CN102145160A - Controlled-release implanting preparation used for injecting LHRH (luteinizing hormone releasing hormone) antagonist - Google Patents
Controlled-release implanting preparation used for injecting LHRH (luteinizing hormone releasing hormone) antagonist Download PDFInfo
- Publication number
- CN102145160A CN102145160A CN2011100540735A CN201110054073A CN102145160A CN 102145160 A CN102145160 A CN 102145160A CN 2011100540735 A CN2011100540735 A CN 2011100540735A CN 201110054073 A CN201110054073 A CN 201110054073A CN 102145160 A CN102145160 A CN 102145160A
- Authority
- CN
- China
- Prior art keywords
- release
- cetrorelix
- cetrorelix acetate
- implant
- controlled
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 46
- 238000013270 controlled release Methods 0.000 title abstract description 11
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 title abstract description 5
- 239000005557 antagonist Substances 0.000 title abstract description 3
- 108700012941 GNRH1 Proteins 0.000 title abstract 4
- KFEFLCOCAHJBEA-ANRVCLKPSA-N cetrorelix acetate Chemical compound CC(O)=O.C([C@@H](C(=O)N[C@H](CCCNC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 KFEFLCOCAHJBEA-ANRVCLKPSA-N 0.000 claims abstract description 89
- 108700008462 cetrorelix Proteins 0.000 claims abstract description 85
- 239000003814 drug Substances 0.000 claims abstract description 78
- 229960001865 cetrorelix acetate Drugs 0.000 claims abstract description 57
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 24
- 239000007924 injection Substances 0.000 claims abstract description 21
- 238000002347 injection Methods 0.000 claims abstract description 21
- 239000000463 material Substances 0.000 claims abstract description 13
- 229940124041 Luteinizing hormone releasing hormone (LHRH) antagonist Drugs 0.000 claims abstract description 10
- 239000002474 gonadorelin antagonist Substances 0.000 claims abstract description 10
- 239000007943 implant Substances 0.000 claims description 58
- 239000000243 solution Substances 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 27
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 claims description 11
- 229920001577 copolymer Polymers 0.000 claims description 10
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 10
- 239000004626 polylactic acid Substances 0.000 claims description 10
- 238000013268 sustained release Methods 0.000 claims description 9
- 239000012730 sustained-release form Substances 0.000 claims description 9
- 238000002513 implantation Methods 0.000 claims description 8
- 230000001093 anti-cancer Effects 0.000 claims description 5
- 238000004090 dissolution Methods 0.000 claims description 5
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 claims description 2
- SJZRECIVHVDYJC-UHFFFAOYSA-N 4-hydroxybutyric acid Chemical compound OCCCC(O)=O SJZRECIVHVDYJC-UHFFFAOYSA-N 0.000 claims description 2
- 102000009027 Albumins Human genes 0.000 claims description 2
- 108010088751 Albumins Proteins 0.000 claims description 2
- 229920002101 Chitin Polymers 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- 229920001503 Glucan Polymers 0.000 claims description 2
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 claims description 2
- 239000012876 carrier material Substances 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 claims description 2
- 210000003205 muscle Anatomy 0.000 claims description 2
- 229920005615 natural polymer Polymers 0.000 claims description 2
- 238000007920 subcutaneous administration Methods 0.000 claims description 2
- 229920001059 synthetic polymer Polymers 0.000 claims description 2
- 210000003462 vein Anatomy 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims 2
- 238000011978 dissolution method Methods 0.000 claims 1
- 238000001035 drying Methods 0.000 claims 1
- 238000001704 evaporation Methods 0.000 claims 1
- 229920000642 polymer Polymers 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 36
- 230000000694 effects Effects 0.000 abstract description 11
- 238000009792 diffusion process Methods 0.000 abstract description 4
- 201000011510 cancer Diseases 0.000 abstract description 2
- 230000002708 enhancing effect Effects 0.000 abstract 1
- 230000002349 favourable effect Effects 0.000 abstract 1
- 229920002521 macromolecule Polymers 0.000 abstract 1
- 239000002861 polymer material Substances 0.000 abstract 1
- 229960003230 cetrorelix Drugs 0.000 description 28
- 230000008961 swelling Effects 0.000 description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 20
- 238000005070 sampling Methods 0.000 description 16
- 239000000758 substrate Substances 0.000 description 16
- 238000012360 testing method Methods 0.000 description 16
- 230000006399 behavior Effects 0.000 description 12
- 238000011084 recovery Methods 0.000 description 12
- 238000005303 weighing Methods 0.000 description 9
- 239000007788 liquid Substances 0.000 description 8
- 239000012528 membrane Substances 0.000 description 8
- 239000013558 reference substance Substances 0.000 description 8
