CN102743329B - Intrauterine sustained control release drug delivery system and preparation method thereof - Google Patents
Intrauterine sustained control release drug delivery system and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to a female intrauterine drug delivery system, and more particularly to a novel intrauterine sustained control release drug delivery system and a preparation method thereof. The present invention provides a novel intrauterine sustained control release drug delivery system and a preparation method thereof, wherein the system has characteristics of short length, light weight, efficiency, and reversibility. The system comprises a sustained control release pipe, a drug core and a tail filament, wherein the sustained control release pipe is wrapped on the external of the drug core, the tail filament is positioned between the sustained control release pipe and the drug core or is accomodated in the middle of the drug core, the drug core is a rod prepared by blending progesterone or an available intrauterine sustained control release drug and a biodegradable polymer, and the sustained control release pipe is made of a silicon rubber. The system of the present invention has characteristics of no stent, no copper ion, safety, practicality, and simple placement technology.
Description
Technical field:
The present invention relates in utero drug-supplying system of a kind of women, more particularly, relate in utero slowly released and controlled-drug delivery system and preparation method thereof of one.
Background technology:
At present, on market containing progesterone in utero drug-supplying system be mainly Man Yuele (Mirena), but it is supporting structure, and certain damage is caused in women's uterus.The in utero drug-supplying system that is used for the treatment of gynaecopathia also normally occurs with the form of intrauterine device.Intrauterine device (Intrauterine Device, IUD) is the contraceptive device being placed in women's cavity of uterus, is a kind of safe, effective, easy, economical, and reversible method of birth control.Within 2002, World Health Organization (WHO) statistical data shows, the whole world has and exceedes 1.56 hundred million women and use IUD, and its utilization rate is in rising trend, and China is used the women of IUD to exceed 100,000,000, accounts for 2/3 of the total number of users in the whole world.
If domestic widely used pastille is drug main indomethacin, the steroid hormone in drug-supplying system in utero, as take market graceful month salable happy as its pastille of IUD of representative be steroid hormone.Graceful month happy is T-shaped support, and transverse arm material is polyethylene, and medicine-releasing system is levonorgestrel (LNG) and Silicone Rubber Blends bank.The intrauterine device of supporting structure; placement technique requires high; while misfitting with uterus shape, can cause the coming off of birth control apparatus, pain, unexpected pregnant and undesired or serious metrorrhagia side reaction; damage to women of child-bearing age's physical and mental health, use graceful month happy women's amenorrhea incidence rate higher simultaneously.Calendar year 2001, a kind of unsupported IUS:(FibroPlant levonorgestrel intrauterine system of Belgium's development), the matrix material of release is ethylene-vinyl acetate copolymer (EVA), medicine is LNG, be used for the treatment of menorrhagia and contraception, effectively reduce amount of bleeding by effective inhibition inner membrance, and reach the effect of contraception.This intrauterine device has two kinds of specifications, discharges respectively LNG14 μ g/d or 20 μ g/d, and useful life is 5 years.Be all the Femilis medicated intrauterine devices of Belgium's development, structure is happy close with graceful month, be all T-shaped IUD, have flexible arm, the matrix material of medicine-releasing system is EVA, discharges LNG20 μ g/d, useful life is 5 years, the another kind of Femilis slim smaller than Femilis size is applicable to menopausal women, and it discharges LNG20 μ g/d, 3 year operating period.Compared with Femilis series intrauterine device is happy with graceful month, simplify the requirement of placement technique.
Another kind of in utero drug-supplying system is by copper and drug synergism, plays the effect of contraception or treatment gynaecopathia.Cupric in utero drug-supplying system discharges a large amount of copper ions in the bottom, palace of uterine cavity, can change the activity of endometrium alkali phosphatase, affect the growth of synchronizeing of endometrium and cytula, there is spermicide and cytotoxic effect simultaneously, increase reliably antifertility effect, but in utero drug-supplying system of cupric, copper ion exists " burst release " phenomenon, the cupric copper ion rate of release that in utero drug-supplying system existed at the initial stage of inserting uterus is far away higher than the phenomenon of the average rate of release after the initial stage.This " burst release " phenomenon causes copper ion concentration in uterine fluid to exceed even decades of times of several times than normal time, too high copper ion concentration not only no longer strengthens the in utero contraceptive effect of drug-supplying system of cupric, can increase the weight of on the contrary endometrial inflammation and tissue injury, the local fibrinolytic of endometrium is increased, finally become and cause in utero drug-supplying system to insert one of reason of initial stage amount of bleeding increase, bleeding time prolongation, pain, pelvic inflammatory disease (PID) etc.
