Scoring
  • the normal distribution data of the count data uses the paired sample t test
  • the measurement data uses the ⁇ 2 test
  • the non-normal distribution data uses the non-parametric test.
  • the results are based on the mean ⁇ standard deviation x+s ) Means that the difference is statistically significant with P ⁇ 0.05.

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Abstract

蒲公英及其单体化合物在制备杀螨产品中的应用。蒲公英可减少螨虫的存活时间，蒲公英单体特别是蒲公英赛醇、香叶木素和蒲公英甾醇醋酸酯可显著缩短蠕形螨存活时间，可用于制备螨虫杀灭和抑制产品。

Description

蒲公英及其单体化合物在杀螨中的应用 技术领域
本发明涉及医药和日护技术领域，具体涉及蒲公英及其单体化合物，特别是蒲公英赛醇、香叶木素和蒲公英甾醇醋酸酯，在杀螨中的应用。
背景技术
螨虫属于节肢动物门蛛形纲广腹亚纲的一类体型微小的动物，身体大小一般都在0.5毫米左右，有些小到0.1毫米，大多数种类小于1毫米。现发现螨虫与人类和动物(如狗、猫等宠物)的健康关系非常密切，诸如革螨、恙螨、疥螨、蠕形螨、粉螨、尘螨和蒲螨等可吸血、侵害皮肤，引起“酒糟鼻”或蠕螨症、过敏症、尿路螨症、肺螨症、肠螨症和疥疮等，严重危害人类和动物的身体健康。
蠕形螨属螨虫(属于蜘蛛纲(Arachnid)和螨目(Acarina))是通常感染皮肤毛囊皮脂腺单位的微观体外寄生虫。在宽范围的所报导物种中，至少毛囊蠕形螨和皮脂蠕形螨已在人类体表上发现，其主要寄居在毛囊和皮脂腺、睑板腺。蠕形螨可吞噬毛囊上皮细胞，引起毛囊扩张和脱毛，表现为临床上的睑缘炎、睑板腺功能障碍、睫毛脱落、睫毛排列异常(abnormal eyelash alignment)、结膜炎和睑结膜炎、翼状胬肉、角膜炎、眼睑基底细胞癌等。蠕形螨还可吞噬脂质，引起干眼。此外，蠕形螨还可以通过机械性的阻塞造成睑板腺排出管道阻塞，引起脂质排出困难和过量的分泌物潴留，导致霰粒肿的形成。蠕形螨感染眼病的临床表现主要包括：反复发作的眼边红痒；眼干、眼烧灼感、眼部异物感、畏光、分泌物增多；可伴有反复睫毛脱落；重者累及角膜时可有视物模糊、视力下降。除了以上眼病，近年有不少研究指出蠕形螨感染和 多种常见的皮肤疾病相关，包括脂溢性皮炎、痤疮、酒糟鼻、毛囊性糠疹、口周皮炎、蠕形螨病、基底细胞癌等。
特别地，螨虫与眼部疾病的关系被得到证实的报道包括：
Human Permanent Ectoparasites；Recent Advances on Biology and Clinical Significance of Demodex Mites:Narrative Review Article(Iranian journal of parasitology 12(1):12-21)表明了短蠕形螨位于皮脂腺和睑板腺，毛囊蠕形螨常占据人类睫毛毛囊部位，感染脸部皮肤后会引起眼病。
Ocular Demodicosis as a Potential Cause of Ocular Surface Inflammation(Cornea 36 Suppl 1(Suppl 1):s9-s14)证明了短蠕形螨和毛囊蠕形螨是两种致使人类患眼螨病的蠕形螨，同时人类年龄与患病风险呈正相关性，眼螨病与眼表炎症状况有很强的正相关性。
Demodex species in human ocular disease:new clinicopathological aspects(International ophthalmology 37(1):303-312)研究表明短蠕形螨和毛囊蠕形螨与外眼疾病的发病机制有关，而眼螨病会导致眼外生态环境失衡。
Ocular Demodex:a systematic review of the clinical literature(Ophthalmic&physiological optics:the journal of the British College of Ophthalmic Opticians(Optometrists)40(4):389-432)中描述了蠕形螨感染是眼表疾病的潜在病因，蠕形螨寄生在眼睛的前部结构如眼睑、睫毛和眼表会致使人类患眼螨病且发病率与年龄呈正相关。
