Restasis | 59865-13-3

• 物质功能分类: 生物化工 - 抑制剂 - 免疫抑制剂
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: Restasis
• 英文别名: 30-ethyl-33-(1-hydroxy-2-methylhex-4-enyl)-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone
• CAS: 59865-13-3
• 化学式: C₆₂H₁₁₁N₁₁O₁₂
• 分子量: 1202.6
• InChiKey: PMATZTZNYRCHOR-UHFFFAOYSA-N

物化性质

• 熔点：
  148-151°C
• 比旋光度：
  D20 -244° (c = 0.6 in chloroform); D20 -189° (c = 0.5 in methanol)
• 沸点：
  838.63°C (rough estimate)
• 密度：
  0.9913 (rough estimate)
• 闪点：
  87℃
• 溶解度：
  乙醇：30 mg/mL
• 物理描述：
  Cyclosporin a appears as white prismatic needles (from acetone) or white powder. (NTP, 1992)
• 颜色/状态：
  Forms white prismatic crystals from acetone
• 旋光度：
  Optical rotation: -244 degrees @ 20 °C (c = 0.6 in chloroform), - 189 degrees @ 20 °C (c = 0.5 in methanol)
• 分解：
  When heated to decomposition it emits toxic fumes of /nitrogen oxides/.
• 稳定性/保质期：
  从-15℃的丙酮中可获得白色针状结晶，熔点为148～151℃，[α]D20值为-244°（在氯仿中的浓度为0.6）。该物质能溶于甲醇、乙醇、丙酮、乙醚或氯仿，并且微溶于水及饱和碳氢化合物。急性毒性实验显示，小鼠、大鼠和兔子通过静脉注射的LD50值分别为107、25和＞10（单位：mg/kg），而口服的LD50值则分别是2329、1480和＞1000（单位：mg/kg）。

计算性质

• 辛醇/水分配系数(LogP)：
  7.5
• 重原子数：
  85
• 可旋转键数：
  15
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  279
• 氢给体数：
  5
• 氢受体数：
  12

ADMET

代谢

环孢素在肝脏中通过细胞色素P450 3A（CYP3A）酶系统进行广泛代谢，在一定程度上也会通过胃肠道和肾脏代谢。在人的胆汁、粪便、血液和尿液中已经鉴定出至少25种代谢物。尽管环孢素的环状肽结构对代谢相对抵抗，但侧链被广泛代谢。所有的代谢物与母药相比，生物活性和毒性都降低了。

Cyclosporine is extensively metabolized in the liver by the cytochrome-P450 3A (CYP3A) enzyme system & to a lesser degree by the GI tract & kidneys. At least 25 metabolites have been identified in human bile, feces, blood, & urine. Although the cyclic peptide structure of cyclosporine is relatively resistant to metab, the side chains are extensively metabolized. All of the metabolites have both reduced biological activity & toxicity compared to the parent drug.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

在几项大型临床试验中，环孢素治疗的开始与血清胆红素水平的轻度升高有关，通常不伴有血清ALT或碱性磷酸酶的显著增加。血清酶的升高也有描述，但较少见。最近，这些并发症似乎较为少见，这可能是由于更谨慎的剂量控制和环孢素水平的监测。此外，在治疗没有移植许多并发症的自身免疫疾病时，环孢素治疗与高达30%的患者出现轻度血清碱性磷酸酶升高有关，但这些异常是无症状的，通常是自限性的，很少需要调整剂量。在一些病例系列中，环孢素治疗也与胆泥和胆石症有关。有临床明显的急性肝损伤的孤立病例报告归因于环孢素。发病时间在开始使用环孢素后的几周内，血清酶升高的模式是胆汁淤积。一旦停止使用环孢素，恢复迅速，尚未有因环孢素引起的慢性肝炎或急性肝衰竭的报道。

