WO2020061874A1 - 人参皂甙ck用于制备治疗中重度寻常型银屑病口服药物中的应用 - Google Patents

人参皂甙ck用于制备治疗中重度寻常型银屑病口服药物中的应用 Download PDF

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WO2020061874A1
WO2020061874A1 PCT/CN2018/107829 CN2018107829W WO2020061874A1 WO 2020061874 A1 WO2020061874 A1 WO 2020061874A1 CN 2018107829 W CN2018107829 W CN 2018107829W WO 2020061874 A1 WO2020061874 A1 WO 2020061874A1
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psoriasis
ginsenoside
drug
cells
application
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PCT/CN2018/107829
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French (fr)
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刘珉宇
崔然然
邓轶方
黄晓玲
于鹏霞
余增洋
刘全海
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上海医药工业研究院
中国医药工业研究总院
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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics

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  • the invention relates to a new application of ginsenoside CK (Compound-K) in the field of pharmaceuticals, in particular to an application of ginsenoside CK in the preparation of an oral medicine for treating moderate to severe psoriasis.
  • ginsenoside CK Compound-K
  • Psoriasis is an immune-related chronic recurrent inflammatory skin disease.
  • the characteristic damage is: red pimples or plaques with multiple layers of silvery white scales, which are common in the limbs, head and back. It spreads throughout the body, with high fever, pustules, erythrodermatous changes, and pathological changes in the size of the body.
  • the incidence of psoriasis in the world is about 2% -3%, and about 125 million patients are affected by age, gender, ethnicity, geographical location, and environment.
  • the prevalence of different populations varies widely, such as in cold regions. The prevalence is higher than in tropical regions. Compared with Europe and the United States, the prevalence of psoriasis in Asian countries such as China and Japan is relatively low.
  • Psoriasis is an autoimmune disease mediated by T cells and can be activated by many factors, such as trauma and injury, infections, drugs, and imiquimod, a local biological response modifier. Studies have proved that it is a complex Diseases are caused by the interaction of multiple genes, immune systems and environmental factors. Related researchers have found that the skin of patients with psoriasis contains a large number of T cells, and Th1 and Th17 cells are particularly important. The initial CD4 + Th can be differentiated into Th1 and Th2. Th1 cells are stimulated to produce IFN- ⁇ to promote cellular immunity; Th2 cells can produce IL-4 and IL-5 to promote antibody production and humoral immunity.
  • T-reg regulatory T-cell
  • Th17 produce IL-17A, IL-17F, IL-22, and TNF- ⁇ .
  • DCs secrete IL-12 and IL-23 after stimulation.
  • IL-12 is an important factor in the maintenance and development of Th1 cells. It can stimulate Th1 to produce IFN- ⁇ .
  • IL-23 is an important factor in the maintenance and development of TH17 cells. Can stimulate the immune response of Th17 cells.
  • the process of IL-23 stimulating TH17 cells to produce pro-inflammatory factors is called the IL-23 / Th17 axis, which can be used as a direction for disease treatment.
  • Antigen-presenting cells and NKs cells can stimulate immune cells to produce inflammatory factors (such as: TNF- ⁇ , IFN ⁇ , IL-22) and chemokines (such as: CCL20, CCL22, CCL5, CCL19) and release them to psoriatic lesions .
  • inflammatory factors such as: TNF- ⁇ , IFN ⁇ , IL-22
  • chemokines such as: CCL20, CCL22, CCL5, CCL19
  • Transcription factors such as nuclear factor ⁇ B (nuclear factor ⁇ B, NF ⁇ B), activator protein-1 (AP-1), and mitogen-activated protein kinase (MAPK) are all in psoriasis, and abnormalities in autoimmunity, including cellular immunity and humoral immunity, cannot be ignored in the pathogenesis, diagnosis, and target of psoriasis.
  • nuclear factor ⁇ B nuclear factor ⁇ B
  • AP-1 activator protein-1
  • MAPK mitogen-activated protein kinase
  • Psoriasis can be divided into mild, moderate, and severe psoriasis according to the area of the lesion and the progress of the disease.
  • topical administration is mainly used, such as calcipotriol, retinoic acid, and leflunomide.
  • Drugs include cytotoxic and immunosuppressive drugs such as methotrexate, glucocorticoids, and tacrolimus. Most of these drugs have severe side effects at higher doses and longer treatment periods.
  • MTX is a cytotoxic anticancer drug.
  • Long-term large-scale application can reduce the body's immune function and cause liver fibrosis and bone marrow suppression. Therefore, caution should be used in patients with moderate to severe psoriasis. When the dose is slightly larger and the drug is taken for a longer period of time, severe toxicity can occur.
  • Carboplatinol is an analogue of vitamin card D. Its medicinal properties are similar to the active metabolite of vitamin D3, calciferol. It can significantly inhibit cell proliferation and stimulate cell differentiation, and increase human keratinocytes and increase keratinization. This layer makes the activity of protein cross-linking enzyme, this product also inhibits epidermal cell proliferation and differentiation, and this product is not easy to cause hypercalcemia, but this product quickly metabolizes and inactivates rats after intravenous injection 50ug / kg 2 is only 4 minutes, so this product is not suitable for systemic medication. No oral medications so far
  • Tazarotene is the first receptor-selective, third-generation aromatic retinoid drug, which mainly selectively binds two retinoid receptors (RAR- ⁇ .RAR- ⁇ ), but does not interact with vitamins.
  • a acid receptor (RAR) binding effectively treats diseases such as psoriasis, but tazarotene's molecule replaces the original single and double bond polyene chain with a linear triple bond to form a hard acetylene structure that can only be applied to some vitamin A Acid receptor. Because there are no isomers, it will not trigger the activity of potentially different retinoic acid receptors.