The relationship between demodex and ocular discomfort(Investigative ophthalmology&visual science 51(6):2906-2911)提出了蠕形螨的数量与眼病的严重程度及患者的年龄呈正相关性。
Demodex mites(Clinics in dermatology 32(6):739-743)提出了蠕形螨感染会引发慢性睑缘炎，慢性睑缘炎患病率与螨虫的数量和患者年龄成正相关。
Quantitative Analysis of the Bacteria in Blepharitis With Demodex Infestation(Frontiers in microbiology 9:1719)研究表明短蠕形螨和毛囊蠕形螨 感染会导致眼部疾病的发生，且患病率与螨虫数量和患者年龄呈正相关。蠕形螨是芽孢杆菌的携带者，其可作为共病原体在睑缘炎的发病机制中发挥作用。
Bacillus oleronius and Demodex mite infestation in patients with chronic blepharitis(Clinical microbiology and infection:the official publication of the European Society of Clinical Microbiology and Infectious Diseases 18(10):1020-1025)认为蠕形螨可导致睑缘炎疾病的发生，且其是一种芽孢杆菌的携带者，其可在睑缘炎的发展过程中起到了共病原体的作用。
Correlation between ocular Demodex infestation and serum immunoreactivity to Bacillus proteins in patients with Facial rosacea(Ophthalmology 117(5):870-877.e871)提出了干眼症患者眼部蠕形螨感染的发生率低于非干眼症患者，螨虫感染和细菌感染可以并存于眼表炎症中。
High prevalence of demodex brevis infestation in chalazia(American journal of ophthalmology 157(2):342-348.e341)研究表明了成人和患有睑板腺囊肿的儿科患者中短蠕形螨病的发病率很高，眼部蠕形螨病是睑板腺囊肿的一大病因。
螨虫引起的疾病(如眼部疾病、皮肤疾病)目前在临床还没有引起足够重视，经常被误诊为细菌性疾病等，常规抗菌药治疗常常无明显疗效。
发明内容
本发明第一方面提供一种蒲公英在制备杀螨产品中的应用。
具体地，上述蒲公英可以作为唯一的杀螨活性组分，也可以与其他相同或不同的活性的组分组合用于杀螨。
本发明第二方面提供一种蒲公英提取物在制备杀螨产品中的应用。
具体地，上述蒲公英提取物可通过本领域已知的适当的中药提取方法得到，如煎煮法、浸渍法、浸漉法、回流法、水蒸气蒸馏法、超声波提取法等 中的一种或多种的组合。在本发明的一个实施例中，上述蒲公英提取物可通过煎煮法得到。
具体地，上述蒲公英提取物通过包括以下步骤的方法制备：
(1)将蒲公英与提取溶剂混合，浸泡；
(2)将步骤(1)的混合物加热至沸腾，然后煎煮，过滤。
在本发明的一个实施例中，上述提取溶剂为水。
具体地，上述浸泡的时间为1-24小时(具体如，1、2、3、4、5、6、12、18、24小时)。
具体地，上述煎煮时间为10-60分钟(具体如，10、15、20、25、30、35、40、45、50、55、60分钟)。
具体地，上述方法还可包括：
(3)将步骤(2)所得滤渣与提取溶剂，加热至沸腾，然后煎煮，过滤；将步骤(2)和(3)所得滤液合并。
任选地，上述方法还可包括将所得滤液进行混匀、浓缩、定量、灭菌等处理步骤中一种或多种。
具体地，上述蒲公英提取物中包含蒲公英甾醇、蒲公英赛醇、蒲公英赛酮、香叶木素、蒲公英甾醇醋酸酯、咖啡酸、乙酰蒲公英萜醇、羽扇烯酮中的一种或多种。
更具体地，上述蒲公英提取物中包含蒲公英赛醇、香叶木素和蒲公英甾醇醋酸酯中的一种或多种。
本发明第三方面提供一种蒲公英单体化合物或其盐、异构体、溶剂化物、衍生物在制备杀螨产品中的应用。
具体地，上述蒲公英单体化合物的盐、异构体、溶剂化物、衍生物为药学上可接受的相应的盐、异构体、溶剂化物、衍生物。
