CN101953774B - 2-methoxy estradiol injectable hydrogel implant - Google Patents
2-methoxy estradiol injectable hydrogel implant Download PDFInfo
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- CN101953774B CN101953774B CN2010102846971A CN201010284697A CN101953774B CN 101953774 B CN101953774 B CN 101953774B CN 2010102846971 A CN2010102846971 A CN 2010102846971A CN 201010284697 A CN201010284697 A CN 201010284697A CN 101953774 B CN101953774 B CN 101953774B
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Abstract
The invention relates to a 2-methoxy estradiol injectable hydrogel implant which can effectively solve the problems of maintaining the effective concentration of the target part of 2-methoxy estradiol and enhancing the treatment effect. The invention has the technical scheme that a temperature sensitive type PLGA-PEG-PLGA segmented copolymer having temperature sensitive hydrogel properties is adopted to be mixed with water to prepare dissolution swelling solution; the solution is mixed with the 2-methoxy estradiol to prepare an injection; the temperature sensitive type PLGA-PEG-PLGA segmented copolymer is uniformly mixed with the water to be kept stewing at 0 to 25 DEG C; the temperature sensitive type PLGA-PEG-PLGA segmented copolymer is fully dissolved and swelled into the solution; and the 2-methoxy estradiol is added to be uniformly mixed with solution at 0 to 25 DEG C on the use day or one day before use. The invention has scientific formula, easy production, low cost and good injection effect, can effectively maintain the effective concentration of the target part of the 2-methoxy estradiol and enhance the treatment effect is enhanced and is the innovation on the path of cancer treatment drug forms and drug administration.
Description
One, technical field
The present invention relates to medicine, particularly a kind of 2-methoxyestradiol injection aquagel implant.
Two, background technology
The 2-methoxyestradiol is a kind of anticarcinogen, mainly generate effect and be used for the treatment of breast carcinoma by angiogenesis inhibitor effect and anti-tumor, diseases such as carcinoma of prostate, the drug resistance of this medicine is fine, toxic and side effects is very little, this be other anticarcinogens the advantage that can't satisfy, also be the advantage place that this anticarcinogen is worth the maximum of exploitation.Be again a kind of anti-inflammatory agent simultaneously, be used for the treatment of arthritis etc.Its dosage form is oral tablet and capsule in the at present external clinical trial, takes 1 time or 2 times in one day, and taking dose is bigger, each 400mg-1200mg.The water solublity of this medicine is very poor, and is fat-soluble strong, has certain liver first-pass effect, widely distributed in the body, is difficult to keep effective blood drug level, thereby is difficult to keep effective treatment concentration of target site, and the curative effect of oral administration is undesirable.Even dosage is double, therapeutic effect does not still have improvement.
Three, summary of the invention
At above-mentioned situation, for overcoming the prior art defective, the present invention's purpose just provides a kind of 2-methoxyestradiol injection aquagel implant, can effectively solve the target site valid density that keeps the 2-methoxyestradiol, improve the problem of therapeutic effect, the technical scheme of its solution is, employing has the responsive to temperature type PLGA-PEG-PLGA block copolymer of thermosensitive hydrogel character, mix with water, make swollen solution, be mixed into injection with the 2-methoxyestradiol again, its responsive to temperature type PLGA-PEG-PLGA block copolymer, water, the percentage by weight of 2-methoxyestradiol is 14-25%, 72-84%, 1-3%, wherein, earlier with responsive to temperature type PLGA-PEG-PLGA block copolymer and water mix homogeneously, under 0-25 ℃, leave standstill, make responsive to temperature type PLGA-PEG-PLGA block copolymer fully be swelled into solution, facing, add the 2-methoxyestradiol with the preceding day before yesterday or the same day (in promptly 24 hours), at 0-25 ℃ of following mix homogeneously, get final product.
Said responsive to temperature type PLGA-PEG-PLGA block copolymer is the commercially available prod, product as the production of Mount Tai, Jinan handle of the Big Dipper bio tech ltd, molecular weight is 4000-5000, and PLGA is a lactic acid-ethanol copolymer, lactic acid (LA): the mol ratio of glycolic (GA) is 1-20: 1; PEG is a Polyethylene Glycol, and molecular weight is 1000 or 1500.