  • the free carboxylic acid portion of the original molecule is replaced with an ethyl prodrug, which is locally Significant therapeutic index in effect and toxicity mode.
  • Nicotinic acid is introduced into the structure to ensure that tazarotene ethyl ester is rapidly metabolized into the form of hydrophilic free acid (tazarotine acid), thereby avoiding drug accumulation in the body.
  • the sulfur atom is introduced into the lipophilic ring to facilitate the appropriate molecular rapid metabolism by cytochrome isoenzymes to the oxidized form of sulfur, namely sulfoxide and sulfone. The body is rapidly metabolized and the activity disappears.
  • tazarotene has little oral or transdermal absorption, and the drug is rapidly (1.8m: n) converted into tazarotene acid by esterase in the blood, and excreted quickly, so generally he Zalortine is not used systemically as an oral dose. It is reported in the literature that the reproductive toxicity test showed that the teratogenicity test was positive when the product was applied externally and orally in rabbits and rats.
  • Leflunomide is an isoxazole derivative with anti-proliferative activity, which can inhibit dihydrolactic acid synthetase and directly inhibit the proliferation of lymphocytes and B cells by inhibiting the full-scale biosynthesis of pyrimidine.
  • the activity of the amino acid kinase inhibits the activation of NF- ⁇ B and gene expression, inhibits the expression of cytokine adhesion molecules, inhibits the secretion of antibodies and the production of NO, so it has an anti-inflammatory effect.
  • Leflunomide mainly has fatigue, upper abdominal discomfort, nausea, dizziness, itching of the skin, rash, etc.
  • immunosuppressive agents such as cyclophosphamide and cyclosporin
  • leflunomide has fewer side effects and is more serious. There are few adverse reactions, and pulmonary interstitial fibrosis does not generally occur, and its tolerance is similar to that of methotrexate.
  • Dithranol The description of dithranol ointment (the first batch of chemicals released by the State Food and Drug Administration) states that systemic absorption can cause symptoms of poisoning, including vomiting, diarrhea or kidney irritation. And nervous system poisoning. Therefore, this product is strictly forbidden to be taken orally. Do not use a penetrating substrate. It is prohibited to use on damaged skin.
  • Adrenal corticosteroids and clobetasol propionate clobetasol propionate cream.
  • the pharmacological and toxicological results indicate that this product has a strong capillary contraction effect, and its anti-inflammatory effect is 112.5 of hydrocortisone Times, 2.3 times of betamethasone sodium phosphate, and 18.7 times of fluocinolone.
  • Systemic adverse reactions were three times that of fluocinolone. Due to systemic absorption, it can cause reversible hypothalamic-pituitary-adrenal (PHA) axis suppression, and some patients may show Cushing's syndrome, hyperglycemia, and urine glucose.
  • PHA hypothalamic-pituitary-adrenal
  • Adrenal corticosteroids can produce a wide range of pharmacological effects at pharmacodynamic doses (at superphysiological doses), becoming one of the most commonly used drugs in the clinic, and one of the strongest anti-inflammatory drugs currently known, with regulation Immune function, the use of this kind of drugs has better controlled the condition of many severe skin diseases, greatly reduced the mortality rate, and improved the effect of comprehensive clinical treatment.
  • the dosage administration time is maintained, and the dosage is not selected properly, it will also have serious side effects and even threaten life.
  • Glucocorticoids have historically been the most controversial drugs.
  • Natural and synthetic glucocorticoids have a wide range of biological activities and vary with different varieties, different doses, different modes of administration and different doses.
  • corticosteroids According to the effect of corticosteroids, it can be divided into systemic administration, topical administration and topical skin administration. Some medicines have a short administration time and some have quite long-lasting effects.
  • dexamethasone has a longer administration time, which can be used for systemic application and external skin application.
  • Prednisone is a medium-effect preparation. It is converted into hydrocortisone in the liver to play a role. It is generally administered as a system, while triamcinolone and skin are easy to apply topically. It has good side effects and few side effects. Its anti-allergic effect is strong and long-lasting. Intramuscular injection is also often used as a cream for external use on skin diseases.
  • corticosteroids can reduce the side effects of water and salt metabolism through structural transformation.
  • corticosteroids the original activity is natural or synthetic, and its basic side effects must still be paid attention to.
  • Heterocyclic compounds for treating psoriasis (national application number: 201580000843.4): We found in research that in animal models, when the drug is administered orally to achieve anti-psoriasis effects, it will cause severe animal toxicity, mainly because of animals Toxicity is caused by excessive drug concentration in the body, but this problem was not found in the topical topical research, so only topical topical research and patents for topical drugs were developed.
  • Ginseng (Panax ginseng CAMeyer) is a perennial herbaceous plant of the family Acanthaceae. It is a traditional precious Chinese herbal medicine in China. Ginseng has a long history of medicinal use and can play an important role in a variety of diseases. Shen Shen Baicao Jing lists ginseng as the top grade, and is known as the "King of Herbs". Its anti-tumor, anti-aging, anti-radiation Many biological activities have attracted the attention of researchers. Since the 1960s, people have recognized that ginseng has a certain inhibitory effect on certain malignant tumors. A large number of subsequent studies have proved that the active component of ginseng's antitumor is mainly ginsenosides.
  • diol-type ginsenoside metabolites are agonists of adrenal cortex hormones in their research, and their article pointed out that diol-type ginsenoside metabolites have anti-inflammatory properties and mainly inhibit pro-inflammatory response factors secreted by macrophages.