具体地，上述单体化合物选自蒲公英甾醇、蒲公英赛醇、蒲公英赛酮、 香叶木素、蒲公英甾醇醋酸酯、咖啡酸、乙酰蒲公英萜醇、羽扇烯酮中的一种或多种。
更具体地，上述单体化合物选自蒲公英赛醇、香叶木素和蒲公英甾醇醋酸酯中的一种或多种。
本发明第四方面提供一种蒲公英赛醇在制备杀螨产品中的应用。
本发明第五方面提供一种香叶木素在制备杀螨产品中的应用。
本发明第六方面提供一种蒲公英甾醇醋酸酯在制备杀螨产品中的应用。具体地，本发明上述杀螨产品可用于治疗/或预防目的，也可用于非治疗/或预防目的。
具体地，本发明上述螨虫可以为蠕形螨、尘螨、疥螨等中的一种或多种。在本发明的一个实施例中，本发明上述螨虫为蠕形螨，如毛囊蠕形螨和皮脂蠕形螨。
在本发明的一个实施方式中，本发明上述杀螨产品为药物组合物。
具体地，上述药物组合物还包含药学上可接受的辅料。
具体地，本发明上述药物组合物用于预防和/或治疗螨虫感染引起的疾病。
具体地，上述疾病可以为眼部疾病、皮肤疾病、过敏性疾病等。
具体地，上述眼部疾病可以为睑缘炎、睑板腺功能障碍、睑板炎、睫毛脱落、睫毛排列异常、青光眼、白内障、眼部毛囊炎、结膜炎、睑结膜炎、翼状胬肉、角膜炎、眼睑松弛和外翻、眼睑基底细胞癌、干眼症、霰粒肿等中的一种或多种；其可具有选自以下的一种或多种症状：眼部红痒、眼干、眼烧灼感、异物感、畏光、眼部分泌物增多、睫毛脱落、视物模糊、视力下降等。
具体地，上述皮肤疾病可以为脂溢性皮炎、痤疮、酒糟鼻、毛囊性糠疹、口周皮炎、蠕形螨病、疥螨病、基底细胞癌等中的一种或多种。
具体地，上述过敏性疾病可以为过敏性哮喘、过敏性鼻炎、过敏性皮炎 等中的一种或多种。
具体地，上述药物组合物可以为任何适宜施用的剂型，如外用制剂，特别是眼用制剂、皮肤外用制剂等。
具体地，上述眼用制剂可以为滴眼剂、眼膏剂、眼用凝胶剂、眼用乳剂、眼用混悬剂、眼用膜剂、洗眼剂、眼内注射剂等。
具体地，所述的眼用制剂可以包括药学上可接受的辅料，例如pH调节剂、助溶剂、渗透压调节剂、粘度调节剂、抗氧化剂、抑菌防腐剂、缓冲剂、助悬剂、局部麻醉剂、表面活性剂、增溶剂、润湿剂、乳化剂、稳定剂、填充剂、保护剂、溶剂等。
具体地，上述皮肤外用制剂可以为气雾剂、粉剂、洗剂、酊剂、搽剂、涂膜剂、软膏剂、凝胶剂、糊剂、乳剂等。
具体地，本发明上述药物组合物的各种剂型可以按照药学领域的常规生产方法制备。例如，眼科制剂技术可以采用《眼科药物与制剂学》(中国轻工业出版社，2010)、《滴眼剂的开发和生产》(化学工业出版社，2009)等。
具体地，本发明上述药物组合物可以含有重量比为0.01-99.5％(具体如，0.01％、0.1％、0.5％、1％、2％、3％、4％、5％、6％、7％、8％、9％、10％、20％、30％、40％、50％、60％、70％、80％、90％、95％、99％、99.5％)的活性成分。
具体地，上述药物组合物可用于人类，也可作为兽用药用于非人类动物，例如非人类哺乳动物，例如宠物动物(如，狗、猫、兔、鼠等)、家畜动物(如，马、牛、羊、猪、狗、兔等)等动物。
在本发明的另一个实施方式中，本发明上述杀螨产品为化妆品。
具体地，上述化妆品还包含化妆品领域可接受的辅料。
具体地，本发明上述化妆品可以为用于面部的化妆品，如洗面奶、香皂、 柔肤水、爽肤水、护肤乳、凝露、面霜、防晒霜、精华液、面膜、凝胶、粉底液、磨砂膏。
具体地，本发明上述化妆品可以为用于面部以外其他部位的化妆品，如颈霜、洗发水、沐浴露、香皂、护发素、身体乳、磨砂膏等。
具体地，本发明上述化妆品还可以为用于眼睛和眼周的化妆品，如眼霜、睫毛膏、眼线粉、眼线膏、眼线笔、眼影粉、眼影膏、眉笔、眉粉等。
具体地，本发明上述化妆品的各种形式可以按照化妆品领域的常规生产方法制备。
具体地，本发明上述化妆品可以含有重量比为0.01-99.5％(具体如，0.01％、0.1％、0.5％、1％、2％、3％、4％、5％、6％、7％、8％、9％、10％、20％、30％、40％、50％、60％、70％、80％、90％、95％、99％、99.5％)的活性成分。
在本发明的另一个实施方式中，本发明上述杀螨产品为杀螨剂，其可用于杀灭和抑制生活环境中物品(如，枕套、枕芯、床单、被褥、床垫、衣物、地毯、坐垫、沙发、凉席、毛绒玩具、空调等等)上可能寄居的螨虫。
具体地、上述杀螨剂可包含可实现所需性能的任何适宜的辅料。
具体地、上述杀螨剂可以为喷雾剂、洗剂、贴片、小包装等形式。
具体地，本发明上述杀螨剂的各种形式可以按照日护产品领域的常规生产方法制备。
具体地，本发明上述杀螨剂可以含有重量比为0.01-99.5％(具体如，0.01％、0.1％、0.5％、1％、2％、3％、4％、5％、6％、7％、8％、9％、10％、20％、30％、40％、50％、60％、70％、80％、90％、95％、99％、99.5％)的活性成分。