To sum up, the in utero drug-supplying system containing progesterone of at present research or be supporting structure, can cause certain damage to women's uterus; Or be in utero drug-supplying system of cupric, wherein the side effect of copper has also caused certain injury to women.Indivedual in utero research of drug-supplying system has advanced to preclinical phase, but also has larger distance apart from practical application, and has the irrational problem of drug-supplying system form.
Summary of the invention:
The present invention is exactly for the problems referred to above, provides a kind of length little, lightweight, efficient, reversible in utero slowly released and controlled-drug delivery system and preparation method thereof.
In order to realize above-mentioned purpose of the present invention, the present invention adopts following technical scheme, comprises slow controlled release tubing, medicated core and tailfiber, and slow controlled release tubing is wrapped in medicated core outside, and tailfiber is between slow controlled release tubing and medicated core or be contained in the middle of medicated core; Described medicated core is progesterone or can be used for sustained and controlled release medicament in utero and bar that biodegradable polymer blending is made; Described slow controlled release tubing is made up of silicone rubber.
In medicated core, progesterone or can be used for sustained and controlled release medicament in utero and the mass ratio of biological degradation polyalcohol is 0.1～30:100.
Tailfiber material is polyethylene or polypropylene.
Described biological degradation polyalcohol is trimethylene carbonate (TMC), linear polymer, star-type polymer or crosslinking polymer to dioxy cyclohexanone (PDO), lactide (LA), caprolactone (CL), Acetic acid, hydroxy-, bimol. cyclic ester (GA).
Described linear polymer is homopolymer or copolymer.
The preparation of crosslinking polymer adopts irradiation method.
Irradiation method is that the medicated core that is linear polymer or star-type polymer by matrix material carries out the irradiation of 1～10M dosage on X ray, electrostatic accelerator or electron linear accelerator.
The length of described in utero slowly released and controlled-drug delivery system is 20～40mm.
The external diameter of slow controlled release tubing is 1.2～3.0mm, wall thickness 0.2～0.5mm.
In utero the burst size of drug-supplying system is 2～40 μ g/d.
In utero the two ends of slowly released and controlled-drug delivery system are all provided with fixed knot, are respectively fixed knot one and fixed knot two.
Progesterone is gestodene (Gestodene), gestrinone (Gestrinone), norgestrienone (Norgestrienone), levonorgestrel (Levonorgestrel), nomegestrol (Nomegestrel), etonogestrel (Etonogestrel), trimegestone (Trimegestone), promegestone (Promegestone), dydrogesterone (Dydrogesterone), drospirenone (Drospirenone), ST-1435 (Nestoron), how sterone (nestorone), desogestrel (Desogestrel), cyproterone acetate (cyproterone acetate), norgestimate (Norgestimate), norethindrone (Norethisterone), medroxyprogesterone (Medroxyprogesterone), megestrol (Megestrol), more than one in 3-ketodesogestrel.
An in utero preparation method for slowly released and controlled-drug delivery system, in the time that biological degradation polyalcohol is linear polymer or star-type polymer, preparation process is,
(1) preparation of medicated core: the progesterone that is 0.1～30:100 by mass ratio or can be used for sustained and controlled release medicament in utero and mix homogeneously with linear polymer or star-type polymer after, then adopt screw extruder method or die pressing that compound is made to the medicated core that matrix material is linear polymer or star-type polymer;
(2) medicated core step (1) being made and tailfiber pack in the slow controlled release tubing of silicone rubber;
(3) utilize silicone rubber adhesive to carry out shutoff to slow controlled release tubing.
In the time that biological degradation polyalcohol is crosslinking polymer, preparation process is,
(1) preparation of medicated core: the progesterone that is 0.1～30:100 by mass ratio or can be used for sustained and controlled release medicament in utero and mix homogeneously with linear polymer or star-type polymer after, then adopt screw extruder method or die pressing that compound is made to the medicated core that matrix material is linear polymer or star-type polymer; Then the medicated core that is linear polymer or star-type polymer by matrix material carries out the irradiation of 1～10M dosage on X ray, electrostatic accelerator or electron linear accelerator, makes the medicated core that matrix material is crosslinking polymer;
(2) medicated core step (1) being made and tailfiber pack in the slow controlled release tubing of silicone rubber;
(3) utilize silicone rubber adhesive to carry out shutoff to slow controlled release tubing.
