WO2020103435A1 - 草乌甲素的用途 - Google Patents

草乌甲素的用途

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Publication number
WO2020103435A1
WO2020103435A1 PCT/CN2019/091049 CN2019091049W WO2020103435A1 WO 2020103435 A1 WO2020103435 A1 WO 2020103435A1 CN 2019091049 W CN2019091049 W CN 2019091049W WO 2020103435 A1 WO2020103435 A1 WO 2020103435A1
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Prior art keywords
use according
pruritus
preparation
injection
skin
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PCT/CN2019/091049
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English (en)
French (fr)
Inventor
刘先国
李彪
吴琼粉
Original Assignee
云南昊邦制药有限公司
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Publication date
Application filed by 云南昊邦制药有限公司 filed Critical 云南昊邦制药有限公司
Priority to KR1020217017775A priority Critical patent/KR102610339B1/ko
Priority to JP2021526786A priority patent/JP7190571B2/ja
Priority to US17/293,941 priority patent/US20220000846A1/en
Priority to EP19888102.1A priority patent/EP3884942B1/en
Publication of WO2020103435A1 publication Critical patent/WO2020103435A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
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    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
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    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
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    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to the field of medicine, and in particular to the use of erythrophanol.
  • Skin pruritus also known as pruritus, is a common sensation phenomenon related to the desire to scratch the itch; there are various causes of skin pruritus, and many diseases in the clinic can cause skin pruritus. People with itchy skin without primary skin rashes are called pruritus or pruritus. Skin pruritus can be divided into systemic skin pruritus and local skin pruritus according to its location. The causes of systemic dermatosis are mostly related to metabolic disorders and endocrine abnormalities. Common reasons are as follows. Senile skin pruritus: As the elderly have decreased sebaceous gland function, poor peripheral circulation, and weakened skin water retention function, the skin is dry, and it is susceptible to itching caused by changes in the surrounding environment.
  • Itching caused by systemic diseases such as tumors, diabetes, kidney disease, abnormal thyroid function, anemia, and biliary tract diseases can cause itching.
  • Itching in diabetic patients is related to the accumulation of pyruvic acid and lactic acid in the skin and nerve tissue during the process of sugar metabolism, which stimulates itching of nerve endings. Patients with diabetes may be accompanied by systemic or localized itching of the skin.
  • Hyperthyroidism is associated with increased basal metabolism, hyperactivity, and hyperhidrosis, while hypothyroidism is associated with dry skin.
  • metabolic wastes such as urea nitrogen and creatinine accumulate in the body, and some urea is discharged from the sweat glands, irritating the skin and causing itching.
  • urea nitrogen and creatinine accumulate in the body, and some urea is discharged from the sweat glands, irritating the skin and causing itching.
  • itching is more obvious.
  • the cause of localized skin pruritus may be the same as systemic pruritus.
  • patients with tumors may have systemic pruritus or local pruritus. This type of pruritus disappears after the primary disease is controlled.
  • Some types of pruritus have a certain relationship with the individual's mental and emotional state. For example, itching and discomfort of the whole body or vulva of patients with STD phobia are typical examples.
  • Systemic skin pruritus can be manifested as systemic itch at the beginning of the disease, or it can be localized and then spread to the whole body. The degree of itching can be light or severe.
  • the commonly used treatment of skin pruritus is oral chlorpheniramine, loratadine, cetirizine, mizolastine and other antihistamine drugs, vitamin C, doxepin, oryzanol, diazepam, calcium gluconate, etc.
  • These drugs have a sleepiness effect Obviously, the side effects of hormone drugs are serious.
  • the main clinical treatments are antihistamine H1 and H2 receptor antagonists, glucocorticoids, immunomodulation, and local UV irradiation treatment. However, they often cannot be used for a long time due to adverse reactions. After the treatment is interrupted, itching quickly recurs. Therefore, safe, effective and affordable drug research for skin pruritus is imminent.
  • Herbaceous Aconitine is an alkaloid of Aconitum plant isolated from the unique medicinal plant of West Yunnan, which has good anti-inflammatory, analgesic and immunomodulatory effects.
  • ureavalin does not belong to NSAID, it can regulate sodium ion channels, has little psychological dependence and organic organ toxicity, and can avoid the possible causes of NSAID and opioid analgesics Gastrointestinal tract and cardiovascular and renal adverse reactions, drug dependence and other potential risks.