本发明还提供一种预防和/或治疗螨虫感染引起的疾病的方法，其包括向需要其的受试者施用蒲公英、或其提取物、其单体化合物(特别是蒲公英赛 醇、香叶木素和蒲公英甾醇醋酸酯)或本发明上述药物组合物的步骤。
具体地，上述疾病可以为眼部疾病、皮肤疾病、过敏性疾病等。
具体地，上述眼部疾病可以为睑缘炎、睑板腺功能障碍、睑板炎、睫毛脱落、睫毛排列异常、青光眼、白内障、眼部毛囊炎、结膜炎、睑结膜炎、翼状胬肉、角膜炎、眼睑松弛和外翻、眼睑基底细胞癌、干眼症、霰粒肿等中的一种或多种；其可具有选自以下的一种或多种症状：眼部红痒、眼干、眼烧灼感、异物感、畏光、眼部分泌物增多、睫毛脱落、视物模糊、视力下降等。
具体地，上述皮肤疾病可以为脂溢性皮炎、痤疮、酒糟鼻、毛囊性糠疹、口周皮炎、蠕形螨病、疥螨病、基底细胞癌等中的一种或多种。
具体地，上述过敏性疾病可以为过敏性哮喘、过敏性鼻炎、过敏性皮炎等中的一种或多种。
具体地，上述受试者可以为接受该预防和/或治疗的任何动物，特别是哺乳动物，如人类、猫、狗、兔、鼠、马、牛、羊、猪等。在本发明的一个实施例中，上述受试者为人类；在本发明的另一个实施例中，上述受试者为非人类动物。
具体地，上述蒲公英、或其提取物、其单体化合物(特别是蒲公英赛醇、香叶木素和蒲公英甾醇醋酸酯)或本发明上述药物组合物的施用量可根据用药途径、受试者的年龄、体重、所治疗的疾病的类型和严重程度等变化，可以一次或多次施用。
本发明第七方面提供蒲公英、蒲公英提取物、蒲公英单体化合物或其盐、异构体、溶剂化物、衍生物在制备治疗和/或预防螨虫引起的眼部疾病的药物中的应用。
本发明第八方面提供一种治疗和/或预防螨虫引起的眼部疾病的方法，所述的方法包括向需要其的受试者施用眼部施用蒲公英、蒲公英提取物、蒲公 英单体化合物或其盐、异构体、溶剂化物、衍生物的步骤。
具体地，上述受试者可以为接受该预防和/或治疗的任何动物，特别是哺乳动物，如人类、猫、狗、兔、鼠、马、牛、羊、猪等。在本发明的一个实施例中，上述受试者为人类；在本发明的另一个实施例中，上述受试者为非人类动物。
具体地，所述眼部施用是以滴眼剂、眼膏剂、眼用凝胶剂、眼用乳剂、眼用混悬剂、眼用膜剂、洗眼剂、眼内注射剂形式施用。
具体地，上述眼部疾病可以为睑缘炎、睑板腺功能障碍、睑板炎、睫毛脱落、睫毛排列异常、青光眼、白内障、眼部毛囊炎、结膜炎、睑结膜炎、翼状胬肉、角膜炎、眼睑松弛和外翻、眼睑基底细胞癌、干眼症、霰粒肿等中的一种或多种；其可具有选自以下的一种或多种症状：眼部红痒、眼干、眼烧灼感、异物感、畏光、眼部分泌物增多、睫毛脱落、视物模糊、视力下降等。所述的螨虫与眼部疾病的关系已经被如下文献所证明：
Global divergence of the human follicle mite Demodex folliculorum:Persistent associations between host ancestry and mite lineages.Proceedings of the National Academy of Sciences of the United States of America 112(52):15958-15963.(睑缘炎)
Human Permanent Ectoparasites；Recent Advances on Biology and Clinical Significance of Demodex Mites:Narrative Review Article.Iranian journal of parasitology 12(1):12-21.(睑板炎、睑缘炎)
Ocular Demodicosis as a Potential Cause of Ocular Surface Inflammation.Cornea 36 Suppl 1(Suppl 1):S9-S14.(睑缘炎、角膜炎、结膜炎、睑结膜炎、睑板炎、睑板腺功能障碍、眼睑基底细胞癌)
Demodex species in human ocular disease:new clinicopathological aspects.International ophthalmology 37(1):303-312(外眼病、干眼病、眼睑炎、倒睫症、眼睑松弛和外翻、睑缘炎)
