WO2023241739A1 - 用于掩盖苦味的产品 - Google Patents

用于掩盖苦味的产品 Download PDF

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WO2023241739A1
WO2023241739A1 PCT/CN2023/112718 CN2023112718W WO2023241739A1 WO 2023241739 A1 WO2023241739 A1 WO 2023241739A1 CN 2023112718 W CN2023112718 W CN 2023112718W WO 2023241739 A1 WO2023241739 A1 WO 2023241739A1
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substances
class
taste
masking
oral
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PCT/CN2023/112718
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English (en)
French (fr)
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张景亮
李晓婷
张东梅
张苗苗
郝笑婉
决利利
谷晨萌
焦琳琳
张广冲
罗佳雪
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张景亮
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Publication of WO2023241739A1 publication Critical patent/WO2023241739A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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
    • A23L5/00—Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
    • A23L5/20—Removal of unwanted matter, e.g. deodorisation or detoxification
    • A23L5/27—Removal of unwanted matter, e.g. deodorisation or detoxification by chemical treatment, by adsorption or by absorption
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/046—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/342—Alcohols having more than seven atoms in an unbroken chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/92—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof
    • A61K8/922—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof of vegetable origin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams

Definitions

  • the present invention relates to the field of daily necessities, food or medicine, especially a product that acts on the oral cavity and is used to mask bitter taste.
  • the present invention specifically relates to a TRPM8 agonist, a TRPA1 agonist or a TRPV1-4 agonist.
  • Use as a substance to mask bitter taste use of one or more substances as a taste masking agent, use of one or more substances in oral sprays or mouthwashes for masking bitter taste, use of one or more substances to mask bitter taste of oral sprays or taste masks.
  • Type I taste cells have glial-like properties and mainly act as supporting cells, while type II taste cells detect bitter, sweet and umami stimuli by activating GPCR pathways.
  • This GPCR pathway consists of a phospholipase C (PLC) signaling cascade that results in the release of calcium (Ca 2+ ) from internal stores and subsequent activation of monovalent-selective transient receptor potential melastatin 5 (TRPM5) channels.
  • Type II cells lack traditional synaptic specializations and instead activate TRPM5 to cause cell depolarization, which stimulates Calhm1 channels and leads to the release of ATP, a neurotransmitter.
  • TRPM5 is unique compared to most TRP channels in that it is voltage-sensitive, monovalent cation-selective, and activated by elevated intracellular Ca.
  • Triphenylphosphine oxide (TPPO) is a reversible and selective TRPM5 channel blocker.
  • Application of TPPO (50 ⁇ M) eliminated the remaining taste-evoked Na + responses in TRPM5-only mice, indicating that these taste-evoked Na + signals are mediated solely by TRPM5. The reaction resumed after TPPO was cleared. Further experiments found that both TRPM4 and TRPM5 are necessary and sufficient for the normal transmission of bitter, sweet and umami stimuli.
  • TRPM4 and TRPM5 in other cell types is their sensitivity to intracellular Ca 2+ .
  • TRPM5 belongs to a type of transient receptor potential (TRP).
  • TRP channels are calcium-permeable, non-selective cation channels. About 28 TRP channels have been identified, and each channel gene has a different number of splice variants. TRP channels are divided into six different subgroups, including TRPV(1-6), TRPM(1-8), TRPC(1-7), TRPA1, TRPP(1-3) and TRPML(1-3), based on their sequence similarity.
  • TRP channels are involved in calcium processing (e.g., intracellular calcium mobilization and calcium reabsorption) and a wide range of sensory modalities, including pain, temperature, taste, etc.
  • TRP channel abnormalities are part of the important mechanism of neurodegenerative diseases, diabetes, inflammatory bowel disease, epilepsy, cancer and many other diseases.
  • TRPV1-4, TRPM8, and TRPA1 also known as "ThermoTRPs”
  • TRPV1 channels mediate thermal hyperalgesia and pain induced by capsaicin and acid.
  • TRPA1 is a nociceptor that integrates many noxious environmental stimuli, including oxidants and electrophiles.
  • gene-deleted animals have been created to study the role of TRP channels in pain and nociception, and TRPV1, TRPV3, TRPV4, and TRPA1 have been shown to be involved in nociception.
  • TRP channel protein sequences are very similar. The stimulation of many molecules will activate several protein channels at the same time, resulting in taste, temperature and pain sensations at the same time. For example, in the experiment conducted by the inventor, six substances can act on the taste pathway. TRPM5, thereby masking taste pathways, but each substance also activates other pathways. For example, menthol can produce a cold sensation, clove oil can produce a heat sensation, chili oil can produce pain and heat sensations, and asarum can produce a numbing sensation.
  • the object of the present invention is to at least partially overcome the shortcomings of the prior art, expand the range of raw materials for taste-masking agents, and provide an application of a TRPM8 agonist, a TRPA1 agonist or a TRPV1-4 agonist as a bitter taste-masking substance, a or
  • a TRPM8 agonist a TRPA1 agonist or a TRPV1-4 agonist
  • a TRPV1-4 agonist a bitter taste-masking substance
  • the use of several substances as taste-masking agents the use of one or several substances in oral sprays or mouthwashes for masking bitter tastes, an oral spray or taste-masking agent for masking bitter tastes.
  • the present invention also aims to provide the application of one or several substances in an oral spray or mouthwash for masking bitter taste and an oral spray or taste masking agent for masking bitter taste, so as to achieve the effect of masking bitter taste. better.
  • the TRPM8 agonist includes one or more of the following substances: menthol derivatives, citral, linalool, eugenol and eucalyptol;
  • menthol derivatives include one or more of the following substances: menthamide, menthol, limonene, 18-cineole, piperine, geranene, menthyl acetate, WS-3((( IR, 2S, 5R)-2-isopropyl-5-methyl-cyclohexanecarboxylic acid acetamide), WS-5([((IR, 2S, 5R)-2-isopropyl-5-methyl ((cyclohexanecarbonyl)-amino]-ethyl acetate), WS-23 (2-isopropyl-2, 3, N-trimethyl-butanamide), menthyl lactate, menthyl succinate , Menthoxypropylene glycol, 2-isopropyl-5-methylcyclohexyl 4-(dimethylamino)-4-oxobutyrate (4-(dimethylamino)-4-oxobutyrate 2-isopropyl-5-methylcycl
  • TRPAl agonist as a substance that masks bitter taste
  • the TRPAl agonist includes one or more of the following substances:
  • Cinnamaldehyde mustard oil, allicin, capsaicin esters, carvacrol, eugenol, piperine, gingerol, wintergreen oil, clove oil, caryophyllene, caryophyllene oxide, citral and menthol.
  • TRPV1-4 agonist as a substance that masks bitter taste
  • the TRPV1 agonist is selected from the group consisting of capsaicin, resiniferatoxin, vitamin D, piperine, evodiamine, zanthoxylin, capsaicin ester, and 6-shogaol , one or more of gingerol, zingerone, shogaol and polyhydric dialdehyde.
  • substances as taste masking agents, the substances being selected from the group consisting of linalool, citral, cinnamaldehyde, caryophyllene, eugenol acetate, menthone, eucalyptus oil, borneol, menthamide, and mentha succinate Alcohol esters, cooling agent WS-5, cooling agent WS-23, gingerol, piperine and allicin.
  • the one or more substances are Class A substances, Class B substances, or a combination of Class A substances and Class B substances;
  • the Class A substance is one or more TRPM8 agonists; the Class B substance is one or more TRPA1 agonists and TRPV1-4 agonists.
  • the one or several substances are Class A substances, and the volume concentration of the Class A substances in the oral spray or mouthwash is 0.001%-0.5%; or
  • the one or more substances are Class B substances, and the volume concentration of the Class B substances in the oral spray or mouthwash is 0.001%-0.5%; or
  • the one or more substances are a combination of Class A substances and Class B substances.
  • the volume concentration of the Class A substances in the oral spray or mouthwash is 0.001%-0.5%.
  • the volume concentration of the Class B substances in the oral cavity is 0.001%-0.5%.
  • the volume concentration in spray or mouthwash is 0.001%-0.5%.
  • the oral spray or mouthwash reaches the peak of the bitter taste masking effect within 5-10 seconds after being sprayed into the oral cavity, and the effect lasts for 30-120 seconds.
  • the oral spray or taste masking agent includes a Class A substance, a Class B substance, or a combination of a Class A substance and a Class B substance;
  • the Class A substance is one or more TRPM8 agonists; the Class B substance is one or more TRPA1 agonists and TRPV1-4 agonists.
  • the oral spray or taste masking agent is used for medicines, and the medicines include anti-tumor drugs, drugs for treating hyperlipidemia, drugs for treating hyperglycemia, analgesics, antibiotics, antipyretics and traditional Chinese medicines. Any one of them, the dosage form of the drug includes any one of tablets, decoctions, dispersions, liquors, granules, mouthwash, liquid oral preparations and aerosols; or
  • the oral spray or taste masking agent is used for food, and the food includes any one of ice cream, custard, cream, beverages and cakes; or
  • the oral spray or taste masking agent is used in oral care products, including any one of toothpaste, mouthwash, chewing gum, breath freshener and mouthwash.
  • the tablets include multi-layer tablets, chewable tablets, soluble tablets, effervescent tablets, orally disintegrating tablets, sustained-release tablets, controlled-release tablets, dispersible tablets, buccal tablets, sublingual tablets and buccal tablets. Any of the patches.
  • TRPM8 receptor agonists TRPV1-4 and TRPA1 agonists all have the effect of masking the bitter taste perception in the mouth
  • TRPM8 receptor agonists stimulate cold channels
  • TRPV1-4 and TRPA1 stimulate hot channels. They can be used The cooling sensation neutralizes the heat sensation and eliminates this pain. The combination of these two drugs completely eliminates the uncomfortable, hot pain and brings a cooler and pleasant pleasure.