- 239000010409 thin film Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000012856 packing Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- FGDQGIKMWOAFIK-UHFFFAOYSA-N acetonitrile;phosphoric acid Chemical group CC#N.OP(O)(O)=O FGDQGIKMWOAFIK-UHFFFAOYSA-N 0.000 description 4
- 238000004140 cleaning Methods 0.000 description 4
- 229940121657 clinical drug Drugs 0.000 description 4
- 230000009514 concussion Effects 0.000 description 4
- 238000013461 design Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 230000003203 everyday effect Effects 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 235000010603 pastilles Nutrition 0.000 description 4
- 230000035515 penetration Effects 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000013112 stability test Methods 0.000 description 4
- 239000012086 standard solution Substances 0.000 description 4
- 238000004659 sterilization and disinfection Methods 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 206010052804 Drug tolerance Diseases 0.000 description 2
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 2
- 239000003005 anticarcinogenic agent Substances 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000003560 cancer drug Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 229910017052 cobalt Inorganic materials 0.000 description 2
- 239000010941 cobalt Substances 0.000 description 2
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 101000904177 Clupea pallasii Gonadoliberin-1 Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 208000005422 Foreign-Body reaction Diseases 0.000 description 1
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 102000009151 Luteinizing Hormone Human genes 0.000 description 1
- 108010073521 Luteinizing Hormone Proteins 0.000 description 1
- 206010033266 Ovarian Hyperstimulation Syndrome Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 102100024028 Progonadoliberin-1 Human genes 0.000 description 1
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000011254 conventional chemotherapy Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 206010016629 fibroma Diseases 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 1
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 description 1
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 108020004084 membrane receptors Proteins 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 210000003716 mesoderm Anatomy 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 210000000280 pituicyte Anatomy 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002195 soluble material Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Images
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention relates to a controlled-release implanting preparation used for injecting an LHRH (luteinizing hormone releasing hormone) antagonist. The invention is characterized in that the LHRH antagonist, namely cetrorelix acetate is loaded into a high polymer material carrier in a certain proportion, and then compressed into an implanting preparation of a certain shape so as to be used for implanting injection, thereby achieving the effect of long-acting controlled release. The controlled-release implanting preparation consists of the cetrorelix acetate with the effective dose for cancer resisting and controlled-release auxiliary materials, and the controlled-release auxiliary materials mainly comprise a biodegradable and biocompatible macromolecule copolymer; and the controlled-release implanting preparation is injected into tumors or around tumors, thereby being favorable for the effective diffusion of the medicament in the solid tumors, selectively improving the local medicament concentration of the tumors, reducing the injection times and the medicament tolerance, enhancing the compliance of patients and facilitating the clinical use and the medication for the patients.
Description
Technical field:
The present invention relates to formulation art, specifically is a kind of slow release implantation preparation of lhrh antagonist injection.
Background technology:
Anticarcinogen cetrorelix (Cetrorelix) is a kind of gonadotropin releasing hormone (LHRH) antagonist of German Asta Medica company development, can control the stimulation of ovary, prevents immature follicle to discharge too early, helps to become pregnant.Cetrorelix by with endogenous LH RH competition pituicyte on membrane receptor, thereby control lutropin (LH) and follicule-stimulating hormone (FSH) (FSH).Cetrorelix is as a kind of new synthetic lhrh antagonist, treat, prevent and alleviate all kinds of diseases by three approach: the one, the hypothalamic-pituitary-gonadal approach suppresses the secretion of dependency hormone, the 2nd, directly suppress the propagation and the transfer of tumor cell, the 3rd, the apoptosis of inducing cancer cell.Studies show that in a large number cetrorelix has curative effect preferably to ovarian cancer, carcinoma of prostate, fibroma uteri, endometriosis and other diseases, and benign prostatauxe and ovarian hyperstimulation syndrome are had prevention and improvement effect.Along with the further investigation of anticancer mechanism and clinical in a large number, cetrorelix will become a kind of widely used curing cancer drug.