Described biological degradation polyalcohol is trimethylene carbonate (TMC), linear polymer, star-type polymer or crosslinking polymer to dioxy cyclohexanone (PDO), lactide (LA), caprolactone (CL), Acetic acid, hydroxy-, bimol. cyclic ester (GA); Linear polymer is homopolymer or copolymer.
The preparation process of medicated core is: by linear polymer or star-type polymer and progesterone or can be used for sustained and controlled release medicament in utero and stir 5～10min or stir 3～8min in high-speed mixer in banbury at 70～110 ℃ and form premix material, subsequently premix material is adopted to screw extruder extrusion molding at 50～150 ℃ of temperature, wherein, screw speed is 8～40r/min, hauling speed is 10～50cm/min, and Melt Pump rotating speed is that 3～10r/min, air mass flow are 5～20ml/min; Or premix is put in the middle of the mould of moulded rod, mould is placed on vulcanizing press, preheating 1～5min at 80～140 ℃, make the complete melting of biological degradation polyalcohol, then 3～the 7Mpa that pressurizes maintains 0.5～5min, the 0.5～3min that takes out, colds pressing, and the last demoulding rapidly can obtain the medicated core take linear polymer or star-type polymer as matrix.Or be that the medicated core of linear polymer or star-type polymer carries out the irradiation of 1～10M dosage on X ray, electrostatic accelerator or electron linear accelerator by matrix material, obtain the medicated core take crosslinking polymer as matrix.
Beneficial effect of the present invention:
1. without support.
Abandon the tradition supporting structure of drug-supplying system in utero, the side reactions such as hemorrhage, the pain of effectively having avoided that support occurs endometrial damage.
2. copper ions not.
For cupric in drug-supplying system in utero in utero drug-supplying system all there is a common problem, there is exactly " burst release " phenomenon of copper ion at the initial stage of inserting uterus, thereby cause and insert initial stage amount of bleeding increase, bleeding time prolongation, pain, pelvic inflammatory disease (PID) etc.The present invention realizes controlled release by biological degradation polyalcohol to medicine, reach rational dosage, do not use and have the copper of stronger side effect, thus can avoid due to the initial stage copper ion of inserting exists that " burst release ", metallic copper directly contact with endometrium, the effective rate of utilization of metallic copper is not high, copper surface is understood roughening and deposit that hard deposit etc. causes as side effect such as pain, hemorrhage and menoxenias.
3. safe, practical, efficient.
In utero drug-supplying system of the present invention merges menorrhagia, endometrial hyperplasia etc. for Hormone Replacement Therapy, treatment dysmenorrhea, menorrhagia, hysteromyoma, simultaneously because progesterone biological activity is high, also there is efficient contraceptive efficacy, take out after drug-supplying system, can recover reproductive function, thereby drug-supplying system of the present invention has efficient, reversible feature.
Accompanying drawing explanation:
Fig. 1 is structural representation of the present invention.
In Fig. 1,1 slow controlled release tubing, 2 medicated core, 3 tailfibers, 4 fixed knot one, 5 fixed knots two.
The specific embodiment:
One is slowly released and controlled-drug delivery system in utero, comprises slow controlled release tubing 1, medicated core 2 and tailfiber 3, and slow controlled release tubing 1 is wrapped in medicated core 2 outsides, and tailfiber 3 is between slow controlled release tubing 1 and medicated core 2 or be contained in medicated core 2 centres.
In utero the length of slowly released and controlled-drug delivery system is 20～40mm.
The external diameter of slow controlled release tubing 1 is 1.2～3.0mm, wall thickness 0.2～0.5mm.
In utero the two ends of slowly released and controlled-drug delivery system are all provided with fixed knot, are respectively fixed knot 1 and fixed knot 25.
Provide the following example so that those skilled in the art are easier to understand and implement the present invention.But they should not be regarded as limiting the scope of the invention, and are only its example and representative.Illustrate below in conjunction with accompanying drawing.
