CN106214682A - Tripterine application in preparing anti-corneal graft rejection eye drop preparation - Google Patents
Tripterine application in preparing anti-corneal graft rejection eye drop preparation Download PDFInfo
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- CN106214682A CN106214682A CN201610804045.3A CN201610804045A CN106214682A CN 106214682 A CN106214682 A CN 106214682A CN 201610804045 A CN201610804045 A CN 201610804045A CN 106214682 A CN106214682 A CN 106214682A
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- tripterine
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- corneal graft
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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- 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
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- 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
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- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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Abstract
The invention belongs to bio-medical material and medical science crossing domain, specifically disclose the application in preparing anti-corneal graft rejection eye drop preparation of a kind of tripterine.Weigh ternary block polymer PEG PCL PEI 7.04 ~ 67.55 g, tripterine 0.68 ~ 2.11 g, be jointly dissolved in the mixed solvent being made up of with volume ratio 1:1 ~ 3 methanol and acetonitrile；Then, under ultrasonic agitation, being added drop-wise to by mixed liquor in the water for injection of dissolving equivalent, vacuum distilling removes organic solvent, and ultrafiltration removes free tripterine, obtains drug-carrying polymer micelle, adds water for injection and be settled to 100mL, obtain eye drop.The present invention, first with PEG PCL PEI as carrier, loads tripterine, is made for eye drop, it is achieved the administering mode of ocular eye dripping, has landmark meaning.
Description
Technical field
The invention belongs to bio-medical material and medical science crossing domain, be specifically related to a kind of tripterine and preparing anti-angle
Application in film transplant rejection eye drop preparation.
Background technology
Keratopathy is one of modal disease of ophthalmology, and blind rate occupies second.Corneal graft is treatment cornea
Blind most effective means.Post-operative cornea transplant rejection is the most important factor of operative failure.Corneal allograft rejection is host
The immunization inflammatory reaction that anti-graft causes.At present, clinically, after keratoplasty, the drug main of prevention and treatment of rejection to wrap
Include: glucocorticoid, Ciclosporin A (CsA), tacrolimus (FK506) etc..Glucocorticoid local life-time service can lure
Sending out glaucoma, cataract etc., the side effect that whole body uses is bigger；CsA molecular weight is big, and poorly water-soluble is difficult to penetrate cornea, medicine
Carrier toxicity is big；The immunosuppressive action of FK506 is strong, but expensive, and prolonged application may result in renal function and nervous system
Function is impaired.Therefore, seek new therapy target and specific medicament, thus research and develop side effect anti-cornea low, high specificity and move
Plant repulsion newtype drug, there is important clinical meaning.
Tripterine is also known as celastrin (Celastrol), already by extracting and developing from Radix Tripterygii Wilfordii Chinese medicine and reflect
Fixed, molecular formula is C29H38O4, molecular weight is 450.61.Celastrol as the biologically active monomer of Radix Tripterygii Wilfordii, have antiinflammatory,
The various biological functions such as antitumor, suppression new vessels formation, have been used for rheumatic arthritis, systemic lupus erythematosus (sle), heavy breathing
Breathe heavily, the research of the multiple disease such as tumor, obesity and treatment.Although Celastrol has relatively strong biological activity, possess antiinflammatory, resist
The potential drug of cornea rebirth blood vessel, but the water solublity of its extreme difference limits its further clinical practice and curative effect, the most still
Do not find to apply it in eye drop to treat the report of ophthalmic diseases.
Summary of the invention
The purpose of the present invention aims to provide a kind of tripterine in preparing anti-corneal graft rejection eye drop preparation
Application.
For achieving the above object, the technical scheme that the present invention takes is as follows:
Tripterine application in preparing anti-corneal graft rejection eye drop preparation, application process is: weigh tri-block
Copolymer p EG-PCL-PEI 7.04 ~ 67.55 g, tripterine 0.68 ~ 2.11 g, be jointly dissolved in by methanol and acetonitrile with
In the mixed solvent of volume ratio 1:1 ~ 3 composition；Then, under ultrasonic agitation, mixed liquor is added drop-wise to dissolve the injection of equivalent
In water, vacuum distilling removes organic solvent, and ultrafiltration removes free tripterine, obtains drug-carrying polymer micelle, adds injection
It is settled to 100mL with water, obtains eye drop.
Most preferably, PEG-PCL-PEI 10.0 g, tripterine 0.75 g are preferably weighed.
In the present invention, ternary block polymer PEG-PCL-PEI can be prepared by prior art, such as list of references
International Journal of Nanomedicine 2015, 10, 6027–6037。
Beneficial effect:
1, tripterine water solublity extreme difference, 37 DEG C of dissolubility in water are only 3.8 micrograms per millilitre, there is no in prior art
Being made into the eye drop treatment for eye surface diseases, the present invention, first with PEG-PCL-PEI as carrier, loads trypterygine
Element, is made for eye drop, it is achieved the administering mode of ocular eye dripping, has landmark meaning；
2, have found optimum feed stock rate of charge be PEG-PCL-PEI 10.0 g, tripterine 0.75 g, most preferably feed intake at this
The eye drop made under Bi has higher drug loading and envelop rate concurrently, has the effect of optimal anti-corneal graft rejection.
