WO2019109590A1 - 眼用药物制剂及其应用 - Google Patents

眼用药物制剂及其应用 Download PDF

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WO2019109590A1
WO2019109590A1 PCT/CN2018/085962 CN2018085962W WO2019109590A1 WO 2019109590 A1 WO2019109590 A1 WO 2019109590A1 CN 2018085962 W CN2018085962 W CN 2018085962W WO 2019109590 A1 WO2019109590 A1 WO 2019109590A1
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ginsenoside
notoginsenoside
pharmaceutical preparation
extract
content
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PCT/CN2018/085962
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English (en)
French (fr)
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谭宁华
王真
唐锴
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中国药科大学
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Priority to US16/769,851 priority Critical patent/US20210169779A1/en
Priority to EP18885969.8A priority patent/EP3721890A4/en
Priority to JP2020547265A priority patent/JP2021505650A/ja
Publication of WO2019109590A1 publication Critical patent/WO2019109590A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/04—Artificial tears; Irrigation solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258—Panax (ginseng)
    • 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
    • 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
    • A61K47/06—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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention belongs to the pharmaceutical technology, and particularly relates to a pharmaceutical preparation for preventing and treating eye fatigue, dry eye pain, eye vascular sclerosis and application thereof.
  • Panax notoginseng contains ginsenosides and notoginsenosides, which can significantly shorten the bleeding and clotting time, has good hemostatic effect; can promote various cell division and growth, increase the number, promote the proliferation and release process of bone marrow cells, increase The number and activity of bone marrow red blood cells can promote hematopoietic function; can significantly inhibit the formation of aortic intima plaque in rabbits with experimental atherosclerosis; excite the central nervous system, improve mental and physical strength, and exhibit fatigue resistance; Significantly increase the phagocytic rate and phagocytic index of macrophages in mice, increase the total number of white blood cells in peripheral blood, reduce the movement index of white blood cells; increase capillary permeability caused by acute inflammation, inflammatory exudation, tissue edema, white blood cells Both migration and gran
  • Panax notoginseng The various pharmacological activities of Panax notoginseng are used in the treatment of various cardiovascular and cerebrovascular diseases, and the extracts are made into drugs such as “Beisaitong”, “Guoxining” and “Thrombus”, which are listed in the category of bruises.
  • drugs such as “Beisaitong”, “Guoxining” and “Thrombus”, which are listed in the category of bruises.
  • the effect of Sanqi's blood circulation and dispersal is also widely used, so that the strained muscle tissue can be recovered.
  • eye diseases such as eye ciliary muscle fatigue and visual fatigue.
  • the Chinese patent discloses a number of patents for visual fatigue, many of which are formulated using Panax notoginseng, such as the patent CN103099977B, which discloses the invention of "an ophthalmic external pharmaceutical composition and its application in the treatment of uveitis”.
  • composition is composed of pimecrolimus eye drops, panax notoginseng saponin Rb1, aqueous extract of forsythia extract, aqueous solution of extract of Rhizoma Imperatae, for eye treatment of uveitis; patent CN103520548B, published " An invention for improving a visual fatigue pharmaceutical composition and a preparation method thereof, wherein the composition is an oral preparation made of medlar, cassia seed, sassafras, licorice, notoginseng, puerarin, light bamboo leaf, bergamot, etc., as a method for improving visual fatigue
  • Patent application CN102960713A discloses an invention of "a health care product for preventing screen pollution", the composition of which consists of Chixiaodou, Zhuqi, Sanqi, American ginseng, pig liver, golden chrysanthemum, paeonol, habitat, earthworm, earthworm.
  • Oral preparations prepared by Hawthorn, Selenium-enriched green tea, Astragalus and Sangkan are used to eliminate the pollution caused by various electronic products to the human body.
  • the object of the present invention is to provide an ophthalmic pharmaceutical preparation for preventing and treating visual fatigue, dry eye pain, eye vascular hardening, preparation method and application thereof.
  • the present invention provides the following technical solutions:
  • An ophthalmic pharmaceutical preparation whose active ingredient is notoginsenoside extract.
  • the notoginsenoside extract is extracted from the preparation of Panax notoginseng.