Embodiment 1
1. be 2 × 10 by molecular weight
4the polycaprolactone of g/mol and gestodene's crystalline powder (mass ratio is 100:4) stir after 5min forms premix material and put in the middle of the mould of pressure bar in banbury at 70 ℃, mould is placed on vulcanizing press, preheating 2min at 80 ℃, then the 5Mpa that pressurizes maintains 1min, 2min takes out, colds pressing, it is the medicated core that 1.8mm contains gestodene that finally demould obtains diameter, and making effective length is the in utero drug-supplying system containing gestodene 8mg/25mm.
2. it is 30mm that the medicated core of being prepared by step 1 and polypropylene tailfiber are encased in length, and external diameter is 3.0mm, in the slow controlled release tubing of silicone rubber that wall thickness is 0.5mm.
3. by the two ends of the slow controlled release tubing of silicone rubber, adopt silicone rubber adhesive to carry out shutoff, obtain in utero drug-supplying system.The effective length of drug-supplying system is 25mm, and burst size is 20 μ g/d, useful life at least 1 year.
Embodiment 2
As different from Example 1, the mass ratio of polycaprolactone and gestodene's crystalline powder is 100:8, makes medicated core contain gestodene 16mg/25mm, and the polycaprolactone molecular weight using is 5.3 × 10
4g/mol, burst size is 20 μ g/d, useful life at least 2 years.
As different from Example 1, the preparation method that contains gestodene's medicated core is extrusion molding, is 2 × 10 by molecular weight
4the polycaprolactone of g/mol and gestodene's crystalline powder (mass ratio is 100:4) stir 5min and form after premix material in banbury at 70 ℃, on Miniature precision extruder, extruding diameter is the medicated core that 1.8mm contains gestodene, screw speed is 20r/min, hauling speed is 20cm/min, Melt Pump rotating speed is 5r/min, and air mass flow is 10ml/min.
Embodiment 4
1. be 2.0 × 10 by molecular weight
5the trimethylene carbonate of g/mol and caprolactone copolymer (mol ratio is 10:90) stir 8min with gestodene's powder (mass ratio is 100:5) and form after premix material in banbury at 130 ℃, on Miniature precision extruder, extruding diameter is the medicated core that 1.8mm contains gestodene, screw speed is 15r/min, hauling speed is 15cm/min, Melt Pump rotating speed is 3r/min, and air mass flow is 5ml/min.Cutting Length is for containing gestodene 8mg/20mm.
2. the medicated core of being prepared by step 1 and polyethylene tailfiber are encased in long 25mm, and external diameter 2.9mm, in the slow controlled release tubing of silicone rubber of wall thickness 0.45mm.
3. by the two ends of the slow controlled release tubing of silicone rubber, adopt silicone rubber adhesive to carry out shutoff, obtain in utero drug-supplying system.The effective length of drug-supplying system is 20mm, and burst size is 10 μ g/d, useful life at least 2 years.
Embodiment 5
As different from Example 4, the mass ratio that changes polymer and gestodene's crystalline powder is 100:19, and making content of dispersion is 30.4mg/30mm, and the x-ray irradiation that it is carried out to 5M dosage is crosslinked, obtains the medicated core that matrix is cross-linking type biological degradation polyalcohol.Burst size is 15 μ g/d, useful life at least 5 years.
Embodiment 6
As different from Example 4, the preparation method that changes the medicated core that contains gestodene is compression molding, 2.0 × 10
5the trimethylene carbonate of g/mol and caprolactone copolymer (mol ratio is 10:90) stir after 5min forms premix material and put in the middle of the mould of moulded rod with gestodene's powder (mass ratio is 100:5) in banbury at 70 ℃, and be placed on vulcanizing press, preheating 5min at 130 ℃, then the 7Mpa that pressurizes maintains 2min, 3min takes out, colds pressing, finally demould, obtains the medicated core containing gestodene.
Embodiment 7
1. be 2.5 × 10 by molecular weight
5the trimethylene carbonate of g/mol and lactide copolymer (mol ratio is 30:70) stir 5min with gestodene's crystalline powder (mass ratio is 100:4) and form after premix material in banbury at 150 ℃, on Miniature precision extruder, extruding diameter is the medicated core that 1.8mm contains gestodene, screw speed is 15r/min, hauling speed is 25cm/min, Melt Pump rotating speed is 3r/min, and air mass flow is 6ml/min.Cutting Length is for containing gestodene 8mg/25mm.