  • Figure 1 shows the changes in sodium ion fluorescence concentration of some groups in the immunofluorescence experiment of sodium ion channels
  • Figure 2 shows the changes in sodium ion fluorescence concentration of some groups in the immunofluorescence experiment of sodium ion channels
  • Figure 3 shows the changes in sodium ion fluorescence concentration of some groups in the immunofluorescence experiment of sodium ion channels
  • Figure 4 shows a comparison of the average fluorescence pixel values of different substances
  • Figure 5 shows a comparison of fluorescence pixel averages for different substances.
  • Figure 6 shows a comparison of fluorescence pixel averages for different substances.
  • Sodium channel blockers mexiletine, propafenone injection, quinidine sulfate, disopyramide phosphate tablets, and moricizine hydrochloride.
  • Calcium channel blockers dihydropyridine drugs, such as nifedipine, amlodipine, felodipine, etc.; representative drugs of non-dihydropyridine drugs, such as verapamil and diltiazem.
  • Cold channel receptors cold channel agonists, including TRPM8 agonists and/or TRPA1 agonists.
  • the TRPM8 agonist is selected from one or more types of menthol, citral, linalool, eugenol and eucalyptol.
  • Transient receptor potential cation channel subfamily M member 8 (TRPM8), also known as cold and menthol receptor I (CMR1), is a protein expressed in sensory neurons and is regulated by cold and coolants such as menthol and menthol.
  • Types of clove oil methyl amyl ketone, clove oil components eugenol (57-85%), caryophyllene (15%), and eugenol acetate (18%).
  • TRPA1 agonist is selected from cinnamic aldehyde, mustard oil, allicin, capsaicin ester, carvacrol, eugenol, piperine, gingerol, wintergreen oil, clove oil, caryophyllene and/or caryophyllene oxide One or more of citral and menthol.
  • the TRPV1 agonist is selected from the group consisting of capsaicin, resiniferatoxin, vitamin D, piperine, evodiamine, zanthoxylin, capsaicin ester, 6-shogaol, gingerol, zingerone, shogaol or hydropolygondialdehyde .
  • TRPV1 antagonists may include one or more of the following: (-)-bornyl acetate; hydroxycitronellal; aplerenone; N, N-dimethyl anthranilic acid methyl ester; 2- Ethoxy-3-ethylpyrazine; L-piperone; isobornyl isobutyrate; 4-acetoxy-2,5-dimethyl-3(2H)-furanone; tripropylamine; dihydrogen Jasmone; 1-methyl-2-pyrrole; 3-octyl acetate; 2-methylbutyl isovalerate; piperonyl isobutyrate; phenoxyethyl propionate; vanillin propylene glycol acetate; octyl Alkenylcyclopentanone; Butyl isobutyrate; Guaiac oil; Tetrahydro-4-methyl-2-(2-methyl-1-propenyl)-2Hpyran.
  • TRPA1 antagonists may include one or more of the following: cinnamon bark oil; ⁇ -laurolactone; vanillic acid; ⁇ -methyldecanolide, trans-2,4-nonadienal ; 4-allyl-2,6-dimethoxyphenol; o-methoxycinnamaldehyde; 4-methyl-2-phenyl-2-pentenal (mixture of cis and trans); 2 -Methoxy-4-propylphenol; 2-methoxy-benzoic acid methyl ester; ⁇ -tetradecanolactone; 1-methyl-2-pyrrole; 3,3,5-trimethylcyclohexane Alcohol; N-(2-hydroxyethyl)lactamide; 2-(3-phenylpropyl)tetrahydrofuran; Anisyl butyrate; methyl 4-phenylbutyrate; 3-heptyldihydro-5-methyl -2(3H)-furanone; 3-acetylthiohexyl acetate; 3-
  • the present invention hopes to find compounds that can affect taste from these chemicals.
  • Experimental principle Simulate the process of drinking medicine and using taste-masking agents. First spray about 0.5ml of oral spray on the throat (3 times). After it takes effect quickly, taste 10ml of bitter standard solution. This screening can be used in advance and can Drugs that mask bitter taste.
  • Standard bitterness sample preparation divide the sample bitterness into five levels, and assign a certain bitterness value range to each level;
  • adding a set of samples with a concentration of 0.025 mmol per liter to be tested can also objectively serve the purpose of examining the reproducibility of the experimental results, that is, by comparing the two sets of samples with the same concentration before and after test results and examine the reproducibility of the test results;
  • Taste-masking experiment then dilute all the selected taste-masking drugs, prepare a solution, put 10 ml into a spray bottle, spray it into the mouth 3 times, stay for 5 seconds, drink 10 ml of the standard bitterness solution, and feel the same. Record the bitterness value and keep the standard bitterness solution in your mouth until you feel the bitterness rise and record the holding time.
  • the experimental data needs to be processed. Specifically, the Grubbs test method is used to circularly test and eliminate outliers in the data, and the two-sided test is used to eliminate outliers in the oral test. Considering the characteristics of biological samples, this experiment Select the detection level as 0.1 and the rejection level as 0.05.
  • the experimental medicinal material processing method mentioned in the above technical solution is as follows: to prepare the bitter standard solution, use 10g coptis powder, add 100ml of purified water above 90 degrees, stir, let it stand for 20 minutes, take the supernatant liquid, and taste it. Use the method to determine the standard bitterness of 4.0 degrees. Dilute it 5 times to determine the standard bitterness of 2.0 degrees. Dilute 2.0 degrees again 5 times to determine the standard bitterness of 0.5 degrees.
  • bitterness rating scale (level 1 means “no bitterness or almost no bitterness”, the bitterness value is 0.5 ⁇ 1.5; level 2 means “slightly bitter”, the bitterness value is 1.5 ⁇ 2.5; level 3 means “bitter but can be Acceptable”, the bitterness value is 2.5 ⁇ 3.5; level 4 means “very bitter, but still tolerable”, the bitterness value is 3.5 ⁇ 4.5; level 5 means “unbearable bitterness”, the bitterness value is 4.5 ⁇ 5.5). Adjust the judgment and recognition of bitter taste.
  • the standard bitterness solution used in this experiment to verify the experimental effect is the coptis solution with a bitterness of 4.0 degrees prepared according to the above method.
  • the gradient bitterness solution the volunteers' bitterness perception was adjusted, and after confirmation, the following experiments were started. There were 32 participants in the experiment. One group with abnormal data was eliminated. Finally, there were 31 groups with valid data. The volunteers were healthy, aged 18-30 years old, 7 boys and 25 girls.
  • Substances to be screened include: linalool, citral, cinnamaldehyde, caryophyllene, eugenol acetate, menthone, menthyl succinate, eucalyptus oil, borneol, probenecid, magnesium sulfate, menthamide, cooling agent WS-5, cooling agent WS-23, vanillic acid, hydroxyvanillin, dihydrojasmone, carvacrol, gingerol, phloretin, piperine, allicin, amlodipine, nifedipine, para Vimimidine, laurolactone, trimethylcyclohexanol, guanolide, eplerenone.
  • the following table records data such as changes in bitterness values when various substances to be screened were used as taste-masking sprays during the above experimental process.
  • Substances (or drugs) that reduce the value by less than 5% of the blank solution are considered completely ineffective.
  • substances with a reduction rate of more than 50% their taste-masking effect is clinically available.
  • the experimental method is still the same as the previous part.
  • Fluorescence microscope BA410 (McAudi Industrial Co., Ltd.), TGL-16B centrifuge (Shanghai Anting Scientific Instrument Factory), sterilization pot YX-280 (Hefei Huatai Medical Equipment Co., Ltd.), sterile ultra-clean workbench SW-CJ- 1F (Suzhou Huayu Purification Equipment Co., Ltd.), sodium ion fluorescence dyeing ENG-2 AM (Shanghai McLean Biochemical Technology Co., Ltd.), dispersant Pluronic F-127 (Shanghai McLean), DMSO (Shanghai McLean), DMEM high Sugar (Hefei Bomei Biotechnology Co., Ltd.), trypsin (Shanghai McLean), calf serum (Hefei Bomei Biotechnology Co., Ltd.), D-Hanks solution (Hefei Bomei Biotechnology Co., Ltd.).
  • Menthol, linalool, citral, cinnamaldehyde, eugenol acetate, menthone, menthyl lactate, menthyl succinate, aminobutyric acid, paravimide, vanillic acid, hydroxyvanillic acid, gingerol, piperine , the above drugs are provided by Shanghai McLean Biochemical Technology Co., Ltd. Triphenylphosphine oxide TPPO (Hefei Bomei Biotechnology Co., Ltd.) WS-5, WS-23 (Ron's reagent); Metronidazole (Shanghai Pulang Biotechnology Co., Ltd.)
  • Sterilization items 1 set of surgical instruments, one box each of pipette tips (10ul, 200ul, 1000ul), about 10 2ml EP tubes and 1.5ml EP tubes, 5 petri dishes, 3 large 50ml centrifuge tubes, and several glass beakers. Others: physiological saline, sterile small syringe (5ml), scissors, cell counting board, petri dish, 95% alcohol, dropper, pipette tip (10ul, 200ul, 1000ul), gun, centrifuge tube, gloves, filter paper.
  • the mouse was sacrificed by dislocation, the tongue was removed (to minimize tongue bleeding), disinfected with alcohol for 2 minutes (sodium citrate was added for anticoagulation), washed with D-Hanks solution or rinsed with 10 ml of physiological saline from a syringe.
  • Proportioning process 5ul of 2mM stock solution + 10ul of Pluronic F-127 stock solution + 980ul of serum-free culture medium, the final concentration is about 10 ⁇ M.
  • Probe loading is achieved in serum-free medium containing an appropriate concentration of AM probe.
  • centrifuge at 100 rpm for 2 minutes, discard the supernatant, add 500ul of cell culture medium without AM probe, blow off the cells, and incubate for 20-60 minutes to ensure that the cells completely deesterify the AM group.