In several large clinical trials, initiation of cyclosporine therapy was associated with mild elevations in serum bilirubin levels, often without significant increases in serum ALT or alkaline phosphatase. Elevations in serum enzymes were also described, but less commonly. Recently, these complications appear to be less frequent, perhaps because of more careful dosing and monitoring of cyclosporine levels. Furthermore, in treatment of autoimmune diseases without the many complications of transplantation, cyclosporine therapy has been associated with mild serum alkaline phosphatase elevations in up to 30% of patients, but the abnormalities are asymptomatic, usually self-limiting and rarely require dose adjustment. In several case series, cyclosporine therapy has also been associated with biliary sludge and cholelithiasis. Isolated case reports of clinically apparent acute liver injury have been attributed to cyclosporine. The time to onset was within a few weeks of starting cyclosporine and the pattern of serum enzyme elevations was cholestatic. Recovery was prompt once cyclosporine was stopped and cases of chronic hepatitis or acute liver failure due to cyclosporine have not been reported.

来源:LiverTox

毒理性

• 致癌性证据

环孢菌素A：已知是一种人类致癌物。

Cyclosporin A: known to be a human carcinogen.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌物分类

国际癌症研究机构致癌物：环孢素

IARC Carcinogenic Agent:Cyclosporine

来源:International Agency for Research on Cancer (IARC)

毒理性

• 致癌物分类

国际癌症研究机构（IARC）致癌物分类：1类：对人类致癌

IARC Carcinogenic Classes:Group 1: Carcinogenic to humans

来源:International Agency for Research on Cancer (IARC)

毒理性

• 致癌物分类

国际癌症研究机构专论集：第50卷：（1990年）药物

IARC Monographs:Volume 50: (1990) Pharmaceutical Drugs

来源:International Agency for Research on Cancer (IARC)

吸收、分配和排泄

环孢素口服给药后，血药浓度达到峰值的时间为1.5-2.0小时。与食物同服会延迟并减少吸收。在给药后30分钟内摄入高脂肪和低脂肪餐分别会使曲线下面积（AUC）减少约13%，最大浓度减少33%。这使得对门诊病人进行个体化剂量方案变得至关重要。环孢素在血管外分布广泛。静脉给药后，稳态分布体积在实体器官移植受者中据报道可高达3-5升/千克。仅有0.1%的环孢素以原形从尿液中排泄...环孢素及其代谢物主要通过胆汁进入粪便排出，仅有大约6%通过尿液排泄。环孢素也通过人乳排出。

Following oral admin of cyclosporine, the time to peak blood concns is 1.5-2.0 hr. Admin with food both delays & decreases absorption. High & low fat meals consumed within 30 min of admin decr the AUC by approx 13% & the max concn by 33%. This makes it imperative to individualize dosage regimens for outpatients. Cyclosporine is distributed extensively outside the vascular compartment. After iv dosing, the steady-state volume of distribution has been reported to be as high as 3-5 liters/kg in solid-organ transplant recipients. Only 0.1% of cyclosporine is excreted unchanged in urine. ... Cyclosporine & its metabolites are excreted principally through the bile into the feces, with only approx 6% being excreted in the urine. Cyclosporine also is excreted in human milk.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

环孢素的吸收在口服给药后是不完全的。吸收的程度取决于包括个体患者和所用配方在内的几个变量。环孢素从血液中的消除通常是双相的，终末半衰期为5-18小时。在肾脏移植的成人接受者中，静脉输注后的清除率约为5-7毫升/分钟/千克，但结果会因年龄和患者群体而异。例如，心脏移植患者的清除率较慢，而在儿童中则较快。在治疗范围内，给药剂量与血浆浓度-时间曲线下面积之间的关系是线性的，但由于个体间变异性很大，因此需要个体监测。