  • RA rheumatoid arthritis
  • osteoarthritis myofibritis
  • neck and shoulder pain waist and leg pain
  • cancer pain and chronic pain caused by various causes.
  • the present invention provides the use of erythrophanin.
  • the application of erythrophanol for the treatment of skin pruritus has definite curative effect, no liver and kidney toxicity side effects, can be taken for a long time, control the recurrence of skin pruritus, avoid unintentional scratching, resulting in rough skin, mossy, can cause eczema, nerves Dermatitis, nodular prurigo and other secondary damage.
  • the present invention provides the use of erythrodin in the preparation and treatment of pruritus or its secondary damage.
  • the dosage of the auconitin is 0.125 mg / kg mouse body weight / d to 0.5 mg / kg mouse body weight / d.
  • the dosage of the auconitin is 0.01375 mg / kg human body weight / d to 0.055 mg / kg human body weight / d.
  • the skin pruritus is neuropathic pruritus.
  • the pruritus is pruritus caused by histamine and / or chloroquine.
  • the medicament includes aucuronine and a pharmaceutically acceptable carrier; the mass percentage of the auconitin in the drug is 0.2% to 88%.
  • the dosage form of the drug is an oral preparation, an injection preparation, or an external preparation.
  • the oral preparation is a hard capsule, dripping pill, granule, tablet, mixture, soft capsule, concentrated pill, oral liquid, or powder.
  • the injection preparation is an injection solution or a lyophilized powder injection.
  • the external preparations are tinctures, ointments, creams, pastes, aerosols, sprays, powders, otic preparations, lotions, rinses, rubs, paints ⁇ Coating agent, gel or patch.
  • the present invention provides a new use of erythrodin, its mechanism of action may be through the regulation of sodium ion channels, thereby inhibiting the specific neurons responsible for pruritus conduction in the peripheral and central nerves; at the same time, it may also be through Regulates sodium ion channels, inhibits the activation and conduction of itching mediators and the selective receptors of itching substances, thereby inhibiting itching.
  • erythrophanol for the treatment of skin pruritus has definite curative effect, no liver and kidney toxicity side effects, can be taken for a long time, control the repeated attacks of skin pruritus, avoid unintentional scratching, resulting in rough skin, mossy, can lead to eczema , Neurodermatitis, nodular prurigo and other secondary damage.
  • turpentine is used for the treatment of skin pruritus, and may relieve the patient's frequent itch and distress.
  • the relief of itching at night seriously affects the patient's sleep and rest, effectively reducing the pain and spirit caused by itching in patients and their families pressure.
  • Figure 1 shows the experimental process
  • BLA urea aurein
  • D days
  • h hours
  • Figure 2 shows the number of scratches within 30 minutes of the histamine group (*: P ⁇ 0.05 compared with the solvent group; ***: P ⁇ 0.001 compared with the solvent group;)
  • Figure 3 shows the number of scratches in the chloroquine group within 30 minutes (**: P ⁇ 0.01 compared to the solvent group; ***: P ⁇ 0.001 compared to the solvent group;)
  • Figure 4 shows the conversion relationship between animal doses. See Table 3 on page 422 of Shi Xinyou's "Medical Experimental Zoology”.
  • the present invention discloses the use of erythrophanol, and those skilled in the art can refer to the content of this article and appropriately improve the process parameters to achieve.
  • all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.
  • the methods and applications of the present invention have been described through preferred embodiments, and it is obvious that relevant personnel can modify or appropriately modify and combine the methods and applications described herein without departing from the content, spirit, and scope of the present invention. Apply the technology of the present invention.
  • Skin pruritus refers to a group of skin diseases characterized by skin pruritus, which includes both pruritus with only skin pruritus and lack of primary skin rash, or coexistence of skin pruritus and primary skin rash Neurodermatitis, pruritus, nodular prurigo, etc.
  • Skin pruritus or its secondary damage refers to conditions such as rough skin, lichenification, eczema, neurodermatitis, and nodular pruritus caused by repeated pruritus and scratching.
  • the raw materials and reagents used in the application of the alaconin provided by the present invention are all commercially available.
  • the purpose of the present invention is to investigate whether gavagein (BLA) gavage can inhibit acute itch caused by histamine and chloroquine.