  • Blank control Add 5 ul of drug solvent (53% alcohol solution) to one side of the cover glass on the cell counting plate. Use absorbent paper to absorb water on the opposite side. After soaking the cells in the solution, observe and take 3-5 photos with a fluorescence microscope. , one picture every 1-2 minutes; then add 5ul of the standard bitter drug on one side of the coverslip on the cell counting plate, absorb water on the opposite side with absorbent paper, soak the cells in the solution, and observe and take pictures with a fluorescence microscope for 3-5 Zhang, one every 1-2 minutes.
  • the drugs tested include: menthol, linalool, citral, cinnamic aldehyde, eugenol acetate, menthone, menthyl lactate, menthyl succinate, aminobutyric acid, paravimide, vanillic acid, hydroxyvanillic acid, Gingerol, piperine.
  • Group 1 is a blank. After bittering agent is added, sodium ion channels are activated and intracellular fluorescence is enhanced, and then the fluorescence naturally decays over time; Group 16 is added with triphenylphosphine oxide, sodium ion channels are blocked, and intracellular fluorescence The internal fluorescence does not increase but only decays and decreases with time. In comparison with other groups, compounds similar to triphenylphosphine oxide TPPO were found, which are compounds that can block the sodium ion channel of the Trpm5 bitter taste receptor.
  • Cold sensation channel agonists include TRPM8 agonists and/or TRPA1 agonists.
  • Typical representatives include menthol, linalool, citral, cinnamaldehyde, eugenol acetate, menthone, menthyl lactate, menthyl succinate, and gingerol.
  • Piperine is the compound that we have verified experimentally, whether it is oral taste test or fluorescence test. Because of the consistency of the principle of action, we believe that this type of compound can act on TRPM5 and block the production of bitter taste.
  • TRPV1 antagonists and TRPA1 antagonists including aminobutyric acid, paravimib, vanillic acid, and hydroxyvanillic acid, do not have the effect of masking bitterness and acting on TRPM5. This is true in both oral taste experiments and fluorescence experiments. It has been verified that because of the consistency of the principle of action, we believe that this type of compound cannot act on TRPM5 and cannot block the production of bitter taste.
  • Sodium channel blockers and calcium channel blockers are used to treat heart and blood vessel diseases.
  • the principle is also related to sodium ion and calcium ion channels, but experimental verification cannot mask the bitter taste.
  • TRPM8 agonists are effective
  • Transient receptor potential cation channel subfamily M member 8 also known as cold and menthol receptor I (CMR1), is a protein expressed in sensory neurons and is regulated by cold and coolants such as menthol and menthol.
  • Analog activation including menthol, citral, linalool, eugenol, eucalyptol, menthol, menthone, limonene, 18-cineole, piperine, geranene, menthyl acetate, Artificial synthesis of WS-3((IR, 2S, 5R)-2-isopropyl-5-methyl-cyclohexanecarboxylic acid acetamide), WS-5([((IR, 2S, 5R)-2- Isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-ethyl acetate), WS-23 (2-isopropyl-2, 3, N-trimethyl-butanamide), menthol lactate Este
  • Representative drugs include: cinnamic aldehyde, mustard oil, allicin, capsaicin esters, carvacrol, eugenol, piperine, gingerol, wintergreen oil, clove oil, caryophyllene and/or caryophyllene oxide, citral and One or more types of menthol.
  • Representative drugs include:
  • the TRPV1 agonist is selected from the group consisting of capsaicin, resiniferatoxin, vitamin D, piperine, evodiamine, zanthoxylin, capsaicin ester, 6-shogaol, gingerol, zingerone, shogaol or hydropolygondialdehyde .
  • TRPV1 antagonists and TRPA1 antagonists may be ineffective
  • TRPV1 antagonists include one or more of the following: (-)-bornyl acetate; hydroxycitronellal; aplerenone; N, N-dimethyl anthranilic acid methyl ester; 2-ethoxy -3-ethylpyrazine; L-piperone; isobornyl isobutyrate; 4-acetoxy-2,5-dimethyl-3(2H)-furanone; tripropylamine; dihydrojasmone; 1-Methyl-2-pyrrole; 3-octyl acetate; 2-methylbutyl isovalerate; piperonyl isobutyrate; phenoxyethyl propionate; vanillin propylene glycol acetate; octenyl ring Pentanone; Butyl isobutyrate; Guaiac oil; Tetrahydro-4-methyl-2-(2-methyl-1-propenyl)-2Hpyran.
  • TRPA1 antagonists include one or more of the following: ⁇ -laurolactone; vanillic acid; ⁇ -methyldecanolide; trans-2,4-nonadienal; 4-allyl- 2,6-dimethoxyphenol; o-methoxycinnamaldehyde; 4-methyl-2-phenyl-2-pentenal (mixture of cis and trans); 2-methoxy-4- Propylphenol; 2-methoxy-benzoic acid methyl ester; ⁇ -tetradecanolactone; 1-methyl-2-pyrrole; 3,3,5-trimethylcyclohexanol; N-(2- Hydroxyethyl)lactamide; 2-(3-phenylpropyl)tetrahydrofuran; Anisyl butyrate; Methyl 4-phenylbutyrate; 3-Heptyldihydro-5-methyl-2(3H)-furan Ketone; 3-acetylthiohexyl acetate; 3-methyl-5-propy
  • the concentration used is between 0.001% and 0.5%. Generally, the effect becomes better as the concentration increases. However, the effect is not obvious when the concentration is increased to about 0.1%, and the irritation becomes more and more serious. Therefore, regardless of economy or practicality, the best choice is A lower concentration with better efficacy is more appropriate.
  • TRPM8 agonists produces a cold sensation, but the administration of TRPV1-4 and TRPA1 agonists can significantly inhibit it, indicating that there is a restrictive relationship between "cold and hot” channels, and they can both act on M5 receptors, causing bitter taste inhibition.
  • TRPV1-4 and TRPA1 agonists can act on pain receptors to produce a hot pain sensation.
  • the painful feeling is weakened, and the cool feeling brings A pleasure. Therefore, the preferred combination is the combination of these two, which can avoid the hot pain while masking the bitter taste, leaving only a cooler pleasure.
  • TRPM8 receptor activators combined with TRPV1-4 and TRPA1 activators reduces irritation and nociception.
  • A+B+sweetener+flavor is preferred.
  • Menthol amide 0.05%, cinnamic aldehyde 0.2%, sucralose 0.1%, cyclamate 0.5%, appropriate amount of flavor.
  • bitter taste is basically no longer felt. Those with a bitterness level exceeding 0.5 degrees can still feel a little bit.
  • TRPM8 receptor agonists TRPV1-4 and TRPA1 agonists all have the effect of masking the bitter taste perception in the mouth
  • TRPM8 receptor agonists stimulate cold channels
  • TRPV1-4 and TRPA1 stimulate hot channels. They can be used The cooling sensation neutralizes the heat sensation and eliminates this pain. The combination of these two drugs completely eliminates the uncomfortable, hot pain and brings a cooler and pleasant pleasure.
  • bitter taste masking formulations may also include solvents, sweeteners, preservatives and flavors.
  • sweeteners and spices can be used to neutralize the unpleasant taste of Class A and Class B substances.
  • the taste-masking agents can be used in pharmaceutical, food or oral care products.
  • the medicines include any one of anti-tumor drugs, drugs for treating hyperlipidemia, drugs for treating hyperglycemia, analgesics, antibiotics, antipyretics and traditional Chinese medicines, and the dosage forms of the drugs include Any of tablets, decoctions, wines, granules, liquid oral preparations and aerosols.
  • the taste masking agent is used in food, the food includes any one of ice cream, custard, cream, beverages and cakes.
  • the taste masking agent is used in an oral care product, the oral care product includes any one of toothpaste, mouthwash, chewing gum, breath freshener and mouthwash.
  • the tablets may include any one of multi-layer tablets, chewable tablets, soluble tablets, effervescent tablets, sustained-release tablets, controlled-release tablets, dispersible tablets, buccal tablets, orally disintegrating tablets, sublingual tablets and oral patches.
  • TRPM8 has multiple synonyms: TRPP8, LTRPC6.CMRI, MGC2849, transient receptor potential cation channel subfamily M member 8. All functional modifications of this receptor are also included, e.g. especially splice variants, isoforms, e.g. TRPM8CRA-a. TRPM8CRA-b.
  • TRP is the same as “trp” or “Trp”, which is the abbreviation of Transient receptor potential Cation channel. There is no difference in the meaning of uppercase and lowercase letters.
  • Forsythia suspensa This product is the dried fruit of Forsythia suspensa (Thunb.) Vahl, a plant in the Oleaceae family. In autumn, when the fruits are first ripe and still green, they are harvested, impurities are removed, steamed, and sun-dried, and are commonly called “Qingqiao”; when fruits are harvested when they are ripe, sun-dried, and impurities are removed, they are commonly known as "Laoqiao.” Calculated as a dry product, this product contains no less than 0.15% of forsythin (C 27 H 34 O 11 ).
  • Gentiana This product is the dried roots and rhizomes of Gentiana manshurica Kitag., Gentiana scabra Bge., Gentiana triflora Pall. or Gentiana rigescens Franch.
  • the first three species are commonly called “gentian” and the latter species are commonly known as “hard gentian”.
  • Melia toosendan Sieb.et Zucc This product is the dried and mature fruit of Melia toosendan Sieb.et Zucc. Harvest the fruits when they are ripe in winter, remove impurities and dry them. Calculated as a dry product, this product contains 0.060% to 0.20% of toosendanin (C 30 H 38 O 11 ).
  • Lotus seed heart This product is the dried young leaves and radicles from the mature seeds of Nelumbo nucifera Gaertn. Take it out and dry it in the sun. Calculated as a dry product, this product contains no less than 0.70% methylnexinine (C 38 H 45 N 2 0 6 ).
