WO2020238621A1 - 三七皂苷提取物在制备眼用药物制剂中的应用 - Google Patents

三七皂苷提取物在制备眼用药物制剂中的应用 Download PDF

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WO2020238621A1
WO2020238621A1 PCT/CN2020/089935 CN2020089935W WO2020238621A1 WO 2020238621 A1 WO2020238621 A1 WO 2020238621A1 CN 2020089935 W CN2020089935 W CN 2020089935W WO 2020238621 A1 WO2020238621 A1 WO 2020238621A1
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ginsenoside
ocular
notoginsenoside
extract
ophthalmic
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PCT/CN2020/089935
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English (en)
French (fr)
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王真
谭宁华
唐锴
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中国药科大学
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Priority to JP2021569926A priority Critical patent/JP2022525254A/ja
Publication of WO2020238621A1 publication Critical patent/WO2020238621A1/zh

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    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • 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
    • 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
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the invention belongs to natural medicine technology, and particularly relates to the application of a notoginsenoside extract in the preparation of ophthalmic pharmaceutical preparations.
  • ginsenosides and notoginsenosides can significantly reduce platelet surface activity, inhibit platelet adhesion and aggregation, achieve anti-thrombosis, improve microcirculation, etc.; it can reduce serum IL-8 levels after ischemia and reperfusion.
  • Produce and release block the activation, infiltration and aggregation of neutrophils, reduce the inflammatory response of ischemic tissues, and protect against ischemia-reperfusion injury; it can enhance the positive expression of GluR2 and inhibit the transcription of caspase-3 mRNA and caspase- 3 Protein lysis and activation, promote the transcription of bcl-2mRNA and the expression of Bcl-2 protein, reduce cell apoptosis, promote neuron survival and damage repair; can significantly shorten the bleeding and clotting time, have good hemostatic effect; can significantly Inhibit the formation of intima plaques in the aorta of experimental atherosclerotic rabbits; it can significantly increase capillary permeability, inflammatory exudation, tissue edema, leukocyte migration and late granulation tissue hyperplasia caused by acute inflammation It can inhibit the high secretion of MMP-1 in fibroblasts induced by UV, promote the expression of vascular endothelial growth factor and basic fibroblast growth factor, and promote
  • Injections have high safety risks; and national adverse drug reaction testing
  • the center receives a large number of relevant adverse reactions reports every year, including systemic damage: fever, chills, allergic reactions, anaphylactic shock, etc.; respiratory system damage: chest tightness, dyspnea, shortness of breath, asthma, throat edema, etc.; skin and Its accessory damage: skin rash, itching, deprivation dermatitis, etc.; heart rate and heart rhythm disorders: palpitations, tachycardia, etc.; central and peripheral nervous system damage: dizziness, headache, convulsions, tremors, etc.; gastrointestinal system damage: nausea, vomiting, etc.
  • Civascular system damage cyanosis, flushing, blood pressure drop, blood pressure increase, etc.; other damages include hematuria, abnormal liver function, etc.
  • Chinese patent CN102688479B discloses an eye patch with polyglutamic acid and cell growth factor as the main active ingredients can prevent dry eye
  • Chinese patent CN102512433B discloses a luteolin glucuronide for the treatment of retinal vein occlusion
  • the Chinese patent discloses a patent of this type of natural product for asthenopia, namely patent CN107898816A, which publishes "Ophthalmic Pharmaceutical Preparations and Their Applications", the composition of which is notoginsenoside R1, notoginsenoside R2, and ginsenoside Rg1 , Ginsenoside Rg2, ginsenoside Re, ginsenoside Rb1, ginsenoside Rb2, ginsenoside Rd, ginsenoside Rf, ginsenoside Rc, ginsenoside Rh1 and esc
  • the dry eye ocular trauma, ocular vascular disease or ocular neurological disease, including but not limited to dry eye, retinal degenerative disease, retinal vein occlusion, retinal vein inflammation, anterior chamber hemorrhage, Vitreous hemorrhage, corneal injury, retinal contusion, glaucomatous optic atrophy, drusen, age-related macular degeneration, and diabetic retinopathy.
  • the dry eye especially refers to those dry eye with excessive evaporation (lacrimia dry eye), but the present invention has a relieving effect on the symptoms of dry eye surface caused by all diseases.
  • the ocular trauma especially refers to anterior chamber hemorrhage and vitreous hemorrhage caused by various reasons, including but not limited to corneal contusion, scleral contusion, retinal concussion and contusion, choroidal rupture, ocular chemical injury, and ocular thermal burn And radiation eye damage.
  • the ocular vascular diseases especially refer to those retinal vein occlusion and diabetic retinopathy, including but not limited to retinal artery occlusion and periretinal venous inflammation (retinal vasculitis).
  • the ocular neurological diseases especially refer to those glaucomatous optic nerve atrophy, including but not limited to retinal degeneration, various chorioretinopathy (central serous chorioretinopathy) and age-related macular degeneration.
  • the notoginsenoside extract can inhibit ocular thrombosis, improve ocular microcirculation, inhibit ocular nerve cell apoptosis, stop bleeding, and promote ocular wound tissue healing.
  • the dosage forms of the drugs described in this application include ophthalmic solutions, ophthalmic gels, ophthalmic ointments, eye lotions or intraocular injections.
  • the compounds of the present invention can be administered topically to the eye, for example, topically, subconjunctival, retrobulbar, periocular, subretinal, suprachoroidal, or intraocular administration.
