CN109248146A - Cancer target type injection Oridonin dry suspensoid agent and preparation method thereof - Google Patents
Cancer target type injection Oridonin dry suspensoid agent and preparation method thereof Download PDFInfo
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- CN109248146A CN109248146A CN201811266944.8A CN201811266944A CN109248146A CN 109248146 A CN109248146 A CN 109248146A CN 201811266944 A CN201811266944 A CN 201811266944A CN 109248146 A CN109248146 A CN 109248146A
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- oridonin
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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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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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
- A61K47/02—Inorganic compounds
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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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses a kind of cancer target type injection Oridonin dry suspensoid agents and preparation method thereof.The cancer target type injection Oridonin dry suspensoid agent percentage, include Oridonin 5%~40%, 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid is coupled graphene complex 40%~60%, wetting agent 0.1%~30%, suspending agent 1%~40%, by in proportion by Oridonin, 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid coupling graphene complex, wetting agent, suspending agent ground and mixed are uniformly sieved afterwards, vacuum degree is sub-packed in cillin bottle lower than 10Pa or less, and is sealed and be can be prepared by.Cancer target type injection Oridonin dry suspensoid agent of the invention significantly improves the tumor-targeting and antitumous effect and its stability of Oridonin by controlling the content of each component.
Description
Technical field
The present invention relates to a kind of cancer target type injection Oridonin dry suspensoid agent and preparation methods, belong to biological doctor
Medicine field of engineering technology.
Background technique
Oridonin (Oridonin) is a kind of kaurene diterpene isolated from Labiatae Rabdosia plant
Class natural organic-compound accounts for 90% or more of Rabdosia rubescens effective component, is antitumor active constituent, is clinically chiefly used in original
The treatment of the entity tumors such as Diagnosis, breast cancer, gastric cancer and cancer of the esophagus.
Due to its good antitumous effect and lesser toxic side effect, extensive concern is obtained in recent years, has β-ring paste
The novel dosage forms such as inclusion compounds, solid-state radar transmitter, PCL-PEO-PCL drug-carrying nanometer particle, polylactic acid nano particle and liposome
Research report.In clinical application at present and each main dosage form of the Oridonin in conceptual phase, Oridonin is easy
Oxidation, stability is poor, biological half-life is short, targeting is low and bioavilability is low, limits its use.
Recent study the result shows that, folacin receptor has high expression on certain solid tumors, such as oophoroma, endometrium
Cancer, the carcinoma of the rectum, breast cancer, lung cancer, liver cancer, neuroendocrine carcinoma and brain metastases etc., and in normal tissue low expression, this property
Matter is provides opportunity using folacin receptor as drug target.
Summary of the invention
The purpose of the present invention is to provide a kind of cancer target type injection Oridonin dry suspensoid agent and preparation method,
On the one hand the tumor-targeting for improving Oridonin, on the other hand improves the stability of Oridonin.
Realize that the technical solution of the object of the invention is as follows:
Cancer target type injection Oridonin dry suspensoid agent, percentage include following component: Rabdosia rubescens
A prime 5%~40%, 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid coupling graphene complex 40%~60%, wetting agent 0.1%~
30%, suspending agent 1%~40%.
Preferably, the cancer target type injection Oridonin dry suspensoid agent, percentage, comprising such as
Lower component: Oridonin 5%~40%, 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid are coupled graphene complex 40%~60%,
Wetting agent 5%~10%, suspending agent 10%~35%.
It is further preferred that percentage, the Oridonin 20%~40%, 2- ammonia -4- hydroxyl -7,8-
Dihydropteroic acid is coupled graphene complex 40%~50%.
The wetting agent is conventional use of wetting agent, can be PLURONICS F87,237,338 or 407.
The suspending agent is conventional use of suspending agent, can be methylcellulose, hydroxyethyl cellulose, hydroxypropyl first
Base cellulose, polyvinylpyrrolidone K15, PVP K30 or PVP K90.
Shown in the structural formula such as formula (I) of 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid coupling graphene complex,
Preparation method is as follows: by 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid be added graphene oxide dispersion in, ultrasound and
Stirring is added N, N- Dicyclohexylcarbodiimide and n-hydroxysuccinimide, stirs under the conditions of 5 DEG C~50 DEG C to being uniformly mixed
Reaction is mixed, is centrifuged, filtering is dried to obtain 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid coupling graphene complex.