  • Andrographis paniculata This product is the dry above-ground part of Andrographis paniculata (Burm.f.) Nees. Cut the stems and leaves in early autumn when they are in full bloom and dry them in the sun. Calculated as dry product, this product contains andrographolide (C 20 H 30 O 5 ), neoandrographolide (C 20 H 30 O 8 ), 14-deoxyandrographolide (C 20 H 30 O 4 ) and dehydrated The total amount of andrographolide (C 20 H 28 O 4 ) shall not be less than 1.5%.
  • This product is the dried root of Angelica pubescens Maxim.f. biserrata Shan et Yuan. Dig the seedlings in early spring when they have just sprouted or when the stems and leaves have withered in late autumn, remove the fibrous roots and sediment, dry them until they are semi-dry, and store them for 2 to 3 days. After they are soft, dry them again. Calculated as a dry product, this product contains not less than 0.50% of osthole (C 15 H 16 O 3 ) and not less than 0.080% of dihydroalvinol angelate (C 19 H 20 O 5 ).
  • the following table shows the Chinese names, aliases, and molecular formulas of some chemical drugs. Easy to compare.
  • Binderness masking refers to the use of a drug (either prior to use or concurrent use) that causes the user to experience no bitter taste or to reduce the perceived bitterness value of the drug.
  • taste masking refers to the use of a drug (whether used before or at the same time) to make the user experience no bitter taste, or to reduce the perceived magnitude of the bitter taste.
  • Ants or “activators” are also called stimulants, which are molecules such as drugs, enzyme agonists and hormones that can enhance the activity of another molecule and promote a certain reaction.
  • Antagonists do not cause biological effects themselves after binding to the receptor, but block the effects mediated by the agonist of the receptor.
  • the compounds may exist in chemically pure or enriched form, as a single stereoisomer or as a mixture of stereoisomers. Furthermore, the compounds may be uncharged or in the form of salts thereof, such as acid addition salts.
  • Functional groups can optionally be replaced by equivalent chemical groups; fluorine atoms can be replaced by other halogen atoms, such as C1, Br or I; oxygen atoms (such as ether groups) can be replaced by corresponding sulfur groups, and vice versa; ketones Groups may be replaced by corresponding thionyl groups.
  • the compounds specifically described above are chemical substances known per se and are commercially available or obtained by conventional organic synthesis methods. Modified forms or derivatives are also functional analogs or functionally equivalent compounds if they also exhibit the desired biological activity.
  • concentrations mentioned in the present invention are all volume concentrations unless otherwise specified.

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Abstract

提供一种TRPM8激动剂、TRPA1激动剂或TRPV1-4激动剂作为掩盖苦味的物质的应用、一种或几种物质作为掩味剂的应用、一种或几种物质在用于掩盖苦味的口腔喷雾剂或漱口液中的应用、一种用于掩盖苦味的口腔喷雾剂或掩味剂。发现TRPM8受体激动剂与TRPV1-4和TRPA1激动剂都有掩盖口腔苦味感知的效果，TRPM8受体激动剂刺激冷通道，TR-PV1-4和TRPA1刺激热通道，可以用凉感来中和热感，消除难受、热辣的痛觉，带来比较凉爽的愉悦的快感。

Description

用于掩盖苦味的产品
相关申请的交叉引用
本申请要求于2022年6月13日递交的中国专利申请CN202210659911.X的权益，其全部内容通过参考并入本文中。
技术领域
本发明涉及生活用品、食品或药品领域，尤其是一种作用于口腔、用于掩盖苦味的产品，围绕着该产品，本发明具体涉及一种TRPM8激动剂、TRPA1激动剂或TRPV1-4激动剂作为掩盖苦味的物质的应用、一种或几种物质作为掩味剂的应用、一种或几种物质在用于掩盖苦味的口腔喷雾剂或漱口液中的应用、一种用于掩盖苦味的口腔喷雾剂或掩味剂。
 背景技术
人的口腔味蕾由很多味觉细胞构成，其中I型味觉细胞具有神经胶质样特性，主要充当支持细胞，而II型味觉细胞通过激活GPCR通路来检测苦味、甜味和鲜味刺激。该GPCR途径由磷脂酶C(PLC)信号级联组成，该级联导致钙(Ca 2+)从内部储存中释放，随后激活单价选择性瞬时受体电位melastatin 5(TRPM5)通道。II型细胞缺乏传统的突触特化，而是激活TRPM5以引起细胞去极化，从而刺激Calhm1通道并导致作为神经递质的ATP释放。与大多数TRP通道相比，TRPM5是独一无二的，因为它是电压敏感的、单价阳离子选择性的，并且被升高的细胞内Ca 2+激活。三苯基氧化膦(TPPO)是一种可逆的、选择性的TRPM5通道阻断剂。TPPO(50μM)的应用消除了仅使用TRPM5的小鼠中剩余的味觉诱发Na +反应，表明这些味觉诱发的Na +信号仅由TRPM5介导。清除TPPO后反应恢复。进一步的实验发现，TRPM4和TRPM5都是苦味、甜味和鲜味刺激的正常传导所需的充要条件，TRPM4和TRPM5在其他细胞类型中的主要区别在于它们对细胞内Ca 2+的敏感性。在HEK-293细胞中的分析发现，TRPM4的半最大电流激活(EC50)的Ca 2+浓度(20.2±4.0μM)远大于TRPM5的EC50(0.70±0.1μM)。如果这些EC50值在味觉细胞中具有可比性，那么我们预测在细胞刺激期间，当细胞溶质Ca 2+水平较低时，TRPM5将首先被激活。随着Ca 2+浓度的增加，TRPM4也将有助于味觉诱发信号。这些发现表明，与TRPM4相比，TRPM5需要较小的胞质Ca 2+增加就能激活。因为苦味、甜味和鲜味刺激信号走的是同一通路，所以甜味、鲜味能通过竞争来掩盖苦味，比如蔗糖掩盖苦味。