  • compositions that are particularly useful for direct application to the eye include aqueous solutions and/or suspensions formulated as eye drops and thickened solutions and/or suspensions formulated as ophthalmic gels (including gel-forming solutions) or ointments, It includes ophthalmic solutions, ophthalmic ointments, eye lotions, intraocular injections, and ophthalmic gels.
  • Other dosage forms used for ophthalmic drug delivery include ocular inserts, intravitreal injections, and implants. Injectable solutions can be injected directly into the cornea, lens, and vitreous or adjacent tissues using fine needles.
  • the application also discloses the application of the notoginsenoside extract in combination with other therapeutic ophthalmic preparations in the preparation of drugs for preventing and treating dry eye syndrome, ocular trauma, ocular vascular diseases or ocular neurological diseases.
  • ophthalmic preparations include, but are not limited to, anti-infective ingredients, anti-inflammatory drugs, anti-allergic drugs (including antihistamines), artificial tear vasoconstrictors, vasodilators, local anesthetics, analgesics, intraocular pressure lowering agents, immunomodulators Agents, antioxidants, vitamins and minerals, enzyme inhibitors and peptidases, cytokine inhibitors, etc.
  • the eye treatment agent that can be used in combination is selected from Acular (ketorolac tromethamine ophthalmic solution) 0.5%, Acuvail (ketorolac tromethamine), AK-Con -A (naphazoline eye drops), Akten (lidocaine hydrochloride), Alamast, Alphagan (brimonidine), Alrex, Astepro (azelastine hydrochloride nasal spray), AzaSite (azithromycin), Bepreve (benzene Bepotastine Sulfonate Ophthalmic Solution), Besivance (Besifloxacin Ophthalmic Suspension), Betaxon, BSS Sterile Lavage Solution, Cosopt, Durezol (Difluprednate), Eylea (Aflibercept), Lotemax, Lucentis (Ranibizumab), Lumigan (Bimatoprost ophthalmic solution), Macugen (Pigatanib), Ocuflox (ofloxacin ophthalmic solution) 0.3%
  • the "effective amount" of the ophthalmic pharmaceutical composition of this type of natural product is the amount that inhibits, prevents or reverses the various ophthalmic diseases in the individual.
  • the ophthalmic pharmaceutical composition of the present invention is administered to a subject in need in an effective amount for treating visual disorders.
  • "therapeutically effective amount” means a dose that reduces at least one of the signs, symptoms, or causes of the various ophthalmic diseases in an individual or any other desired changes in the biological system.
  • prophylactically effective dose means a dose administered to patients who are susceptible to or at risk of a specific disease, and it may be the same or different dose as the therapeutically effective dose.
  • the effective amount of the composition for a particular individual may depend on the individual, the severity of the individual's condition, the type of formulation applied, the frequency of administration, and the duration of treatment. According to the present invention, even if the ophthalmic pharmaceutical preparation of the present invention is administered at a relatively low concentration in liquid drops, for example, any concentration within 10 -9 M to 103 M, it can be administered only once, twice, Apply three or more times to reverse such visual impairment and proceed so quickly.
  • the notoginsenoside extract is selected from notoginsenoside R1, notoginsenoside R2, ginsenoside Rg1, ginsenoside Rg2, ginsenoside Re, ginsenoside Rb1, ginsenoside Rb2, ginsenoside Rd, ginsenoside Rf, One or more of ginsenoside Rc, ginsenoside Rh1 and esculin IX.
  • the panax notoginsenoside extract contains the following components with a total content of 60-90%: notoginsenoside R1, notoginsenoside R2, ginsenoside Rg1, ginsenoside Rg2, ginsenoside Re, ginsenoside Rb1, ginseng Saponins Rb2, ginsenoside Rd, ginsenoside Rf, ginsenoside Rc, ginsenoside Rh1 and aescin IX.
  • the content of notoginsenoside R1 is more than 3.0%, the content of ginsenoside Rg1 is more than 20.0%, the content of ginsenoside Re is more than 1.5%, and the content of ginsenoside Rb1 is more than 25.0%, The content of ginsenoside Rd is more than 2.5%.
  • Panax notoginseng saponins extract include but are not limited to Panax notoginseng, Panax ginseng and the like. Among them, Panax notoginseng is selected from the dried roots, rhizomes, stems, flowers and fruits of Panax notoginseng (Burk.) F.H Chen.
  • the medicine can use notoginsenoside extract as the only effective ingredient.
  • the mass percentage of the Panax notoginseng saponins extract is 0.02-30.0%, preferably 0.1%-10.0%, and the remaining 60.0-99.9% are pharmaceutically acceptable carriers and/or excipients.
  • the pharmaceutically acceptable carrier is water, buffer or sodium chloride solution. In some embodiments, the pharmaceutically acceptable carrier is sterile. In other embodiments, the pharmaceutically acceptable carrier is an ointment. In other embodiments, the pharmaceutically acceptable carrier is a gel. The gel can be formulated using gel formulation materials known in the art.
  • the notoginsenoside extract in the present invention can also be replaced with its corresponding pharmaceutically acceptable free acid, free base, salt (for example, acid or base addition salt), hydrate or prodrug, etc.
  • the "pharmaceutically acceptable salt” or “pharmaceutically acceptable acid” refers to a pharmaceutically acceptable organic or inorganic salt or acid of this type of natural product, respectively.
  • the counterion can be any organic or inorganic moiety that stabilizes the charge on the parent compound.
  • a pharmaceutically acceptable salt (or acid) may have more than one charged atom in its structure. Examples in which multiple charged atoms are part of a pharmaceutically acceptable salt (or acid) may have multiple counter ions. Therefore, a pharmaceutically acceptable salt (acid) may have one or more charged atoms and/or one or more counter ions.