... Absorption of cyclosporine is incomplete following oral admin. The extent of absorption depends upon several variables, including the individual patient & formulation used. The elimination of cyclosporine form the blood is generally biphasic, with a terminal half-life of 5-18 hr. After iv infusion, clearance is approx 5-7 ml/min/kg in adult recipients of renal transplants, but results differ by age & patient populations. For example, clearance is slower in cardiac transplant patients & more rapid in children. The relationship between admin dose & the area under the plasma concn-vs-time curve is linear within the therapeutic range, but the intersubject variability is so large that individual monitoring is required.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

临床医生可以在移植后的前几天通过持续静脉输液给予环孢素，然后通过每天两次的口服剂量，以达到血浆环孢素浓度（通过高效液相色谱法测量）为75-150 ng/ml（相当于通过放射免疫分析法测量的全血环孢素浓度为300-600 ng/ml）。维持大约75-150 ng/ml的血浆谷值环孢素浓度似乎是安全的；然而，这并不一定保证免受肾毒性。由于环孢素及其代谢物优先分布进入红细胞，血药水平通常高于血浆水平。当通过放射免疫分析法测量的血液环孢素水平为300-600 ng/ml时，脑脊液水平范围为10-50 ng/ml。10岁以下儿童的表观分布体积约为35 l/kg，成人为4.7 l/kg。

Clinicians can administer cyclosporine by continuous iv infusion during the first few days after transplantation, then orally by twice-daily doses, to achieve plasma cyclosporine concns (measured by HPLC) of 75-150 ng/ml (equivalent to whole blood cyclosporine concns of 300-600 ng/ml measured by radioimmunoassay). It appears safe to maintain a trough plasma cyclosporine concn of about 75-150 ng/ml; however, this does not necessarily guarantee safety from nephrotoxicity. Because of preferential distribution of cyclosporine & its metabolites into red blood cells, blood levels are generally higher than plasma levels. When blood cyclosporine levels are 300-600 ng/ml by radioimmunoassay, cerebrospinal fluid levels range from 10-50 ng/ml. The apparent volume of distribution in children under 10 yr of age is about 35 l/kg, & in adults, 4.7 l/kg.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

口服环孢素350毫克的消除半衰期是8.9小时；在服用1400毫克剂量后，半衰期是11.9小时。环孢素的消除主要是通过肝脏代谢形成18-25种代谢物。环孢素的代谢物几乎没有免疫抑制作用。环孢素在肝脏中通过细胞色素P450IIIA氧化酶广泛代谢；然而，神经毒性和可能的肾毒性通常与环孢素代谢物血药水平升高有关。只有0.1%的剂量以原形排泄。

The elimination half-life of an oral cyclosporine dose of 350 mg is 8.9 hr; after a 1400 mg dose, the half-life is 11.9 hr. Elimination occurs predominantly by metab in the liver to form 18-25 metabolites. Metabolites of cyclosporine possess little immunosuppressive activity. Cyclosporine is extensively metabolized in the liver by cytochrome P450IIIA oxidase; however, neurotoxicity & possibly nephrotoxoicity usually correlate with raised blood levels of cyclosporine metabolites. Only 0.1% of a dose ix s excreted unchanged.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  T
• 安全说明：
  S22,S24/25,S36/37,S45,S53
• 危险类别码：
  R60,R22,R45
• WGK Germany：
  3
• 海关编码：
  2941909000
• 危险品运输编号：
  NONH for all modes of transport
• RTECS号：
  GZ4120000

SDS

Cyclosporin A Revision number: 5
SAFETY DATA SHEET

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Section 1. IDENTIFICATION
Product name: Cyclosporin A