  • the experiment used C57 mice (weight 17-20 grams, animals from Sun Yat-sen University Experimental Animal Center) for 6-8 weeks.
  • the mice were randomly divided into four groups: solvent + histamine control group, BLA + histamine group, solvent + chloroquine control group and BLA + chloroquine group.
  • Three days before the start of the experiment the hair on the back of the neck (at least 3 ⁇ 5 cm) was shaved during brief anesthesia with isoflurane, which is convenient for subcutaneous injection and observation scratching.
  • Control group 50 ⁇ l of histamine (2 mg / ml) or chloroquine (4 mg / ml) was injected subcutaneously, and the solvent (carboxymethyl cellulose) was intragastrically 2 hours before injection.
  • mice were placed in separate transparent acrylic boxes, each box measuring 15 ⁇ 15 ⁇ 20 cm. There are two small openings above each box to allow air circulation. Since the scratching behavior of the mouse is basically facing the upper angle of the mouse's back, the camera is placed above the mouse to record their scratching behavior in a video.
  • Scratching behavior is easily suppressed by distracting attention.
  • a small amount of litter is placed in each transparent box to absorb any urine excreted by the mouse, and the ambient temperature is maintained at 23-27 ° C.
  • all personnel left the scene during recording. The experiment was conducted between 9: 00-14: 00h.
  • the rats were acclimated in the transparent box for one hour at 9:00 and 13:00 two days before the official experiment. Since the scratching process of mice is often very fast, it is regarded as a scratching behavior to start scratching the hind paw of the mouse until the hind paw falls to the ground or put it in the mouth to clean the dander.
  • Table 2 The number of scratches of mice in the histamine group by intragastric administration of BLA for two hours to two and a half hours
  • the curcuminoids of the present invention can be made into medicines with different dosage forms.
  • the curcuminoids can be made into dosage forms including oral preparations, injection preparations or external preparations.
  • the specific medicine may include ureavalin and other pharmaceutically acceptable carriers.
  • the dosage of each component in the drug can be adjusted according to the ratio of ingredients in the pharmaceutical preparation, and the effective content of ureavalin can also be adjusted. It can be calculated according to the conventional dosage form requirements such as different dosage forms.
  • the body weight / d of 0.01375 mg / kg to 0.055 mg / kg described in Example 1 is provided here. This example provides only a reference value range, which is not specifically limited.
  • the pharmaceutically acceptable carrier may use flavoring agents, fillers, disintegrating agents, coloring agents, thickeners and the like.
  • Flavoring agents such as glucose, sorbitol, mannitol, etc., but not limited to these flavoring agents, thickeners, etc .; fillers such as microcrystalline cellulose, etc .; disintegrants such as hydroxymethyl starch potassium, etc.
  • a tablet containing ureavalin each tablet contains 0.275mg ureavalin and 130mg film-coated tablets.
  • Dissolve acetaminophen in food grade or medicinal grade ethanol mix 20 mg of lactose adjuvant, 25 mg of powdered sugar, 40 mg of microcrystalline cellulose and 10 mg of hydroxypropyl cellulose, and then add acetaminophen ethanol solution to mix, then add Appropriate amount of purified water is mixed to make soft material, which is then granulated and dried. To the dried granules, 5 mg of magnesium stearate and 30 mg of sodium carboxymethyl starch are added for tableting, and then film-coated.
  • each capsule contains 0.4mg arbutin and 165mg adjunct
  • the adjunct is powdered sugar 80mg, starch 25mg, microcrystalline cellulose 20mg, low substituted hydroxypropyl cellulose 15mg, magnesium stearate 5mg and phthalate 5mg, then add a wetting agent to make ethanol into a soft material, and then pelletized and dried, and then enteric coated acrylic resin 15mg. After the dried pellets are put to room temperature, they are coated with acrylic resin, and the coated pellets are filled with hard capsules, and then filled in and out to obtain the finished pellet capsules.
  • a curcuminolide controlled-release tablet each containing 0.98 mg of curcuminoids, a matrix material (hypromellose 125 mg), and a lubricant (magnesium stearate 1 mg), mixed and compressed with a tablet machine Tablets, compressed tablets are coated with a coating material using a film coating machine.
  • a kind of erythrophanin injection containing 2mg of ureapyrin per ml, weighed 2000mg of ureacetin, dissolved with 5ml of dilute sulfuric acid, added water for injection to 1000ml, adjusted the pH to 5.0, filtered, potted, extinguished Get the bacteria.