TRPM5属于瞬时受体电位(TRP)的一种，TRP通道是钙可渗透的非选择性阳离子通道，已经确定了大约28个TRP通道，每个通道基因的剪接变体数量不同。TRP通道被分为六个不同的子组，包括TRPV(1-6)、TRPM(1-8)、TRPC(1-7)、TRPA1、TRPP(1-3)和TRPML(1-3)，根据它们的序列相似性。一般而言，TRP通道涉及钙处理（例如，细胞内钙动员和钙的重吸收）和广泛的感觉形态，包括疼痛，温度，味道等。TRP通道异常是神经退行性疾病、糖尿病、炎症性肠病、癫痫、癌症等多种疾病的重要机制的一部分。TRP家族的几个成员、TRPV1-4、TRPM8和TRPA1，也被称为“ThermoTRP”，参与检测温度变化，从而充当我们身体的分子温度计。此外，它们还是多模态伤害感受器，可整合有害温度和化学伤害等疼痛刺激。例如，TRPV1通道介导由辣椒素和酸诱导的热痛觉过敏和疼痛。TRPA1是一种伤害感受器，它整合了许多有害的环境刺激，包括氧化剂和亲电子剂。最近，基因缺失动物已被创造来研究TRP通道在疼痛和伤害感受中的作用，并且已经证实TRPV1、TRPV3、TRPV4和TRPA1参与伤害感受。
TRP通道蛋白序列相似度很高，很多分子的刺激会同时激活几个蛋白通道，从而产生味觉、温度觉和疼觉同时出现，比如发明人所做的实验中六种物质都可以作用于味觉通路TRPM5，从而掩盖味觉通道，但每种物质还可以激活其他通路。比如薄荷醇可以产生冷觉、丁香油产生热觉、辣椒油产生疼觉和热觉、细辛产生麻觉。
 发明内容
本发明的目的在于至少部分地克服现有技术的缺陷，扩展掩味剂的原料范围，提供一种TRPM8激动剂、TRPA1激动剂或TRPV1-4激动剂作为掩盖苦味的物质的应用、一种或几种物质作为掩味剂的应用、一种或几种物质在用于掩盖苦味的口腔喷雾剂或漱口液中的应用、一种用于掩盖苦味的口腔喷雾剂或掩味剂。
本发明的目的还在于提供一种或几种物质在用于掩盖苦味的口腔喷雾剂或漱口液中的应用和一种用于掩盖苦味的口腔喷雾剂或掩味剂，使得掩盖苦味的效果更好。
为达到上述目的或目的之一，本发明的技术解决方案如下：
一种TRPM8激动剂作为掩盖苦味的物质的应用，所述TRPM8激动剂包括如下物质中的一种或多种：薄荷醇衍生物、柠檬醛、芳樟醇、丁香酚和桉油精；
其中，薄荷醇衍生物包括如下物质中的一种或多种：薄荷酰胺、荷薄酮、柠檬烯、18-桉叶素、胡椒碱、大根香叶烯、乙酸薄荷醇酯、WS-3((IR, 2S, 5R)-2-异丙基-5-甲基-环己烷羧酸乙酰胺)、WS-5([((IR, 2S, 5R)-2-异丙基-5-甲基-环己烷羰基)-氨基]-乙酸乙酯)、WS-23(2-异丙基-2, 3, N-三甲基-丁酰胺)、乳酸薄荷醇酯、琥珀酸薄荷醇酯、薄荷氧基丙二醇、2-异丙基-5-甲基环己基4-(二甲基氨基)-4-氧代丁酸酯(4-(二甲基氨基)-4-氧代丁酸2-异丙基-5-甲基环己基酯)。
一种TRPA1激动剂作为掩盖苦味的物质的应用，所述TRPA1激动剂包括如下物质中的一种或多种：
肉桂醛、芥子油、大蒜素、辣椒素酯、香芹酚、丁香酚、胡椒碱、姜辣素、冬绿油、丁香油、石竹烯、石竹烯氧化物、柠檬醛和薄荷醇。
一种TRPV1-4激动剂作为掩盖苦味的物质的应用，所述TRPV1激动剂选自辣椒素、树脂毒素、维生素D、胡椒碱、吴茱萸碱、花椒麻素、辣椒素酯、6-姜烯酚、姜辣素、姜油酮、姜酮酚和水蓼二醛中的一种或多种。
一种或几种物质作为掩味剂的应用，所述物质选自芳樟醇、柠檬醛、肉桂醛、石竹烯、乙酸丁香酚、薄荷酮、桉叶油、冰片、薄荷酰胺、琥珀酸薄荷醇酯、凉味剂WS-5、凉味剂WS-23、姜酚、胡椒碱和大蒜素。
一种或几种物质在用于掩盖苦味的口腔喷雾剂或漱口液中的应用，
所述一种或几种物质为A类物质、B类物质、或A类物质与B类物质的组合；
所述A类物质为TRPM8激动剂中的一种或多种；所述B类物质为TRPA1激动剂和TRPV1-4激动剂中的一种或多种。
根据本发明的一个优选实施例，所述一种或几种物质为A类物质，所述A类物质在口腔喷雾剂或漱口液中的体积浓度为0.001%-0.5%；或者
所述一种或几种物质为B类物质，所述B类物质在口腔喷雾剂或漱口液中的体积浓度为0.001%-0.5%；或者
所述一种或几种物质为A类物质与B类物质的组合，所述A类物质在口腔喷雾剂或漱口液中的体积浓度为0.001%-0.5%，所述B类物质在口腔喷雾剂或漱口液中的体积浓度为0.001%-0.5%。
根据本发明的一个优选实施例，所述口腔喷雾剂或漱口液在被喷施于口腔内后5-10秒内达到掩盖苦味效果的峰值，并且效果持续时间为30-120秒。
一种用于掩盖苦味的口腔喷雾剂或掩味剂，
所述口腔喷雾剂或掩味剂包括A类物质、B类物质、或A类物质与B类物质的组合；
所述A类物质为TRPM8激动剂中的一种或多种；所述B类物质为TRPA1激动剂和TRPV1-4激动剂中的一种或多种。
根据本发明的一个优选实施例，所述口腔喷雾剂或掩味剂用于药物，所述药物包括抗肿瘤药物、治疗高血脂药物、治疗高血糖药物、止痛剂、抗生素、退热剂和中药中的任意一种，药物的剂型包括片剂、汤剂、分散剂、酒剂、颗粒剂、漱口水、液体口服剂和气雾剂中的任意一种；或者
所述口腔喷雾剂或掩味剂用于食物，所述食物包括冰激凌、奶油冻、乳油、饮料和糕饼中的任意一种；或者
所述口腔喷雾剂或掩味剂用于口腔护理产品，所述口腔护理产品包括牙膏、漱口水、口香糖、口气清新剂和漱口剂中的任意一种。
根据本发明的一个优选实施例，所述片剂包括多层片、咀嚼片、可溶片、泡腾片、口崩片、缓释片、控释片、分散片、含片、舌下片和口腔贴片中的任意一种。
本发明的有益效果：发现TRPM8受体激动剂与TRPV1-4和TRPA1激动剂都有掩盖口腔苦味感知的效果，而且TRPM8受体激动剂刺激冷通道，TRPV1-4和TRPA1刺激热通道，可以用凉感来中和热感，消除这种痛苦。这两种药物的组合，完全消除了难受、热辣的痛觉，带来比较凉爽的愉悦的快感。
 附图说明
图1为钠离子通道的免疫荧光实验中部分组别的钠离子荧光浓度变化图；
图2为钠离子通道的免疫荧光实验中部分组别的钠离子荧光浓度变化图；
图3为钠离子通道的免疫荧光实验中部分组别的钠离子荧光浓度变化图；
图4示出了不同物质的荧光像素平均值的比较；
图5示出了不同物质的荧光像素平均值的比较；以及
图6示出了不同物质的荧光像素平均值的比较。
 具体实施方式
下面结合附图详细描述本发明的示例性的实施例，其中相同或相似的标号表示相同或相似的元件。另外，在下面的详细描述中，为便于解释，阐述了许多具体的细节以提供对本披露实施例的全面理解。然而明显地，一个或多个实施例在没有这些具体细节的情况下也可以被实施。在其他情况下，公知的结构和装置以图示的方式体现以简化附图。
发明人研究发现，针对味觉产生原理，钠离子通道、钙离子通道阻滞剂可能会影响味觉产生，TRP家族的几个成员、TRPV1-4、TRPM8和TRPA1，它们的拮抗剂和激活剂可能会影响味觉的产生，相关的产品代表如下：
1、钠通道阻滞剂：美西律、普罗帕酮注射剂、硫酸奎尼丁、磷酸丙吡胺片、盐酸莫雷西嗪。
2、钙通道阻滞剂：二氢吡啶类药物，比如硝苯地平、氨氯地平、非洛地平等；非二氢吡啶类的代表药物，比如维拉帕米、地尔硫䓬。
3、冷通道受体：冷觉通道激动剂，包括TRPM8激动剂和/或TRPA1激动剂。TRPM8激动剂选自薄荷醇、柠檬醛、芳樟醇、丁香酚和桉油精的一种或多种。
瞬时受体电位阳离子通道亚家族M成员8(TRPM8)，亦称为冷和薄荷醇受体I(CMRl)，是在感觉神经元中表达的蛋白质，并且由低温和冷却剂如薄荷醇和薄荷醇衍生物：主要包括薄荷酰胺、荷薄酮、柠檬烯、18-桉叶素、胡椒碱、大根香叶烯、乙酸薄荷醇酯、WS-3((IR, 2S, 5R)-2-异丙基-5-甲基-环己烷羧酸乙酰胺)、WS-5([((IR, 2S, 5R)-2-异丙基-5-甲基-环己烷羰基)-氨基]-乙酸乙酯)、WS-23(2-异丙基-2, 3, N-三甲基-丁酰胺)、乳酸薄荷醇酯(Frescolat ML)、琥珀酸薄荷醇酯、薄荷氧基丙二醇(冷却剂10)、2-异丙基-5-甲基环己基4-(二甲基氨基)-4-氧代丁酸酯(4-(二甲基氨基)-4-氧代丁酸2-异丙基-5-甲基环己基酯)。
丁香油类型物：甲基戊基甲酮、丁香油成分丁香酚（57-85%）、石竹烯（15%）、丁香酚乙酸酯（18%）。
4、TRPA1激动剂选自肉桂醛、芥子油、大蒜素、辣椒素酯、香芹酚、丁香酚、胡椒碱、姜辣素、冬绿油、丁香油、石竹烯和/或石竹烯氧化物、柠檬醛和薄荷醇中的一种或多种。
TRPV1激动剂选自辣椒素、树脂毒素、维生素D、胡椒碱、吴茱萸碱、花椒麻素、辣椒素酯、6-姜烯酚、姜辣素、姜油酮、姜酮酚或水蓼二醛。