Preferably, described in the preparation method of above-mentioned 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid coupling graphene complex
Ultrasound and mixing time are 0.5h~5h.
Preferably, described in the preparation method of above-mentioned 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid coupling graphene complex
It is stirred to react 0.5h~for 24 hours.
Preferably, described in the preparation method of above-mentioned 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid coupling graphene complex
Centrifugation time is 10min~120min, revolving speed 500rpm~15000rpm.
Preferably, described in the preparation method of above-mentioned 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid coupling graphene complex
It is dry that vacuum degree is -0.05Mpa~-0.1Mpa, and temperature is 30 DEG C~100 DEG C for vacuum drying, drying time be 0.5h~
24h。
The present invention also provides the preparation method of above-mentioned cancer target type injection Oridonin dry suspensoid agent, including it is as follows
Step:
Oridonin, 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid are coupled graphene complex, wetting agent, suspending in proportion
Agent ground and mixed uniformly crosses 120 mesh~200 meshes afterwards, and vacuum degree is sub-packed in cillin bottle lower than 10Pa or less, and is sealed, and is made
Cancer target type injection Oridonin dry suspensoid agent.
Compared with prior art, the invention has the following advantages that
Cancer target type injection Oridonin dry suspensoid agent of the invention, by controlling the content of each component, a side
Face significantly improves Oridonin tumor-targeting and antitumous effect, on the other hand significantly improves the stabilization of Oridonin
Property.
Specific embodiment
In order to make the objectives, technical solutions and advantages of the present invention clearer, below by embodiment, to the present invention into
Row is further described.However, it should be understood that the specific embodiments described herein are merely illustrative of the present invention, and do not have to
In limiting the scope of the invention.Wetting agent is by taking PLURONICS F87 as an example in following embodiment, and suspending agent is by taking methylcellulose as an example
The present invention is described in detail, it should be understood that other wetting agents such as poloxamer 237,338 or 407, other suspending agents
Such as hydroxyethyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone K15, PVP K30 or polyethylene pyrrole
The present invention equally may be implemented in pyrrolidone K90.
The preparation of comparative example Oridonin injection
The preparation of Oridonin injection sequentially includes the following steps: and weighs 40mg Oridonin and 40mg table no food
Sub- catechin and gallate is dissolved in the 0.5% Tween-80 normal saline solution of 30mL to obtain the final product.
Embodiment 1
The preparation step that 1.2- ammonia -4- hydroxyl -7,8- dihydropteroic acid is coupled graphene complex is as follows:
(1) by graphene oxide (length: 0.5 μm -3 μm；Thickness: 0.55nm-1.2nm) it is added to distilled water, at 5 DEG C
Ultrasound and stirring (revolving speed are as follows: 50rpm/min) 0.5h, obtain dispersion liquid.
(2) dispersion liquid is placed in and disperses to grind in colloid mill, obtain finely dispersed graphene oxide dispersion.
(3) ultrasound and stirring 0.5h in graphene oxide dispersion is added in 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid, obtains 2-
The dispersion liquid of ammonia -4- hydroxyl -7,8- dihydropteroic acid and graphene oxide mixing.
(4) N, N- Dicyclohexylcarbodiimide and n-hydroxysuccinimide is added into step (3) resulting dispersion liquid,
It is stirred to react 0.5h at 5 DEG C, obtains reaction solution.
(5) it is centrifuged 10min to the resulting reaction solution 500rpm of step (4), after centrifugation, discards supernatant liquid, must precipitates
Object.
(6) distilled water is added after mixing evenly into step (5) resulting sediment, with miillpore filter (aperture: 0.45 μ
M) it filters, discards filtrate, obtain filter cake.
(7) step (6) resulting filter cake is placed in a vacuum drying oven (vacuum degree: -0.05Mpa；Temperature: 30 DEG C) it is dry
0.5h obtains 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid coupling graphene complex.