Blood vessel in the mesenchyma stroma of tumors, connective tissue, stromatin, fibrin and collagen protein etc. not only provide support and requisite nutrient substance for the growth of tumor cell, also influenced around the chemotherapeutics and the infiltration in the tumor tissues and diffusion because entity tumor excessive expansion hypertrophy, the viscosity of matter was high than its normal surrounding tissue all between matter pressure, tissue elasticity pressure, fluid pressure reached therebetween, therefore, conventional chemotherapy, be difficult to tumor by local and form effective drug level, improve the restriction that dosage is subjected to general reaction again merely.Moreover the cancer drug therapy of low dosage not only can increase the Drug tolerance of cancerous cell, but also can promote its infiltrative growth.
Therefore, be convenient to keep high drug level and increase tumor cell the preparation and the method for the sensitivity of medicine just become an important subject at tumor by local.The anticarcinogen cetrorelix is made the sustained-release implant of injection, not only help the effective diffusion of medicine in entity tumor, can also optionally improve simultaneously the drug level of tumor by local, reduce drug resistance, strengthen the therapeutic effect of non-operative treatment such as chemotherapeutics and radiotherapy.
Summary of the invention:
The present invention is directed to the deficiencies in the prior art, providing a kind of is the slow release implantation preparation of the injection of active component with the lhrh antagonist cetrorelix acetate.Said preparation helps the effective diffusion of medicine in entity tumor, can optionally improve the drug level of tumor by local, reduces frequency injection and Drug tolerance, improves compliance of patients, convenient clinical use and patient's medication.
Main component of the present invention is a holder with the bio-soluble material, so do not cause foreign body reaction.Support to place in the object back degradable and absorb, so no longer operation is taken out.Cause discharges contained drug at tumor by local, thereby optionally improves and prolong local drug concentration, can reduce the general toxic reaction that is caused by the conventional route administration simultaneously.
The present invention has prepared a kind of sustained-release implant that contains the injection of lhrh antagonist cetrorelix acetate medicine, it is characterized in that cetrorelix acetate is loaded in the polymeric carrier material of being made up of certain proportion, be compressed into the implant of definite shape, for implantable injection; Described preparation is made up of the cetrorelix acetate and the slow-release auxiliary material of effective anticancer, and slow-release auxiliary material is mainly biodegradable and has the high-molecular copolymer of biocompatibility.
The present invention has prepared a kind of sustained-release implant that contains the injection of lhrh antagonist cetrorelix acetate medicine, and the shape of its implant is selected from graininess, spherical, block, needle-like, bar-shaped, column, membranaceous etc., and is preferably cylindric; Implantable injections such as its route of administration is selected from vein, subcutaneous, Intradermal, muscle, intracavity, the tumor, tumor week are in the preferred tumor or all implantable injections of tumor; The percentage by weight of its effective anticancer cetrorelix acetate is 5-30%, and the percentage by weight of high-molecular copolymer slow-release auxiliary material is 50%-95%; It is that lactic acid-ethanol copolymer (PLGA), polylactide Acetic acid, hydroxy-, bimol. cyclic ester (PLCG), polylactic acid (PLA), poly-own propyl ester (PCL), poly hydroxybutyric acid (PHB) or natural polymer are one of gelatin, glucosan, albumin, chitin etc. or its combination that its high-molecular copolymer slow-release auxiliary material is selected from synthetic polymer; The preferred PLGA of its high-molecular copolymer slow-release auxiliary material (1: 1), PLCG (3: 1), PLA, PCL.
In addition, the present invention also provides the method for preparing the sustained-release implant of the injection that contains lhrh antagonist cetrorelix acetate medicine, and its technology is as follows:
1 takes by weighing slow-release auxiliary material to container, adds the certain amount of organic solvent dissolving evenly;
2 add the principal agent cetrorelix acetate, stir;
3 remove organic solvent, vacuum drying;
4 with dried solid composite, fashions into different shape as required;
Ray sterilizing is standby after 5 packing.
Description of drawings:
Fig. 1, Fig. 2, Fig. 3, Fig. 4 are respectively per stage release amount-time plot of cetrorelix in the implant of each embodiment.
The specific embodiment:
The present invention is including but not limited to following examples.