  • compositions can also be prepared by dissolving the composition of the present invention in a suitable solvent.
  • suitable solvents include, but are not limited to, water, salt solutions (e.g., NaCl), buffer solutions, ointments, gels, or other solvents.
  • the aqueous solution and diluent for suspension used in the preparation of eye drops may include distilled water, physiological saline and the like.
  • compositions can be formulated in the following manner: according to conventional methods, the compound is optionally combined with appropriate pharmaceutical additives such as excipients, disintegrants, binders, lubricants, diluents, buffers, preservatives, wetting agents Agents, emulsifiers, dispersants, stabilizers and dissolution aids are mixed together, diluted or dissolved, and formulated in a conventional manner according to the dosage form.
  • Various additives may be included in eye drops, eye gels, and/or eye ointments as needed. These additives may include additional ingredients, additives, or carriers suitable for contact with or around the eyes without excessive toxicity, incompatibility, instability, irritation, allergies, etc.
  • Additives such as solvents, bases, cosolvents, suspending agents, thickeners, emulsifiers, stabilizers, buffers, isotonicity regulators, pH regulators, chelating agents, soothing agents, Preservatives, flavoring agents, flavoring agents, coloring agents, excipients, binders, lubricants, surfactants, absorption promoters, dispersants, preservatives, solubilizers, etc.
  • eye drops can be formulated by dissolving the compound in sterile water in which a surfactant is dissolved, and optionally adding appropriate pharmaceutical additives such as preservatives, stabilizers, buffers, antioxidants, and viscosity improvers.
  • a buffer is added to keep the pH constant, and the buffer may include a pharmaceutically acceptable buffer, such as borate buffer, citrate buffer, tartrate buffer, phosphate buffer, and the like.
  • an isotonic agent can also be added to the eye drops to prepare a preparation that is isotonic with tear fluid.
  • Isotonic agents include, but are not limited to, sugars, polyols, and salts.
  • the isotonic agent is added in such an amount that the osmotic pressure of the eye drops is equal to the osmotic pressure of tear fluid.
  • Preservatives may be added to maintain the integrity of the eye drops and/or ophthalmic ointment.
  • thickeners are used to increase the viscosity of ophthalmic formulations such as eye drops, ophthalmic gels, and/or ophthalmic ointments.
  • Eye drops, ophthalmic gels, and/or ophthalmic ointments may be prepared by aseptic operation, or alternatively, sterilized at an appropriate stage of preparation.
  • a sterile pharmaceutical composition can be prepared by aseptically mixing sterile ingredients.
  • the sterile pharmaceutical composition can be prepared by first mixing the ingredients and then sterilizing the final formulation. Sterilization methods may include, but are not limited to, heat sterilization, radiation, and filtration. Ophthalmic ointments (eye ointments) can be aseptically prepared by mixing the active ingredients into a base for preparing ophthalmic ointments, and then formulating them into pharmaceutical preparations by any method known in the art.
  • kits containing components that can be used to treat and/or prevent symptoms associated with various ophthalmic diseases Such a kit includes a container containing the natural product composition of the present invention in a pharmaceutically acceptable carrier, and the application of the natural product composition of the present invention is related to dry eye, ocular trauma, ocular vascular disease and ocular diseases. At least one symptom related to a neurological disease has been improved or prevented.
  • the container included in some of the kits referred to herein is a dropper for administering eye drops. In other embodiments, the container is a tube for dispensing ointment or gel.
  • the container is any suitable container for drug delivery, including but not limited to syringes or other containers suitable for ocular delivery or topical administration of drugs.
  • syringes or other containers suitable for ocular delivery or topical administration of drugs.
  • the present invention uses the activities of this type of natural product to resist thrombosis, improve microcirculation, promote neuron survival and damage repair, hemostasis and promote wound tissue healing, and make a dosage form specifically for ocular diseases.
  • Pharmacological experiments have proved that the drug has a healing effect on the damage to the eyes and vision caused by dry eye, ocular trauma, ocular vascular diseases and ocular neurological diseases.
  • the mode of local administration to the eye adopted by the present invention has many advantages such as low dose of useful drugs, high safety, few adverse reactions, and good patient compliance, avoiding safety risks caused by injection administration and changing the route of administration. Later, its metabolic pathways and mechanism of action are different from injections, and it has a good clinical application prospect.
  • Figure 1 is the optical microscopy result of Example 12, in which Figure 1a is the result of the retinal test, and Figure 1b is the result of the choroid test;
  • Fig. 2 is a statistical diagram of the drug of the present application for relieving dry eyes.
  • Poloxamer 188 to emulsify, add glycerin and propylene glycol and mix uniformly to make an eye ointment base. Take 3000 grams of the base, add 30 grams of this type of natural compound, and mix well to obtain this type of natural compound ophthalmic ointment, which is sterilely divided into 3 grams each to obtain 1,000.
  • the measured osmotic pressure is between 296.000-308.000 mOsm/l.
  • the administration group used this type of natural compound eye drops (dissolved in physiological saline) at a concentration of 1.25% for one week, once a day, 35 ⁇ l each time, and the model group was given physiological saline in parallel.
  • the eyeball was dissected, the material was taken after fixation, dehydrated, embedded in paraffin, prepared (4 ⁇ m thick), and stained with HE. Observe the retina and choroid under an optical microscope to check for lesions, type and degree of lesions.
  • the retention time of this type of natural compound eye drops on the ocular surface is more than five times that of normal saline, with high bioavailability, significantly increasing the stability of the tear film, and alleviating ocular surface dryness.