5、TRPV1拮抗剂可包括下列中的一种或多种：(-)-乙酸冰片酯；羟基香茅醛；阿普利酮；N, N-二甲基邻氨基苯甲酸甲酯；2-乙氧基-3-乙基吡嗪；L-胡椒酮；异丁酸异冰片酯；4-乙酰氧基-2,5-二甲基-3(2H)-呋喃酮；三丙胺；二氢茉莉酮；1-甲基-2-吡咯醛；3-乙酸辛酯；2-甲基丁基异戊酸酯；异丁酸胡椒酯；丙酸苯氧基乙酯；香草醛丙二醇乙酸酯；辛烯基环戊酮；异丁酸丁酯；愈创木油；四氢-4-甲基-2-(2-甲基-1-丙烯基)-2H吡喃。
6、TRPA1拮抗剂可包括下列中的一种或多种：肉桂皮油；γ-十二酸内酯；香草酸；γ-甲基癸内酯，反式-2,4-壬二烯醛；4-烯丙基-2,6-二甲氧基苯酚；邻甲氧基肉桂醛；4-甲基-2-苯基-2-戊烯醛(顺式和反式的混合物)；2-甲氧基-4-丙基苯酚；2-甲氧基-苯甲酸甲酯；δ-十四内酯；1-甲基-2-吡咯醛；3,3,5-三甲基环己醇；N-(2-羟乙基)乳酰胺；2-(3-苯丙基)四氢呋喃；丁酸茴香酯；4-苯基丁酸甲酯；3-庚基二氢-5-甲基-2(3H)-呋喃酮；3-乙酰基硫基己基乙酸酯；3-甲基-5-丙基-2-环己烯-1-酮；异丁酸异冰片酯；戊酸龙脑酯；香茅醇乙酸酯；(2S,5S,6S)-6-)羟基-二氢茶螺烷；反式-2-己烯醛。
本发明希望从这些化学品中找到能影响味觉的化合物。
在味觉评价方法中，人群口感试验曾是首选方法，但该方法存在主观性较强、不确定性和原料药安全性问题。随后出现了替代性的溶出度、电子舌和动物实验等方法。但是本发明的实验所选用的药物都是食品级，国家药监局认定的药品或食品，所以不存在安全性问题，而且实验的结果要直接指导应用，因此人群口感试验就是首选方法。
一、口腔喷雾剂形式的物质筛选
实验目的：筛选出5秒内起效，持续30-120秒，在持续时间内使用药物不能感受到味道的化合物。
实验原理：模拟喝药与使用掩味剂的过程，先用口腔喷雾剂喷雾于喉咙0.5ml左右(3下)，迅速起作用后，口尝苦味标准液10ml，以此筛选可以预先使用而能够掩盖苦味的药物。
实验步骤：
1：志愿者筛选，课题组对招募的志愿者进行严格筛选，最终选择健康志愿者作为受试者，在试验前签订知情同意书；
2：标准苦度样品制备，将样品苦味分为五级，每个级别再赋予一定的苦度值范围；
3：用口尝评价法矫正感觉标准，即通过志愿者口感评价与参比样品组既定苦度值之间的对比，矫正感觉标准。具体步骤：在志愿者进行口尝测试时将各浓度的参比溶液放于口尝杯中，由志愿者含于口中，计时，在口腔做漱口动作，以使舌根及舌侧的苦味感受区能够充分感受药物苦味，并被告知该参比溶液的苦度分级和具体苦度值，吐出，漱口5次，至口腔内无苦味，15分钟后测定另一浓度的参比溶液，期间将数据进行记录；由于口尝法的主观性强，增加一组0.025mmol每升浓度待测样品，客观上还能够起到考察实验结果重现性的目的，即通过对比前后两组同浓度样品的测试结果，考察测试结果的重现性；
4：掩味实验，接着对所有被筛选掩味剂药品稀释，配置溶液，取10毫升装入喷雾瓶中，喷入口腔3下，停留时间5秒后，喝10ml标准苦度溶液，感觉并记下苦度值，标准苦度溶液保持口中，直到感觉苦度上升，记录保持时间。
5：质量控制，为了保证口尝评价结果的准确性，课题组采取了一系列的控制评价质量的措施，包括使样品浓度逐级增加以减少饱和效应的影响，为减少志愿者意识惯性而部分打乱样品浓度顺序，同一样品多次测试以考察重现性，每次尝味后口腔休息十五到三十分钟，对离群值进行必要的处理；
6：对实验数据进行处理，由于本实验对象为生物样本，且不同受试者间存在个体差异，实验测试数据中可能有个别异常值，采用Grubbs检验法对数据进行了异常值的排除，接着将实验数据绘制表格、曲线图，进行数据分析。
需要对实验数据进行处理，具体为采用Grubbs检验法对数据进行了异常值的循环检验和剔除，采用双侧检验对口尝试验中的异常值进行剔除，考虑到生物样本的特点，故本次实验选择检出水平为0.1，剔除水平为0.05。
在上述技术方案中提到的实验药材处理方法如下：苦味标准液的制备，使用10g黄连粉，加入100ml、90度以上的纯净水，搅拌，静置20分钟，取上清液使用，口尝法确定标准苦度4.0度，稀释5倍，确定标准苦度2.0度，对2.0度再稀释5倍，确定标准苦度0.5度。对照苦味评分表，（1级表示“无苦味或者几乎无苦味”，苦度值为0.5~1.5；2级表示“略有苦味”，苦度值1.5~2.5；3级为“有苦味但是可接受”，苦度值2.5~3.5；4级表示“很苦，但是仍可忍受”，苦度值3.5~4.5；5级为“不能忍受的苦味”，苦度值4.5~5.5）。调校对于苦味的判断与认知。
本实验所用的验证实验效果的标准苦度溶液就是按上文方法制作的苦度为4.0度的黄连溶液。通过梯度苦度溶液，对志愿者的苦度认知进行调校，确定后开始进行下述实验。参加实验人数32名，异常数据剔除1组，最后有效数据31组，志愿者健康，年龄18-30周岁，7名男生，25名女生。
待筛选物质包括：芳樟醇、柠檬醛、肉桂醛、石竹烯、乙酸丁香酚、薄荷酮、琥珀酸薄荷醇酯、桉叶油、冰片、丙磺舒、硫酸镁、薄荷酰胺、凉味剂WS-5、凉味剂WS-23、香草酸、羟基香草醛、二氢茉莉酮、香芹酚、姜酚、根皮素、胡椒碱、大蒜素、氨氯地平、硝苯地平、帕拉维米、十二内酯、三甲基环己醇、葵内酯、依普利酮。
下表记录了在上述实验过程中，各种待筛选物质作为掩味喷雾剂时苦度值变化等数据。
降低幅度低于空白溶液的5%的物质（或药物），被认为是完全无效果的。而降低幅度超过50%的物质，其掩盖味道效果是临床上可用的。
二、对中药饮片的广谱掩盖味道效果的验证
按照10g干燥中药饮片水煎出100ml液体（水煎方法，用不锈钢容器，沸腾后停留20分钟）的标准，从常用300种中药饮片中，结合中国药典，筛选药典中写明性味苦或极苦的20多味中药，分别为白芨、秦皮、防已、苦杏仁、射干、独活、莲子心、川楝子、穿心莲、山豆根、黄连、龙胆、连翘、槐角、黄柏、黄芩、桔梗、羌活、防风、紫苏、两面针、九里香、苦参、野菊花等24种。
最后，通过5度分度法，筛选出苦度高于3.5（中度苦度）的2种，和所有高于5度苦度（高度苦，极苦、伴恶心）的7种，共9种（独活、莲子心、川楝子、穿心莲、山豆根、黄连、龙胆、连翘、槐角）作为苦度代表，参与掩盖苦味实验。（说明：黄连饮片水煎20分钟苦度可以达到5.2，参比标准溶液是90度水冲泡黄连粉，自动降温得到溶液，苦度口尝为4.0。因为黄连作为标准苦味液体用过，故不再使用）。
实验方法还是等同于前述部分。
通过上表可以看出，表中列举的掩味剂对极苦药物都是有一定效果的，效果最好的是肉桂醛，其次的柠檬醛、薄荷酰胺，最后是芳樟醇。
三、钠离子通道的免疫荧光实验
对苦味剂刺激导致的钠离子荧光浓度变化进行观察，根据结果判断被试药物对钠离子通道有无阻滞作用。
1.1实验动物
小白鼠10只（郑州华兴实验动物有限公司）
1.2实验器材
荧光显微镜BA410（麦克奥迪实业有限公司）、TGL-16B离心机（上海安亭科学仪器厂）、灭菌锅YX-280（合肥华泰医疗设备有限公司）、无菌超净工作台SW-CJ-1F（苏州市华宇净化设备有限公司）、钠离子荧光染色ENG-2 AM（上海麦克林生化科技有限公司）、分散剂Pluronic F-127（上海麦克林）、DMSO（上海麦克林）、DMEM高糖（合肥博美生物科技有限公司）、胰蛋白酶（上海麦克林）、小牛血清（合肥博美生物科技有限公司）、D-Hanks溶液（合肥博美生物科技有限公司）。
薄荷醇、芳樟醇、柠檬醛、肉桂醛、乙酸丁香酚、薄荷酮、乳酸薄荷酯、琥珀酸薄荷酯、氨基丁酸、帕拉维米、香草酸、羟基香草酸、姜酚、胡椒碱，以上这些药物由上海麦克林生化科技有限公司提供。三苯基氧化膦TPPO（合肥博美生物科技有限公司）WS-5,WS-23（罗恩试剂）；甲硝唑（上海普琅生物科技有限公司）
灭菌物品：手术器械1套，枪头（10ul、200ul、1000ul）各一盒，2mlEP管、1.5mlEP管各10个左右，培养皿5个，大50ml离心管3个，玻璃烧杯数个。其他：生理盐水、无菌小注射器（5ml）、剪刀、细胞计数板、培养皿、95%酒精、滴管、枪头（10ul、200ul、1000ul）、枪、离心管、手套、滤纸。
1.3实验步骤
（一）取舌
小鼠脱臼处死，取舌（尽量减少舌出血），酒精消毒2min（加入柠檬酸钠抗凝），用D-Hanks溶液清洗或注射器抽取生理盐水10ml冲洗。
（二）分离细胞制备细胞混悬液
将取出的舌头放在2mlEP管中，加入0.25%胰蛋白酶溶液1-1.5ml，37℃恒温箱中孵育30min。
从恒温培养箱取出离心管，震荡2分钟，用枪头吹打几次未消化的舌体，取出舌体，盖上EP管盖，放入离心机，3000转离心3分钟，弃去上清液，加入细胞培养液（含10%灭活血清），吹打分散细胞，放置在37°C恒温培养箱中30min，让细胞恢复一下。
（三）钠离子荧光染色
（1）将已配好的ENG-2 AM储存液取出于室温回温备用，注意避光。预先配好的母液浓度是2mM，-18度储存备用。
（2）用无血清培养基将ENG-2 AM + DMSO储存液稀释到1-10μM的工作液。
配比过程：2mM的母液5ul+ Pluronic F-127母液10ul+980ul无血清培养基，终浓度约为10μM.