  • the notoginsenoside extract contains the following components in a total content of 45-95%: notoginsenoside R1, notoginsenoside R2, ginsenoside Rg1, ginsenoside Rg2, ginsenoside Re, ginsenoside Rb1, ginsenoside Rb2, ginsenoside Rd, ginsenoside Rf, ginsenoside Rc, ginsenoside Rh1 and esculin IX.
  • the notoginsenoside extract contains the following components in a total amount of 75 to 90%: notoginsenoside R1, ginsenoside Rg1, ginsenoside Re, ginsenoside Rb1, and ginsenoside Rd.
  • the content of notoginsenoside R1 (C 47 H 80 O 18 ) is 3.0% or more, and the content of ginsenoside Rg1 (C 42 H 72 O 14 ) is 15.0% or more, and ginsenoside Re
  • the content of (C 48 H 82 O 18 ) is 1.0% or more
  • the content of ginsenoside Rb1 (C 54 H 92 O 23 ) is 20.0% or more
  • the content of ginsenoside Rd (C 48 H 82 O 19 ) is 2.5% or more.
  • the content of notoginsenoside R1 (C 47 H 80 O 18 ) is 5.0% or more, and the content of ginsenoside Rg1 (C 42 H 72 O 14 ) is 25.0% or more, ginsenoside
  • the content of Re(C 48 H 82 O 18 ) is 2.5% or more
  • the content of ginsenoside Rb1 (C 54 H 92 O 23 ) is 30.0% or more
  • the content of ginsenoside Rd (C 48 H 82 O 19 ) is 5% or more.
  • the content of the notoginsenoside extract in the pharmaceutical preparation is 0.1 to 30% by mass.
  • the mass percentage of the notoginsenoside extract in the pharmaceutical preparation is 0.2 to 10%.
  • the dosage form of the preparation is an eye wash, an eye drop, an ophthalmic ointment or an ophthalmic patch.
  • the patch may be prepared by impregnating or loading the prepared eye drops and eye ointments on the film material.
  • the notoginsenoside extract in the pharmaceutical preparation is the sole active ingredient, and is composed of 0.1 to 30% by weight of notoginsenoside extract and 70 to 99.9% by weight of a pharmaceutically acceptable carrier and/or Or excipients are prepared. Further, it is prepared from 0.2 to 10% by weight of notoginsenoside extract and 90 to 99.8% by weight of a pharmaceutically acceptable carrier and/or adjuvant.
  • the pharmaceutically acceptable carrier is one or more selected from the group consisting of water, physiological saline, petrolatum, liquid paraffin, lanolin, and glycerin.
  • the pharmaceutical preparation is: adding the active ingredient notoginsenoside extract to artificial tears or various types of eye drops medicines having therapeutic effects.
  • the artificial tear is well known to those skilled in the art, and may be composed of glucose anhydride-70, polyethylene glycol 400, carboxymethyl fiber sodium soda eye drops, vitamin A, carbomer sorbic acid, hyaluronic acid. One or more of sodium, polyvinyl alcohol, and the like.
  • the present invention applies Sanqi's activity of activating blood circulation, relieving swelling and relieving pain, and preparing a dosage form for treating eye diseases.
  • Pharmacological experiments prove that the drug is safe and effective without irritation, dry eyes, pain, and vision. Fatigue and ocular sclerosis have a healing effect on eye and vision damage, and have good clinical application prospects.
  • each component was determined to be saponin R1 (C 47 H 80 O 18 ): 6.2%, ginsenoside Rg1 (C 42 H 72 O 14 ): 28.4% Ginsenoside Re (C 48 H 82 O 18 ): 3.1%, ginsenoside Rb1 (C 54 H 92 O 23 ): 32.7%, ginsenoside Rd (C 48 H 82 O 19 ): 5.8%.
  • the content of each component was determined to be notoginsenoside R1 (C 47 H 80 O 18 ): 5.5%, ginsenoside Rg1 (C 42 H 72 O 14 ): 31.9% Ginsenoside Re (C 48 H 82 O 18 ): 4.2%, ginsenoside Rb1 (C 54 H 92 O 23 ): 34.9%, ginsenoside Rd (C 48 H 82 O 19 ): 6.2%.