2. cancer target type injection Oridonin dry suspensoid agent, percentage include following component:
Oridonin 5%, 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid are coupled graphene complex 60%, and it is husky that wetting agent moors Lip river
Nurse 188 10%, suspending agent methylcellulose 25%.
3. the preparation method of cancer target type injection Oridonin dry suspensoid agent, includes the following steps:
(1) each component of recipe quantity in above-mentioned cancer target type injection Oridonin dry suspensoid agent is weighed, grinding is mixed
120 meshes are crossed after closing uniformly, it is spare.
(2) step (1) resulting material is sub-packed in cillin bottle in vacuum degree lower than 10Pa or less, and sealed to get institute
The cancer target type injection Oridonin dry suspensoid agent stated.
Cancer target type injection Oridonin dry suspensoid agent is placed 6 months under the conditions of 60 DEG C, cancer target type
The content of Oridonin does not have to change (deviation range≤2%) substantially in injection Oridonin dry suspensoid agent.By 60 DEG C
Under the conditions of the cancer target type injection Oridonin dry suspensoid agent placed 6 months be scattered in sterilized water for injection in 48h
Interior holding is stablized.HePG-2 cell inoculation is subcutaneous in kunming mice, mouse liver tumor model is established, respectively by cancer target
Type injection Oridonin dry suspensoid agent (with being before scattered in sterilized water for injection) and Oridonin injection mouse tail
After intravenously administrable, different time points (0.05h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 12h, for 24 hours, 48h) mouse is put to death, take
Tumor mass, with Determination of oridonin in HPLC analysis tumor tissues.The result shows that cancer target type injection Oridonin
Opposite targeting rate of the dry suspensoid agent in tumor tissues is 7.18.
HePG-2 cell inoculation is subcutaneous in kunming mice, mouse liver tumor model is established, respectively by cancer target type
Injection Oridonin dry suspensoid agent (with being before scattered in sterilized water for injection) and Oridonin injection are through mouse tail
Intravenously administrable, treatment is primary daily, and nude mice is put to death in continuous treatment after 10 days, and removing tumour calculates the tumor suppression of lotus human liver cancer nude mice
Rate.The result shows that dosage is 1.68 × 10- 2g·Kg- 1·d- 1Tumour inhibiting rate is distinguished both when (being calculated with Oridonin)
For 89.3% and 39.6%.
Embodiment 2
The preparation step that 1.2- ammonia -4- hydroxyl -7,8- dihydropteroic acid is coupled graphene complex is as follows:
(1) by graphene oxide (length: 0.5 μm -3 μm；Thickness: 0.55nm-1.2nm), it is added to distilled water, at 50 DEG C
Lower ultrasound and stirring (revolving speed are as follows: 500rpm) 5h, obtain dispersion liquid.
(2) (1) resulting dispersion liquid is placed in and disperses to grind in colloid mill, obtain finely dispersed graphene oxide dispersion
Liquid.
(3) ultrasound is added into (2) resulting graphene oxide dispersion in 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid and stirred
5h is mixed, the dispersion liquid of 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid and graphene oxide mixing is obtained.
(4) N, N- Dicyclohexylcarbodiimide and n-hydroxysuccinimide is added into step (3) resulting dispersion liquid,
It is stirred to react at 50 DEG C for 24 hours, obtains reaction solution.
(5) to 120min is centrifuged under the resulting reaction solution 15000rpm of step (4), after centrifugation, liquid is discarded supernatant, is obtained
Sediment.
(6) distilled water is added after mixing evenly into step (5) resulting sediment, with miillpore filter (aperture: 0.45 μ
M) it filters, discards filtrate, obtain filter cake.
(7) step (6) resulting filter cake is placed in a vacuum drying oven (vacuum degree: -0.1Mpa；Temperature: 100 DEG C) it is dry
For 24 hours, 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid coupling graphene complex is obtained.
2. cancer target type injection Oridonin dry suspensoid agent percentage includes following component:
Oridonin 10%, 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid are coupled graphene complex 50%, and wetting agent moors Lip river
Husky nurse 188 10%, suspending agent methylcellulose 30%.