Scientific formulation of the present invention is easily manufactured, and cost is low, and injection is effective, can effectively keep the target site valid density of 2-methoxyestradiol, improves therapeutic effect, is the innovation on treatment cancer dosage form and the route of administration.
Four, the specific embodiment
Below in conjunction with embodiment concrete performance of the present invention is elaborated.
Embodiment 1
2-methoxyestradiol injection aquagel implant of the present invention in the specific implementation, with percentage by weight: responsive to temperature type PLGA-PEG-PLGA block copolymer 24.6%, ultra-pure water 73.9%, 2-methoxyestradiol 1.5% are made, wherein earlier with responsive to temperature type PLGA-PEG-PLGA block copolymer and ultra-pure water mix, put and place 2 days (48 hours in the refrigerator at low temperatures, as follows), make the abundant swelling of responsive to temperature type PLGA-PEG-PLGA block copolymer, get final product behind the adding 2-methoxyestradiol mixing before the subcutaneous injection; Or the ultra-pure water of 0.75g responsive to temperature type PLGA-PEG-PLGA block copolymer and 2.25g mixed, put and placed at low temperatures in the refrigerator 2 days, make the abundant swelling of responsive to temperature type PLGA-PEG-PLGA block copolymer, get final product behind the adding 0.045g 2-methoxyestradiol mixing before the subcutaneous injection;
The molecular weight of wherein said responsive to temperature type PLGA-PEG-PLGA block copolymer is 4000, lactic acid: the mol ratio of glycolic is 3: 1, the molecular weight 1000 of Polyethylene Glycol.
Embodiment 2
The present invention in the specific implementation, also can be by weight percent meter: responsive to temperature type PLGA-PEG-PLGA block copolymer 14.8%, ultra-pure water 83.7%, 2-methoxyestradiol 1.5% are made, wherein earlier with responsive to temperature type PLGA-PEG-PLGA block copolymer and ultra-pure water mix, put and placed at low temperatures in the refrigerator 2 days, make the abundant swelling of responsive to temperature type PLGA-PEG-PLGA block copolymer, use to add the 2-methoxyestradiol in preceding 12 hours, mixing gets final product before the subcutaneous injection; Or the ultra-pure water of 0.45g responsive to temperature type PLGA-PEG-PLGA block copolymer and 2.55g mixed, put and placed at low temperatures in the refrigerator 2 days, make the abundant swelling of responsive to temperature type PLGA-PEG-PLGA block copolymer, use to add 0.045g 2-methoxyestradiol in preceding 12 hours, mixing gets final product before the subcutaneous injection;
The molecular weight of wherein said responsive to temperature type PLGA-PEG-PLGA block copolymer is 4500, lactic acid: the mol ratio of glycolic is 6: 1, the molecular weight 1500 of Polyethylene Glycol.
Embodiment 3:
The present invention in the specific implementation, also can be by weight percent meter: responsive to temperature type PLGA-PEG-PLGA block copolymer 24.3%, ultra-pure water 72.8%, 2-methoxyestradiol 2.9% are made, wherein, earlier with responsive to temperature type PLGA-PEG-PLGA block copolymer and ultra-pure water mix, put and placed at low temperatures in the refrigerator 2 days, make the abundant swelling of responsive to temperature type PLGA-PEG-PLGA block copolymer, use to add the 2-methoxyestradiol in preceding 6 hours, mixing gets final product before the subcutaneous injection; Or the ultra-pure water of 0.75g responsive to temperature type PLGA-PEG-PLGA block copolymer and 2.25g mixed, put and placed at low temperatures in the refrigerator 2 days, make the abundant swelling of responsive to temperature type PLGA-PEG-PLGA block copolymer, use to add 0.090g 2-methoxyestradiol in preceding 6 hours, mixing gets final product before the subcutaneous injection;
The molecular weight of wherein said responsive to temperature type PLGA-PEG-PLGA block copolymer is 5000, lactic acid: the mol ratio of glycolic is 12: 1, the molecular weight 1500 of Polyethylene Glycol.