  • Example 1 100 g of the obtained notoginsenoside extract was prepared in Example 1, dissolved in 300 ml of physiological saline, 0.3 g of activated carbon was added, stirred, allowed to stand for 8 hours, filtered, and filtered by 0.22 ⁇ m membrane, diluted to a volume of 1000 ml, sealed. , high temperature sterilization, dispensing to eye drops, 1 ml per bottle, get 1000 drops.
  • the eye drops prepared in Example 4 were infiltrated into a 100 cm 2 non-woven fabric to obtain a notoginsenoside eye patch.
  • the eye drops prepared in Example 9 were mixed with artificial tears 1:1, and dripped into the eyes to eliminate discomfort caused by dry eyes and pain and ocular hardening of the eyes.
  • artificial tears are one or more of glucosinolate-70, polyethylene glycol 400, carboxymethyl fiber soda eye drops, vitamin A, carbomer sorbic acid, sodium hyaluronate, polyvinyl alcohol, and the like. Composition.
  • the eye drops prepared in Example 9 were mixed with commercially available eye drops in a ratio of 1:1 and dropped into the eyes. In the treatment of various types of snoring diseases of the eyes, the discomfort caused by dry eye pain and ocular hardening of the eyes was also eliminated.
  • the obtained extract of Panax notoginseng saponin prepared in Example 1 was accurately transferred, and purified water was added to prepare a gradient solution of different concentrations, that is, the eye drops of the test were obtained.
  • Mode of administration gently lower the eyelids, pipette 30 microliters, and then close the eyes for five seconds.
  • Stimulating dosing frequency nine times a day, once every hour.
  • the grouping criteria were: a total of eight rabbits, randomly divided into groups A and B, four in each group, four different concentrations were set in the group for experiments.
  • the irritative experiment and the pharmacological experiment were performed simultaneously, all of which were administered in the right eye, and the left eye was compared with the same dose of physiological saline.
  • the observed data were performed on the basis of the left eye control. See the Draize score sheet for the scoring criteria and see Table (1) for the observations.
  • Dosing concentration 1.25%.
  • Each rabbit was administered to the right eye and the left eye was given the same amount of normal saline.
  • Mode of administration gently lower the eyelids, pipette 30 microliters, and then close the eyes for five seconds.
  • Stimulating dosing frequency nine times a day, once every hour.
  • the eyeballs were taken, fixed, dehydrated, embedded in paraffin, and prepared (4 ⁇ m thick), stained with HE, and the parts of the retina were observed under an optical microscope to check for the presence or absence of lesions and the type and extent of the lesion. According to the severity of the lesion, the semi-quantitative order was mild (0.5 points), mild (1 point), moderate (2 points), severe (3 points), and no lesions were negative (0 points).
  • the retina has ten layers of structure: from the inside to the outside, 1) the inner limiting membrane: a very thin, cell-free membrane; 2) the nerve fiber layer: composed of unmyelinated axons of ganglion cells, narrow 3) ganglion cell layer: composed of the ganglion cell body, the cells are connected to each other as a monolayer; 4) the inner plexiform layer: the axon of bipolar cells and the dendrites of ganglion cells , no obvious cells; 5) inner nuclear layer: composed of bipolar cells connecting cones and rod cells, about 4 layers; 6) outer plexiform layer: foot processes of retinal cells, dendrites of bipolar cells Compatible with each other, no obvious cells; 7) outer nuclear layer: the cell nucleus of the visual cell, about 8 to 10 cells; 8) ⁇ 10) followed by the outer membrane, the visual cell layer, the pigment epithelial layer (rabbit no pigment).
  • each layer of the retina is clear, and there are 3 rabbit retinal nerve fiber layers with mild edema in the nerve fiber layer, which is characterized by loose tissue and obvious vacuoles.
  • the number of cells in one rabbit ganglion cell layer was reduced, and a small number of nuclear condensed cells were observed.
  • Two other ganglion cell layers showed a small number of nuclear condensed cells.
  • the inner nuclear layer there were 3 rabbit retinal inner nuclear cells with a slight decrease in the number of cells and 2 mild edema.
  • each layer of the retina was clear, and no obvious lesions were found in the ganglion cell layer.
  • the nerve fiber layer has a slight edema of a rabbit retinal nerve fiber layer.
  • the ganglion cell layer there are three rabbit ganglion cell layers with a few nuclear condensed cells. No obvious lesions were seen in the inner nuclear layer, outer nuclear layer and other layers.