3. the preparation method of cancer target type injection Oridonin dry suspensoid agent, includes the following steps:
(1) each component of recipe quantity in above-mentioned cancer target type injection Oridonin dry suspensoid agent is weighed, is ground
200 meshes are crossed after mixing, it is spare.
(2) step (1) resulting material is sub-packed in cillin bottle in vacuum degree lower than 10Pa or less, and sealed to get institute
The cancer target type injection Oridonin dry suspensoid agent stated.
Cancer target type injection Oridonin dry suspensoid agent is placed 6 months under the conditions of 60 DEG C, cancer target type
The content of Oridonin does not have to change (deviation range≤2%) substantially in injection Oridonin dry suspensoid agent.By 60 DEG C
Under the conditions of the cancer target type injection Oridonin dry suspensoid agent placed 6 months be scattered in sterilized water for injection in 48h
Interior holding is stablized.HePG-2 cell inoculation is subcutaneous in kunming mice, mouse liver tumor model is established, respectively by cancer target
Type injection Oridonin dry suspensoid agent (with being before scattered in sterilized water for injection) and Oridonin injection mouse tail
After intravenously administrable, different time points (0.05h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 12h, for 24 hours, 48h) mouse is put to death, take
Tumor mass, with Determination of oridonin in HPLC analysis tumor tissues.The result shows that cancer target type injection Oridonin
Opposite targeting rate of the dry suspensoid agent in tumor tissues is 7.28.
HePG-2 cell inoculation is subcutaneous in kunming mice, mouse liver tumor model is established, respectively by cancer target type
Injection Oridonin dry suspensoid agent (with being before scattered in sterilized water for injection) and Oridonin injection are through mouse tail
Intravenously administrable, treatment is primary daily, and nude mice is put to death in continuous treatment after 10 days, and removing tumour calculates the tumor suppression of lotus human liver cancer nude mice
Rate.The result shows that dosage is 1.68 × 10- 2g·Kg- 1·d- 1Tumour inhibiting rate is distinguished both when (being calculated with Oridonin)
For 90.8% and 39.6%.
Embodiment 3
The preparation step that 1.2- ammonia -4- hydroxyl -7,8- dihydropteroic acid is coupled graphene complex is as follows:
(1) by graphene oxide (length: 0.5 μm -3 μm；Thickness: 0.55nm-1.2nm), it is added to distilled water, at 20 DEG C
Lower ultrasound and stirring (revolving speed are as follows: 300rpm) 2h, obtain dispersion liquid.
(2) (1) resulting dispersion liquid is placed in colloid mill further dispersion to grind, obtains finely dispersed graphene oxide
Dispersion liquid.
(3) ultrasound is added into (2) resulting graphene oxide dispersion in 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid and stirred
2h is mixed, the dispersion liquid of 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid and graphene oxide mixing is obtained.
(4) N, N- Dicyclohexylcarbodiimide and n-hydroxysuccinimide is added into step (3) resulting dispersion liquid,
It is stirred to react 10h at 20 °C, obtains reaction solution.
(5) it is placed in supercentrifuge to step (4) resulting reaction solution and is centrifuged 60min, revolving speed 2000rpm/min, from
After the heart, liquid is discarded supernatant, obtains sediment.
(6) distilled water is added after mixing evenly into step (5) resulting sediment, with miillpore filter (aperture: 0.45 μ
M) it filters, discards filtrate, obtain filter cake.
(7) step (6) resulting filter cake is placed in a vacuum drying oven (vacuum degree: -0.08Mpa；Temperature: 60 DEG C) it is dry
12h obtains 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid coupling graphene complex.
2. cancer target type injection Oridonin dry suspensoid agent percentage includes following component:
Oridonin 20%, 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid are coupled graphene complex 40%, and wetting agent moors Lip river
Husky nurse 188 5%, suspending agent methylcellulose 35%.
3. the preparation method of cancer target type injection Oridonin dry suspensoid agent, includes the following steps:
(1) each component of recipe quantity in above-mentioned cancer target type injection Oridonin dry suspensoid agent is weighed, is ground
160 meshes are crossed after mixing, it is spare.
(2) step (1) resulting material is sub-packed in cillin bottle in vacuum degree lower than 10Pa or less, and sealed to get institute
The cancer target type injection Oridonin dry suspensoid agent stated.