Ocular Demodex:a systematic review of the clinical literature.Ophthalmic&physiological optics:the journal of the British College of Ophthalmic Opticians(Optometrists)40(4):389-432.(睑板腺功能障碍、眼睑结膜炎、睑缘结膜炎、疱疹病毒性角膜炎、复发性角膜炎、疱疹角膜炎、干眼病、眼睑炎、睑板炎、睑板腺囊肿、基底细胞癌、青光眼、白内障、眼部毛囊炎、慢性和复发性的眼睑边缘炎症、角膜缘炎、眼睑炎症、睫毛紊乱和松弛症)
The relationship between demodex and ocular discomfort.Investigative ophthalmology&visual science 51(6):2906-2911.(睑板腺功能障碍、睑缘炎(慢性睑缘炎、青光眼)
Demodex mites.Clinics in dermatology 32(6):739-743.(睑缘炎、短睑缘炎慢性睑缘炎、毛囊性睑缘炎、前睑炎、后睑炎、睑板腺功能障碍、角膜结膜炎)
Quantitative Analysis of the Bacteria in Blepharitis With Demodex Infestation.Frontiers in microbiology 9:1719.(睑缘炎、慢性睑缘炎、混合性睑缘炎、眼睑炎、前睑炎、后睑炎、睑板腺功能障碍)
Bacillus oleronius and Demodex mite infestation in patients with chronic blepharitis.Clinical microbiology and infection:the official publication of the European Society of Clinical Microbiology and Infectious Diseases 18(10):1020-1025.(慢性睑缘炎、中度睑缘炎、重度睑缘炎、睑缘炎、结膜炎睑板腺功能障碍、眼睑炎)
Correlation between ocular Demodex infestation and serum immunoreactivity to Bacillus proteins in patients with Facial rosacea.Ophthalmology 117(5):870-877.e871.(眼睑缘炎、干眼症、眼表炎症、结膜松弛症)
High prevalence of demodex brevis infestation in chalazia.American journal of ophthalmology 157(2):342-348.e341.(睑板腺囊肿、睑缘炎、结膜炎、角膜炎)
Dissecting lipid metabolism in meibomian glands of humans and mice:an integrative study reveals a network of metabolic reactions not duplicated in other tissues.Biochimica et Biophysica Acta(BBA)-Molecular and Cell Biology of Lipids 1861(6):538-553.(干眼症、睑板腺囊肿)
Notch signaling in meibomian gland epithelial cell differentiation.Investigative ophthalmology&visual science 57(3):859-865.(睑板腺功能障碍、干眼症)
通过对比多味中药材对螨虫的杀灭效果发现，蒲公英可有效减少螨虫的存活时间，进一步筛选多种蒲公英单体化合物，进行螨虫的杀灭实验，通过对比发现，与对照组相比，这些单体化合物均可减少螨虫的存活时间，特别是蒲公英赛醇、香叶木素和蒲公英甾醇醋酸酯可显著缩短螨虫存活时间，可用于螨虫杀灭和抑制产品(如药品、化妆品、日用品等)。本发明提供的应用可有效地利用自然资源，提高蒲公英的利用价值和商业价值。
具体实施方式
除非另有定义，本发明中所使用的所有科学和技术术语具有与本发明涉及技术领域的技术人员通常理解的相同的含义。
除非另外指出，在本发明中，蒲公英是指中药材蒲公英，其为菊科植物蒲公英、碱地蒲公英或同属数种植物的干燥全草，炮制：，除去杂质，洗净，切段，晒干；性寒，味苦、甘；归肝、胃经；功效：清热解毒，消肿散结，利尿通淋等。