  • TNF- ⁇ and IL-1 ⁇ down-regulate the expression of ERK and Art protein, thereby blocking the activity of NF- ⁇ B; at the same time inhibiting the activity of AP-1 induced by TPA-induced cox-2 gene activator, and finally inhibiting COX-2 (Cyclooxygenase-2) expression; and can effectively inhibit the TGE-induced PGE 2 (prostaglandin 2 ) and restore it to normal levels.
  • ginsenoside CK Compound K, CK
  • ginsenoside CK Compound-K
  • the purpose of the present invention is to provide a ginsenoside CK for use in the preparation of oral medicine for moderate to severe psoriasis for systemic use. Due to the low toxicity of ginsenoside CK, its oral drug can also be used in patients with mild psoriasis.
  • the structural formula and molecular formula of ginsenoside CK according to the present invention are:
  • FIG. 1 shows the distribution of CK skin and plasma at different times after C-K 22.5 mg / kg in rats in Example 1.
  • FIG. 2 shows the effect of CK-induced differentiation of HaCaT cells by immunohistochemical method in Example 2.
  • Figure 3 is the data of the effect of Example 6 on the blood glucose of mice, where * P ⁇ 0.05 and ** P ⁇ 0.01 compared with the blank.
  • the test results showed that compared with the blank group, the cytoplasmic staining in the 300ng / ml group was dark brown, indicating that K19 expression was significantly increased, indicating that ginsenoside C-K had a certain induction effect on HaCaT cells.
  • Psoriasis involves dermal angiogenesis and an increase in tube diameter during the onset of the disease.
  • the chick embryo allantoic membrane was used as an in vivo model for studying angiogenesis in psoriasis.
  • Fresh eggs were incubated for 6 consecutive days at 37 ° C and 50% humidity. The surviving eggs were opened on the 6th day, and the experimental drugs with different concentrations were dropped on the filter paper and air-dried on the allantoic membrane. After sealing the small window with scotch tape, continue to incubate for 48 hours, take pictures, count the number of blood vessels, and calculate the inhibition rate.
  • Inhibition rate (1-number of neovascularization in the drug effect group / number of neovascularization in the negative control group) ⁇ 100%
  • test results show that compared with the blank control group, CK can significantly inhibit angiogenesis.
  • the mouse vaginal epithelial cells change with the change of mouse estrous cycle.
  • the mitosis of the vaginal epithelial cells of the mouse will be very active. Therefore, the vaginal epithelial cells of the mouse can be placed in the pre-estrous or estrous phase by injecting estradiol into the mature female mouse. There are many mitotic cells. If the drug can inhibit this change, the drug is considered to have an inhibitory effect on mitosis and can be used for the treatment of excessive keratosis of psoriasis.
  • Female mature mice were orally administered with estradiol for 3 consecutive days, and mice in estrus phase were selected and administered with test drugs for 3 consecutive days.
  • the colchicine was injected intraperitoneally 10 mg / kg 2 hours after the last administration. . Animals were sacrificed 6 hours after the last administration, vaginal tissues were taken, fixed with 10% formaldehyde, and HE stained. The number of mitosis was counted under a light microscope. The test results are shown in Table 2:
  • the 2.5 mg / kg and 5 mg / kg dose groups can significantly inhibit mitosis of vaginal epithelial cells in mice, and the mitotic index is comparable to that of the positive drug, and there is no statistical difference in mitotic index between the dose groups. Therefore, C-K can inhibit cell mitosis and have a certain therapeutic effect on the pathological state of keratinocyte hyperproliferation of psoriasis.
  • the scale epithelium in the tail of normal mice lacks a granular layer, and there are residual cell nuclei in the stratum corneum. It is a natural abnormal keratosis, similar to the pathophysiological changes of psoriasis and keratosis, so it can be used directly to detect drugs for psoriasis The role of incompleteness.
  • 0.5ml / piece was administered to the stomach respectively for 14 consecutive days. The mice were killed 1 hour after the next administration. A strip of skin at the administration site was taken and fixed with a 10% formaldehyde solution. Paraffin-embedded, HE stained, and tail scales of each mouse were observed under a light microscope. The test results are shown in Table 3:
  • the 2.5 mg / kg and 5 mg / kg dose groups can significantly promote the formation of epidermal granule layers in the tail scales of mice, and the effect is equivalent to that of the positive drug.
  • the test drug CK has no such effect. Therefore, CK can significantly promote the formation of epidermal granule layers in the tail scales of mice, and has a certain therapeutic effect on the pathological state of psoriasis keratosis and has good safety.
  • Imiquimod is an agonist of TLR7 / 8. It is used to treat external genital warts. It has been found in clinical application that this drug can cause psoriasis in humans. Multiple studies have found that Imiquimod can induce silver on the back of Balb / c mice. Psoriasis-like changes, the mechanism of which mainly depends on the IL23 / 17 axis, is similar to the pathogenesis of psoriasis in humans, and has now become a common animal model of psoriasis.
  • mice healthy male Balb / c mice were shaved on the back. Except for the normal control group, the other animals were uniformly applied to the back skin with imiquimod cream once a day. After 6 days, they were divided into groups, and the corresponding drugs were orally administered for 15 consecutive days. During administration, except for the normal control group, the other groups were applied with imiquimod cream every other day. Mice were sacrificed 1 h after the last administration, and the skin on the back was taken and fixed with 10% formaldehyde solution, embedded in paraffin, and stained with HE. Pathological sections of the skin on the back of the mice were observed under an optical microscope. The test results are shown in Table 4:
  • Imiquimod-induced Balb / c mouse psoriasis model is very similar to human plaque-type psoriasis, with plaques, thickened skin, scales, thickened epidermis, keratosis, and angiogenesis. Inflammatory cell infiltration. From the test results in Table 4, it can be seen that CK in the 2.5 mg / kg to 40 mg / kg dose group can significantly inhibit the back skin thickening and inflammatory cell infiltration of Balb / c mice induced by imiquimod.