  • This experiment used 5% Bengal red ear vein injection, laser irradiation of the eye model, the model group rabbit retinopathy mainly showed nerve fiber layer or inner layer edema, nuclear pyknosis cells, the number of cells in the inner layer decreased.
  • Panax notoginseng saponin eye drops are safe for rabbit eyes, and have a healing effect on eye and vision damage caused by dry eyes, pain, eye fatigue and ocular hardening of the eyes.

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Abstract

一种眼用药物制剂，该药物制剂的有效成分为三七皂苷提取物，其中三七皂苷提取物中含有含量总和为45～95％的三七皂苷R1、三七皂苷R2、人参皂苷Rg1、人参皂苷Rg2、人参皂苷Re、人参皂苷Rb1、人参皂苷Rb2、人参皂苷Rd、人参皂苷Rf、人参皂苷Rc、人参皂苷Rh1和七叶胆苷Ⅸ。所述药物制剂对眼干涩胀痛、视疲劳及眼部血管硬化对眼睛及视力造成的损伤有治愈作用。

Description

眼用药物制剂及其应用 技术领域
本发明属于药物技术，具体涉及一种防治眼部疲劳、眼干涩胀痛、眼部血管硬化的药物制剂及其应用。
背景技术
随着社会的进步，互联网的通畅，办公无纸化、智能手机和电视等屏幕产品的普及与广泛应用，人们的工作、学习、生活方式已经改变，眼不离屏已成为了一种基本习惯。长期用眼近距离对着不断闪烁的屏幕，眼睫状肌长时收缩得不到放松，容易引起眼睛干涩、涨痛、视疲劳及眼部血管硬化等症，对眼睛及视力造成损伤。
三七味甘、微苦，性温。具有活血散淤、消肿定痛、止血疗伤的功效。现代科学证明三七中含有人参皂苷和三七皂苷类成分，能明显缩短出血和凝血时间，具有良好的止血功效；能促进各类血细胞分裂生长、增加数目，促进骨髓细胞增殖和释放过程，增加骨髓红细胞的数量和活性，达到促进造血的功能；能显著抑制实验性动脉粥样硬化家兔的主动脉内膜斑块形成；能兴奋中枢神经，提高脑力和体力，表现出抗疲劳性；能显著提高小鼠的巨噬细胞的吞噬率和吞噬指数，提高外围血中白细胞总数，减少白细胞的移动指数；能对急性炎症引起的毛细血管通透性增加、炎性渗出、组织水肿、白细胞游走以及后期肉芽组织增生均有明显的抑制作用；能减少机体内脂质过氧化物，具有抗衰老作用。三七的多种药理活性被用于各类心脑血管疾病的治疗，其提取物被制成“血塞通”、“冠心宁”和“血栓通”等药物上市，在跌打损伤类药物中，也广泛应用三七的活血散淤功效，使劳损肌肉组织得到康复。然而一直没有一款针对眼睫状肌疲劳、视疲劳等眼部问题的三七产品问市。
中国专利公开了许多针对视疲劳的专利，其中许多都使用了三七进行组方配制，如专利CN103099977B，公布了“一种眼科外用药物组合物及其在治疗葡萄膜炎中的应用”的发明，其组合物由吡美莫司滴眼液、三七人参皂苷Rb1、连翘提取物水溶液、白茅提取物水溶液制成的滴眼液，用于眼科治疗葡萄膜炎；专利CN103520548B，公布了“一种改善视疲劳药物组合物及其制备方法”的发明，其 组合物由枸杞、决明子、巴戟天、甘草、三七、葛根、淡竹叶、佛手等制成的口服制剂，作为改善视疲劳的药物；专利申请CN102960713A，公开了一种“防治屏幕污染的保健品”的发明，其组合物由赤小豆、竹荪、三七、西洋参、猪肝、金菊花、丹皮、生地、枸杞、茯苓、山楂、富硒绿茶、黄芪和桑堪制备的口服制剂，用于消除各种电子产品给人体造成的污染，防治电子屏幕对人体眼睛、造血功能、神经及免疫系统的损害等。目前，未见使用三七皂苷用于防治眼部疲劳、眼干涩胀痛、眼部血管硬化的药物制剂及其新剂型。