中药单体是指从单味中药获得(例如通过提取得到)的化合物，特别是具有治疗作用或有益健康等作用的化合物，例如，本发明中所描述的蒲公英单体化合物是指从蒲公英中获得的单体化合物，例如，但不限于，蒲公英甾醇(CAS：1059-14-9)、蒲公英赛醇(CAS：127-22-0)、蒲公英赛酮(CAS：514-07-8)、香叶木素(CAS：520-34-3)、蒲公英甾醇醋酸酯(CAS：6426-43-3)、 咖啡酸(CAS：331-39-5)、乙酰蒲公英萜醇(CAS：2189-80-2)、羽扇烯酮(CAS：1617-70-5)。
在本发明中，术语“动物”一般是指脊椎动物，特别是哺乳动物，包括人类。术语“非人类动物”是指除了人类之外的任何脊椎动物，特别是哺乳动物。在本发明的一些实施方案中，本发明中所述非人类动物为家养动物，即由人类饲养驯化，且可以人为控制其繁殖的动物，用于例如食用、劳役、毛皮、宠物、实验等功能，例如经济动物、宠物动物、实验动物等。经济动物，如家畜，例如猪、牛、羊、马、驴、狐、貉、貂、骆驼等。宠物动物，如狗、猫、兔、鼠(如豚鼠、仓鼠、沙鼠、龙猫、松鼠等)等。实验动物，如猴、狗、兔、猫、鼠(如大鼠、小鼠)等。
下面将结合本发明实施例，对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1
一、实验方法：
1.实验对象
本研究严格遵循赫尔辛基宣言(The Declaration of Helsinki)、《涉及人的生物医学研究伦理审查办法》的伦理准则。本研究收集确诊为眼蠕形螨感染患者的蠕形螨。符合入选标准的予以知情谈话并签署知情同意书后入组。
2.蠕形螨检测
按照常规的睫毛镜检方法进行蠕形螨检测(12,20)，每个眼睑拔取3根睫毛，共拔取12根睫毛，拔下的睫毛立即置于载玻片上，每三根睫毛一片，置于普通光学显微镜下观察。将所有时期的蠕形螨均纳入计数并根据形态学进行分类(具体标准为：头身比为1:1的为皮脂蠕形螨，头身比为1:3～1:4的为毛囊蠕形螨)。 只取完全暴露于视野中的成虫作为实验对象(幼虫及虫卵因在生命早期更为脆弱故不作为研究对象)。
3.蠕形螨体外培养
在上述蠕形螨检测的基础上，每张玻片上加入35μl不同溶液，每2个小时观察一次虫体是否存活。通过显微镜下观察虫体是否活动(身体，四肢等)来判断其是否死亡，实验过程中由两位熟练的蠕形螨相关实验者分别观察并判定，若判定结果不相同，则请第三位熟练的实验者进行独立判定。体外培养在气候箱中进行，温度20℃，湿度96％，玻片在观察中湿盒运输已保证高湿状态。
4.药物
4.1中草药7种
本实验所选取的中药饮片(金银花，蒲公英，白鲜皮，黄芩，鱼腥草，秦皮，菊花)均购置于广东省中医院中药房。其中，金银花、蒲公英、黄芩、鱼腥草、菊花来源于康美药业股份有限公司，白鲜皮、秦皮来源于岭南中药饮片有限公司。
4.2中药水煎剂的制备方法
用电子天平称取干燥中药饮片60g放置于砂锅中，加10倍水量(600ml)泡过夜，武火加热至药液沸腾后改用文火煎15-30分钟(花草类15分钟，根茎类为30分钟)，纱网过滤，滤渣加500ml水同法煎煮，过滤后合并两次滤液于同一烧杯中，混合均匀后，加热蒸发使药液浓缩至100ml后放凉至室温，并置于100ml容量管中定容。
实验组为分别按照上述方法制备的不同中药煎煮液，阴性对照组为灭菌水。
4.3阳性对照为茶树精油及茶树精油的主要成分4-松油醇
茶树油(Tea Tree Oil，TTO)及4-松油醇(Terpinen-4-ol，T4O)购于Milwaukee(WI,USA)，均稀释于灭菌水，终浓度为10％。
5.统计方法
本实验采用SPSS22.0统计软件进行统计，因共用Shapiro-Wilk检验进行正 态性检验，Bartlett检验进行方差齐性检验，对符合正态分布且方差齐的数据进行单因素方差分析(One-way ANOVA)，有统计学意义时应用Bonferroni法进行组间两两比较；数据不符合正态分布时使用Kruskal-Wallis检验进行统计分析，检验标准＝0.05。
6.实验结果：
1.蒲公英能显著缩短体外蠕形螨存活时间
在湿度96％，温度20℃的环境下体外培养蠕形螨，动态观察蠕形螨存活情况并记录存活时间。实验结果如表1所示。与阴性对照组相比，蒲公英组的蠕形螨体外存活时间显著缩短(21.61±11.95vs.50.81±19.90,P＜0.01)，且显著较目前认为可有效杀螨的TTO及T4O存活时间更短(21.61±11.95vs.41.39±19.33，21.61±11.95vs.40.50±13.12，P＜0.05)；其余6种中药与阴性对照组、TTO及T4O组相比，蠕形螨体外存活时间未见明显差异(P＞0.05)。有趣的是，以往被认为能体外杀螨的TTO及其主要有效成分T4O在本体外培养实验中，与阴性对照水溶液相比，蠕形螨存活时间并未见显著差异(P＞0.05)。