2. the medicated core of being prepared by step 1 and polyethylene tailfiber are encased in long 30mm, and external diameter 3.0mm, in the slow controlled release tubing of silicone rubber of wall thickness 0.5mm.
3. by the two ends of the slow controlled release tubing of silicone rubber, adopt silicone rubber adhesive to carry out shutoff, obtain in utero drug-supplying system.The effective length of drug-supplying system is 25mm, and burst size is 10 μ g/d, useful life at least 2 years.
Embodiment 8
1. be 1.0 × 10 by molecular weight
5g/mol stirs after 7min formation premix material with levonorgestrel powder (mass ratio is 100:5) dioxy cyclohexanone and caprolactone (mol ratio is 20:80) in banbury at 70 ℃, on Miniature precision extruder, extrude the medicated core that diameter is 2.0mm, and it is crosslinked that medicated core material is carried out to the x-ray irradiation of 2M, obtains the medicated core that matrix material is cross-linking type biological degradation polyalcohol.Cutting Length is for containing levonorgestrel 8mg/20mm.
2. the medicated core of being prepared by step 1 and polyethylene tailfiber are encased in long 25mm, and external diameter 2.8mm, in the slow controlled release tubing of silicone rubber of wall thickness 0.3mm.
3. by the two ends of the slow controlled release tubing of silicone rubber, adopt silicone rubber adhesive to carry out shutoff, obtain in utero drug-supplying system.The effective length of drug-supplying system is 20mm, and burst size is 10 μ g/d, useful life at least 2 years.
Embodiment 9
1. by 1.5 × 10
5g/mol stirs after 6min forms premix material and puts in the middle of the mould of moulded rod with levonorgestrel powder (mass ratio is 100:3) dioxy cyclohexanone and caprolactone (mol ratio is 10:90) in banbury at 70 ℃, and be placed on vulcanizing press, preheating 5min at 80 ℃, then the 5Mpa that pressurizes maintains 5min, 5min takes out, colds pressing, finally demould, obtaining diameter is the medicated core that 1.5mm contains levonorgestrel, and the x-ray irradiation that carries out 2M is crosslinked, obtains the medicated core that matrix material is cross-linking type biological degradation polyalcohol.Cutting Length is for containing levonorgestrel 8.4mg/35mm.
2. the medicated core of being prepared by step 1 and polyethylene tailfiber are encased in long 40mm, and external diameter 2.0mm, in the slow controlled release tubing of silicone rubber of wall thickness 0.2mm.
3. by the two ends of the slow controlled release tubing of silicone rubber, adopt silicone rubber adhesive to carry out shutoff, obtain in utero drug-supplying system.The effective length of drug-supplying system is 35mm, and burst size is 15 μ g/d, useful life at least 1.5 years.
By embodiment 1～9 list, as shown in table 1.
Table 1
Embodiment 10
Prepare in utero drug-supplying system according to the identical method of embodiment 1, but be first to carry out compression molding after poly tailfiber is directly put into premix material centre by material, tailfiber is directly contained in the middle of medicated core, obtain directly with tailfiber and take linear polymer or star-type polymer as matrix containing gestodene's medicated core.
Embodiment 11
Prepare in utero drug-supplying system according to the identical method of embodiment 9, but be first to carry out compression molding after poly tailfiber is directly put into premix material centre by material, tailfiber be directly contained in the middle of medicated core, obtain directly with tailfiber containing gestodene's medicated core.By with tailfiber containing gestodene's medicated core carry out the x-ray irradiation of 2M crosslinked after, obtain directly with tailfiber and take crosslinking polymer as matrix containing gestodene's medicated core.
Embodiment 12
By 3 arm star copolymers of trimethylene carbonate and caprolactone (mol ratio is 67:33), (molecular weight is 8 × 10
4g/mol) in mixer, at 50 ℃, stir after 3min forms premix material and put in the middle of the mould of moulded rod with gestodene's crystalline powder (mass ratio is 100:6), mould is placed on vulcanizing press, preheating 1.5min at 60 ℃, then the 3Mpa that pressurizes maintains 1min, 3min takes out, colds pressing, it is the medicated core that 1.8mm contains gestodene that finally demould obtains diameter, and on electron linear accelerator, carry out the cross-linking radiation of 5M, obtain the medicated core that matrix material is cross-linking type biological degradation polyalcohol.Cutting Length is for containing gestodene 12mg/25mm.