Cancer target type injection Oridonin dry suspensoid agent is placed 6 months under the conditions of 60 DEG C, cancer target type
The content of Oridonin does not have to change (deviation range≤2%) substantially in injection Oridonin dry suspensoid agent.By 60 DEG C
Under the conditions of the cancer target type injection Oridonin dry suspensoid agent placed 6 months be scattered in sterilized water for injection in 48h
Interior holding is stablized.HePG-2 cell inoculation is subcutaneous in kunming mice, mouse liver tumor model is established, respectively by cancer target
Type injection Oridonin dry suspensoid agent (with being before scattered in sterilized water for injection) and Oridonin injection mouse tail
After intravenously administrable, different time points (0.05h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 12h, for 24 hours, 48h) mouse is put to death, take
Tumor mass, with Determination of oridonin in HPLC analysis tumor tissues.The result shows that cancer target type injection Oridonin
Opposite targeting rate of the dry suspensoid agent in tumor tissues is 7.82.
HePG-2 cell inoculation is subcutaneous in kunming mice, mouse liver tumor model is established, respectively by cancer target type
Injection Oridonin dry suspensoid agent (with being before scattered in sterilized water for injection) and Oridonin injection are through mouse tail
Intravenously administrable, treatment is primary daily, and nude mice is put to death in continuous treatment after 10 days, and removing tumour calculates the tumor suppression of lotus human liver cancer nude mice
Rate.The result shows that dosage is 1.68 × 10- 2g·Kg- 1·d- 1Tumour inhibiting rate is distinguished both when (being calculated with Oridonin)
For 91.6% and 39.6%.
Embodiment 4
The preparation step that 1.2- ammonia -4- hydroxyl -7,8- dihydropteroic acid is coupled graphene complex is as follows:
(1) by graphene oxide (length: 0.5 μm -3 μm；Thickness: 0.55nm-1.2nm), it is added to distilled water, at 25 DEG C
Lower ultrasound and stirring (revolving speed are as follows: 500rpm) 5h, obtain dispersion liquid.
(2) (1) resulting dispersion liquid is placed in colloid mill further dispersion to grind, obtains finely dispersed graphene oxide
Dispersion liquid.
(3) ultrasound is added into (2) resulting graphene oxide dispersion in 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid and stirred
2h is mixed, the dispersion liquid of 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid and graphene oxide mixing is obtained.
(4) N, N- Dicyclohexylcarbodiimide and n-hydroxysuccinimide is added into step (3) resulting dispersion liquid,
It is stirred to react 5h under the conditions of 30 DEG C, obtains reaction solution.
(5) it is placed in supercentrifuge to step (4) resulting reaction solution and is centrifuged 30min, revolving speed 2000rpm/min, from
After the heart, liquid is discarded supernatant, obtains sediment.
(6) distilled water is added after mixing evenly into step (5) resulting sediment, with miillpore filter (aperture: 0.45 μ
M) it filters, discards filtrate, obtain filter cake.
(7) step (6) resulting filter cake is placed in a vacuum drying oven (vacuum degree: -0.08Mpa；Temperature: 50 DEG C) it is dry
10h obtains 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid coupling graphene complex.
2. cancer target type injection Oridonin dry suspensoid agent percentage includes following component:
Oridonin 40%, 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid are coupled graphene complex 40%, and wetting agent moors Lip river
Husky nurse 188 10%, suspending agent methylcellulose 10%.
3. the method for cancer target type injection Oridonin dry suspensoid agent, includes the following steps:
(1) each component of recipe quantity in above-mentioned cancer target type injection Oridonin dry suspensoid agent is weighed, grinding is mixed
160 meshes are crossed after closing uniformly, it is spare.
(2) step (1) resulting material is sub-packed in cillin bottle in vacuum degree lower than 10Pa or less, and sealed to get institute
The cancer target type injection Oridonin dry suspensoid agent stated.