  • a kind of ureacarin for injection each containing 0.2mg of ureacarin, weighed 200mg of ureacarpone, dissolved with 5ml of dilute sulfuric acid, added water for injection to 500ml, dissolved with 200g of mannitol, then added water for injection To 1000ml, adjust the pH to 5.0, filter, encapsulate 1000 pieces, add stopper, freeze dry and press stopper to get.
  • Herba Uechin Patches each containing melanin 4mg, weigh in it 4000mg, silicone pressure sensitive adhesive 150000mg, eucalyptus oil 2000mg, add 100ml ethanol to dissolve the herbin, then mix it with silicone Mix the pressure-sensitive adhesive and eucalyptus oil on the protective layer of PTFE film to control the thickness of the coating.
  • the coating is 1000 stickers, dried, covered with a non-woven backing layer, and cut into appropriate Just shape and size.
  • a tablet containing erythrodin each tablet contains 3.3 mg of chrysopyridine.
  • a tablet containing erythrodin each tablet contains 3.3 mg of chrysopyridine.

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  • Health & Medical Sciences (AREA)
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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

本发明属于药物领域，公开了草乌甲素用于治疗皮肤瘙痒或其继发性损害的用途，尤其是组胺和/或氯喹引起的瘙痒。

Description

草乌甲素的用途
本申请要求于2018年11月19日提交中国专利局、申请号为201811376531.5、发明名称为“草乌甲素的用途”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及药物领域，特别涉及草乌甲素的用途。
背景技术
皮肤瘙痒症又称皮痒症，是与抓痒欲望相关的普通感觉现象；引起皮肤瘙痒原因有多种多样，临床上很多疾病均会引起皮肤瘙痒，其病因也比较复杂，但临床上将仅有皮肤瘙痒而无原发性皮肤发疹者称为瘙痒症或皮肤瘙痒症。皮肤瘙痒症根据其发病部位，可分为全身性皮肤瘙痒症和局性皮肤瘙痒症。全身性皮肤症的病因多与机体代谢紊乱和内分泌异常有关。常见的原因有以下几种。老年性皮肤瘙痒症：因老年人皮脂腺功能减退，末梢循环差，皮肤保水功能减弱，致使皮肤干燥，易受周围环境冷热变化的刺激而引起瘙痒。另外，老年人激素水平如性激素水平降低，也是引起瘙痒的原因之一，绝经期妇女多见。季节性皮肤瘙痒症：冬季因皮肤干燥，夏季出汗汗液刺激均可引起瘙痒的发生。系统性疾病引起的皮肤瘙痒症如肿瘤、糖尿病、肾病、甲状腺功能异常、贫血、胆道疾病等均可引起瘙痒。糖尿病患者出现瘙痒，与糖代谢过程中丙酮酸及乳酸在皮肤及神经组织中堆积有关，刺激神经末梢出现瘙痒。糖尿病患者可伴全身或限局性皮肤瘙痒。甲状腺功能亢进与患者基础代谢增高、亢奋、多汗有关，而甲状腺功能低下与皮肤干燥有关。肾病患者由于代谢废物，如尿素氮、肌酐在体内堆积，部分尿素从汗腺排出，刺激皮肤而出现瘙痒。特别是肾病晚期的尿毒症患者，瘙痒更加明显。