The present invention is effective to as cancer therapy drug, is used for the treatment of cancers such as breast carcinoma and carcinoma of prostate, and drug resistance is good, toxic and side effects is very little, be other cancer therapy drug can't compare, and obtained valid certificates through animal experiment and clinical trial, relevant testing data is as follows:
One, animal experiment
The active test data of anti-Subcutaneous tumor of the present invention is specific as follows:
1. animal: SPF level KM mice, female, 42 scholars, 2 ages in days, body weight 19 ± 2g is provided by Zhengzhou University's Experimental Animal Center.Quality certification numbering: SCXK (Henan) 2010-0001.Every treated animal number: 20 of negative control group, 10 of administration groups, and in 3 years through many batches of tests repeatedly.
2. transplanted tumor: murine sarcoma S-180, by the preservation of going down to posterity of KM mouse ascites.
3. anti-tumor activity in the body: get well-grown 7-11 days S-180 tumor kind, tumor tissue is made 1-2 * 10
-7/ ml cell suspension, KM right side of mice armpit subcutaneous vaccination 0.2ml/ are only.Divide cage at random behind the inoculation 10d, according to the grouping different dosing.Negative control group 1 continuous intravenous injection normal saline every day was injected 21 days continuously; Positive controls 5-fluorouracil (5-FU) 0,3,6,9,12,15,18 day intravenously administrable (i.v) totally 7 times.Blank vehicle group and administration group, in 0 day blank carrier of subcutaneous injection or medicinal liquid in the tumor next door.Put to death animal on the 21st day, weigh, tumor is heavy, calculate that respectively to organize average tumor heavy, obtain tumor control rate and carry out the t check, optimize the optimal treatment group, the results are shown in Table 1.
The anti-tumor in vivo effect of 2-methoxyestradiol injectable implant
Above-mentioned test is in different time, and repeated trials repeatedly all draws identical or close result, and the negative control group in the table 1 is quiet notes normal saline.
By the research of subcutaneous year tumor pharmacodynamics in Mice, with the negative contrast of quiet notes normal saline, with the positive contrast of abdominal part injection 5-fluorouracil, draw by table 1, three dosage groups of hydrogel implant of the present invention all have tangible anti-Subcutaneous tumor effect, and along with the increase of dosage, the antineoplastic effect increases thereupon.Simultaneously proved that also this gel has the effect of slow release long-acting really.
Two, clinic trial data
Through clinic trial, obtained promising result, concrete clinical data is as follows:
297 routine women patient with breast cancers, 21～62 years old age, the course of disease 2 months～10 years, therapeutic scheme is, local subcutaneous injection implant 2ml, pastille 30mg, 1 month is a course of treatment, the evaluation curative effect is as follows after 2 courses of treatment: symptom significantly improves, tumor disappears and is produce effects, produce effects person's 30 examples (10.1%), and symptom improves, pain relief is effective, responder's 266 examples (89.6%), symptom does not have improvement, even the becoming for invalid of deterioration arranged, nonresponder's 1 example (0.3%), total effective 296 examples (99.7%).
In sum, the present invention can local targeting and is concentrated in the Subcutaneous tumor position, significantly improve curative effect, make the medicine focus of going directly by the local subcutaneous drug administration by injection, make focus keep higher treatment concentration for a long time, thereby greatly improve curative effect, avoided the distribution of the first pass effect and the whole body of liver, convenient drug administration has avoided conventional solid-state implant to need the misery of minor operation, and administration in 1 month 1 time, greatly improve the compliance of patient's medication, said preparation preparation technology is simple in addition, does not need special equipment and instrument, and remarkable economical and social benefit are arranged.