Cancer target type injection Oridonin dry suspensoid agent is placed 6 months under the conditions of 60 DEG C, cancer target type
The content of Oridonin does not have to change (deviation range≤2%) substantially in injection Oridonin dry suspensoid agent.By 60 DEG C
Under the conditions of the cancer target type injection Oridonin dry suspensoid agent placed 6 months be scattered in sterilized water for injection in 48h
Interior holding is stablized.HePG-2 cell inoculation is subcutaneous in kunming mice, mouse liver tumor model is established, respectively by cancer target
Type injection Oridonin dry suspensoid agent (with being before scattered in sterilized water for injection) and Oridonin injection mouse tail
After intravenously administrable, different time points (0.05h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 12h, for 24 hours, 48h) mouse is put to death, take
Tumor mass, with Determination of oridonin in HPLC analysis tumor tissues.The result shows that cancer target type injection Oridonin
Opposite targeting rate of the dry suspensoid agent in tumor tissues is 8.31.
HePG-2 cell inoculation is subcutaneous in kunming mice, mouse liver tumor model is established, respectively by cancer target type
Injection Oridonin dry suspensoid agent (with being before scattered in sterilized water for injection) and Oridonin injection are through mouse tail
Intravenously administrable, treatment is primary daily, and nude mice is put to death in continuous treatment after 10 days, and removing tumour calculates the tumor suppression of lotus human liver cancer nude mice
Rate.The result shows that dosage is 1.68 × 10- 2g·Kg- 1·d- 1Tumour inhibiting rate is distinguished both when (being calculated with Oridonin)
For 92.5% and 39.6%.
Comparative example 1
This comparative example is substantially the same manner as Example 4, the difference is that cancer target type injection Oridonin dry suspensoid agent
Percentage includes following component:
Oridonin 3%, 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid are coupled graphene complex 30%, and it is husky that wetting agent moors Lip river
Nurse 188 17%, suspending agent methylcellulose 50%.
Cancer target type injection Oridonin dry suspensoid agent is placed 6 months under the conditions of 60 DEG C, cancer target type
The content of Oridonin does not have to change (deviation range≤2%) substantially in injection Oridonin dry suspensoid agent.By 60 DEG C
Under the conditions of the cancer target type injection Oridonin dry suspensoid agent placed 6 months be scattered in sterilized water for injection in 48h
Interior holding is stablized.HePG-2 cell inoculation is subcutaneous in kunming mice, mouse liver tumor model is established, respectively by cancer target
Type injection Oridonin dry suspensoid agent (with being before scattered in sterilized water for injection) and Oridonin injection mouse tail
After intravenously administrable, different time points (0.05h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 12h, for 24 hours, 48h) mouse is put to death, take
Tumor mass, with Determination of oridonin in HPLC analysis tumor tissues.The result shows that cancer target type injection Oridonin
Opposite targeting rate of the dry suspensoid agent in tumor tissues is 3.56.
HePG-2 cell inoculation is subcutaneous in kunming mice, mouse liver tumor model is established, respectively by cancer target type
Injection Oridonin dry suspensoid agent (with being before scattered in sterilized water for injection) and Oridonin injection are through mouse tail
Intravenously administrable, treatment is primary daily, and nude mice is put to death in continuous treatment after 10 days, and removing tumour calculates the tumor suppression of lotus human liver cancer nude mice
Rate.The result shows that dosage is 1.68 × 10- 2g·Kg- 1·d- 1Tumour inhibiting rate is distinguished both when (being calculated with Oridonin)
For 60.1% and 39.6%.
Comparative example 2
This comparative example is substantially the same manner as Example 4, the difference is that cancer target type injection Oridonin dry suspensoid agent
Percentage includes following component:
Oridonin 50%, 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid are coupled graphene complex 30%, and wetting agent moors Lip river
Husky nurse 188 10%, suspending agent methylcellulose 10%.
Cancer target type injection Oridonin dry suspensoid agent is placed 6 months under the conditions of 60 DEG C, cancer target type
The content of Oridonin does not have to change (deviation range≤2%) substantially in injection Oridonin dry suspensoid agent.By 60 DEG C
Under the conditions of the cancer target type injection Oridonin dry suspensoid agent placed 6 months be scattered in sterilized water for injection in 48h
Interior holding is stablized.HePG-2 cell inoculation is subcutaneous in kunming mice, mouse liver tumor model is established, respectively by cancer target
Type injection Oridonin dry suspensoid agent (with being before scattered in sterilized water for injection) and Oridonin injection mouse tail
After intravenously administrable, different time points (0.05h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 12h, for 24 hours, 48h) mouse is put to death, take
Tumor mass, with Determination of oridonin in HPLC analysis tumor tissues.The result shows that cancer target type injection Oridonin
Opposite targeting rate of the dry suspensoid agent in tumor tissues is 4.21.