发明内容
本发明的目的在于提供一种防治视疲劳、眼干涩胀痛、眼部血管硬化的眼用药物制剂及其制备方法与应用。
为了实现本发明的上述目的，本发明提供了如下技术方案：
一种眼用药物制剂，其有效成分为三七皂苷提取物。所述三七皂苷提取物由三七制备提取所得。
其中，所述三七皂苷提取物中含有含量总和为45～95％的下列成分：三七皂苷R1、三七皂苷R2、人参皂苷Rg1、人参皂苷Rg2、人参皂苷Re、人参皂苷Rb1、人参皂苷Rb2、人参皂苷Rd、人参皂苷Rf、人参皂苷Rc、人参皂苷Rh1和七叶胆苷Ⅸ。
进一步优选的，所述三七皂苷提取物中含有含量总和为75～90％的以下成分：三七皂苷R1、人参皂苷Rg1、人参皂苷Re、人参皂苷Rb1和人参皂苷Rd。
进一步的，所述三七皂苷提取物中，三七皂苷R1(C 47H 80O 18)含量为3.0％以上、人参皂苷Rg1(C 42H 72O 14)含量为15.0％以上、人参皂苷Re(C 48H 82O 18)含量为1.0％以上、人参皂苷Rb1(C 54H 92O 23)含量为20.0％以上、人参皂苷Rd(C 48H 82O 19)含量为2.5％以上。
更进一步的，所述三七皂苷提取物中，三七皂苷R1(C 47H 80O 18)含量为5.0％以上、人参皂苷Rg1(C 42H 72O 14)含量为25.0％以上、人参皂苷Re(C 48H 82O 18)含量为2.5％以上、人参皂苷Rb1(C 54H 92O 23)含量为30.0％以上、人参皂苷Rd(C 48H 82O 19)含量为5％以上。
作为一个优选方案，所述药物制剂中三七皂苷提取物的质量百分含量为0.1～30％。
进一步的，所述药物制剂中三七皂苷提取物的质量百分含量为0.2～10％。
所述制剂的剂型为洗眼剂、滴眼剂、眼用软膏或眼用贴剂。其中的贴剂可以是将制成的眼药水、眼药膏浸渍或负载在薄膜材料上制成。
作为另一个优选方案，所述药物制剂中的三七皂苷提取物为唯一有效成分，并且由0.1～30％重量的三七皂苷提取物和70～99.9％重量的药学上可接受的载体和/或辅料制备而成。进一步的，由0.2～10％重量的三七皂苷提取物和90～99.8％重量的药学上可接受的载体和/或辅料制备而成。
其中，所述药学上可接受的载体选自水、生理盐水、凡士林、液体石蜡、羊毛脂、甘油中的一种或几种。
作为又一个优选方案，所述药物制剂为：将有效成分三七皂苷提取物加入到人工泪液或具有治疗作用的各类滴眼液药品中即可。其中，所述人工泪液为本领域技术人员所公知的，可以由葡萄糖酐-70、聚乙二醇400、羧甲基纤维索钠滴眼液、维生素A、卡波姆山梨酸、透明质酸钠、聚乙烯醇等中的一种或几种构成。
其中，所述具有治疗作用的各类滴眼液药品为市售购买获取。
上述药物制剂在制备防治视疲劳、眼干涩胀痛、眼部血管硬化的药物中的应用也在本发明的保护范围内。
有益效果：本发明应用了三七具有的活血散淤、消肿定痛功能，制成专门针对眼部疾患用药的剂型，药理实验证明该药物安全有效无刺激，对眼睛干涩、胀痛、视疲劳及眼部血管硬化等对眼睛及视力造成的损伤有治愈作用，具有较好的临床应用前景。
具体实施方式
下面结合具体实施例对本申请作出详细说明。
实施例1
三七皂苷提取物的制备1