  • glucocorticoids are mainly used to treat those that are difficult to control, or that are ineffective with other treatment drugs or some special psoriasis, and medium-strong glucocorticoids can be used as Choice of local treatment for psoriasis. But glucocorticoids can cause serious side effects such as hyperglycemia and osteoporosis.
  • C-K batch number: 090101; purity: 99.9%; properties: white powder; storage conditions: room temperature.
  • Animal feeding conditions indoor temperature in the animal room: 25 ⁇ 1 ° C; humidity in the animal room: 50 to 70%; light in the animal room: alternating lighting for 12 hours; drinking water: free drinking water; feed: pellet feed.
  • mice were randomly divided into 7 groups, namely the normal saline group, 2.4 mg / kg, 12 mg / kg, 36 mg / kg dexamethasone acetate 2 dose groups, 2.5 mg / kg, 75 mg / kg, 225 mg / kg CK 3 dose groups. Mice were given different doses of dexamethasone acetate and C-K by gavage for 6 consecutive days. A full blood test was performed at 1 h after the last dose.
  • Hematological data showed that compared with the blank control, the percentage of lymphocytes in the dexamethasone 2.4 mg / kg, 12 mg / kg, and 36 mg / kg dose groups were significantly reduced, the percentage of neutrophils was significantly increased, and dexamethasone 12 mg / kg In the 36 mg / kg dose group, the white blood cell count was significantly reduced, and the percentage of monocytes was significantly increased; but the test drugs at different concentrations did not cause hematological changes.
  • C-K batch number: 090101; purity: 99.9%; properties: white powder; storage conditions: room temperature.
  • Animal feeding conditions indoor temperature in the animal room: 25 ⁇ 1 ° C; humidity in the animal room: 50 to 70%; light in the animal room: alternating lighting for 12 hours; drinking water: free drinking water; feed: pellet feed.
  • mice were randomly divided into 7 groups, namely the saline group, the 3 dose groups of 12mg / kg, 36mg / kg, 108mg / kg dexamethasone acetate, 25mg / kg, 75mg / kg, 225mg / kg Dose groups. Mice were given different doses of dexamethasone acetate and C-K by gavage for 6 consecutive days, fasting was started at about 8:00 am on the sixth day, and tail vein blood glucose was measured at about 4:00 the next day.

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Abstract

一种人参皂甙CK在制备治疗中重度寻常型银屑病口服药物中的应用。