  • Trial personnel 45 people with equal male and female ratio, aged between 18 and 60 years old, who have not used eye preparations recently.
  • the trial users are divided into two groups, short-term trial group and long-term trial group, among which, short-term trial A group of 40 people, and a long-term trial group of 5 people.
  • Short-term trial group The trial users use this product after looking at the electronic product screen for a long time and feel uncomfortable, and fill in the questionnaire several times after the same interval.
  • the content includes whether it is comfortable to use, whether it is irritating, whether it improves visual fatigue, Are there any side effects, etc.
  • Long-term trial group According to the trial situation of the short-term trial group, the long-term trial group uses the product for a long time within one month, and follow-up follow-up to understand the effectiveness of the product and ensure the safety of the trial users.
  • Observed indicator symptoms blurred vision, eye muscle soreness, dry eye, abnormal discharge, eye burning, eye itching, foreign body sensation in the eye, tearing, etc.; items are described by scores, It is divided into 0-5 points, 0 is asymptomatic, 1-2 is mild symptoms, 3-4 is obvious symptoms, 5 is severe symptoms; the volunteer feedback information is analyzed by variance analysis, P ⁇ 0.05 For relief, P ⁇ 0.01 is significant relief.
  • Figure 2 is the statistics on the effect of applying the eye drops of this application to relieve the dryness of the eyes. According to the figure, it can be seen that after trying this type of natural compound eye drops for a period of time, it can significantly improve the dryness of the eyes.

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Abstract

本发明公开了三七皂苷提取物在制备防治干眼症、眼部外伤、眼部血管性疾病或眼部神经性疾病药物中的应用，所述干眼症、眼部外伤、眼部血管性疾病或眼部神经性疾病，包括但不限于干眼症、视网膜退行性病症、视网膜静脉阻塞、视网膜静脉周围炎、前房出血、玻璃体出血、角膜损伤、视网膜挫伤、青光眼性视神经萎缩、玻璃膜疣、年龄相关性黄斑变性和糖尿病视网膜病变。本发明采用的眼部局部给药的模式有用药剂量少，安全性高，不良反应少，患者顺应性好等诸多优势，避免了注射给药带来的安全风险，且改变给药途径后，其代谢途径、作用机制等方面均与注射剂不同，具有较好的临床应用前景。

Description

三七皂苷提取物在制备眼用药物制剂中的应用 技术领域
本发明属于天然药物技术，特别是涉及一种三七皂苷提取物在制备眼用药物制剂中的应用。
背景技术
目前用眼不当现象普遍存在，干眼症发病率增加；随着生活水平的提高，视网膜静脉阻塞、糖尿病性视网膜病变、脉络膜视网膜病变、年龄相关性黄斑病变、青光眼性视神经萎缩等致盲性疾病也严重困扰着中老年人的日常生活；前房出血与玻璃体出血等眼外伤虽然发病率不高，但其带来的疼痛感与急性反应也严重影响着患者的生活质量。