称取三七20公斤，湿法粉碎成粗粉，分别用重量比1:10、1:8、1:8的60％乙醇回流提取3次，每次3小时，收集提取液，滤过。取滤液回收乙醇至无醇味，加水制成每1ml含0.5～1.0g生药的溶液，上大孔吸附树脂柱，分别用水、70％～90％乙醇液洗脱，收集80％乙醇洗脱液，浓缩，干燥，得三七皂苷提取物。
按中国药典一部三七总皂苷含量测定方法，测得各组分含量为三七皂苷R1(C 47H 80O 18)：6.2％、人参皂苷Rg1(C 42H 72O 14)：28.4％、人参皂苷Re(C 48H 82O 18)： 3.1％、人参皂苷Rb1(C 54H 92O 23)：32.7％，人参皂苷Rd(C 48H 82O 19)：5.8％。
实施例2
三七皂苷提取物的制备2
称取三七20公斤，湿法粉碎成粗粉，分别用重量比1:10、1:8、1:8的70％乙醇回流提取3次，每次3小时，收集提取液，滤过。取滤液回收乙醇至无醇味，加水制成每1ml含0.5～1.0g生药的溶液，上大孔吸附树脂柱，分别用水、70％～90％乙醇液洗脱，收集80％乙醇洗脱液，浓缩，干燥，得三七皂苷提取物。
按中国药典一部三七总皂苷含量测定方法，测得各组分含量为三七皂苷R1(C 47H 80O 18)：8.3％、人参皂苷Rg1(C 42H 72O 14)：31.4％、人参皂苷Re(C 48H 82O 18)：7.1％、人参皂苷Rb1(C 54H 92O 23)：34.7％，人参皂苷Rd(C 48H 82O 19)：6.8％。
实施例3
三七皂苷提取物的制备3
称取三七20公斤，湿法粉碎成粗粉，分别用重量比1:10、1:8、1:8的80％乙醇回流提取3次，每次3小时，收集提取液，滤过。取滤液回收乙醇至无醇味，加水制成每1ml含0.5～1.0g生药的溶液，上大孔吸附树脂柱，分别用水、70％～90％乙醇液洗脱，收集80％乙醇洗脱液，浓缩，干燥，得三七皂苷提取物。
按中国药典一部三七总皂苷含量测定方法，测得各组分含量为三七皂苷R1(C 47H 80O 18)：5.5％、人参皂苷Rg1(C 42H 72O 14)：31.9％、人参皂苷Re(C 48H 82O 18)：4.2％、人参皂苷Rb1(C 54H 92O 23)：34.9％，人参皂苷Rd(C 48H 82O 19)：6.2％。
实施例4
三七皂苷滴眼液
取实施例1制备所得三七皂苷提取物100克，溶于300毫升生理盐水，加0.3克活性碳，搅拌、静置8小时、过滤、0.22μm膜精滤，稀释定容至1000毫升，密封，高温灭菌，分装至滴眼瓶，每瓶1毫升，得1000只滴眼液。
实施例5
三七皂苷眼贴
取实例4制得的滴眼液，浸润100平方厘米的无纺布，得三七皂苷眼贴。
实施例6
三七皂苷眼膏
取医用黄凡士林、甘油、羊毛脂，按8:2:1比例混合均匀，制成眼药膏基质。取3000克基质，加入实施例1制备所得三七皂苷30克，混匀，得到三七皂苷眼药膏，无菌分装，每支3克，得1000支。
实施例7
三七皂苷水凝胶
取2％卡波姆凝胶30克，甘油5克，透明质酸0.5克，纯净水45克，混均，然后加入实施例1制备所得三七皂苷提取物20克，尼泊金乙酯0.1克，用均质机搅拌均匀，真空除气泡，装瓶，即得。
实施例8
三七皂苷人工泪液
取每毫升含聚乙烯醇15毫克无菌溶液80克，加入每毫升含三七皂苷50毫克无菌溶液20克，混均，滤过，即得。
实施例9
精密称取实施例1制备所得三七皂苷提取物20.0克，加纯净水980.0克，配制成浓度为2％的溶液，即得眼药水，然后用无纺布浸渍该溶液后，贴在眼框处，可缓解眼部疲劳，及眼睛的酸胀感。
实施例10
取实施例9配制的眼药水与人工泪液1:1混合，滴入眼睛，可消除眼干涩胀痛、眼部血管硬化引起的不适。其中，人工泪液由葡萄糖酐-70、聚乙二醇400、羧甲基纤维索钠滴眼液、维生素A、卡波姆山梨酸、透明质酸钠、聚乙烯醇等中的一种或几种构成。
实施例11