Description

人参皂甙CK用于制备治疗中重度寻常型银屑病口服药物中的应用 技术领域
本发明涉及人参皂甙CK(Compound-K)在制药领域中的新应用，尤其是涉及一种人参皂甙CK在制备治疗中重度寻常型银屑病口服药物中的应用。
背景技术
银屑病(Psoriasis)为免疫相关的慢性复发性炎症性皮肤病，特征性损害为：红色丘疹或斑块上覆有多层银白色鳞屑，多发于四肢、头部和背部，严重皮损可泛发全身，并出现高热、脓疱、红皮病样改变以及全身大小关节病变。银屑病在全世界发病率约为2％-3％，约1.25亿患者，受年龄、性别、种族、地理位置、环境的影响，不同人群的患病率差异较大，例如寒冷地区患病率较热带地区患病率高，与欧美地区相比，中国、日本等亚洲国家银屑病的患病率相对较低，2004-2009年文献报道西方国家银屑病的患病率为2-4％，2007-2008年中国六省市调查的银屑病患病率为0.47％，发病年龄为4-78岁，使得银屑病患者生活质量受到严重影响，甚至连就业和收入也成问题。特别是目前有大量统计显示，银屑病和其他一些疾病共发，包括银屑病关节炎、心血管疾病、高血压、肥胖和Grohn’s病等，这些疾病对患者的预后产生很大的影响，并且给银屑病的治疗带来很多的复杂因素。
银屑病是一个由T细胞介导的自身免疫性疾病，可以被许多因素所激活，如创伤和损伤、感染、药物、局部生物反应调节剂咪喹莫特等，研究证明它是一种复杂的疾病，由多种基因、免疫系统和环境因素相互作用所引起。相关研究人员研究发现，银屑病患者病变部位皮肤中含有大量的T细胞，Th1、Th17细胞尤为重要。初始CD4+Th可分化为Th1和Th2，Th1细胞受到刺激能够产生IFN-γ从而促进机体的细胞免疫；Th2细胞能产生IL-4和IL-5促进抗体的产生和体液免疫。近年研究中，发现了CD4+T cell的新亚型，包括：T-reg(regulatory T-cell)、Th17、Th22细胞等。Th17细胞产生IL-17A、IL-17F、IL-22、TNF-α。DCs受到刺激后分泌IL-12、IL-23，IL-12是Th1细胞的维持和发展过程中的重要因子，能够刺激Th1产生IFN-γ，IL-23是TH17细胞的维持和发展的重要因子，能够刺激Th17细胞的免疫应答。IL-23刺激TH17细胞产生促炎症因子这一过程被称为IL-23/Th17轴，均可作为疾病治疗的方向。抗原提呈细胞、NKs cell可以刺激免疫细胞产生炎症因子(例如：TNF-α、IFNγ、IL-22)及趋化因子(例如：CCL20,CCL22,CCL5、CCL19)并释放到银屑病病变部位。各个炎症因子可引起银屑病的多种病理特点。转录因 子，例如核因子κB(nuclear factorκB,NFκB)、激活因子蛋白-1(activator protein-1,AP-1)和分裂素激活的蛋白激酶(mitogen-activated protein kinase,MAPK)均在银屑病的发病机制中起着重要的作用，而自身免疫的异常，包括细胞免疫、体液免疫在银屑病发病、诊断及作为治疗的靶标等方面都是不可忽视的。
银屑病根据皮损面积和病情的进展情况可分为轻、中、重度银屑病，对于轻度银屑病主要采用局部外用给药，例如卡泊三醇、维A酸、来氟米特等药物，而对于中、重度银屑病局部外用药仅作为辅助手段，必须要给予全身治疗，因为病情和病理、病理生理状况需要全身给药才能控制病情的发展，而且中、重度银屑病面积太大，局部应用也会产生皮肤刺激，皮肤病变，甚至大面积的外用药，一旦吸收入血，也会产生毒性，所以中、重度银屑病常采用系统的治疗，常用的系统治疗的药物有甲氨蝶呤、糖皮质激素、他克莫司等细胞毒类和免疫抑制类药物，这类药大多数在剂量稍大、疗程稍长均会有严重的毒副反应，
例如，MTX是一种细胞毒类的抗癌药，长期大量应用可使机体免疫功能下降，而且会导致肝脏纤维化和骨髓抑制。所以在中重度银屑病患者应用要谨慎。当剂量稍大和用药时间较长时，会产生严重的毒性。
卡铂三醇是维生素卡D的类似物，药效性质和维生素D3的活性代谢产物骨化醇类似，他能明显抑制细胞的增殖和刺激细胞的分化，并增加人角化细胞并增加角化层内使蛋白交联酶的活性，本品也抑制表皮细胞增殖和分化，尚且本品不易引起高钙血症，但是本品服后迅速代谢和灭活大鼠静脉注射50ug/kg t 1/2仅为4分钟，所以本品不适宜全身用药。至今未见口服
他扎罗汀是第一个受体选择性，第三代芳香维A酸类药物，主要是选择性的结合二种维A酸受体(RAR-β.RAR-γ)，但是不与维A酸受体(RAR)结合，有效地治疗银屑病等疾病，但是他扎罗汀的分子以直线状三键取代原单双键多烯链形成坚硬的乙炔结构只能适用于某些维A酸受体。因没有异构体，不会引发潜在的不同维A酸受体的活动，该药在结构的设计上，将原分子中游离羧酸部分用乙酯前体药的形式代替，后者在局部效应和毒性模式上显较好的治疗指数，结构中引入烟酸，以保证他扎罗汀乙酯迅速代谢成亲水性的游离酸(他扎罗汀酸)的形式，从而避免了药物在体内积蓄及嗜脂性维A酸半衰期长的问题，将硫原子引入嗜脂环以利于分子适当的被细胞色素同工酶快速代谢成硫的氧化型，即亚砜和砜，这种氧化途径使药物在体内迅速代谢，活性消失，由于他扎罗汀口服或透皮吸收甚少，而且药物在血液中迅速(1.8m:n)被酯酶转化为他扎罗汀酸，而排泄迅速，所以一般他扎罗汀不作为口服而全身应用。文献报道，生殖毒性试验显示家兔和大鼠外用和 口服本品时，致畸试验呈阳。
来氟米特为具有抗增殖活性的异恶唑类衍生物，能抑制二氢乳酸合成酶，通过抑制嘧啶的全程生物合成，从而直接抑制淋巴细胞和B细胞的增殖，本品尚有抑制络氨酸激酶的活性抑制NF-κB的活化和基因的表达，抑制细胞因子粘附分子的表达，抑制抗体的产生分泌和NO的生成，故具有抗炎作用。