Claims (7)
1. 2-methoxyestradiol injection aquagel implant, it is characterized in that, adopt responsive to temperature type PLGA-PEG-PLGA block copolymer, mix with water, make swollen solution, be mixed into injection with the 2-methoxyestradiol again, its responsive to temperature type PLGA-PEG-PLGA block copolymer, water, the percentage by weight of 2-methoxyestradiol is 14-25%, 72-84%, 1-3%, wherein, earlier with responsive to temperature type PLGA-PEG-PLGA block copolymer and water mix homogeneously, under 0-25 ℃, leave standstill, make responsive to temperature type PLGA-PEG-PLGA block copolymer fully be swelled into solution, facing, add the 2-methoxyestradiol with the preceding day before yesterday or the same day, at 0-25 ℃ of following mix homogeneously, get final product;
Said responsive to temperature type PLGA-PEG-PLGA block copolymer amount is 4000-5000, and PLGA is a lactic acid-ethanol copolymer, lactic acid: the mol ratio of glycolic is 1-20: 1; PEG is a Polyethylene Glycol, and molecular weight is 1000 or 1500.
2. 2-methoxyestradiol injection aquagel implant according to claim 1, it is characterized in that, by percentage by weight: responsive to temperature type PLGA-PEG-PLGA block copolymer 24.6%, ultra-pure water 73.9%, 2-methoxyestradiol 1.5% is made, wherein earlier responsive to temperature type PLGA-PEG-PLGA block copolymer and ultra-pure water are mixed, under 0-25 ℃ low temperature, placed 2 days, make the abundant swelling of responsive to temperature type PLGA-PEG-PLGA block copolymer, get final product after adding 2-methoxyestradiol mixing before the subcutaneous injection, the molecular weight of wherein said responsive to temperature type PLGA-PEG-PLGA block copolymer is 4000, lactic acid: the mol ratio of glycolic is 3: 1, the molecular weight 1000 of Polyethylene Glycol.
3. 2-methoxyestradiol injection aquagel implant according to claim 1, it is characterized in that, the ultra-pure water of 0.75g responsive to temperature type PLGA-PEG-PLGA block copolymer and 2.25g is mixed, under 0-25 ℃ low temperature, placed 2 days, make the abundant swelling of responsive to temperature type PLGA-PEG-PLGA block copolymer, get final product behind the adding 0.045g 2-methoxyestradiol mixing before the subcutaneous injection; The molecular weight of wherein said responsive to temperature type PLGA-PEG-PLGA block copolymer is 4000, lactic acid: the mol ratio of glycolic is 3: 1, the molecular weight 1000 of Polyethylene Glycol.
4. 2-methoxyestradiol injection aquagel implant according to claim 1, it is characterized in that, by weight percent meter: responsive to temperature type PLGA-PEG-PLGA block copolymer 14.8%, ultra-pure water 83.7%, 2-methoxyestradiol 1.5% are made, wherein earlier responsive to temperature type PLGA-PEG-PLGA block copolymer and ultra-pure water are mixed, under 0-25 ℃ low temperature, placed 2 days, make the abundant swelling of responsive to temperature type PLGA-PEG-PLGA block copolymer, use to add the 2-methoxyestradiol in preceding 12 hours, mixing gets final product before the subcutaneous injection; The molecular weight of wherein said responsive to temperature type PLGA-PEG-PLGA block copolymer is 4500, lactic acid: the mol ratio of glycolic is 6: 1, the molecular weight 1000 of Polyethylene Glycol.
5. 2-methoxyestradiol injection aquagel implant according to claim 1, it is characterized in that, the ultra-pure water of 0.45g responsive to temperature type PLGA-PEG-PLGA block copolymer and 2.55g is mixed, under 0-25 ℃ low temperature, placed 2 days, make the abundant swelling of responsive to temperature type PLGA-PEG-PLGA block copolymer, use to add 0.045g 2-methoxyestradiol in preceding 12 hours, mixing gets final product before the subcutaneous injection; The molecular weight of wherein said responsive to temperature type PLGA-PEG-PLGA block copolymer is 4500, lactic acid: the mol ratio of glycolic is 6: 1, the molecular weight 1500 of Polyethylene Glycol.