现代研究证明，人参皂苷和三七皂苷类成分，能显著降低血小板表面活性、抑制血小板黏附和聚集、达到抗血栓形成、改善微循环等作用；能通过降低缺血再灌注后血清IL-8的产生和释放，阻断中性粒细胞激活、浸润和聚集，减轻缺血组织的炎症反应，对缺血再灌注损伤有保护作用；能增强GluR2阳性表达，抑制caspase-3 mRNA的转录及caspase-3蛋白的裂解活化，促进bcl-2mRNA的转录与Bcl-2蛋白的表达，减少细胞凋亡，促进神经元的存活及损伤修复；能明显缩短出血和凝血时间，具有良好的止血功效；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，并能抑制UV诱导的成纤维细胞MMP-1高分泌，促进血管内皮生长因子与碱性成纤维生长因子的表达，促进创伤组织的愈合。
该类型天然产物的多种药理活性已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。然而一直没有一款针对眼部外伤、眼部血管性疾病与眼部神经性疾病等眼部问题的安全有效产品问市。血栓通、血塞通注射剂也在临床被广泛地用于治疗视网膜静脉栓塞，该类注射剂用药剂量大，疗程长(一个月)，注射给药存在较高的安全风险；且国家药品不良反应检测中心每年都会收到大量的有关不良反应报告，包括全身性损害：发热、寒战、过敏样反应、过敏性休克等；呼吸系统损害：胸闷、呼吸困难、呼吸急促、哮喘、喉水肿等；皮肤及其附件损害：皮疹、瘙痒、剥夺性皮炎等；心率及心律紊乱：心悸、心动过速等；中枢及外周神经系统损害：头晕、头痛、抽搐、震颤等；胃肠系统损害：恶心、呕吐等；心血管系统损害：紫绀、潮红、血压下降、血压升高等；其他损害包括血尿、肝功能异常等。中国专利CN102688479B公开了一种以多聚谷氨酸与细胞生长因子为主要有效成分的眼贴膜能预防干眼症；中国专利 CN102512433B公开了一种木犀草素葡萄糖醛酸苷用于治疗视网膜静脉阻塞的用途；中国专利公开了一个该类型天然产物针对视疲劳的专利，即专利CN107898816A，公布了“眼用药物制剂及其应用”，其组合物三七皂苷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等，用于缓解视疲劳有较好的效果；中国专利CN102813666A“三七皂苷R1在防治神经眼科疾病的药物中的应用”指出通过静脉注射的给药方式，单体化合物三七皂苷R1对许多眼部神经性疾病均有较好的治疗效果。目前，未见使用该类天然产物组合物通过眼部局部给药用于防治眼部外伤、眼部血管性疾病与眼部神经性疾病等的药物制剂及其新剂型。
发明内容
发明目的：针对上述现有技术，本申请提供了一种三七皂苷提取物在制备眼用药物制剂中的应用。
技术方案：本发明所述的三七皂苷提取物在制备防治干眼症、眼部外伤、眼部血管性疾病或眼部神经性疾病药物中的应用。
其中，所述干眼症、眼部外伤、眼部血管性疾病或眼部神经性疾病，包括但不限于干眼症、视网膜退行性病症、视网膜静脉阻塞、视网膜静脉周围炎、前房出血、玻璃体出血、角膜损伤、视网膜挫伤、青光眼性视神经萎缩、玻璃膜疣、年龄相关性黄斑变性和糖尿病视网膜病变。
所述干眼症尤其指那些蒸发过强型干眼症(泪液缺乏型干眼症)，但本发明对所有疾病带来的眼表干涩症状均有缓解作用。其中，所述的眼部外伤尤其指那些各种原因造成的前房出血与玻璃体出血，也包括但不限于角膜挫伤、巩膜挫伤、视网膜震荡与挫伤、脉络膜破裂、眼化学伤、眼部热烧伤与辐射性眼损伤。其中，所述的眼部血管性疾病尤其指那些视网膜静脉阻塞与糖尿病视网膜病变，也包括但不限于视网膜动脉阻塞与视网膜静脉周围炎(视网膜血管炎)。其中，所述的眼部神经性疾病尤其指那些青光眼性视神经萎缩，也包括但不限于视网膜退行变性、多种脉络膜视网膜病变(中心性浆液性脉络膜视网膜病变)与年龄相关性黄斑变性。
进一步的，所述三七皂苷提取物通过抑制眼部血栓形成，改善眼部微循环，抑制眼部神经细胞凋亡、止血与促进眼部创伤组织愈合。
本申请所述药物的剂型包括眼用溶液、眼用凝胶、眼用软膏、眼用洗剂或眼内注射剂。本发明的化合物可局部施用于眼，例如，局部、结膜下、眼球后、眼周、视网膜下、脉络膜上或眼内施用。对于直接施用于眼睛特别有用的药物组合物包括配制成滴眼剂的水溶液和/或悬浮液和配制成眼用凝胶(包括凝胶形成溶 液)或软膏的增稠溶液和/或悬浮液，其为眼用溶液、眼用软膏、眼用洗剂、眼内注射剂与眼用凝胶等。用于眼用药物递送的其他剂型包括眼用插入物(ocular insert)、玻璃体内注射剂和植入物。可注射溶液可使用细针直接注入角膜、晶状体和玻璃体或其临近组织中。
本申请还公开了所述三七皂苷提取物联合其他具有治疗作用的眼用制剂在制备防治干眼症、眼部外伤、眼部血管性疾病或眼部神经性疾病药物中的应用。
其他眼用制剂包括但不限于抗感染成分、消炎药、抗过敏药(包括抗组胺药)、人工泪液血管收缩剂、血管扩张剂、局部麻醉剂、镇痛药、眼压降低剂、免疫调节剂、抗氧化剂、维生素和矿物质、酶抑制剂和肽酶、细胞因子抑制剂等。
进一步的，所述可联合使用的眼部治疗剂选自安贺拉(Acular)(酮咯酸氨丁三醇眼用溶液)0.5％、Acuvail(酮咯酸氨丁三醇)、AK-Con-A(萘甲唑啉眼药)、Akten(盐酸利多卡因)、Alamast、Alphagan(溴莫尼定)、Alrex、Astepro(盐酸氮斯汀鼻喷雾剂)、AzaSite(阿奇霉素)、Bepreve(苯磺酸贝他斯汀眼用溶液)、Besivance(贝西沙星眼用悬浮液)、Betaxon、BSS无菌灌洗液、Cosopt、Durezol(二氟泼尼酯)、Eylea(阿柏西普)、Lotemax、Lucentis(雷珠单抗)、Lumigan(比马前列素眼用溶液)、Macugen(哌加他尼)、Ocuflox(氧氟沙星眼用溶液)0.3％、OcuHist、Ozurdex(地塞米松)、Quixin(左氧氟沙星)、Rescula(乌诺前列酮异丙基眼用溶液)0.15％、Restasis(环孢菌素眼用乳液)、Salagen片剂、Travatan(曲伏前列素眼用溶液)、Valcyte(盐酸缬更昔洛韦)、三氟胸苷(Viroptic)、Vistide(西多福韦)、Visudyne(注射用维替泊芬)、Vitrasert植入物、福米韦生注射剂、ZADITOR、Zioptan(他氟前列素眼用溶液)、Zirgan(更昔洛韦眼用凝胶)、Zymaxid(加替沙星眼用溶液)、阿托品、氟比洛芬、毒扁豆碱(Physostimine)、派立明(Azopt)、庆大霉素、匹鲁卡品(Proparacaine)、杆菌肽、羟丙甲纤维素眼液(Goniosol)、多粘菌素B、聚维酮碘(Betadine)、短杆菌肽、泼尼松龙、倍他洛尔、Humorsol、丙美卡因、倍他洛尔眼液(Betoptic)、Hylartin、Propine、布林佐胺、高渗NaCl、Puralube、BSS、吲哚菁绿(Indocycanine Green)、玫瑰红(Rose Bengal)、卡巴胆碱、伊曲康唑、透明质酸钠、头孢唑啉、拉坦前列素、舒洛芬、潇莱威(Celluvisc)、甘露糖醇、土霉素、氯霉素、醋甲唑胺、噻吗洛尔、Ciloxan、咪康唑、妥布霉素、环丙沙星、Miostat、曲安西龙、Cosopt、Muro 128、三氟尿苷、Demecarium、新霉素、托吡卡胺、地塞米松、甲醋唑胺(Neptazane)、Trusopt、地匹福林、Ocuflox、阿糖腺苷、多佐胺、氧氟沙星、Vira-A、肾上腺素、氧四环素、三氟胸苷、荧光素、苯肾上腺素和适利达(Xalatan)。
其中，抑制、预防或逆转功能障碍并不需要100％抑制、预防、消灭或逆转。 该类型天然产物的眼用药物组合物的“有效量”为抑制、预防或逆转个体所述多种眼科疾病的量。本发明的眼用药物组合物以治疗视觉障碍的有效量施用于有需要的受试者。如本文所用的，“治疗有效量”意指减轻个体所述多种眼科疾病的体征、症状或病因或任何其他所需生物系统改变中的至少一种的剂量。在预防性应用中，术语“预防有效量”意指施用于易患特定疾病或处于特定疾病风险下的患者的剂量，其可以是与治疗有效量相同或不同的剂量。用于特定个体的组合物的有效量可取决于个体、个体状况的严重程度、施加的制剂的类型、给药频率和治疗持续时间。根据本发明，本发明的眼用药物制剂即使在液体滴剂中以相对较低的浓度，例如10 -9M至10 3M内的任何浓度施用，也可以通过每日仅一次、两次、三次或多次施加来逆转这样的视觉障碍，并且如此快速地进行。
进一步的，所述三七皂苷提取物选自三七皂苷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中的一种或多种。
优选的，所述三七皂苷提取物中含有含量总和为60～90％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。
进一步优选的，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20.0％以上、人参皂苷Re含量为1.5％以上、人参皂苷Rb1含量为25.0％以上、人参皂苷Rd含量为2.5％以上。
所述三七皂苷提取物的药材来源包括但不限于三七、人参与西洋参等。其中三七选自中药五加科植物三七Panax notoginseng(Burk.)F.H Chen的干燥根、根茎、茎、花以及果。
所述药物可以以三七皂苷提取物作为唯一有效成分。其中，三七皂苷提取物的质量百分含量为0.02～30.0％，优选为0.1％-10.0％，其余60.0～99.9％为药学上可接受的载体和/或辅料。
所述药学上可接受的载体为水、缓冲液或氯化钠溶液。在一些实施方案中，该药学上可接受的载体是无菌的。在其他实施方案中，该药学上可接受的载体为软膏。在其他实施方案中，该药学上可接受的载体为凝胶。凝胶可以使用本领域公知的凝胶配制材料进行配制。
本发明中所述三七皂苷提取物还可以替换成其对应的药学上可接受的游离酸、游离碱、盐(例如，酸或碱加成盐)、水合物或前药等。所述“药学上可接受的盐”或“药学上可接受的酸”分别是指该类型天然产物药学上可接受的有机或无 机盐或酸。反荷离子可为稳定母体化合物上的电荷的任何有机或无机部分。此外，药学上可接受的盐(或酸)可在其结构中具有多于一个带电原子。多个带电原子为药学上可接受的盐(或酸)的一部分的实例可具有多个反荷离子。因此，药学上可接受的盐(酸)可具有一个或多个带电原子和/或一个或多个反荷离子。
也可以通过将本发明组合物溶解在适当的溶剂中来制备药物组合物。适当的溶剂包括但不限于水、盐溶液(例如，NaCl)、缓冲溶液、软膏、凝胶或其他溶剂。在制备滴眼剂中使用的用于悬浮液的水溶液和稀释剂可包括蒸馏水、生理盐水等。这些药物组合物可通过以下方式配制：根据常规方法将化合物任选地与适当的药物添加剂如赋形剂、崩解剂、粘合剂、润滑剂、稀释剂、缓冲剂、防腐剂、润湿剂、乳化剂、分散剂、稳定剂和溶解助剂一起混合、稀释或溶解，并根据剂型以常规方式配制。多种添加剂可根据需要被包含在滴眼剂、眼用凝胶和/或眼用软膏中。这些添加剂可包括适于接触眼或在眼周围使用而没有过度毒性、不相容性、不稳定性、刺激性、变态反应等的附加成分、添加剂或载体。可在适当情况下向制剂中加入添加剂如溶剂、基质、助溶剂、悬浮剂、增稠剂、乳化剂、稳定剂、缓冲剂、等渗性调节剂、pH调节剂、螯合剂、舒缓剂、防腐剂、矫味剂、调味剂、着色剂、赋形剂、粘合剂、润滑剂、表面活性剂、吸收促进剂、分散剂、防腐剂、增溶剂等。