（3）在含适当浓度AM探针的无血清培养基中实现探针加载。
取出培养箱中的细胞，离心，弃去培养液。用D-Hanks溶液清洗1次细胞，离心后弃去培养液。再次加入1ml培养液，然后加入300ul的钠离子探针稀释液，吹打分散细胞，室温或37°C孵育细胞1小时。
孵育结束，离心100转2分钟，弃去上清液，加入不含AM探针的细胞培养液500ul，吹散细胞，孵育20-60min，以确保细胞将AM基团完全去酯化。
（4）取10ul孵育液滴入细胞计数板中央，盖上载玻片，到荧光显微镜下观察。
（5）低倍镜找到细胞，打开荧光通路，用荧光显微镜检测荧光信号，换高倍镜，找到合适的观察细胞，观察并拍照记录初始信号。
（四）检测药物效果（被测试苦味药物是2%的甲硝唑溶液）
（1）空白对照：加药物溶剂（53%酒精溶液）5ul于细胞计数板上盖玻片一侧，用吸水纸在对侧吸水，使溶液浸泡细胞后，用荧光显微镜观察拍照3-5张，每隔1-2分钟一张；然后再加标准苦味药物5ul于细胞计数板上盖玻片一侧，用吸水纸在对侧吸水，使溶液浸泡细胞后，用荧光显微镜观察拍照3-5张，每隔1-2分钟一张。
（2）实验药物：加被试药物5ul于细胞计数板上盖玻片一侧，用吸水纸在对侧吸水，使溶液浸泡细胞后，用荧光显微镜观察拍照3-5张，每隔1-2分钟一张；然后再加标准苦味药物5ul于细胞计数板上盖玻片一侧，用吸水纸在对侧吸水，使溶液浸泡细胞后，用荧光显微镜观察拍照3-5张，每隔1-2分钟一张。
被试药物包括:薄荷醇、芳樟醇、柠檬醛、肉桂醛、乙酸丁香酚、薄荷酮、乳酸薄荷酯、琥珀酸薄荷酯、氨基丁酸、帕拉维米、香草酸、羟基香草酸、姜酚、胡椒碱。
（3）阻滞剂对照：权威研究认为TRPM5阻滞剂三苯基氧化膦(TPPO)是一种可逆的、选择性的TRPM5通道阻断剂；最后用三苯基氧化膦(TPPO)当做被试药物，重复上述步骤。
（4）观察分析：通过对上述过程的钠离子荧光变化包括：起作用时间点，持续时长，强度等因素进行统计观察，比较加入的筛选化合物，对标准苦味剂刺激导致的钠离子荧光浓度变化，根据结果判断被试药物对钠离子通道有无阻滞作用。结果如图1-3所示。
（5）数据分析，通过Image J-Fiji软件对图片进行分析，对其荧光像素平均值比较，去除基数后列表比较，画出图4-6，并使用SPSS18.0进行卡方检验，比较数据组的差异。
结果分析：第1组是空白，加入苦味剂后，钠离子通道被激活，胞内荧光增强，而后随时间荧光自然衰减；16组，加入三苯基氧化膦，钠离子通道被阻滞，胞内荧光无增强仅随时间衰减下降。其他组别与之对比，找到类似三苯基氧化膦TPPO的化合物，即为能阻断Trpm5苦味受体钠离子通道的化合物。2-9组和14-15组在加苦味药物0S时，荧光没有增强，随后都保持衰减趋势；即薄荷醇、芳樟醇、柠檬醛、肉桂醛、乙酸丁香酚、薄荷酮、乳酸薄荷酯、琥珀酸薄荷酯、姜酚、胡椒碱都有类似三苯基氧化膦TPPO的效果，即为能阻断Trpm5苦味受体钠离子通道的化合物。10、11、13组在加苦味药物0S时，荧光增强，超过基线，随后都保持衰减趋势；而12组在加苦味药物0S时，荧光没有增强，但在加药物120S时，却逆势增加，超过基线。因此认为氨基丁酸、帕拉维米、香草酸、羟基香草酸效果较差，没有掩盖苦味效果。
使用SPSS18.0进行卡方检验，比较数据组的差异，发现2-9组和14-15组与16组三苯基氧化膦组无差异（p>0.05），但与空白组差异显著（p<0.01）；而10-13组则相反，与16组三苯基氧化膦组有差异（p<0.05），但与空白组无差异（p>0.05）。这些验证了上述结果。
冷觉通道激动剂包括TRPM8激动剂和/或TRPA1激动剂，典型代表包括薄荷醇、芳樟醇、柠檬醛、肉桂醛、乙酸丁香酚、薄荷酮、乳酸薄荷酯、琥珀酸薄荷酯、姜酚、胡椒碱，就是我们实验验证的化合物，无论是口尝法实验还是荧光实验，因为作用原理的一致性，我们认为本类化合物可以作用于TRPM5，起到阻断苦味产生的效果。
TRPV1拮抗剂与TRPA1拮抗剂起代表产物，氨基丁酸、帕拉维米、香草酸、羟基香草酸，都不具有掩盖苦味、作用于TRPM5的效果，这在口尝法实验和荧光实验中都得到了验证，因为作用原理的一致性，我们认为本类化合物不能作用于TRPM5，无法起到阻断苦味产生的效果。
钠通道阻滞剂与钙通道阻滞剂，用在治疗心脏与血管类疾病，原理也与钠离子、钙离子通道有关，但实验验证无法起到掩盖苦味的效果。
通过以上实验推测：
（1）TRPM8激动剂有效
瞬时受体电位阳离子通道亚家族M成员8(TRPM8)，亦称为冷和薄荷醇受体I(CMRl)，是在感觉神经元中表达的蛋白质，并且由低温和冷却剂如薄荷醇和薄荷醇类似物激活：包括薄荷醇、柠檬醛、芳樟醇、丁香酚、桉油精、薄荷脑、荷薄酮、柠檬烯、18-桉叶素、胡椒碱、大根香叶烯、乙酸薄荷醇酯、人工合成WS-3((IR, 2S, 5R)-2-异丙基-5-甲基-环己烷羧酸乙酰胺)、WS-5([((IR, 2S, 5R)-2-异丙基-5-甲基-环己烷羰基)-氨基]-乙酸乙酯)、WS-23(2-异丙基-2, 3, N-三甲基-丁酰胺)、乳酸薄荷醇酯(Frescolat ML)、薄荷氧基丙二醇(冷却剂10)、2-异丙基-5-甲基环己基4-(二甲基氨基)-4-氧代丁酸酯(4-(二甲基氨基)-4-氧代丁酸2-异丙基-5-甲基环己基酯)、甲基戊基甲酮、石竹烯、丁香酚乙酸酯。
（2）TRPA1激动剂有效
代表药物包括：肉桂醛、芥子油、大蒜素、辣椒素酯、香芹酚、丁香酚、胡椒碱、姜酚、冬绿油、丁香油、石竹烯和/或石竹烯氧化物、柠檬醛和薄荷醇中的一种或多种。
（3）TRPV1-4激动剂有效
代表药物包括：
TRPV1激动剂选自辣椒素、树脂毒素、维生素D、胡椒碱、吴茱萸碱、花椒麻素、辣椒素酯、6-姜烯酚、姜辣素、姜油酮、姜酮酚或水蓼二醛。
（4）TRPV1拮抗剂和TRPA1拮抗剂可能无效
TRPV1拮抗剂包括下列中的一种或多种：(-)-乙酸冰片酯；羟基香茅醛；阿普利酮；N, N-二甲基邻氨基苯甲酸甲酯；2-乙氧基-3-乙基吡嗪；L-胡椒酮；异丁酸异冰片酯；4-乙酰氧基-2,5-二甲基-3(2H)-呋喃酮；三丙胺；二氢茉莉酮；1-甲基-2-吡咯醛；3-乙酸辛酯；2-甲基丁基异戊酸酯；异丁酸胡椒酯；丙酸苯氧基乙酯；香草醛丙二醇乙酸酯；辛烯基环戊酮；异丁酸丁酯；愈创木油；四氢-4-甲基-2-(2-甲基-1-丙烯基)-2H吡喃。
TRPA1拮抗剂包括下列中的一种或多种：γ-十二酸内酯；香草酸；γ-甲基癸内酯；反式-2,4-壬二烯醛；4-烯丙基-2,6-二甲氧基苯酚；邻甲氧基肉桂醛；4-甲基-2-苯基-2-戊烯醛(顺式和反式的混合物)；2-甲氧基-4-丙基苯酚；2-甲氧基-苯甲酸甲酯；δ-十四内酯；1-甲基-2-吡咯醛；3,3,5-三甲基环己醇；N-(2-羟乙基)乳酰胺；2-(3-苯丙基)四氢呋喃；丁酸茴香酯；4-苯基丁酸甲酯；3-庚基二氢-5-甲基-2(3H)-呋喃酮；3-乙酰基硫基己基乙酸酯；3-甲基-5-丙基-2-环己烯-1-酮；异丁酸异冰片酯；戊酸龙脑酯；香茅醇乙酸酯；(2S,5S,6S)-6-)羟基-二氢茶螺烷；反式-2-己烯醛。
四、使用浓度以及组合获取最好效果
使用浓度在0.001%到0.5%之间，一般随浓度升高效果越好，但是到0.1%左右再升高效果不明显，而且刺激性越来越大，故无论经济性还是实用性，选起效较好的较低浓度比较合适。
应用TRPM8激动剂产生冷感，但给予TRPV1-4和TRPA1激动剂可以得到明显抑制，说明“冷、热”通道之间存在制约关系，他们又都可以作用于M5受体，引起苦味抑制。TRPV1-4和TRPA1激动剂可以作用于痛觉受体，产生热辣的痛觉感，而当用凉感来中和热感之后，这种痛苦的感觉就减弱了，清凉的感觉，带来的是一种愉悦。所以优选的是这两种的组合，在掩盖苦味的同时，可以避免自身热辣的痛觉，只留下比较凉爽的快感。
我们优选的组合TRPM8受体激活剂与TRPV1-4和TRPA1激活剂组合，可以降低刺激性和伤害感。
也可以单用一种，虽然有刺激性，可是刺激可以给人带来一种事后的畅快感。
五、具体配方的效果
A物质TRPM8激动剂和B物质TRPA1激动剂，A+B+甜味剂+香精；或单独A或B+甜味剂+香精。
优选A+B+甜味剂+香精。
比如：薄荷酰胺0.05%、肉桂醛0.2%、三氯蔗糖0.1%、甜蜜素0.5%、香精适量。
针对这些苦味药物，基本已经感觉不到苦味了。超过0.5度苦度的还略微有感觉。
本发明的有益效果：发现TRPM8受体激动剂与TRPV1-4和TRPA1激动剂都有掩盖口腔苦味感知的效果，而且TRPM8受体激动剂刺激冷通道，TRPV1-4和TRPA1刺激热通道，可以用凉感来中和热感，消除这种痛苦。这两种药物的组合，完全消除了难受、热辣的痛觉，带来比较凉爽的愉悦的快感。
这些药物可以在多种制剂中得到应用，为药物适口性多一个选择。其适合的浓度范围为0.001%-0.5%。掩盖苦味的制剂中还可以包括溶剂、甜味剂、防腐剂和香料。特别是，可以借助甜味剂和香料来中和A类物质与B类物质自身的不适味道。并且，所述掩味剂可用于药物、食物或口腔护理产品。