本品是系统性给药，几乎未见有局部外用。来氟米特的副作用主要有乏力、上腹部不适、恶心、头晕、皮肤瘙痒、皮疹等，与环磷酰胺，环孢菌素A等免疫抑制剂相比来氟米特的副作用少，且严重不良反应少，一般不出现肺间质性纤维化，其耐受性与甲氨喋呤相似。
临床试验发现来氟米特可引起ALT升高，白细胞下降，严重的肝损伤和明确的乙肝或丙肝血清学指标阳性患者慎用。而且本品因肝毒性大而被多国禁用，在大规模研究后发现1、血液系统：白细胞增多、血小板增多或全血细胞减少；2、心血管系统：高血压、胸痛；3、中枢神经系统；4、胃肠道和肝脏毒性等。应用时应谨慎。
地蒽酚：地蒽酚软膏说明书(国家药监局公布第一批化学药品)中指出，全身吸收会出现中毒症状，包括呕吐、腹泻或肾脏刺激，大量的地蒽酚也可使肝、肠及神经系统中毒，因此，本品严禁口服，不能用穿透性强的基质，禁用于破损皮肤。
肾上腺皮质激素类药物和丙酸氯倍他索：丙酸氯倍他索乳膏，药理毒理结果指出，本品具有较强的毛细血管收缩作用，其抗炎作用为氢化可的松的112.5倍，倍他米松磷酸钠的2.3倍，氟轻松的18.7倍。全身不良反应为氟轻松的3倍。由于全身性吸收作用，可造成可逆性下丘脑-垂体-肾上腺(PHA)轴的抑制，部分患者可出现库欣综合征、高血糖及尿糖等表现。在兔和小鼠试验中，在皮下给药时，要比其他作用弱的皮质类固醇有更强的致畸作用(毒理研究)。本品疗程不得超过2周，不能采用封包方法(用法用量)。药代动力学指出，本品外用吸收良好，很容易通过表皮皮层吸收，但由于表皮基层向真皮移动时受阻，在涂擦表皮层会很长时间贮留，很少进入血液。所以氯倍他索在临床上外用药很广泛，但是至今无全身用药的制剂，在全身用药方面实用性很差。
肾上腺皮质激素类药物在药效学剂量下(超生理剂量下)可以产生广泛的药理作用，成为临床上最常用的药物之一，是目前所知的最强的抗炎药物之一，具有调节免疫功能，这类药物的使用已使众多的危重型皮肤疾病的病情得到较好的控制，大大降低了死亡率，提高了临床综合治疗的效果。但是如果选择的品种，剂量给药时间维持给药的时间、剂量选择不当，也会产生严重的副作用，甚至威胁生命。糖皮质激素从历史上来说是争论最多 的药物。
天然和人工合成的糖皮质激素具有广泛的生物学活性并随着不同品种、不同剂量、不同的给药方式和不同的剂量而不同。
根据皮质激素的作用可以分为系统给药、局部给药和皮肤外用给药。有的药给药时间短、有的作用相当持久，例地塞米松给药时间较长，可作全身应用，又可作为皮肤外用。泼尼松是中效制剂，在肝脏中转化为氢化可的松才发挥作用，一般作系统给药，而曲安奈德和肤轻松局部外用疗效好，而副作用少，其抗过敏作用强而持久，可肌注也常作乳膏用作皮肤疾病的外用。
但是这类皮质激素类药物通过结构改造，可以减少水盐代谢方面的副作用，但是作为皮质激素类药物，原活是天然的还是人工合成的，其基本的副作用仍旧是必须注意的。
用于治疗银屑病的杂环化合物(国家申请号：201580000843.4)：我们在研究中发现，动物模型中，口服该药后在达到抗银屑病效果时，会引起动物严重毒性，主要因为动物体内药物浓度过高而引起毒性作用，但局部外用研究中未发现此问题，故只开发了局部外用研究及申报了外用药的专利。
综上所述，卡泊三醇半衰期很短，其达到的稳态血药浓度是无法发挥药效作用的，故口服应用存在实用性问题；他扎罗汀已明确其致畸作用，提示本品不能口服；地蒽酚软膏指出，本品严禁口服；丙酸氯倍他索乳膏的指出，该药外用经表皮层吸收时，由于表皮基层向真皮移动受阻，药物很少进入血液，本品大面积使用不得超过2周，否则会因为全身性吸收作用，产生库欣综合征等副作用，动物试验证明本品皮下给药会引起致畸作用，可见该药物全身用药一般是不允许的。
人参(Panax ginseng C.A.Meyer)为五加科多年生草本植物，是我国传统的名贵中草药材。人参的药用历史悠久，在多种疾病中均可发挥重要作用，《神农百草经》就把人参列为上品，素有“百草药王”之美誉，其抗肿瘤、抗衰老、抗辐射等诸多的生物学活性已为研究者所瞩目。20世纪60年代开始，人们已经认识到人参对某些恶性肿瘤具有一定的抑制作用，随后大量的研究证明，人参抗肿瘤的活性成分主要是人参皂苷(Ginsenosides)。多项药效学研究证明，其化合物具有强大的抗炎作用。Chul-Su yang等在研究中阐明二醇型人参皂苷代谢物是肾上腺皮质激素的激动剂，其文章指出二醇型人参皂苷代谢物具有抗炎性，主要抑制巨噬细胞分泌的促炎症反应因子TNF-α和IL-1β；下调了ERK和Art蛋白的表达，从而阻断了NF-κB的活性；同时抑制了TPA诱导的cox-2基因激活物AP-1的活性，最终抑制COX-2(环氧合酶-2)的表达；并且能有效抑制TPA诱导产生的PGE 2(前列腺素 2)， 使其恢复到正常水平。前期研究中，人参皂甙C-K(Compound K，C-K)已申请用于治疗类风关(200610116197.0)和局部外用的轻度寻常型银屑病(201511029119.2)。至今我们尚未发现利用人参皂苷C-K治疗中重度银屑病全身应用的报道。我们近期研究发现口服C-K皮肤中的浓度高于相同时间的血药浓度。故确定C-K具有治疗银屑病的药效。
发明内容
研究人参皂甙CK(Compound-K)在其他领域应用的可能性，发现人参皂甙在制药中的新用途或应用。本发明目的就在于提供了一种人参皂甙CK用于制备中重度寻常型银屑病口服药物中应用，以用于全身用药。由于人参皂甙CK的毒性很低，其口服药物也可用于轻型银屑病患者。
本发明涉及的人参皂甙CK结构式与分子式为：
结构式：如下所示
分子式：C 36H 62O 8