Accompanying drawing explanation
Fig. 1: postoperative 8th day, matched group (a) and tripterine eye drops in treatment group (b) corneal photographs.
Detailed description of the invention
Embodiment 1
Weigh ternary block polymer PEG-PCL-PEI 10.0 g, tripterine 3.0 g, be jointly dissolved in 20mL by methanol
In the mixed solvent formed with volume ratio 1:1 with acetonitrile；Then, under ultrasonic agitation, mixed liquor is added drop-wise to the injection of 50mL
With in water, vacuum distilling removes organic solvent, then is removed for 3 times by ultrafiltration apparatus (molecular cut off is: 100,000 Da) ultrafiltration
Remove the tripterine dissociated, obtain drug-carrying polymer micelle, add water for injection and be settled to 100mL, obtain tripterine and drip
Ocular fluid.
Embodiment 2
It is with the difference of embodiment 1: PEG-PCL-PEI 10.0 g, tripterine 1.5 g, the other the same as in Example 1.
Embodiment 3
It is with the difference of embodiment 1: PEG-PCL-PEI 10.0 g, tripterine 0.75 g, the other the same as in Example 1.
Embodiment 4
It is with the difference of embodiment 1: PEG-PCL-PEI 10.0 g, tripterine 0.3 g, the other the same as in Example 1.
Embodiment 5
It is with the difference of embodiment 1: PEG-PCL-PEI 10.0 g, tripterine 0.1 g, the other the same as in Example 1.
Different rate of charges are on drug-carrying polymer micelle drug loading and the impact of entrapment efficiency
Drug loading and the mensuration of envelop rate:
Drug loading is defined as tripterine percentage by weight in drug-carrying polymer micelle.In order to determine drug loading, will
The vacuum lyophilization in advance of gained drug-carrying polymer micelle, lyophilizing micelle of weighing, it is re-dissolved in dimethyl sulfoxide/chloroform (1/
1, volume ratio).By the concentration of ultraviolet spectra detection sample, detection wavelength is 425 nm.Tripterine according to preparation in advance
Standard curve calculates.Drug loading (DLC, weight %) and envelop rate (DLE, weight %) calculate according to following equation:
DLC=(the tripterine quality/drug-carrying polymer micelle quality loaded) × 100%；
DLE=(the original quality that feeds intake of tripterine quality/medicine carrying medicine loaded) × 100%.
On the impact of drug-carrying polymer micelle drug loading and entrapment efficiency, (carrier refers to different rate of charges as shown in table 1
PEG-PCL-PEI, medicine refers to tripterine), result shows: in the case of carrier amount is identical, drug loading is along with medicine feeding
The increase of amount and increase, but corresponding envelop rate declines the most therewith.In embodiment 1, although it is higher to obtain drug loading
(9.02%), but envelop rate the lowest (33.05%)；And in embodiment 5, although obtaining the highest envelop rate (95.12%), but carry
Dose the lowest (0.94%)；But embodiment 3 is taken into account the two simultaneously, there is higher drug loading (6.35%) and envelop rate
(90.48%).From table 1 data: embodiment 1 and 2, required dispensing thing is more, and utilization ratio of drug is low；Embodiment 4 and 5 is then
Carrier uses more, is easily generated extra toxicity；Only embodiment 3 is proper, i.e. carrier amount be 10.0g, medication amount be
During 0.75g optimal.
The drug level of embodiment 3 eye drop is (0.75 × 1000 × 90.48%)/100=6.786 mg/mL.Use this
Tripterine drug level in water (37 DEG C) can be brought up to 6.786 from 3.8 micrograms per millilitre by inventive technique scheme
Milligram every milliliter.
Animal experiment
Inventor uses tripterine eye drop prepared by embodiment 3, with cornea of rats transplant rejection model as animal model,
The anti-corneal graft rejection effect of assessment tripterine eye drop.Concrete implantation method is with reference to publishing an article (European
Journal of Pharmaceutical Sciences 2014:62,115-123), detailed step is as follows:
10% chloral hydrate lumbar injection induction SD rat body anesthesia, 4 mL/kg body weight pressed by anesthetis.Physiological saline solution each 5
ML flush operation eye conjunctival sac, near the eyes, 0.5% proxymetacaine hydrochloride eye drop carries out ocular local anesthesia to iodophor disinfection respectively.
Wistar rat is cooked donor, and SD rat is cooked receptor, plants sheet diameter 3.5mm, plant bed diameter 3.0mm, 10/0 nylon seam
Line, interrupted suture 8 pin.Art finishes tobramycin eye ointment and is applied in conjunctival sac, and prevention is infected.Corneal graft rejection standard uses
Holland ' s standard (see Table 2) (Cornea. 1991;10 (5): 374-80), when corneal graft transparency, edema, new
Indices scoring sum >=6 timesharing of angiogenic, is repulsion.
Postoperative every day, conjunctival sac partial points ocular administration, embodiment 3 tripterine eye drop is treatment group, normal saline
For matched group.Treatment group and matched group, three times, homogeneous sky, each one.Postoperative every day observes Operation eye feelings under slit lamp
Condition.