Embodiment 1:
10% cetrorelix acetate, 90%PLGA.Its preparation technology is as follows:
Precision weighing cetrorelix acetate 600mg adds 150ml acetone and makes it dissolving in tool plug conical flask; Precision weighing PLGA 5400mg adds the 150ml acetone solution, above-mentioned two solution mixed, and kept at room temperature overnight, it is sticky shape transparency liquid that the vortex concussion makes its abundant mix homogeneously, solution.Divide several to be poured on the horizontal glass template of a cleaning it, water-soluble heating reaches 24h for 40 ℃, and acetone is fully volatilized, and formation thickness is about having of 1mm certain elastic white pastille PLGA thin film.Thin film is intactly taken off, put into mould, be pressed into column type in 50 ℃ water-bath, room temperature is placed 2d, more than the lyophilization 24h.After the packing, use cobalt
60Sterilization.The implant of gained is cylindric, and diameter is 0.2cm, and length is 1.0cm.
Make 200 of the sustained-release implants of cetrorelix acetate injection by present embodiment, every contains principal agent 3mg.By the mensuration of release, its slow release effect and clinical drug safety are investigated.
1.1 the chromatographic condition chromatographic column is Zorbax SB-Aq C
18(4.6mm * 15cm, P.N); Mobile phase is acetonitrile-phosphate buffer (pH5.8) (40: 60); Flow velocity is 1.0ml/min; The detection wavelength is 254nm; Sample size is 20 μ L.
1.2 homemade work reference substance is got in the preparation of standard curve, being made into mass concentration is the cetrorelix acetate series standard solution of 0.01-5mg/ml.Drawing concentration respectively is each 20 μ L injecting chromatograph of solution of 0.01mg/ml, 0.05mg/ml, 0.25mg/ml, 0.50mg/ml, 1.25mg/ml, 2.50mg/ml, 5.00mg/ml, measures peak area by above-mentioned chromatographic condition.With the peak area is vertical coordinate, and the concentration of cetrorelix acetate is abscissa, the drawing standard curve, record cetrorelix acetate in 0.01～5mg/ml scope, peak area and drug level are good linear relationship, and regression equation is Y=50.35X-1.08, r=0.9995.
1.3 the recovery test precision is measured each 9 parts of a certain amount of self-control work reference substances, add the 10ml normal saline, get this solution 100 μ L and be diluted to 100ml with purified water, 0.22 μ m microporous filter membrane filters, both got need testing solution,, drawn 20 μ L sample introductions by the chromatographic condition under " 1.1 " item, measure it and indicate content and calculate recovery rate, result such as following table.
Table 1-1 recovery test result
1.4 stability test is got the cetrorelix acetate implant, add 50ml DMF and make its dissolving, add the extraction of 10ml normal saline, by the method preparation under " 1.3 " item, respectively 1,2,4,8,12,24h, each draws 20 μ L sample introductions, measures its peak area, and the RSD of cetrorelix acetate solution in 24h is 1.56% (n=5) as a result.Show that need testing solution is stable in 24h.
1.5 the mensuration of release in vitro degree is undertaken by Chinese Pharmacopoeia version drug release determination in 2010 method.Select for use the 1000ml normal saline as release medium, temperature is located at (37 ± 0.5) ℃, and rotating speed is 50r/min, because implant density is littler than normal saline, so select the basket method of changeing for use, the assurance preparation immerses in the release medium fully.The design sample time is 2,4,6,8,12,24h, sampling every day afterwards once, after the 10d, every 3d sampling once, after obvious swelling set takes place in the medicine profile, once every the 1d sampling.Each sampling 5ml replenishes the normal saline with volume simultaneously.It is stable that cetrorelix acetate solution all keeps in 10d, higher for preventing because of release medium Chinese medicine concentration, and influences the release of medicine, and preceding 10 days, every 1d changed release medium, and behind the 10d, every 3d changes release medium one time.Discharge liquid and filter through 0.22 μ m microporous filter membrane, get subsequent filtrate 20 μ L by chromatographic condition sample introduction under " 1.1 " item, measure peak area, substitution standard curve calculating concentration draws per stage release amount, the results are shown in Table 1-2.
In 600h, cetrorelix discharges fully in the implant.
Per stage release amount (μ g) of cetrorelix in the table 1-2 implant
1.6 the research of external release rule adopts various math equations that release profiles is carried out match respectively for the rule that cetrorelix in the explanation cetrorelix acetate implant discharges, and the results are shown in Table 1-3.1-3 can find out by table; Cetrorelix is inequality at different time period release behaviors in this preparation.At preceding 10 days that discharge, use the Higuchi equation model, good relationship, after the 10d, release profiles is better with the zero level equation model, and the release that this time period medicine is described is with more stable speed constant release, behind the 600h, the release of medicine almost completely, the dependency of Mt/M ∞ t good (r=0.9949, P=0.000).And the release behavior of whole implant is than Higuchi equation.