HePG-2 cell inoculation is subcutaneous in kunming mice, mouse liver tumor model is established, respectively by cancer target type
Injection Oridonin dry suspensoid agent (with being before scattered in sterilized water for injection) and Oridonin injection are through mouse tail
Intravenously administrable, treatment is primary daily, and nude mice is put to death in continuous treatment after 10 days, and removing tumour calculates the tumor suppression of lotus human liver cancer nude mice
Rate.The result shows that dosage is 1.68 × 10- 2g·Kg- 1·d- 1Tumour inhibiting rate is distinguished both when (being calculated with Oridonin)
For 64.3% and 39.6%.
Claims (10)
1. cancer target type injection Oridonin dry suspensoid agent, which is characterized in that percentage, comprising such as the following group
Part: Oridonin 5%~40%, 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid are coupled graphene complex 40%~60%, wetting
Agent 0.1%~30%, suspending agent 1%~40%.
2. cancer target type injection Oridonin dry suspensoid agent according to claim 1, which is characterized in that by weight
Percentage meter includes following component: Oridonin 5%~40%, and it is multiple that 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid is coupled graphene
Close object 40%~60%, wetting agent 5%~10%, suspending agent 10%~35%.
3. cancer target type injection Oridonin dry suspensoid agent according to claim 2, which is characterized in that by weight
Percentage meter, the Oridonin 20%~40%, 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid are coupled graphene complex
40%~50%.
4. cancer target type injection Oridonin dry suspensoid agent according to any one of claims 1 to 3, feature exist
In the wetting agent is selected from PLURONICS F87,237,338 or 407, and the suspending agent is selected from methylcellulose, ethoxy
Cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone K15, PVP K30 or polyvinylpyrrolidone
K90。
5. cancer target type injection Oridonin dry suspensoid agent according to any one of claims 1 to 3, feature exist
In, shown in the structural formula such as formula (I) of 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid coupling graphene complex,
6. cancer target type injection Oridonin dry suspensoid agent according to claim 5, which is characterized in that described
2- ammonia -4- hydroxyl -7,8- dihydropteroic acid be coupled graphene complex the preparation method is as follows: by 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid
It is added in graphene oxide dispersion, N, N- Dicyclohexylcarbodiimide and N- hydroxyl is added to being uniformly mixed in ultrasound and stirring
Succinimide is stirred to react under the conditions of 5 DEG C~50 DEG C, is centrifuged, and filtering is dried to obtain 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid
It is coupled graphene complex.
7. cancer target type injection Oridonin dry suspensoid agent according to claim 6, which is characterized in that described
Ultrasound and mixing time are 0.5h~5h, the described 0.5h~for 24 hours of being stirred to react.
8. cancer target type injection Oridonin dry suspensoid agent according to claim 6, which is characterized in that described
Centrifugation time is 10min~120min, revolving speed 500rpm~15000rpm.
9. cancer target type injection Oridonin dry suspensoid agent according to claim 6, which is characterized in that described
It is dry that vacuum degree is -0.05Mpa~-0.1Mpa, and temperature is 30 DEG C~100 DEG C for vacuum drying, drying time be 0.5h~
24h。
10. cancer target type injection Oridonin dry suspensoid agent according to any one of claims 1 to 3, feature exist
In preparation method includes the following steps: that Oridonin, 2- ammonia -4- hydroxyl -7,8- dihydropteroic acid are coupled graphene in proportion
Compound, wetting agent, suspending agent ground and mixed uniformly cross 120 mesh~200 meshes afterwards, and vacuum degree is sub-packed in west lower than 10Pa or less
It in woods bottle, and seals, cancer target type injection Oridonin dry suspensoid agent is made.