表1：中草药煎剂体外对毛囊蠕形螨存活时间的影响
药物名称 存活时间(小时) 蠕形螨数量(N)
水 50.81±19.90 12
TTO 41.39±19.33 22
T4O 40.50±13.12 21
金银花 37.06±23.43 14
蒲公英 21.61±11.95 aBC 13
菊花 31.33±13.26 15
鱼腥草 49.57±16.40 11
白鲜皮 32.57±19.80 18
黄芩 34.13±21.90 16
秦皮 31.84±15.12 22
用Bonferroni法进行多重比较，与水相比，P A表示P＜0.05，P a表示P＜0.001，P a’表示P＜0.001；与TTO比较：P B表示P＜0.05，P b表示P＜0.01，P b’表示P＜0.001；与T4O比较，P C表示P＜0.05，P c表示：P＜0.01，P c’表示P＜0.001。
实施例2：体外初筛中药单体对蠕形螨生存时间的影响
方法：
1.中药单体
根据实施例1的实验结果，蒲公英能显著缩短蠕形螨体外存活时间，故选取此味中药的单体，单体中英文名称及分子式见下表：
单体购于成都瑞芬思生物科技有限公司，为标准品。
表2：中药单体中英文名称及分子式
Figure PCTCN2021089110-appb-000001
2.中药单体溶液的制备
将表2中所示中草药单体参考品粉末先于二甲基亚砜(DMSO)溶解，再用 灭菌双蒸水稀释，使DMSO的终浓度为10％，经对照试验，此浓度不能缩短蠕形螨存活时间。阴性对照为与灭菌水混合的DMSO，终浓度为10％。
3.蠕形螨体外培养
同实施例1，每张玻片上加入35μl不同溶液，每2个小时在光学显微镜下观察一次虫体是否存活。通过显微镜下观察虫体是否活动(身体，四肢等)来判断其是否死亡，实验过程中由两位熟练的蠕形螨相关实验者分别观察并判定，若判定结果不相同，则请第三位熟练的实验者进行独立判定。体外培养在气候箱中进行，温度20℃，湿度96％，玻片在观察中湿盒运输已保证高湿状态。
4.统计方法
本实验采用SPSS22.0统计软件进行统计，因共用Shapiro-Wilk检验进行正态性检验，Bartlett检验进行方差齐性检验，对符合正态分布且方差齐的数据进行单因素方差分析(One-way ANOVA)，有统计学意义时应用Bonferroni法进行组间两两比较；数据不符合正态分布时使用Kruskal-Wallis检验进行统计分析，检验标准α＝0.05。
5.实验结果：
中草药单体对毛囊蠕形螨存活时间的影响
在湿度96％，温度20℃的环境下体外培养蠕形螨，动态观察蠕形螨存活情况并记录存活时间。结果如表3所示。与阴性对照10％DMSO相比，蒲公英单体化合物均可缩短蠕形螨体外存活时间，特别是，蒲公英赛醇组的蠕形螨体外存活时间显著缩短(37.91±20.96vs.80.79±25.34,P＝0.006)，香叶木素组的蠕形螨体外存活时间显著缩短(35.92±14.82vs.80.79±25.34,P＝0.001)，蒲公英甾醇醋酸酯组的蠕形螨体外存活时间较对照组显著缩短(37.91±20.96vs.80.79±25.34,P＜0.001)。
表3：中药单体外对毛囊蠕形螨存活时间的影响
编号 单体名称 存活时间(小时) 蠕形螨数量(N)
对照 10％DMSO 80.79±25.34 36
1 蒲公英甾醇 68.28±31.30 6
2 蒲公英赛醇 37.91±20.96 ** 11
3 蒲公英赛酮 62.06±28.97 8
4 香叶木素 35.92±14.82 ** 10
5 蒲公英甾醇醋酸酯 34.14±22.96 *** 13
6 咖啡酸 66.45±24.24 5
7 乙酰蒲公英萜醇 70.57±27.45 12
8 羽扇烯酮 66.25±31.22 5
用Duncan法进行多重比较，与对照组相比，P *：P＜0.05，P **：P＜0.01，P ***＜0.001。
实施例3：治疗螨虫感染致干眼的临床研究
(一)纳入与排除标准
1.病例纳入标准
(1)经询问病史，符合干眼诊断标准的患者；
(2)年龄18-70岁；
(3)性别不限；
(4)能够配合治疗者；
2.病例排除标准
(1)裂隙灯检查有虹睫炎患者；
(2)高眼压或低眼压患者
(3)眼睑皮肤有破溃伤口和角膜表面有角膜上皮浸润病灶的患者
(4)排除系统疾病，例如肝肾功能损害的患者干燥综合征；
(5)年龄18岁以下或70岁以上者；
(6)精神状态不能配合评价者；
(7)妊娠、哺乳期妇女。
3.脱落及剔除标准：
(1)治疗过程中因伴发其他疾病，不能或不愿继续治疗者；
(2)治疗过程中不能合作者或症状恶化而不愿继续治疗者；