Treatment group and matched group often organize six, add up corneal graft mean survival time.
Results of animal shows: matched group, and postoperative the 1-2 days corneal grafts of corneal transplantation are transparent, a small amount of new vessels
Blastogenesis is long；Postoperative the 3-4 days, occur that corneal graft edema, transparency decline, new vessels length about 0.6-1mm；Postoperative
5-9 days, planting sheet edema and increase the weight of, transparency is decreased obviously, and new vessels is up to corneal graft edge or grows into and plants sheet；Corneal graft
Postoperative about the 5-9 days, all repel, mean survival time 7.1 days；Tripterine eye drops in treatment group, postoperative the 5-9 days
Corneal graft is transparent, and iris texture is high-visible, corneal graft mean survival time 27.7 days, hence it is evident that extends corneal graft and deposits
Live.Wherein, postoperative 8th day, matched group (a) and tripterine eye drops in treatment group (b) corneal photographs were shown in Fig. 1, can by Fig. 1
Knowing: matched group, as shown in arrow in (a), corneal graft is muddy and has a large amount of cornea rebirth blood vessel；Tripterine eye drop is controlled
Treatment group, as shown in arrow in (b), through transparent corneal graft, it can be seen that iris vessels clearly.Therefore, trypterygine
Element eye drop can be obviously prolonged corneal graft life span.
To sum up, tripterine is hydrophobic drug, and the present invention utilizes carrier PEG-PCL-PEI to load tripterine system
For going out tripterine eye drop, greatly strengthen the apparent solubility of tripterine.Zoopery shows, tripterine
Eye drop can substantially alleviate corneal allograft rejection, hence it is evident that extends corneal graft life span, has anti-corneal graft rejection
Effect.
Claims (2)
1. tripterine application in preparing anti-corneal graft rejection eye drop preparation, it is characterised in that application process is:
Weigh ternary block polymer PEG-PCL-PEI 7.04 ~ 67.55 g, tripterine 0.68 ~ 2.11 g, be jointly dissolved in by
In the mixed solvent that methanol and acetonitrile form with volume ratio 1:1 ~ 3；Then, under ultrasonic agitation, it is added drop-wise to mixed liquor dissolve
In the water for injection of equivalent, vacuum distilling removes organic solvent, and ultrafiltration removes free tripterine, obtains drug-carrying polymer glue
Bundle, adds water for injection and is settled to 100mL, obtain eye drop.
Apply the most as claimed in claim 1, it is characterised in that: weigh PEG-PCL-PEI 10.0 g, tripterine 0.75 g.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610804045.3A CN106214682B (en) | 2016-09-06 | 2016-09-06 | Celastrol is preparing the application in anti-corneal graft rejection eye drop preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610804045.3A CN106214682B (en) | 2016-09-06 | 2016-09-06 | Celastrol is preparing the application in anti-corneal graft rejection eye drop preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106214682A true CN106214682A (en) | 2016-12-14 |
| CN106214682B CN106214682B (en) | 2019-04-26 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610804045.3A Active CN106214682B (en) | 2016-09-06 | 2016-09-06 | Celastrol is preparing the application in anti-corneal graft rejection eye drop preparation |
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| CN (1) | CN106214682B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114392229A (en) * | 2022-01-06 | 2022-04-26 | 河南省立眼科医院（河南省眼科研究所） | Thermo-sensitive hydrogel for inhibiting corneal stroma fibrosis and preparation method thereof |
| CN114533703A (en) * | 2022-03-08 | 2022-05-27 | 河南省人民医院 | Tripterine composite membrane and preparation method and application thereof |
| CN114533703B (en) * | 2022-03-08 | 2024-05-31 | 河南省人民医院 | Tripterine composite film and preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105085927A (en) * | 2015-08-19 | 2015-11-25 | 河南省眼科研究所 | Tri-block copolymer, preparation method thereof and eye drop prepared from tri-block copolymer |
-
2016
- 2016-09-06 CN CN201610804045.3A patent/CN106214682B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105085927A (en) * | 2015-08-19 | 2015-11-25 | 河南省眼科研究所 | Tri-block copolymer, preparation method thereof and eye drop prepared from tri-block copolymer |
Non-Patent Citations (2)
| Title |
|---|
| 刘法 等: "角膜新生血管的治疗新进展", 《现代生物医学进展》 * |
| 杨杰 等: "雷公藤红素对大鼠视网膜血管内皮细胞增生和凋亡的影响", 《眼科新进展》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114392229A (en) * | 2022-01-06 | 2022-04-26 | 河南省立眼科医院（河南省眼科研究所） | Thermo-sensitive hydrogel for inhibiting corneal stroma fibrosis and preparation method thereof |
| CN114533703A (en) * | 2022-03-08 | 2022-05-27 | 河南省人民医院 | Tripterine composite membrane and preparation method and application thereof |
| CN114533703B (en) * | 2022-03-08 | 2024-05-31 | 河南省人民医院 | Tripterine composite film and preparation method and application thereof |
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| CN106214682B (en) | 2019-04-26 |
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