Revision number: 5

---

Section 2. HAZARDS IDENTIFICATION
GHS classification
PHYSICAL HAZARDS Not classified
HEALTH HAZARDS
Acute toxicity (Oral) Category 4
Category 1A
Carcinogenicity
Reproductive toxicity Category 1B
Reproductive toxicity (Effects on or via lactation) Additional category for effects on or via lactation
ENVIRONMENTAL HAZARDS Not classified
GHS label elements, including precautionary statements
Pictograms or hazard symbols
Signal word Danger
Hazard statements Harmful if swallowed
May cause cancer
May damage fertility or the unborn child
May cause harm to breast-fed children
Precautionary statements:
Obtain special instructions before use.
[Prevention]
Do not handle until all safety precautions have been read and understood.
Do not breathe dust/fume/gas/mist/vapours/spray.
Avoid contact during pregnancy/while nursing.
Do not eat, drink or smoke when using this product.
Wash hands thoroughly after handling.
Use personal protective equipment as required.
[Response] IF SWALLOWED: Call a POISON CENTER or doctor/physician if you feel unwell.
Rinse mouth.
IF exposed or concerned: Get medical advice/attention.
[Storage] Store locked up.
[Disposal] Dispose of contents/container through a waste management company authorized by
the local government.

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Section 3. COMPOSITION/INFORMATION ON INGREDIENTS
Substance
Substance/mixture:
Cyclosporin A

---

Section 3. COMPOSITION/INFORMATION ON INGREDIENTS
Components: Cyclosporin A
Percent: >97.0%(LC)(N)
CAS Number: 59865-13-3
Synonyms: Cyclosporin
Chemical Formula: C62H111N11O12

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Section 4. FIRST AID MEASURES
Inhalation: Remove victim to fresh air and keep at rest in a position comfortable for breathing.
Get medical advice/attention.
Skin contact: Remove/Take off immediately all contaminated clothing. Gently wash with plenty of
soap and water. Get medical advice/attention.
Eye contact: Rinse cautiously with water for several minutes. Remove contact lenses, if present
and easy to do. Get medical advice/attention.
Ingestion: Get medical advice/attention.Rinse mouth.
Protection of first-aiders: A rescuer should wear personal protective equipment, such as rubber gloves and air-
tight goggles.

---

Section 5. FIRE-FIGHTING MEASURES
Suitable extinguishing Dry chemical, foam, water spray, carbon dioxide.
media:
Specific hazards arising Take care as it may decompose upon combustion or in high temperatures to
from the chemical: generate poisonous fume.
Precautions for firefighters: Fire-extinguishing work is done from the windward and the suitable fire-extinguishing
method according to the surrounding situation is used. Uninvolved persons should
evacuate to a safe place. In case of fire in the surroundings: Remove movable
containers if safe to do so.
Special protective When extinguishing fire, be sure to wear personal protective equipment.
equipment for firefighters:

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Section 6. ACCIDENTAL RELEASE MEASURES
Use extra personal protective equipment (P3 filter respirator for toxic particles). Keep
Personal precautions,
protective equipment and people away from and upwind of spill/leak. Entry to non-involved personnel should
emergency procedures: be controlled around the leakage area by roping off, etc.
Environmental precautions: Prevent product from entering drains.
Methods and materials for Sweep dust to collect it into an airtight container, taking care not to disperse it.
containment and cleaning Adhered or collected material should be promptly disposed of, in accordance with
up: appropriate laws and regulations.

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Section 7. HANDLING AND STORAGE
Precautions for safe handling
Technical measures: Handling is performed in a well ventilated place. Wear suitable protective equipment.
Prevent dispersion of dust. Wash hands and face thoroughly after handling.
Use a closed system if possible. Use a local exhaust if dust or aerosol will be
generated.
Advice on safe handling: Avoid all contact!
Conditions for safe storage, including any
incompatibilities
Storage conditions: Keep container tightly closed. Store in a refrigerator.
Store locked up.
Store away from incompatible materials such as oxidizing agents.
Heat-sensitive
Comply with laws.
Packaging material:

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Section 8. EXPOSURE CONTROLS / PERSONAL PROTECTION
Engineering controls: Install a closed system or local exhaust. Also install safety shower and eye bath.
Cyclosporin A

---

Section 8. EXPOSURE CONTROLS / PERSONAL PROTECTION
Personal protective equipment
Respiratory protection: Dust respirator, self-contained breathing apparatus(SCBA), supplied air respirator,
etc. Use respirators approved under appropriate government standards and follow
local and national regulations.
Hand protection: Impervious gloves.
Safety goggles. A face-shield, if the situation requires.
Eye protection:
Skin and body protection: Impervious protective clothing. Protective boots, if the situation requires.