局限性皮肤瘙痒症的病因可与全身性瘙痒症相同，如肿瘤患者既可出现全身瘙痒，亦可引起局部瘙痒。这一类瘙痒症在原发疾病得到控制后瘙痒症状亦随之消失。有些类型的瘙痒症与患者个体的精神、情绪亦有一定 关系，如性病恐怖症患者出现的全身或外阴部位的瘙痒及不适就是典型例子。全身性皮肤瘙痒症可表现为疾病初发即为全身性瘙痒，也可以表现为局部，进而扩展至全身。瘙痒程度可轻可重，轻者仅为夜间瘙痒，不影响正常工作及生活；重者不论白天黑夜都瘙痒难忍、痛苦不堪，常不自觉搔抓直至皮破血流，更有甚者用利器，如刀叉、剪、钉等刺伤皮肤直至产生剧痛感而罢休。此类患者由于长期瘙痒烦恼往往伴随一定的精神紧张，脾气暴躁，稍有不顺即大发雷霆，一定程度上也加重了病情。此外，因为长期不自觉搔抓，致使皮肤粗糙，苔藓化，可导致湿疹、神经性皮炎、结节性痒疹等继发性损害。患者常常为瘙痒而苦恼。而且瘙痒在夜间好发，严重影响睡眠和休息，给患者及其家庭带来极大痛苦和精神压力。
目前，治疗皮肤瘙痒症的常用是口服扑尔敏、氯雷他定、西替利嗪、咪唑斯汀等抗组胺药物、维生素C、多塞平、谷维素、地西泮、葡萄糖酸钙等药物，重症患者口服镇静催眠类药物，皮质类固醇制剂，普鲁卡因静脉封闭，外用药如炉甘石洗剂、炉甘石薄荷脑洗剂、乳膏或霜剂等，这些药存在嗜睡作用较明显，激素类药物副作用大等问题。临床主要以抗组胺H1和H2受体拮抗剂、糖皮质激素、免疫调节及局部UV照射治疗为主，但常因出现不良反应无法长期应用，治疗间断后,瘙痒迅速复发。所以，安全有效且价格可接受的针对皮肤瘙痒症的药物研究迫在眉睫。
草乌甲素(BLA)是从滇西特有药用植物滇西嘟啦中分离出来的乌头属植物生物碱，具有良好的抗炎镇痛及免疫调节作用。草乌甲素作为新型第三类镇痛药物，不属于NSAID，可对钠离子通道进行调节，很少有心理依赖性和器质性器官毒性作用，可避免NSAID和阿片类镇痛药物可能导致的胃肠道和心血管及肾脏不良反应、药物依赖等潜在危险。目前，临床上广泛用于治疗类风湿关节炎(RA)、骨关节炎、肌纤维炎、颈肩痛、腰腿痛、癌性疼痛以及各种原因导致的慢性疼痛。但是，对于草乌甲素在治疗皮肤瘙痒症的作用与功效迄今为止尚未见相关报道；同时，该草乌甲素药物单体是从中药中提取出来的活性药物，具有安全性好，副作用较少，无成瘾性的特点。因此，对于中草药提取物草乌甲素药物进一步深入研究具有一定市场前景。
发明内容
有鉴于此，本发明提供了草乌甲素的用途。应用草乌甲素制备用于治疗皮肤瘙痒症疗效确切，无肝肾毒性副作用，可以长期服药，控制皮肤瘙痒症反复发作，避免不自觉搔抓，致使皮肤粗糙，苔藓化，可导致湿疹、神经性皮炎、结节性痒疹等继发性损害。
为了实现上述发明目的，本发明提供以下技术方案：
本发明提供了草乌甲素在制备治疗和/或预防皮肤瘙痒症或其继发性损害的药物中的应用。
在本发明的一些具体实施方案中，所述草乌甲素的剂量为0.125mg/kg小鼠体重/d～0.5mg/kg小鼠体重/d。
在本发明的一些具体实施方案中，所述草乌甲素的剂量为0.01375mg/kg人体体重/d～0.055mg/kg人体体重/d。
在本发明的一些具体实施方案中，所述皮肤瘙痒症为神经病理性瘙痒。
在本发明的一些具体实施方案中，所述皮肤瘙痒症为组胺和/或氯喹引起的瘙痒。
在本发明的一些具体实施方案中，所述药物包括草乌甲素及药学上可接受的载体；所述草乌甲素在所述药物中的质量百分含量为0.2％～88％。