Figure PCTCN2018107829-appb-000001
人参皂苷CK结构
附图说明
图1是实施例1大鼠口服C-K 22.5mg/kg后不同时间的CK皮肤和血浆分布。
图2是实施例2免疫组化法观察CK诱导HaCaT细胞分化的作用。
图3是实施例6对小鼠血糖的影响的数据，其中，与空白相比，*P＜0.05，**P＜0.01。
具体实施方式
实施例1 人参皂甙CK的皮肤和血浆浓度比较
予以6只SD大鼠22.5mg/kg剂量口服给药，给药后1.5h、3h、6h眼眶采血，血液用肝素抗凝，10000rpm离心5分钟，血浆转移至2mL聚丙烯管，置于-40℃冰箱，待测。高浓度样品用空白大鼠血浆稀释。
SD大鼠18只，22.5mg/kg剂量口服给药，给药后1.5h、3h、6h处死，每一时间点，处理6只动物，分别取背部皮肤组织约200mg，按组织样品的处理方法，测定组织匀浆中C-K的含量，计算组织中药物的含量。高浓度样品用空白组织稀释。
如图1所示，研究显示灌胃给予22.5mg/kg C-K后3h后皮肤中的药物浓度高于相同时间的血药浓度。
实施例2 形态学检查人参皂甙CK对HaCaT分化的影响
应用免疫组织化学染色方法，观察人参皂甙CK对HaCaT细胞分化的影响。将生长至一定程度的HaCaT细胞调整适当浓度，接种于6孔板，加入相应药物后，37℃培养72h后进行K1免疫组化染色。试验结果如图2所示。
试验结果显示，与空白组相比，300ng/ml组中胞质染色呈深褐色，说明K19表达明显增多，表明人参皂甙C-K对HaCaT细胞有一定的诱导分化作用。
实施例3 人参皂甙CK对血管生成的影响人参皂甙CK对鸡胚尿囊膜血管生成的作 用
鸡胚在发育5-10天内，富含血管网的尿囊膜新生毛细血管不断出现，正式观察血管形成的最佳时期，银屑病在发病过程中涉及到真皮血管新生及管径增大，用鸡胚尿囊膜作为研究银屑病血管新生的体内模型。将新鲜种蛋在37℃、50％湿度的条件下连续孵化6天，第6天取存活的鸡蛋进行开窗，分别将不同浓度的实验药物滴在滤纸上，风干后放在尿囊膜上。透明胶带封好小窗后，继续孵48h，拍照，统计血管数量，计算抑制率。
抑制率＝(1-药物作用组新生血管数/阴性对照组新生血管数)×100％
实验结果如表1所示
表1 人参皂甙CK对鸡胚新生血管生成的作用
Figure PCTCN2018107829-appb-000002
Figure PCTCN2018107829-appb-000003
Figure PCTCN2018107829-appb-000004
注：与PBS组相比，P*＜0.05，P**＜0.01
试验结果显示，与空白对照组相比，CK可以显著抑制血管新生。
实施例4 天然模拟银屑病部分病症状的动物模型
4.1人参皂甙CK对小鼠阴道上皮细胞有丝分裂的影响
小鼠阴道上皮细胞随着小鼠动情周期的变化而发生一定的变化。当小鼠处于动情前期或动情期时，小鼠阴道上皮细胞有丝分裂会非常活跃，故可通过给成熟的雌性小鼠腹腔注射雌二醇，使得小鼠阴道上皮细胞处于动情前期或动情期，此时有丝分裂的细胞很多，若药物能抑制此变化，则认为该药物对有丝分裂有抑制作用，可针对银屑病角化过度而用于治疗。将雌性性成熟小鼠连续3天口服灌胃雌二醇，挑选处于动情期小鼠，分别灌胃试验药物，连续3天，于最后1次给药后2小时腹腔注射秋水仙碱10mg/kg。于最后一次给药后6小时处死动物，取阴道组织，10％甲醛固定，HE染色。在光学显微镜下记数有丝分裂数。试验结果如表2所示：
表2 CK对小鼠阴道上皮细胞有丝分裂的影响
Figure PCTCN2018107829-appb-000005
Figure PCTCN2018107829-appb-000006
注：与生理盐水组比较，*P＜0.05，**P＜0.01
与生理盐水组相比，2.5mg/kg和5mg/kg剂量组均可显著抑制小鼠阴道上皮细胞有丝分裂，有丝分裂指数较阳性药相当，且各剂量组间有丝分裂指数无统计学差异。因此，C-K可抑制细胞有丝分裂，对银屑病的角质细胞过度增殖这一病理状态有一定的治疗作用。
4.2CK对小鼠尾部鳞片表皮模型的影响
正常小鼠尾部鳞片上皮缺乏颗粒层，角质层内有残留的细胞核，为自然角化异常，类似银屑病角化不全病理生理改变，故无需造模可直接用于检测药物对银屑病角化不全的作用。根据给药剂量分别灌胃0.5ml/只，连续14天，于次给药后1小时杀死小鼠，取给药部位皮肤一长条，用10％甲醛溶液固定。石蜡包埋，HE染色，在光学显微镜下观察每个小鼠的尾部鳞片。试验结果如表3：
表3 人参皂甙CK对小鼠尾部鳞片表皮模型的影响
Figure PCTCN2018107829-appb-000007
注：与生理盐水组比较，*P＜0.05，**P＜0.01
与生理盐水组相比，2.5mg/kg和5mg/kg剂量组均可明显促进小鼠尾部鳞片表皮颗粒层形成，效果与阳性药相当。由体重数据可得，连续口服灌胃阳性药14天可引起小鼠体重下降，但试验药CK无此影响。因此CK可明显促进小鼠尾部鳞片表皮颗粒层形成，对银屑病角化不全这一病理状态有一定的治疗作用且安全性较好。
实施例5 药物诱导的银屑病动物模型
5.1人参皂甙CK对咪喹莫特诱导的Balb/c小鼠银屑病模型的影响
咪喹莫特是TLR7/8的激动剂，用于治疗外生殖器湿疣，临床应用发现此药能引起人银屑病，多项研究发现，咪喹莫特能诱导Balb/c小鼠背部皮肤银屑病样改变，其作用机制主要依赖于IL23/17轴，与人的银屑病发病机制相似，目前已成为一种常见的银屑病动物模型。
实验采用健康雄性Balb/c小鼠，背部剃毛，除正常对照组外，其余动物均用咪喹莫特乳膏均匀涂抹于背部皮肤，每天一次。6天后进行分组，分别灌胃相应药物，连续给药15天。给药期间，除正常对照组外，其余各组每隔一天涂抹咪喹莫特乳膏一次。于最后一次给药后1h处死小鼠，取背部皮肤，用10％甲醛溶液固定，石蜡包埋，HE染色，于光学显微镜下观察小鼠背部皮肤病理切片。试验结果如表4所示：