取实施例9配制的眼药水与市售眼药水1:1混合，滴入眼睛，在治疗眼睛的各类痰症疾患时，亦可消除眼干涩胀痛、眼部血管硬化引起的不适。
实施例12
缓解视疲劳药物刺激性实验一
精密移取实施例1制备所得的三七皂苷提取物，加纯净水配制成不同浓度梯度溶液，即得试验用眼药水。
1.分组：每只兔子右眼给药(按照浓度梯度)，左眼给等量生理盐水。
给药方式：轻拉下眼睑，移液枪给药30微升，后闭合眼部五秒。
刺激性给药频率：一日九次，每隔1小时给一次。
共给药一天，最后一次给药1小时后观察，并记录观察结果。
分组标准为：共八只兔子，随机分为A和B组，每组四只，组内设置四个不同浓度进行实验。刺激性实验和药理实验同步进行，均为右眼给药，左眼为同剂量生理盐水做对照，观察的数据是在左眼对照的基础下进行的。评分标准参见Draize评分表，观察结果见表(一)。
兔刺激性实验评分表(一)
Figure PCTCN2018085962-appb-000001
注：表中记录均为与右眼空白对照后的左眼情况，得分三分及以下被认为没有刺激性。
2.待兔完全恢复，改变浓度梯度，按上述过程重复一次刺激性实验，观察结果见表(二)。
兔刺激性实验评分表(二)
Figure PCTCN2018085962-appb-000002
缓解视疲劳药物刺激性实验二
给药浓度：1.25％。
分组：每只兔子右眼给药，左眼给等量生理盐水。
给药方式：轻拉下眼睑，移液枪给药30微升，后闭合眼部五秒。
刺激性给药频率：一日九次，每隔1小时给一次。
共给药五天，每天最后一次给药1小时后观察，观察结果见表(三)。
兔刺激性实验评分表(三)
Figure PCTCN2018085962-appb-000003
上述刺激性实验结果表明，三七皂苷滴眼药物对兔眼是安全的，无毒无刺激作用。
实施例13
缓解视疲劳病理实验一
一、材料和方法：
(一)实验动物及分组：新西兰兔7只，分为3组，正常组2只兔(编号为A、B)，共四只眼球，剩余5只兔(编号为C、D、E、F、G)，左眼给予生理盐水为模型组，右眼给予三七总皂苷滴眼液为给药组。
(二)实验材料：孟加拉红，三七总皂苷提取物，生理盐水。
(三)送检脏器：兔眼球HE切片(送检样品为左眼在其编号后加L，若为右眼则加R，如AL指A兔的左眼)。
(四)检查方法：模型组与给药组兔5％孟加拉红耳缘静脉注射5ml，托吡卡胺滴眼作为扩瞳剂，普鲁卡因滴眼后作为局部麻醉剂，绿色激光(532nm)照射眼部造模，正常组不做处理。给药组使用浓度为1.25％三七总皂苷滴眼液(生理盐水溶解)滴眼一周，一日一次，每次35ul，模型组平行给予生理盐水。实验结束后剖取眼球，固定后取材，脱水，石蜡包埋，制片(4μm厚)，HE染色，在光学显微镜下观察视网膜各部位，检查有无病变及病变类型、程度。根据病变轻重程度，依次半定量为轻微(0.5分)，轻度(1分)，中度(2分)，重度(3分)，无病变组织为阴性(0分)。
缓解视疲劳病理实验二
实验动物及分组同实验一
(一)正常眼球4只，各层次结构清楚，无明显病变。光镜下视网膜有十层结构组成：从内向外依次为1)内界膜：为极薄的、无细胞的薄膜；2)神经纤维层：由神经节细胞的无髓鞘轴突组成，狭窄、薄层状；3)神经节细胞层：由神经节细胞的胞体组成，细胞互相连接，为单层细胞；4)内丛状层：为双极细胞的轴突和神经节细胞的树突，无明显细胞；5)内核层：由连接视锥细胞和视杆细胞的双极细胞构成，约为4层左右；6)外丛状层：视网膜细胞的足突、双极细胞的树突互相吻合而成，无明显细胞；7)外核层：视细胞的的细胞核所在地，约为8～10层细胞；8)～10)依次为外界膜，视细胞层，色素上皮层(兔无色素)。
(二)模型组(5只)：