在本发明的一些具体实施方案中，所述药物的剂型为口服制剂、注射制剂或外用制剂。
在本发明的一些具体实施方案中，所述口服制剂为硬胶囊、滴丸、颗粒、片剂、合剂、软胶囊、浓缩丸、口服液或散剂。
在本发明的一些具体实施方案中，所述注射制剂为注射液或冻干粉针剂。
在本发明的一些具体实施方案中，所述外用制剂为酊剂、软膏剂、乳膏剂、糊剂、气雾剂、喷雾剂、散剂、耳用制剂、洗剂、冲洗剂、搓剂、涂剂、涂膜剂、凝胶剂或贴剂。
本发明提供了草乌甲素的新用途，其作用机理可能是通过对钠离子通道调节，从而对外周和中枢神经专门负责瘙痒感传导的特异性神经元起到 抑制作用；同时也可能是通过对钠离子通道调节，抑制瘙痒介质激活和传导以及致痒物质的选择性受体的调节，从而抑制瘙痒。
1、将草乌甲素制备用于治疗皮肤瘙痒症，避免应用抗组胺类、激素类等药物引起不良反应无法长期应用，只能间断用药，导致瘙痒复发的情况。
2、应用草乌甲素制备用于治疗皮肤瘙痒症疗效确切，无肝肾毒性副作用，可以长期服药，控制皮肤瘙痒症反复发作，避免不自觉搔抓，致使皮肤粗糙，苔藓化，可导致湿疹、神经性皮炎、结节性痒疹等继发性损害。
3、应用草乌甲素制备用于治疗皮肤瘙痒症，及可能解除患者常为瘙痒而苦恼，解除瘙痒夜间好发严重影响患者睡眠和休息，有效减轻患者及其家庭瘙痒带来的痛苦和精神压力。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍。
图1示实验流程；BLA：草乌甲素；D：天；h：小时；
图2示组胺组的30min内的搔抓次数(*：与溶剂组相比P<0.05；***:与溶剂组相比P<0.001；)
图3示氯喹组的30min内的搔抓次数(**：与溶剂组相比P<0.01；***:与溶剂组相比P<0.001；)
图4示动物剂量之间的换算关系，详见施新猷的《医用试验动物学》第422页表3。
具体实施方式
本发明公开了草乌甲素的用途，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与 组合，来实现和应用本发明技术。
术语解释：
皮肤瘙痒症：是指以皮肤瘙痒为主要特征的一组皮肤病，其中既包括仅有皮肤瘙痒而缺乏原发性皮肤发疹的瘙痒症，也有皮肤瘙痒与原发性皮肤发疹同时并存的神经性皮炎、痒疹、结节性痒疹等。
皮肤瘙痒症或其继发性损害：“继发性损害”是指因皮肤瘙痒症反复发作，搔抓导致的皮肤粗糙，苔藓化，湿疹，神经性皮炎，结节性痒疹等病症。
本发明提供的草乌甲素的用途中所用原料及试剂均可由市场购得。
下面结合实施例，进一步阐述本发明：
实施例1
实验目的：
多年来的研究表明，瘙痒主要是由两类C纤维传导的，一类对组胺敏感，另一类对氯喹敏感。因此，皮下注射组胺或氯喹引起的动物搔抓反应是国际公认的急性瘙痒模型。本发明旨在探究草乌甲素(BLA)灌胃能否抑制组胺和氯喹引起的急性瘙痒。
实验材料与方法：
实验采用6-8周C57小鼠(体重17-20克，动物来源于中山大学实验动物中心)。把小鼠随机分为四组：溶剂+组胺对照组、BLA+组胺组、溶剂+氯喹对照组和BLA+氯喹组。在实验开始前三天，在用异氟烷短暂麻醉时刮掉了颈背部的毛(至少3×5cm)，便于皮下注射和观察搔抓。对照组：皮下注射组胺(2mg/ml)或氯喹(4mg/ml)50μl，在注射前2小时溶剂(羧甲基纤维素)灌胃。实验组：在注射组胺或氯喹前2小时，灌胃不同剂量的BLA(0.125、0.25和0.5mg/kg)。提前2小时使用BLA是因为从灌胃到起效需要1.5-2小时。以往的研究中表明，组胺和氯喹诱导的急性搔抓反应在注射药物30分钟后消退，于是我们计数各组在此期间的总的搔抓次数并进行对比。实验流程见图1。
实验记录时小鼠被放置在单独的、透明的亚克力盒子中，每个盒子规 格为15×15×20厘米。每个盒子上方有两个小开口允许空气流通。由于老鼠搔抓颈背部的行为基本都是正对老鼠背部上方视角，所以将摄像机放置在老鼠上方，以录像记录他们的搔抓行为。