表4 CK对咪喹莫特诱导的Balb/c小鼠银屑病模型背部皮肤厚度的影响
Figure PCTCN2018107829-appb-000008
注：模型组与空白比较，给药组与模型组比较，*P＜0.05，**P＜0.01
咪喹莫特诱导的Balb/c小鼠银屑病模型与人斑块型银屑病的特点十分相似，出现斑块，皮肤增厚，鳞屑，表皮基层增厚、角化不全，血管生成，炎细胞浸润等。从表4的试验结果可见，2.5mg/kg～40mg/kg剂量组的CK均可显著抑制咪喹莫特诱导的Balb/c小鼠背部皮肤增厚、炎细胞浸润。
实施例6.人参皂甙C-K用于寻常型银屑病的安全性研究
《中国银屑病治疗指南》中指出，系统应用糖皮质激素主要用于治疗那些难以控制的，或者使用其它治疗药物无效或某些特殊的银屑病，且中强效的糖皮质激素可作为局部治疗银屑病的选择。但糖皮质激素可产生高血糖、骨质疏松等严重的副作用。
6.1C-K对小鼠血液学指标的影响
6.1.1试验目的
观察C-K连续高剂量使用是否会产生糖皮质激素类的副作用，评估安全性。
6.1.2试剂和仪器
C-K：批号：090101；纯度：99.9％；性状：白色粉末；保存条件：室温。以吐温为溶媒研磨分散均匀后，吐温量不超过4％，边研磨边加入0.5％CMCNa，以等量倍增法边研磨边加至全量。
醋酸地塞米松片：上海信谊药厂有限公司，0.75mg/片，批号：130927，用0.5％CMCNa溶解至所需剂量。
6.1.3试验动物
品系和种属：ICR，提供单位：上海斯莱克实验动物有限公司，体重18-22g，性别：雄性，每组动物数：6只。动物饲养条件：动物房室内温度：25 ±1℃；动物房湿度：50～70％；动物房光照：12小时交替照明；饮水：自由饮水；饲料：颗粒饲料。
6.1.4试验方法
35只ICR小鼠，随机分为7组，即生理盐水组，2.4mg/kg、12mg/kg、36mg/kg醋酸地塞米松2个剂量组，2.5mg/kg、75mg/kg、225mg/kg C-K 3个剂量组。分别灌胃给予小鼠不同剂量的醋酸地塞米松及C-K，连续6天，于末次给药后1h取足量血测血常规。
6.1.5试验结果
表5-1 C-K血液学检查数据
Table 5-1Blood result data of C-K
Figure PCTCN2018107829-appb-000009
Figure PCTCN2018107829-appb-000010
注：与空白相比，*P＜0.05，**P＜0.01
6.1.6试验结论
血液学数据显示，与空白对照相比，地塞米松2.4mg/kg、12mg/kg、36mg/kg剂量组的淋巴细胞百分比均显著降低、中性粒细胞百分比显著增加，地塞米松12mg/kg、36mg/kg剂量组白细胞计数显著降低、单核细胞百分比显著增加；但不同浓度的试验药则未引起血液学相关变化。
6.2C-K对小鼠血糖的影响
6.2.1试验目的
观察C-K连续高剂量使用是否会产生糖皮质激素类的副作用，评估安全性。
6.2.2试剂和仪器
C-K：批号：090101；纯度：99.9％；性状：白色粉末；保存条件：室温。以吐温为溶媒研磨分散均匀后，吐温量不超过4％，边研磨边加入0.5％CMCNa，以等量倍增法边研磨边加至全量。
醋酸地塞米松片：上海信谊药厂有限公司，0.75mg/片，批号：130927，用0.5％CMCNa溶解至所需剂量。
6.2.3试验动物
品系和种属：ICR，提供单位：上海斯莱克实验动物有限公司，体重18-22g，性别：雄性，每组动物数：6只。动物饲养条件：动物房室内温度：25 ±1℃；动物房湿度：50～70％；动物房光照：12小时交替照明；饮水：自由饮水；饲料：颗粒饲料。
6.2.4试验方法
35只ICR小鼠，随机分为7组，即生理盐水组，12mg/kg、36mg/kg、108mg/kg醋酸地塞米松3个剂量组，25mg/kg、75mg/kg、225mg/kg C-K 3个剂量组。分别灌胃给予小鼠不同剂量的醋酸地塞米松及C-K，连续6天，于第6天晨8:00左右开始禁食，于次日4:00左右，测尾静脉血糖。
6.2.5试验结果
如图3所示。
6.2.6试验结论
血糖数据显示，与空白对照相比，地塞米松12mg/kg、36mg/kg、108mg/kg剂量组均不同程度的引起小鼠血糖升高；但不同浓度的试验药则未引起血糖相关变化。
从药理学评价中可知C-K的药效较银屑病一线药物甲氨蝶呤与糖皮质激素地塞米松相当，但却不会引起动物体重下降。作为选择性糖皮质激素，库欣综合征、骨质疏松、血糖升高等糖皮质激素类副作用也是需要考虑的，故而设计了本节的两个试验，从试验结果可以看出，即使给药量达到最低有效剂量的90倍，也未引起动物血液学和血糖的异常变化，安全性高于地塞米松。
本发明虽然已以较佳实施例公开如上，但其并不是用来限定本发明，任何本领域技术人员在不脱离本发明的精神和范围内，都可以利用上述揭示的方法和技术内容对本发明技术方案做出可能的变动和修改，因此，凡是未脱离本发明技术方案的内容，依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化及修饰，均属于本发明技术方案的保护范围。

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  1. 人参皂甙CK用于制备治疗中重度寻常型银屑病口服药物中的应用。
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