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Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101167718A (en) * | 2007-10-19 | 2008-04-30 | 浙江大学 | Rebescensine A powder injection and preparing process thereof |
| CN101669915A (en) * | 2009-10-19 | 2010-03-17 | 佟丽 | Oridonin dry emulsion and preparation method thereof |
| CN101700222A (en) * | 2009-11-17 | 2010-05-05 | 佟丽 | Oridonin solid dispersion preparation |
| CN102614152A (en) * | 2012-01-13 | 2012-08-01 | 河南大学 | Method for preparing vesicle medicinal nanoparticles |
| CN104146959A (en) * | 2014-09-02 | 2014-11-19 | 深圳市健元医药科技有限公司 | Oridonin sustained release liposome and preparation method thereof |
| CN104224717A (en) * | 2014-04-25 | 2014-12-24 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | Application of oridonin powder aerosol in treatment of acute lung injury |
| CN104490784A (en) * | 2014-12-18 | 2015-04-08 | 南京理工大学 | Folate targeted ultrasound priming oridonin lipid microbubble and application thereof |
| CN104548125A (en) * | 2014-12-30 | 2015-04-29 | 北京大学 | Preparation and application of PEG-PTX-NCs (pegylation-paclitaxel-nanocrystals) |
| CN106924732A (en) * | 2017-03-09 | 2017-07-07 | 南京理工大学 | A kind of ultrasonic therapy cancer target type haematoporphyrin injection and preparation method thereof |
-
2018
- 2018-10-29 CN CN201811266944.8A patent/CN109248146B/en active Active
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101167718A (en) * | 2007-10-19 | 2008-04-30 | 浙江大学 | Rebescensine A powder injection and preparing process thereof |
| CN101669915A (en) * | 2009-10-19 | 2010-03-17 | 佟丽 | Oridonin dry emulsion and preparation method thereof |
| CN101700222A (en) * | 2009-11-17 | 2010-05-05 | 佟丽 | Oridonin solid dispersion preparation |
| CN102614152A (en) * | 2012-01-13 | 2012-08-01 | 河南大学 | Method for preparing vesicle medicinal nanoparticles |
| CN102614152B (en) * | 2012-01-13 | 2015-04-15 | 南京拉克森生物医药科技有限公司 | Method for preparing vesicle medicinal nanoparticles |
| CN104224717A (en) * | 2014-04-25 | 2014-12-24 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | Application of oridonin powder aerosol in treatment of acute lung injury |
| CN104146959A (en) * | 2014-09-02 | 2014-11-19 | 深圳市健元医药科技有限公司 | Oridonin sustained release liposome and preparation method thereof |
| CN104490784A (en) * | 2014-12-18 | 2015-04-08 | 南京理工大学 | Folate targeted ultrasound priming oridonin lipid microbubble and application thereof |
| CN104548125A (en) * | 2014-12-30 | 2015-04-29 | 北京大学 | Preparation and application of PEG-PTX-NCs (pegylation-paclitaxel-nanocrystals) |
| CN106924732A (en) * | 2017-03-09 | 2017-07-07 | 南京理工大学 | A kind of ultrasonic therapy cancer target type haematoporphyrin injection and preparation method thereof |
Non-Patent Citations (5)
| Title |
|---|
| CHUAN-JIN WANG ET AL: "Preparation, In Vitro, and In Vivo Antitumor Activity of Folate Receptor-Targeted Nanoliposomes Containing Oridonin", 《DRUG DEVELOPMENT RESEARCH》 * |
| CHUANJIN WANG ET AL: "The Anti-tumor Effect of Folate-targeted Liposome Microbubbles Loaded with Oridonin as Ultrasound-triggered Tumor-targeted Therapeutic Carrier System", 《JOURNAL OF DRUG TARGETING》 * |
| PENG HUANG ET AL: "Folic Acid-conjugated Graphene Oxide loaded with Photosensitizers for Targeting Photodynamic Therapy", 《THERANOSTICS》 * |
| 徐志远 等: "功能化石墨烯负载冬凌草甲素抗肿瘤制剂的研究", 《有机化学》 * |
| 徐懋琳 等: "冬凌草甲素靶向给药系统研究进展", 《中国现代应用药学》 * |
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