抓挠行为容易因分散注意力而被抑制。为了增大限度地减少意力转移，消除紧张感，每个透明盒子中都放置少量的垫料，以吸收任何由老鼠排出的尿液，环境温度保持在23-27℃。为了保障实验环境安静，记录时所有人员离场。实验在9：00-14：00h之间进行。为了让动物适应试验环境，在正式实验前两天每天9:00和13:00让老鼠在透明盒子中适应一个小时。由于小鼠的搔抓进行过程往往很快，将小鼠后爪开始搔抓颈背部至其后爪落地或者放入嘴中进行清洁皮屑视为一次搔抓行为。
统计学方法：搔抓次数用均值±标准差表示，用Turkeytest比较不同组间的差异。
相关溶液的配制及应用方法：称取0.05g的BLA溶于1000ml的0.5％的羧甲基纤维素纳溶液中。组胺与氯喹均是用0.9％无菌生理盐水配制，组胺的剂量为100μg，氯喹为200μg。为了尽量使得注射部位的皮肤损伤最小化，在微量注射器针口接上了一段更细的0.3ml的胰岛素针头来降低对小鼠造成的损伤。
实验结果：
在皮下注射组胺或氯喹前30分钟内，小鼠的搔抓次数为3.42±2.40，而在注射组胺或氯喹后的30分钟内搔抓次数分别上升到29.42±16.63(n＝12)或73.75±34.11(n＝12)，表明模型制作成功，试验结果见表1。BLA灌胃剂量依赖性地抑制组胺或氯喹引起的瘙痒。如表2-3和图2-3所示，剂量为0.5mg/kg时，BLA可完全抑制(P<0.001)对组胺或氯喹引起急性瘙痒的抑制作用最强，但小鼠有嗜睡现象；剂量为0.25mg/kg时，BLA显著抑制组胺(P<0.05)或氯喹(P<0.01)引起的搔抓反应；而剂量为0.125mg/kg时，BLA对组胺引起的瘙痒无抑制作用，对氯喹引起的急性瘙痒仅有轻度抑制作用，但未达到统计学显著水平(P>0.05)。在后两个剂量小鼠未见嗜睡现象和其他副作用。
表1 注射前后瘙痒次数对比
Figure PCTCN2019091049-appb-000001
表2 组胺组灌胃BLA两个小时到两个半小时小鼠的搔抓次数
Figure PCTCN2019091049-appb-000002
Figure PCTCN2019091049-appb-000003
Figure PCTCN2019091049-appb-000004
表3 氯喹组灌胃BLA两个小时到两个半小时小鼠的搔抓次数
Figure PCTCN2019091049-appb-000005
Figure PCTCN2019091049-appb-000006
上述试验结果表明：口服草乌甲素可剂量依赖性地抑制组胺或氯喹引起的瘙痒。因此，口服草乌甲素可用于治疗多种疾病和药物引起的神经病理性瘙痒。
我们测试的小鼠浓度大致相当于成年人的0.11*0.125mg/kg＝0.01375mg/kg，0.11*0.25mg/kg＝0.0275mg/kg，0.11*0.5mg/kg＝0.055mg/kg，即在测试相当于人的0.01375mg/kg到0.055mg/kg的浓度中，草乌甲素都具有一定的抑制急性瘙痒的作用。
实施例2
本发明的草乌甲素在神经病理性瘙痒方面的应用，可以将草乌甲素制成不同剂型的药物使用。具体来说，可以将草乌甲素制成包括口服制剂、注射制剂或外用制剂等剂型。具体的药物可包括草乌甲素和其它药学上可 接受的载体，对于药物中各成分的用量可以按照药物制剂中对于成分的配比要求进行调整即可，对于草乌甲素的有效含量也可以按照不同剂型等常规的剂型要求计算，实施例1中描述的0.01375mg/kg到0.055mg/kg人体体重/d，本实施例在此只提供一个参考值范围，并不是具体的限定。更进一步说明，其中药学上可接受的载体可以采用矫味剂、填充剂、崩解剂、着色剂和增粘剂等。矫味剂如葡萄糖、山梨醇、甘露醇等，但并不限定于这些矫味剂，增粘剂等；填充剂如微晶纤维素等；崩解剂如羟甲基淀粉钾等。
实施例3