6. 2-methoxyestradiol injection aquagel implant according to claim 1, it is characterized in that, by weight percent meter: responsive to temperature type PLGA-PEG-PLGA block copolymer 24.3%, ultra-pure water 72.8%, 2-methoxyestradiol 2.9% are made, wherein, earlier responsive to temperature type PLGA-PEG-PLGA block copolymer and ultra-pure water are mixed, under 0-25 ℃ low temperature, placed 2 days, make the abundant swelling of responsive to temperature type PLGA-PEG-PLGA block copolymer, use to add the 2-methoxyestradiol in preceding 6 hours, mixing gets final product before the subcutaneous injection; The molecular weight of wherein said responsive to temperature type PLGA-PEG-PLGA block copolymer is 5000, lactic acid: the mol ratio of glycolic is 12: 1, the molecular weight 1500 of Polyethylene Glycol.
7. 2-methoxyestradiol injection aquagel implant according to claim 1, it is characterized in that, the ultra-pure water of 0.75g responsive to temperature type PLGA-PEG-PLGA block copolymer and 2.25g is mixed, under 0-25 ℃ low temperature, placed 2 days, make the abundant swelling of responsive to temperature type PLGA-PEG-PLGA block copolymer, use to add 0.090g 2-methoxyestradiol in preceding 6 hours, mixing gets final product before the subcutaneous injection; The molecular weight of wherein said responsive to temperature type PLGA-PEG-PLGA block copolymer is 5000, lactic acid: the mol ratio of glycolic is 12: 1, the molecular weight 1500 of Polyethylene Glycol.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102846971A CN101953774B (en) | 2010-09-17 | 2010-09-17 | 2-methoxy estradiol injectable hydrogel implant |
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| CN2010102846971A CN101953774B (en) | 2010-09-17 | 2010-09-17 | 2-methoxy estradiol injectable hydrogel implant |
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| CN101953774B true CN101953774B (en) | 2011-11-23 |
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| CN104606129B (en) * | 2015-01-21 | 2018-05-04 | 中国人民解放军广州军区武汉总医院 | Ropivacaine long-acting injection thermo-sensitive gel and preparation method thereof |
| CN107412161A (en) * | 2017-05-22 | 2017-12-01 | 河南科技大学 | A kind of methoxyestradiol intravenous injection of self-emulsifying 2 and preparation method thereof |
| CN109481449A (en) * | 2018-10-10 | 2019-03-19 | 浙江大学 | Sustained release for endometriosis Establishment of mouse model mixes liquid and preparation method |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060083778A1 (en) * | 2002-05-03 | 2006-04-20 | Dean Allison | Controlled release compositions of estradiol metabolites |
| CN1946352A (en) * | 2004-04-09 | 2007-04-11 | 狄科特康坦特公司 | Methods and articles for the delivery of medicaments to the eye for the treatment of posterior segment diseases |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060083778A1 (en) * | 2002-05-03 | 2006-04-20 | Dean Allison | Controlled release compositions of estradiol metabolites |
| CN1946352A (en) * | 2004-04-09 | 2007-04-11 | 狄科特康坦特公司 | Methods and articles for the delivery of medicaments to the eye for the treatment of posterior segment diseases |
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Inventor after: Zhang Zhenzhong Inventor after: Guo Xinhong Inventor after: Xing Yabing Inventor after: Zhang Hongling Inventor after: Zhang Zhengquan Inventor after: Hu Haiying Inventor after: Mei Qian Inventor after: Li Junmei Inventor before: Zhang Zhenzhong Inventor before: Guo Xinhong Inventor before: Zhang Zhengquan Inventor before: Zhang Hongling Inventor before: Hu Haiying Inventor before: Xing Yabing Inventor before: Mei Qian |
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Free format text: CORRECT: INVENTOR; FROM: ZHANG ZHENZHONG GUO XINHONG ZHANG ZHENGQUAN ZHANG HONGLING HU HAIYING XINGYABING MEI QIAN TO: ZHANG ZHENZHONG GUO XINHONG XING YABING ZHANG HONGLING ZHANG ZHENGQUAN HU HAIYING MEI QIAN LI JUNMEI |
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