(3)违背试验方案，中途使用其他非本试验应用的药物者；
(4)最终资料不全，无法判断疗效者。
(二)终点指标
患者于治疗前及治疗每周后均进行眼表不适症状评分、一般眼科检查(视力、眼压、裂隙灯检查)、干眼三项(结膜充血评分，BUT试验，Schirmer I试验)、眼表疾病指数评分(OSDI)，干眼仪以及眼部蠕形螨检查。
(三)数据统计
1、样本含量估计
考虑到干眼为临床常见眼表疾病，眼部蠕形螨阳性率达到23.8％～90.0％。采用定量资料的优效性检验样本量计算公式得出：实验组及对照组患者各30例。
2、研究数据的统计与分析
运用SPSS20.0软件及excel进行统计学处理，计数资料的正态分布数据采用配对样本t检验，计量资料采用χ2检验，非正态分布数据采用非参数检验，结果以均值±标准差x+s)表示，以P<0.05为差异有统计学意义。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换等，均应包含在本发明的保护范围之内。
本发明中描述的前述实施例和方法可以基于本领域技术人员的能力、经验和偏好而有所不同。
在本发明中仅按一定顺序列出方法的步骤并不构成对方法步骤顺序的任 何限制。

Claims (17)

  1. 一种蒲公英在制备杀螨产品中的应用。
  2. 一种蒲公英提取物在制备杀螨产品中的应用。
  3. 如权利要求2所述的应用，其特征在于，所述蒲公英提取物中包含蒲公英甾醇、蒲公英赛醇、蒲公英赛酮、香叶木素、蒲公英甾醇醋酸酯、咖啡酸、乙酰蒲公英萜醇、羽扇烯酮中的一种或多种；
    优选地，所述蒲公英提取物中包含蒲公英赛醇、香叶木素和蒲公英甾醇醋酸酯中的一种或多种。
  4. 一种蒲公英单体化合物或其盐、异构体、溶剂化物、衍生物在制备杀螨产品中的应用。
  5. 如权利要求4所述的应用，其特征在于，单体化合物选自蒲公英甾醇、蒲公英赛醇、蒲公英赛酮、香叶木素、蒲公英甾醇醋酸酯、咖啡酸、乙酰蒲公英萜醇、羽扇烯酮中的一种或多种；
    优选地，所述单体化合物选自蒲公英赛醇、香叶木素和蒲公英甾醇醋酸酯中的一种或多种。
  6. 一种蒲公英赛醇在制备杀螨产品中的应用。
  7. 一种香叶木素在制备杀螨产品中的应用。
  8. 一种蒲公英甾醇醋酸酯在制备杀螨产品中的应用。
  9. 如权利要求1-8任一项所述的应用，其特征在于，所述螨虫为蠕形螨、尘螨、疥螨中的一种或多种。
  10. 如权利要求1-8任一项所述的应用，其特征在于，所述杀螨产品为药物组合物、化妆品或杀螨剂。
  11. 如权利要求10所述的应用，其特征在于，所述药物组合物为用于预防和/或治疗螨虫感染引起的疾病的药物组合物；
    所述疾病选自：眼部疾病、皮肤疾病、过敏性疾病；
    优选地，所述眼部疾病选自：睑缘炎、睑板腺功能障碍、睑板炎、睫毛 脱落、睫毛排列异常、青光眼、白内障、眼部毛囊炎、结膜炎、睑结膜炎、翼状胬肉、角膜炎、眼睑松弛和外翻、眼睑基底细胞癌、干眼症、霰粒肿；
    优选地，所述皮肤疾病选自：脂溢性皮炎、痤疮、酒糟鼻、毛囊性糠疹、口周皮炎、蠕形螨病、疥螨病、基底细胞癌；
    优选地，所述过敏性疾病选自：过敏性哮喘、过敏性鼻炎、过敏性皮炎。
  12. 如权利要求11所述的应用，其特征在于，所述药物组合物为外用制剂，优选为眼用制剂或皮肤外用制剂；
    优选地，所述眼用制剂选自：滴眼剂、眼膏剂、眼用凝胶剂、眼用乳剂、眼用混悬剂、眼用膜剂、洗眼剂、眼内注射剂；
    优选地，所述皮肤外用制剂选自：气雾剂、粉剂、洗剂、酊剂、搽剂、涂膜剂、软膏剂、凝胶剂、糊剂、乳剂。
  13. 如权利要求11所述的应用，其特征在于，所述药物组合物为人用药物组合物或兽用药物组合物。
  14. 如权利要求10所述的应用，其特征在于，所述化妆品的形式选自：洗面奶、香皂、柔肤水、爽肤水、护肤乳、凝露、面霜、防晒霜、精华液、面膜、凝胶、粉底液、磨砂膏、颈霜、洗发水、沐浴露、护发素、身体乳、眼霜、睫毛膏、眼线粉、眼线膏、眼线笔、眼影粉、眼影膏、眉笔、眉粉。
  15. 如权利要求10所述的应用，其特征在于，所述杀螨剂的形式选自：喷雾剂、洗剂、贴片、小包装。
  16. 一种治疗和/或预防螨虫引起的眼部疾病的方法，所述的方法包括向需要其的受试者的眼部施用蒲公英、蒲公英提取物、蒲公英单体化合物或其盐、异构体、溶剂化物、衍生物的步骤。
  17. 蒲公英、蒲公英提取物、蒲公英单体化合物或其盐、异构体、溶剂化物、衍生物在制备治疗和/或预防螨虫引起的眼部疾病的药物中的应用。
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