例如，可通过将化合物溶解在溶有表面活性剂的无菌水中并任选地添加适当的药物添加剂如防腐剂、稳定剂、缓冲剂、抗氧化剂和粘度改善剂来配制滴眼剂。例如，添加缓冲剂以保持pH恒定，并且该缓冲剂可包括药学上可接受的缓冲剂，如硼酸盐缓冲液、柠檬酸盐缓冲液、酒石酸盐缓冲液、磷酸盐缓冲液等。除了缓冲液之外，还可以向滴眼剂中添加等渗剂以制备与泪液等渗的制剂。等渗剂包括但不限于糖类，多元醇，以及盐。以使滴眼剂的渗透压等于泪液渗透压的量添加等渗剂。可以添加防腐剂以维持滴眼剂和/或眼用软膏的完整性。在一些实施方案中，使用增稠剂来增加眼用制剂如滴眼剂、眼用凝胶和/或眼用软膏的粘度。滴眼剂、眼用凝胶和/或眼用软膏可通过无菌操作来制备，或者可替代地在制备的合适阶段进行灭菌。例如，无菌药物组合物可以通过无菌地混合无菌成分来制备。或者，该无菌药物组合物可通过先将成分混合随后将最终制剂灭菌来制备。灭菌方法可包括但不限于热灭菌、辐射和过滤。眼用软膏(眼膏)可通过将活性成分混合至用于制备眼膏的基质中，随后采用本领域已知的任何方法配制成药物制剂来无菌制备。
本发明的某些实施方案还涉及包含可用于治疗和/或预防与多种眼科疾病相关的症状的组分的试剂盒。这样的试剂盒包含含有在药学上可接受的载体中的本 发明天然产物组合物的容器，以及关于施用本发明天然产物组合物使得与干眼症、眼部外伤、眼部血管性疾病与眼部神经性疾病等相关的至少一种症状得到改善或预防的说明。包含在本文涉及的一些试剂盒中的容器是用于施用滴眼剂的滴管。在其他实施方案中，该容器是用于分配软膏或凝胶的管。在其他实施方案中，该容器是用于药物递送的任何合适的容器，包括但不限于注射器或适于药物的眼部递送或局部施用的其他容器。除非另有定义，本文使用的所有技术和科学术语均具有与本发明所属领域的普通技术人员通常所理解的含义相同的含义。虽然与本文所述的那些类似或等同的任何方法、装置和材料可用于本发明的实施或测试，但现在描述的是优选的方法、装置和材料。
有益效果：本发明应用了该类型天然产物具有的抗血栓形成、改善微循环、促进神经元的存活及损伤修复、止血与促进创伤组织愈合等活性，制成专门针对眼部疾患用药的剂型，药理实验证明该药物对干眼症、眼部外伤、眼部血管性疾病与眼部神经性疾病等对眼睛及视力造成的损伤有治愈作用。同时，本发明采用的眼部局部给药的模式有用药剂量少，安全性高，不良反应少，患者顺应性好等诸多优势，避免了注射给药带来的安全风险，且改变给药途径后，其代谢途径、作用机制等方面均与注射剂不同，具有较好的临床应用前景。
附图说明
图1是实施例十二的光学显微结果，其中图1a是视网膜试验结果，图1b是脉络膜试验结果；
图2是本申请药物缓解眼部干涩感的统计图示。
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。
实施例一
该类型天然化合物多剂量滴眼液(一)
取该类型天然化合物10克，溶于300毫升生理盐水，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10毫升，得100只滴眼液。
实施例二
该类型天然化合物多剂量滴眼液(二)
取该类型天然化合物5克，溶于300毫升生理盐水，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10毫升，得100只滴眼液。
实施例三
该类型天然化合物单剂量滴眼液(一)
取该类型天然化合物10克，溶于300毫升生理盐水，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0.4毫升，得25000只滴眼液。
实施例四
该类型天然化合物单剂量滴眼液(二)
取该类型天然化合物5克，溶于300毫升生理盐水，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0.4毫升，得25000只滴眼液。
实施例五
该类型天然化合物眼内注射剂(一)
取该类型天然化合物4克，溶于300毫升生理盐水，0.22μm膜精滤，稀释定容至1000毫升，分装至安瓿瓶，每瓶2毫升，密封，高温灭菌，得500只眼内注射剂。
实施例六
该类型天然化合物眼内注射剂(二)
取该类型天然化合物8克，溶于300毫升生理盐水，0.22μm膜精滤，稀释定容至1000毫升，分装至安瓿瓶，每瓶2毫升，密封，高温灭菌，得500只眼内注射剂。
实施例七
该类型天然化合物眼内注射剂(冻干)
取该类型天然化合物配制成冻干原液,除去热原，微滤后分装，灭菌，在-80℃冰箱预冻6h，冷冻干燥12h，即得该类型天然化合物眼内注射剂冻干粉针。
实施例八
该类型天然化合物眼内用眼膏
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，加入该类型天然化合物30克，混匀，得到该类型天然化合物眼药膏，无菌分装，每支3克，得1000支。
实施例九
该类型天然化合物外用眼霜
取泊洛沙姆188乳化，加入甘油、丙二醇混合均匀制成眼药膏基质。取3000克基质，加入该类型天然化合物30克，混匀，得到该类型天然化合物眼药膏，无菌分装，每支3克，得1000支。
实施例十
该类型天然化合物眼用洗剂
按照中国药典第四部洗剂规定，取该类型天然化合物20克，加注射用水配置的等渗溶液至1000毫升，搅匀，分装于100毫升盐水瓶中，加塞，铝盖封口，100℃流通蒸汽消毒30min即可。
实施例十一
渗透压测定
分别取上述实施例一到实施例七中产品，按照《中国药典》第四部0632规定，测得渗透压在296.000—308.000mOsm/l之间。
实施例十二
治疗视网膜静脉栓塞实验
(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，右眼给予该类型天然化合物滴眼液为给药组。
(二)实验材料：1％阿托品、2％普鲁卡因、该类型天然化合物滴眼液、生理盐水。