视网膜各层结构清晰，神经纤维层有3只兔视网膜神经纤维层轻度水肿，表现为组织疏松、明显处形成空泡。神经节细胞层有1只兔神经节细胞层细胞数减 少，可见极少数核固缩细胞，另有2只兔神经节细胞层可见极少数核固缩细胞。内核层有3只兔视网膜内核层细胞数轻度减少，2只轻度水肿。
(三)给药组(5只)
视网膜各层结构清晰，神经节细胞层未见明显病变。神经纤维层有1只兔视网膜神经纤维层轻度水肿。神经节细胞层有3只兔神经节细胞层可见少数核固缩细胞。内核层、外核层及其它各层未见明显病变。
缓解视疲劳病理实验三
实验动物及分组同实验一
1.本实验用5％孟加拉红耳缘静脉注射，激光照射眼部造模，模型组兔视网膜病变主要表现为神经纤维层或内核层水肿，出现核固缩细胞，内核层细胞数减少。
2.药物应用后上述病变例数显著减少，程度显著减轻。说明药物是安全有效的。
视网膜病变病理检查表
Figure PCTCN2018085962-appb-000004
上述实验显示，三七总皂苷滴眼液对兔眼是安全的，对眼睛干涩、胀痛、视疲劳及眼部血管硬化等对眼睛及视力造成的损伤有治愈作用。

Claims (10)

  1. 一种眼用药物制剂，其特征在于，所述眼用药物制剂的有效成分为三七皂苷提取物。
  2. 根据权利要求1所述的眼用药物制剂，其特征在于，所述药物制剂中三七皂苷提取物的质量百分含量为0.1～30％。
  3. 根据权利要求2所述的眼用药物制剂，其特征在于，所述药物制剂中三七皂苷提取物的质量百分含量为0.2～10％。
  4. 根据权利要求1所述的眼用药物制剂，其特征在于，所述三七皂苷提取物为唯一有效成分，所述药物制剂由0.1～30％重量的三七皂苷提取物和70～99.9％重量的药学上可接受的载体和/或辅料制备而成。
  5. 根据权利要求1-4中任一所述的眼用药物制剂，其特征在于，所述三七皂苷提取物中含有含量总和为45～95％的下列成分：三七皂苷R1、三七皂苷R2、人参皂苷Rg1、人参皂苷Rg2、人参皂苷Re、人参皂苷Rb1、人参皂苷Rb2、人参皂苷Rd、人参皂苷Rf、人参皂苷Rc、人参皂苷Rh1和七叶胆苷Ⅸ。
  6. 根据权利要求5所述的眼用药物制剂，其特征在于，所述三七皂苷提取物中含有含量总和为75～90％的以下成分：三七皂苷R1、三七皂苷R2、人参皂苷Rg1、人参皂苷Rg2、人参皂苷Re、人参皂苷Rb1、人参皂苷Rb2、人参皂苷Rd、人参皂苷Rf、人参皂苷Rc、人参皂苷Rh1和七叶胆苷Ⅸ。
  7. 根据权利要求1-4中任一所述的眼用药物制剂，其特征在于，所述三七皂苷提取物中，三七皂苷R1含量为3.0％以上、人参皂苷Rg1含量为15.0％以上、人参皂苷Re含量为1.0％以上、人参皂苷Rb1含量为20.0％以上、人参皂苷Rd含量为2.5％以上。
  8. 根据权利要求7所述的眼用药物制剂，其特征在于，所述三七皂苷提取物中，三七皂苷R1含量为5.0％以上、人参皂苷Rg1含量为25.0％以上、人参皂苷Re含量为2.5％以上、人参皂苷Rb1含量为30.0％以上、人参皂苷Rd含量为5％以上。
  9. 根据权利要求1所述药物制剂，其特征在于，将有效成分三七皂苷提取物加入到人工泪液或具有治疗作用的各类滴眼液药品中即可。
  10. 权利要求1所述药物制剂在制备防治视疲劳、眼干涩胀痛、眼部血管硬化的药物中的应用。
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CN107898816A (zh) * 2017-12-04 2018-04-13 中国药科大学 眼用药物制剂及其应用
CN108451963A (zh) * 2018-05-14 2018-08-28 孙水 一种治疗角膜炎的滴眼液
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