这里，所述掩味剂用于药物时，所述药物包括抗肿瘤药物、治疗高血脂药物、治疗高血糖药物、止痛剂、抗生素、退热剂和中药中的任意一种，药物的剂型包括片剂、汤剂、酒剂、颗粒剂、液体口服剂和气雾剂中的任意一种。所述掩味剂用于食物时，所述食物包括冰激凌、奶油冻、乳油、饮料和糕饼中的任意一种。所述掩味剂用于口腔护理产品时，所述口腔护理产品包括牙膏、漱口水、口香糖、口气清新剂和漱口剂中的任意一种。
所述片剂可以包括多层片、咀嚼片、可溶片、泡腾片、缓释片、控释片、分散片、含片、口崩片、舌下片和口腔贴片中的任意一种。
通用术语定义：在本申请中，“TRPM8”有多个同义词：TRPP8、LTRPC6.CMRI、MGC2849、瞬时受体电位阳离子通道亚家族M成员8。该受体的所有功能性修饰也包括在内，例如尤其是剪接变体，亚型，例如TRPM8CRA-a.TRPM8CRA-b。
在本申请中，“TRP”与“trp”或“Trp”是一样的，即Transient  receptor potential Cation channel的缩写，字母大小写表达意思没有区别。
在本发明的内容中，中药饮片类药物根据中国药典-2020年版选用。
连翘：本品为木犀科植物连翘Forsythia suspensa（Thunb.）Vahl的干燥果实。秋季果实初熟尚带绿色时釆收，除去杂质，蒸熟，晒干，习称“青翘”；果实熟透时采收，晒干，除去杂质，习称“老翘”。本品按干燥品计算，含连翘苷（C 27H 34O 11）不得少于0.15%。
龙胆：本品为龙胆科植物条叶龙胆Gentiana manshurica Kitag.、龙胆Gentiana scabra Bge.、三花龙胆Gentiana triflora Pall.或坚龙胆Gentiana rigescens Franch.的干燥根和根茎。前三种习称“龙胆”，后一种习称“坚龙胆”。春、秋二季采挖，洗净，干燥。本品按干燥品计算，龙胆含龙胆苦苷（C 16H 20O 9）不得少于3.0%；坚龙胆含龙胆苦苷（C 16H 20O 9）不得少于1.5%。
川楝子：本品为楝科植物川楝Melia toosendan Sieb.et Zucc.的干燥成熟果实。冬季果实成熟时采收，除去杂质，干燥。本品按干燥品计算，含川楝素（C 30H 38O 11）应为0.060%～0.20%。
莲子心：本品为莲科莲植物莲Nelumbo nucifera Gaertn.的成熟种子中的干燥幼叶及胚根。取岀，晒干。本品按干燥品计算，含甲基莲心碱（C 38H 45N 20 6）不得少于0.70%。
穿心莲：本品为爵床科植物穿心莲Andrographis paniculata（Burm.f.）Nees的干燥地上部分。秋初茎叶茂盛时采割，晒干。本品按干燥品计算，含穿心莲内酯（C 20H 30O 5）、新穿心莲内酯（C 20H 30O 8）、14-去氧穿心莲内酯（C 20H 30O 4）和脱水穿心莲内酯（C 20H 28O 4）的总量不得少于1.5%。
山豆根：本品为豆科植物越南槐Sophora tonkinensis Gagnep.的干燥根和根茎。秋季采挖，除去杂质，洗净，干燥。【含量测定】同药材，含苦参碱（C 15H 24N 2O）和氧化苦参碱（C 15H 24N 2O 2）的总量不得少于0.60%。
独活：本品为伞形科植物重齿毛当归Angelica pubescens Maxim.f. biserrata Shan et Yuan的干燥根。春初苗刚发芽或秋末茎叶枯萎时釆挖，除去须根和泥沙，烘至半干，堆置2～3天，发软后再烘至全干。本品按干燥品计算，含蛇床子素（C 15H 16O 3）不得少于0.50%，含二氢欧山芹醇当归酸酯（C 19H 20O 5）不得少于0.080%。
下表是部分化学药物的中文名称、别名、分子式。便于对照。
“掩盖苦味”是指使用一种药物（无论是预先使用还是同时使用）使使用者感受不到苦味或感受到的苦味苦度值降低。“掩味”是指使用一种药物（无论是预先使用还是同时使用）使使用者感受不到苦味，或感受到的苦味的感觉幅度降低。
“激动剂”或“激活剂”也称兴奋剂，能增强另一种分子活性、促进某种反应的药物、酶 激动剂和激素一类的分子。
“拮抗剂”与受体结合后本身不引起生物学效应，但阻断该受体激动剂介导的作用。
其中化合物可以化学纯或富集形式存在，为单个立体异构体或立体异构体混合物形式。此外，所述化合物可以是不带电的或其盐形式，例如酸加成盐。官能团可任选被等价的化学基团替换；氟原子可被其他卤素原子，例如C1、Br或I替换；氧原子(例如醚基)可被相应的硫基团替换，反之亦然；酮基团可被相应的亚硫酰基替换。上面具体描述的化合物是本身已知的化学物质，可商购或通过常规有机合成方法获得。如果修饰形式或衍生物也表现出需要的生物学活性，那么它们也是功能类似物或功能等价化合物。
本发明所提到的浓度，如果未经特别说明，均为体积浓度。
尽管已经示出和描述了本发明的实施例，对于本领域的普通技术人员而言，可以理解在不脱离本发明的原理和精神的情况下可以对这些实施例进行变化。本发明的适用范围由所附权利要求及其等同物限定。

Claims (10)

  1.  一种TRPM8激动剂作为掩盖苦味的物质的应用，其特征在于，所述TRPM8激动剂包括如下物质中的一种或多种：薄荷醇衍生物、柠檬醛、芳樟醇、丁香酚和桉油精；其中，薄荷醇衍生物包括如下物质中的一种或多种：薄荷酰胺、荷薄酮、柠檬烯、18-桉叶素、胡椒碱、大根香叶烯、乙酸薄荷醇酯、WS-3((IR, 2S, 5R)-2-异丙基-5-甲基-环己烷羧酸乙酰胺)、WS-5([((IR, 2S, 5R)-2-异丙基-5-甲基-环己烷羰基)-氨基]-乙酸乙酯)、WS-23(2-异丙基-2, 3, N-三甲基-丁酰胺)、乳酸薄荷醇酯、琥珀酸薄荷醇酯、薄荷氧基丙二醇、2-异丙基-5-甲基环己基4-(二甲基氨基)-4-氧代丁酸酯(4-(二甲基氨基)-4-氧代丁酸2-异丙基-5-甲基环己基酯)。
  2.  一种TRPA1激动剂作为掩盖苦味的物质的应用，其特征在于，所述TRPA1激动剂包括如下物质中的一种或多种：肉桂醛、芥子油、大蒜素、辣椒素酯、香芹酚、丁香酚、胡椒碱、姜辣素、冬绿油、丁香油、石竹烯、石竹烯氧化物、柠檬醛和薄荷醇。
  3.  一种TRPV1-4激动剂作为掩盖苦味的物质的应用，其特征在于，所述TRPV1激动剂选自辣椒素、树脂毒素、维生素D、胡椒碱、吴茱萸碱、花椒麻素、辣椒素酯、6-姜烯酚、姜辣素、姜油酮、姜酮酚和水蓼二醛中的一种或多种。
  4.  一种或几种物质作为掩味剂的应用，其特征在于，所述物质选自芳樟醇、柠檬醛、肉桂醛、石竹烯、乙酸丁香酚、薄荷酮、桉叶油、冰片、薄荷酰胺、琥珀酸薄荷醇酯、凉味剂WS-5、凉味剂WS-23、姜酚、胡椒碱和大蒜素。
  5.  一种或几种物质在用于掩盖苦味的口腔喷雾剂或漱口液中的应用，其特征在于：所述一种或几种物质为A类物质、B类物质、或A类物质与B类物质的组合；所述A类物质为TRPM8激动剂中的一种或多种；所述B类物质为TRPA1激动剂和TRPV1-4激动剂中的一种或多种。
  6.  根据权利要求5所述的一种或几种物质在用于掩盖苦味的口腔喷雾剂或漱口液中的应用，其特征在于：所述一种或几种物质为A类物质，所述A类物质在口腔喷雾剂或漱口液中的体积浓度为0.001%-0.5%；或者所述一种或几种物质为B类物质，所述B类物质在口腔喷雾剂或漱口液中的体积浓度为0.001%-0.5%；或者所述一种或几种物质为A类物质与B类物质的组合，所述A类物质在口腔喷雾剂或漱口液中的体积浓度为0.001%-0.5%，所述B类物质在口腔喷雾剂或漱口液中的体积浓度为0.001%-0.5%。
  7.  根据权利要求5所述的一种或几种物质在用于掩盖苦味的口腔喷雾剂或漱口液中的应用，其特征在于：所述口腔喷雾剂或漱口液在被喷施于口腔内后5-10秒内达到掩盖苦味效果的峰值，并且效果持续时间为30-120秒。
  8.  一种用于掩盖苦味的口腔喷雾剂或掩味剂，其特征在于：所述口腔喷雾剂或掩味剂包括A类物质、B类物质、或A类物质与B类物质的组合；所述A类物质为TRPM8激动剂中的一种或多种；所述B类物质为TRPA1激动剂和TRPV1-4激动剂中的一种或多种。
  9.  根据权利要求8所述的用于掩盖苦味的口腔喷雾剂或掩味剂，其特征在于：所述口腔喷雾剂或掩味剂用于药物，所述药物包括抗肿瘤药物、治疗高血脂药物、治疗高血糖药物、止痛剂、抗生素、退热剂和中药中的任意一种，药物的剂型包括片剂、汤剂、分散剂、酒剂、颗粒剂、漱口水、液体口服剂和气雾剂中的任意一种；或者所述口腔喷雾剂或掩味剂用于食物，所述食物包括冰激凌、奶油冻、乳油、饮料和糕饼中的任意一种；或者所述口腔喷雾剂或掩味剂用于口腔护理产品，所述口腔护理产品包括牙膏、漱口水、口香糖、口气清新剂和漱口剂中的任意一种。
  10.  根据权利要求9所述的用于掩盖苦味的口腔喷雾剂或掩味剂，其特征在于：所述片剂包括多层片、咀嚼片、可溶片、泡腾片、口崩片、缓释片、控释片、分散片、含片、舌下片和口腔贴片中的任意一种。
PCT/CN2023/112718 2022-06-13 2023-08-11 用于掩盖苦味的产品 WO2023241739A1 (zh)

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