一种含草乌甲素的片剂，每片含0.275mg草乌甲素与辅料130mg的薄膜衣片。将草乌甲素用食用级或药用级乙醇溶解；将辅料乳糖20mg、糖粉25mg、微晶纤维素40mg和羟丙基纤维素10mg混合，然后加入草乌甲素乙醇液混合，再加适量纯化水混合制成软材，再制成颗粒后干燥，在干燥的颗粒中加入硬酯酸镁5mg和羧甲基淀粉钠30mg压片，然后包薄膜衣制得。
实施例4
一种草乌甲素胶囊，每粒胶囊含0.4mg草乌甲素与辅料165mg，辅料为糖粉80mg、淀粉25mg、微晶纤维素20mg、低取代羟丙基纤维素15mg、硬酯酸镁5mg和邻苯二甲酸酯5mg，然后加入润湿剂制乙醇成软材，再制成微丸后干燥，然后包肠溶衣丙烯酸树脂15mg制得。干燥微丸放至室温后，用丙烯酸树脂包衣，包衣后的微丸用硬胶囊进行装填后进行内包、外包后即得微丸剂胶囊成品。
实施例5
一种草乌甲素控释片，每片含0.98mg草乌甲素、骨架材料(羟丙甲纤维素125mg)、润滑剂(硬酯酸镁1mg)混匀和，用压片机进行压片，压制好的片子用包衣材料用薄膜包衣机进行包衣制得。
实施例6
一种草乌甲素注射液，每ml含草乌甲素2mg，称取草乌甲素2000mg，加稀硫酸5ml溶解后，加注射用水至1000ml，调pH至5.0，过滤，灌封，灭菌即得。
实施例7
一种注射用草乌甲素，每支含草乌甲素0.2mg，称取草乌甲素200mg，加稀硫酸5ml溶解后，加注射用水至500ml，加甘露醇200g溶解后，加注射用水至1000ml，调pH至5.0，过滤，灌封为1000支，加塞，冷冻干燥后压塞即得。
实施例8
草乌甲素贴剂，每贴含草乌甲素4mg，称取草乌甲素4000mg，硅酮压敏胶150000mg，桉油2000mg，加100ml乙醇使草乌甲素溶解后，再与硅酮压敏胶和桉油混匀，涂布在聚四氟乙烯薄膜保护层上，控制涂布的厚度，涂布为1000贴，烘干，覆上无纺布背衬层，剪切成适当的形状和大小即可。
实施例9
一种含草乌甲素的片剂，每片含草乌甲素3.3mg。将草乌甲素3300mg与乳糖3000mg、羟丙基纤维素1500mg、硬酯酸镁50mg、羧甲基淀粉钠400mg混匀，采用直接压片，压制为1000片。
实施例10
一种含草乌甲素的片剂，每片含草乌甲素3.3mg。将草乌甲素3300mg与乳糖250mg、羟丙基纤维素100mg、硬酯酸镁50mg、羧甲基淀粉钠50mg混匀，采用直接压片，压制为1000片。
以上对本发明所提供的草乌甲素的用途进行了详细介绍。本文应用了具体个例对本发明的原理及实施方式进行了阐述，以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。

Claims (10)

  1. 草乌甲素在制备治疗和/或预防皮肤瘙痒症或其继发性损害的药物中的应用。
  2. 如权利要求1所述的应用，其特征在于，所述草乌甲素的剂量为0.125mg/kg小鼠体重/d～0.5mg/kg小鼠体重/d。
  3. 如权利要求1所述的应用，其特征在于，所述草乌甲素的剂量为0.01375mg/kg人体体重/d～0.055mg/kg人体体重/d。
  4. 如权利要求1至3任一项所述的应用，其特征在于，所述皮肤瘙痒症为神经病理性瘙痒。
  5. 如权利要求4所述的应用，其特征在于，所述皮肤瘙痒症为组胺和/或氯喹引起的瘙痒。
  6. 如权利要求1至5任一项所述的应用，其特征在于，所述药物包括草乌甲素及药学上可接受的载体；所述草乌甲素在所述药物中的质量百分含量为0.2％～88％。
  7. 如权利要求6所述的应用，其特征在于，所述药物的剂型为口服制剂、注射制剂或外用制剂。
  8. 如权利要求7所述的应用，其特征在于，所述口服制剂为硬胶囊、滴丸、颗粒、片剂、合剂、软胶囊、浓缩丸、口服液或散剂。
  9. 如权利要求7所述的应用，其特征在于，所述注射制剂为注射液或冻干粉针剂。
  10. 如权利要求7所述的应用，其特征在于，所述外用制剂为酊剂、软膏剂、乳膏剂、糊剂、气雾剂、喷雾剂、散剂、耳用制剂、洗剂、冲洗剂、搓剂、涂剂、涂膜剂、凝胶剂或贴剂。
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