2. the medicated core of being prepared by step 1 and polyethylene tailfiber are encased in long 30mm, and external diameter 3.0mm, in the slow controlled release tubing of silicone rubber of wall thickness 0.5mm.
3. by the two ends of the slow controlled release tubing of silicone rubber, adopt silicone rubber adhesive to carry out shutoff, obtain in utero drug-supplying system.The effective length of drug-supplying system is 25mm, and burst size is 30 μ g/d, useful life at least 1 year.
Claims (3)
1. a slowly released and controlled-drug delivery system in utero, is characterized in that, comprises slow controlled release tubing, medicated core and tailfiber, and slow controlled release tubing is wrapped in medicated core outside, and tailfiber is between slow controlled release tubing and medicated core or be contained in the middle of medicated core; Described medicated core is progesterone or can be used for sustained and controlled release medicament in utero and bar that biodegradable polymer blending is made; Described slow controlled release tubing is made up of silicone rubber;
Described biological degradation polyalcohol is trimethylene carbonate (TMC), linear polymer, star-type polymer or crosslinking polymer to dioxy cyclohexanone (PDO), and described linear polymer is homopolymer or copolymer;
In medicated core, progesterone or can be used for sustained and controlled release medicament in utero and the mass ratio of biological degradation polyalcohol is 0.1 ~ 30:100;
In the time that biological degradation polyalcohol is linear polymer or star-type polymer, preparation process is,
(1) preparation of medicated core: the progesterone that is 0.1 ~ 30:100 by mass ratio or can be used for sustained and controlled release medicament in utero and mix homogeneously with linear polymer or star-type polymer after, then adopt screw extruder method or die pressing that compound is made to the medicated core that matrix material is linear polymer or star-type polymer;
(2) medicated core step (1) being made and tailfiber pack in the slow controlled release tubing of silicone rubber;
(3) utilize silicone rubber adhesive to carry out shutoff to slow controlled release tubing;
In the time that biological degradation polyalcohol is crosslinking polymer, preparation process is,
(1) preparation of medicated core: the progesterone that is 0.1 ~ 30:100 by mass ratio or can be used for sustained and controlled release medicament in utero and mix homogeneously with linear polymer or star-type polymer after, then adopt screw extruder method or die pressing that compound is made to the medicated core that matrix material is linear polymer or star-type polymer; Then the medicated core that is linear polymer or star-type polymer by matrix material carries out the irradiation of 1 ~ 10M dosage on X ray, electrostatic accelerator or electron linear accelerator, makes the medicated core that matrix material is crosslinking polymer;
(2) medicated core step (1) being made and tailfiber pack in the slow controlled release tubing of silicone rubber;
(3) utilize silicone rubber adhesive to carry out shutoff to slow controlled release tubing.
2. in utero slowly released and controlled-drug delivery system according to claim 1, is characterized in that, the external diameter of slow controlled release tubing is 1.2～3.0 mm, wall thickness 0.2 ~ 0.5 mm, and in utero the length of slowly released and controlled-drug delivery system is 20～40 mm, burst size is 2～40 μ g/d.
3. in utero slowly released and controlled-drug delivery system according to claim 1, is characterized in that, in utero the two ends of slowly released and controlled-drug delivery system are all provided with fixed knot, is respectively fixed knot one and fixed knot two.
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| CN101209238A (en) * | 2006-12-27 | 2008-07-02 | 辽宁省计划生育科学研究院 | Biological degradation type long-acting hypodermal contraception implant containing gestodene and preparation thereof |
| CN101926783A (en) * | 2010-08-31 | 2010-12-29 | 中国医学科学院生物医学工程研究所 | Drug slow control releaser and preparation method thereof |
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| CN101209238A (en) * | 2006-12-27 | 2008-07-02 | 辽宁省计划生育科学研究院 | Biological degradation type long-acting hypodermal contraception implant containing gestodene and preparation thereof |
| CN101926783A (en) * | 2010-08-31 | 2010-12-29 | 中国医学科学院生物医学工程研究所 | Drug slow control releaser and preparation method thereof |
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Effective date of registration: 20210623 Address after: 110031 no.10-4, Puhe street, Huanggu District, Shenyang City, Liaoning Province Patentee after: Yang Liqun Address before: 110031, No. 10, Po River Street, Huanggu District, Liaoning, Shenyang Patentee before: LIAONING Research Institute OF FAMILY PLANNING |