---

Section 9. PHYSICAL AND CHEMICAL PROPERTIES
Physical state (20°C): Solid
Crystal- Powder
Form:
Colour: White - Almost white
No data available
Odour:
pH: No data available
Melting point/freezing point:151°C
Boiling point/range: No data available
Flash point: No data available
Flammability or explosive
limits:
Lower: No data available
Upper: No data available
Relative density: No data available
Solubility(ies):
[Water] No data available
[Other solvents]
Very soluble: Methanol, Ether, Acetone, Ethanol
Soluble: Chloroform
Log Pow: 2.92

---

Section 10. STABILITY AND REACTIVITY
Chemical stability: Stable under proper conditions.
Possibility of hazardous No special reactivity has been reported.
reactions:
Incompatible materials: Oxidizing agents
Hazardous decomposition Carbon monoxide, Carbon dioxide, Nitrogen oxides (NOx)
products:

---

Section 11. TOXICOLOGICAL INFORMATION
Acute Toxicity: orl-rat LD50:1480 mg/kg
ipr-rat LD50:147 mg/kg
scu-rat LD50:286 mg/kg
ivn-rat LD50:24 mg/kg
Skin corrosion/irritation: No data available
Serious eye No data available
damage/irritation:
Germ cell mutagenicity: sce-hmn-lym 1 mg/L
oms-hmn-lym 50 mg/L
Carcinogenicity: orl-man TDLo:259 mg/kg/2W-C
IARC = Group 1 (Carcinogenic to humans)
NTP = a (Known to be carcinogens)
No data available
Reproductive toxicity:
RTECS Number: GZ4120000

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Section 12. ECOLOGICAL INFORMATION
Ecotoxicity:
Fish: No data available
Crustacea: No data available
Cyclosporin A

---

Section 12. ECOLOGICAL INFORMATION
Algae: No data available
Persistence / degradability: No data available
Bioaccumulative No data available
potential(BCF):
Mobility in soil
2.92
Log Pow:
Soil adsorption (Koc): No data available
No data available
Henry's Law
constant(PaM3/mol):

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Section 13. DISPOSAL CONSIDERATIONS
Recycle to process, if possible. Consult your local regional authorities. You may be able to dissolve or mix material
with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber system.
Observe all federal, state and local regulations when disposing of the substance.

---

Section 14. TRANSPORT INFORMATION
Does not correspond to the classification standard of the United Nations
Hazards Class:
UN-No: Not listed

---

Section 15. REGULATORY INFORMATION
Safe management ordinance of dangerous chemical product (State Council announces on January 26, 2002
and revised on February 16,2011): Safe use and production, the storage of a dangerous chemical, transport,
loading and unloading were prescribed.

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

根据提供的信息,以下是关于环孢素的主要内容总结:

化学性质:

• 白色针状结晶
• 溶于甲醇、乙醇、丙酮或乙醚,微溶于水
• [α]D20 -244°(C=0.6，氯仿)
• 急性毒性LD50: 小鼠107mg/kg, 大鼠2329mg/kg, 兔子>1000mg/kg

用途:

• 新型免疫抑制剂
• 抑制T细胞受体信号传导路径,用于分子生物学研究
• 临床用于肾移植、肝肺移植等器官移植
• 治疗自身免疫性疾病
• 对白血病、癌症、结核病有一定疗效
• 具有抗炎作用

副作用:

• 肾毒性:蛋白尿、管型尿等
• 肝毒性:高胆红素血症等
• 神经系统症状:小脑共济失调、感觉异常等
• 消化道反应:恶心呕吐等

生产方法: 以多孢木霉菌为生产菌株,经过发酵提取粗品,再纯化得到环孢素和环孢菌素C组分。

总结来说,环孢素是一种重要的免疫抑制剂,广泛应用于临床器官移植及自身免疫病治疗,但需要注意其潜在的毒副作用。

反应信息

• 作为产物：
  描述：

  7,8-Secocyclosporin-7-carboxylic acid 以67的产率得到Restasis
  参考文献：
  名称：

  J. Am. Chem. Soc. 2012, 134, 2378-2384

  摘要：

  DOI：

文献信息

• SUSTAINED RELEASE BIODEGRADABLE INTRACANALICULAR INSERTS COMPRISING A HYDROGEL AND CYCLOSPORINE
  申请人：Ocular Therapeutix, Inc.

  公开号：EP3973952A1

  公开（公告）日：2022-03-30

  Provided herein are sustained release biodegradable intracanalicular insert comprising a hydrogel and cyclosporine, methods of treating or preventing an ocular disease in a subject in need thereof by administering such inserts as well as methods of manufacturing such inserts.

  本文提供了由水凝胶和环孢素组成的缓释生物可降解鞘内插片、通过使用这种插片治疗或预防有需要的受试者眼部疾病的方法以及制造这种插片的方法。
• PEGylated lipid nanoparticle with bioactive lipophilic compound
  申请人：Eyesiu Medicines B.V.

  公开号：US10945966B2

  公开（公告）日：2021-03-16

  The invention relates to nanoparticles for the systemic or topical delivery of lipophilic diagnostic or therapeutic agents to a subject in need thereof. The nanoparticles of the invention comprise a water soluble polymer and at least one of a biocompatible lipid and a lipophilic agent. The invention further relates to ophthalmic treatment using the nanoparticles of the invention. In addition, the invention pertains to compositions and formulations comprising the nanoparticle of the invention. Such formulation may be an eye drop formulation.

  本发明涉及向有需要的受试者全身或局部递送亲脂性诊断或治疗剂的纳米颗粒。本发明的纳米颗粒包括水溶性聚合物以及生物相容性脂质和亲油剂中的至少一种。本发明进一步涉及使用本发明纳米颗粒的眼科治疗。此外，本发明还涉及包含本发明纳米颗粒的组合物和制剂。此类制剂可以是滴眼液制剂。
• Sustained release biodegradable intracanalicular inserts comprising a hydrogel and cyclosporine
  申请人：Ocular Therapeutix, Inc.

  公开号：US11331267B2

  公开（公告）日：2022-05-17

  Provided herein are sustained release biodegradable intracanalicular insert comprising a hydrogel and cyclosporine, methods of treating or preventing an ocular disease in a subject in need thereof by administering such inserts as well as methods of manufacturing such inserts.

  本文提供了由水凝胶和环孢素组成的缓释生物可降解鞘内插片、通过使用这种插片治疗或预防有需要的受试者眼部疾病的方法以及制造这种插片的方法。
• PEGYLATED LIPID NANOPARTICLE WITH BIOACTIVE LIPOPHILIC COMPOUND
  申请人：Eyesiu Medicines B.V.

  公开号：US20180235896A1

  公开（公告）日：2018-08-23

  The invention relates to nanoparticles for the systemic or topical delivery of lipophilic diagnostic or therapeutic agents to a subject in need thereof. The nanoparticles of the invention comprise a water soluble polymer and at least one of a biocompatible lipid and a lipophilic agent. The invention further relates to ophthalmic treatment using the nanoparticles of the invention. In addition, the invention pertains to compositions and formulations comprising the nanoparticle of the invention. Such formulation may be an eye drop formulation.
• J. Am. Chem. Soc. 2012, 134, 2378-2384
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