(三)送检脏器：兔眼底组织。
(四)检查方法：兔静脉或腹腔注射10％水合氯醛全麻，麻醉后，眼睑内滴注1％阿托品5μL扩瞳，15min后滴加2％普鲁卡因5μL进行角膜麻醉。静脉注射虎红20mg·kg-1,体积1mL·kg，1min后在手术前置镜与离体定位仪介导下进行冷激光照射视网膜静脉，制备视网膜静脉栓塞模型。正常组不做处理。给药组使用浓度为1.25％该类型天然化合物滴眼液(生理盐水溶解)滴眼一周，一日一次，每次35μl，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与脉络膜各部位，检查有无病变及病变类型、程度。
(五)检查结果：结果见图1a、图1b，根据图示可见，给药组内核层水肿消失、空泡减少，核固缩现象减轻；脉络膜血管内血栓块消失或变小。由此可见，本产品对实验性视网膜静脉栓塞有较好的治疗作用。
实施例十三
缓解干眼症实验一
(一)实验方法：荧光素钠标记法或泪液定性定量分析法(有条件下进行)初步表征本产品的眼部药代动行为。
(二)实验动物及分组：新西兰兔4只，分为4组，每只兔左右眼为一组(编 号为A、B、C、D),左眼给予生理盐水为模型组，右眼给予该类型天然化合物滴眼液为给药组。
(三)实验材料：该类型天然化合物滴眼液、生理盐水。
(四)实验过程：
Figure PCTCN2020089935-appb-000001
(五)检查方法：每组在相同多个时间段，在紫外灯下连续观测荧光层强弱。
(六)检查结果：
滞留时间 A B C D
左眼(生理盐水) 45秒 45秒 30秒 45秒
右眼(滴眼液) 4分45秒 5分30秒 5分30秒 4分30秒
根据上述统计可见，该类型天然化合物滴眼液眼表的滞留时间是生理盐水的五倍以上，生物利用度较高，显著增加泪膜稳定性，缓解眼表干燥。
实施例十四
缓解干眼症实验二
(一)实验方法：试用体验调查
(二)实验材料：该类型天然化合物滴眼液、珍视明滴眼液
(三)试用人员：男女比例均等、年龄在18～60岁之间、近期未曾使用眼部制剂45人，将试用者分为两组，分别为短期试用组及长期试用组，其中，短期试用组40人，长期试用组5人。
(四)实验过程：
1.短期试用组：试用者长期注视电子产品屏幕感到不适后使用本产品，在间隔相同时段后多次填写调查问卷，内容包括是否使用舒适度，是否有刺激感，是否对视疲劳有改善，是否有副作用等。
2.长期试用组：依据短期组试用者试用情况，长期组试用者在一个月内长期使用本产品，对其跟踪随访，了解本产品的有效性，保证试用者用药安全。
(五)试用者调查结果：
1、试用该类型天然化合物滴眼液后，干眼症缓解效果强，同时使用感和顺应性好，统计结果见下表：
评价中提到视疲劳症状有缓解的志愿者比例 91.67％
评价中提到视疲劳症状有显著缓解的志愿者比例 58.33％
愿意再次使用本产品的志愿者比例 87.50％
观测的指标症状：视物模糊感、眼部肌肉酸痛感、眼部干涩感、异样分泌物、眼部灼烧感、眼部瘙痒、眼部有异物感、流泪等；项目用评分进行描述，分为0‐5分，0分为无症状，1‐2分为有轻微症状，3‐4分为有明显症状，5分为出现严重症状；将志愿者反馈信息进行方差分析，P<0.05为有缓解，P<0.01为显著缓解。
2、图2为对适用者使用本申请滴眼液缓解眼部干涩感的效果统计，根据图示可见，试用该类型天然化合物滴眼液一段时间后，能够明显改善眼部干涩。

Claims (10)

  1. 三七皂苷提取物在制备防治干眼症、眼部外伤、眼部血管性疾病或眼部神经性疾病药物中的应用。
  2. 根据权利要求1所述的应用，其特征在于，所述干眼症、眼部外伤、眼部血管性疾病或眼部神经性疾病，包括但不限于干眼症、视网膜退行性病症、视网膜静脉阻塞、视网膜静脉周围炎、前房出血、玻璃体出血、角膜损伤、视网膜挫伤、青光眼性视神经萎缩、玻璃膜疣、年龄相关性黄斑变性和糖尿病视网膜病变。
  3. 根据权利要求1或2所述的应用，其特征在于，所述药物通过抑制眼部血栓形成，改善眼部微循环，抑制眼部神经细胞凋亡、止血与促进眼部创伤组织愈合，达到治疗目的。
  4. 根据权利要求1或2所述的应用，其特征在于，所述药物的剂型包括眼用溶液、眼用凝胶、眼用软膏、眼用洗剂或眼内注射剂。
  5. 三七皂苷提取物联合其他具有治疗作用的眼用制剂在制备防治干眼症、眼部外伤、眼部血管性疾病或眼部神经性疾病药物中的应用。
  6. 根据权利要求1或2所述的应用，其特征在于，所述三七皂苷提取物选自三七皂苷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中的一种或多种。
  7. 根据权利要求6所述的应用，其特征在于，所述三七皂苷提取物中含有含量总和为60～90％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。
  8. 根据权利要求6所述的应用，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20.0％以上、人参皂苷Re含量为1.5％以上、人参皂苷Rb1含量为25.0％以上、人参皂苷Rd含量为2.5％以上。
  9. 根据权利要求1或2所述的应用，其特征在于，所述三七皂苷提取物在所述药物中的质量百分含量为0.02～30.0％。
  10. 根据权利要求1或2所述的应用，其特征在于，所述药物以三七皂苷提取物作为唯一有效成分；其中，三七皂苷提取物的质量百分含量为0.1～40.0％，其余60.0～99.9％为药学上可接受的载体和/或辅料。
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