3 kinds of fit equation of cetrorelix release profiles in the table 1-3 cetrorelix acetate implant
The dispose procedure of implant: after implant runs into release medium,, make substrate PLGA swelling at first at moistened surface, the surface drug stripping, this process belongs to the rapid release process, and the swelling of top layer substrate does not have influence to the release of surface drug.Therefore the phase relation number average after the preceding 10 days release behavior match is not high; After the 10d, the swollen PLGA in top layer continues aquation swelling under the effect of release medium, the stripping substantially of surface drug this moment, form a large amount of ducts, release medium is continued to the implant internal penetration, and the dissolving internal drug makes its outside stripping, this stage is exactly the controlled release stage of implantation slow releasing preparation, is subjected to the influence and the restriction of substrate swelling rate.Constant swelling rate makes medicine, and dissolution rate is relatively stable from inside to outside, can guarantee to keep constant drug level; Along with the increase of medicine stripping, increasing duct has appearred, and release medium enters the inside of substrate in a large number, makes the abundant swelling degraded of PLGA, and medicine discharges fully.
Embodiment 2:
15% cetrorelix acetate, 85%PLCG.Its preparation technology is as follows:
Precision weighing cetrorelix acetate 900mg adds 230ml acetone and makes it dissolving in tool plug conical flask; Precision weighing PLCG 5100mg adds the 140ml acetone solution, above-mentioned two solution is mixed kept at room temperature overnight.It is sticky shape transparency liquid that the vortex concussion makes its abundant mix homogeneously, solution.Divide several to be poured on the horizontal glass template of a cleaning it, heating in water bath reaches 24h for 40 ℃, and acetone is fully volatilized, and forms thickness and is about the certain elastic white pastille PLCG thin film of having of 1mm.Thin film is intactly taken off, put into mould, be pressed into column type in 50 ℃ water-bath, room temperature is placed 2d, more than the lyophilization 24h.After the packing, with boring
60Sterilization.The implant of gained is cylindric, and diameter is 0.2cm, and length is 1.0cm.
Make 300 of the sustained-release implants of cetrorelix acetate injection by present embodiment, every contains principal agent 3mg.By the mensuration of release, its slow release effect and clinical drug safety are investigated.
2.1 the chromatographic condition chromatographic column is Zorbax SB-Aq C
18(4.6mm * 15cm, P.N); Mobile phase is acetonitrile-phosphate buffer (pH5.8) (40: 60); Flow velocity is 1.0ml/min; The detection wavelength is 254nm; Sample size is 20 μ L.
2.2 homemade work reference substance is got in the preparation of standard curve, being made into mass concentration is the cetrorelix acetate series standard solution of 0.01-5mg/ml.Drawing concentration respectively is each 20 μ L injecting chromatograph of solution of 0.01mg/ml, 0.05mg/ml, 0.25mg/ml, 0.50mg/ml, 1.25mg/ml, 2.50mg/ml, 5.00mg/ml, measures peak area by above-mentioned chromatographic condition.With the peak area is vertical coordinate, and the concentration of cetrorelix acetate is abscissa, the drawing standard curve, record cetrorelix acetate in the 0.01-5mg/ml scope, peak area and drug level are good linear relationship, and regression equation is Y=50.35X-1.08, r=0.9995.
2.3 the recovery test precision is measured each 9 parts of a certain amount of self-control work reference substances, add the 10ml normal saline, get this solution 100 μ L and be diluted to 100ml with purified water, 0.22 μ m microporous filter membrane filters, both got need testing solution,, drawn 20 μ L sample introductions by the chromatographic condition under " 2.1 " item, measure it and indicate content and calculate recovery rate, result such as following table.
Table 2-1 recovery test result
2.4 stability test is got the cetrorelix acetate implant, add 50ml DMF and make its dissolving, add the extraction of 10ml normal saline, by the method preparation under " 2.3 " item, respectively 1,2,4,8,12,24h, each draws 20 μ L sample introductions, measures its peak area, and the RSD of cetrorelix acetate solution in 24h is 1.93% (n=5) as a result.Show that need testing solution is stable in 24h.
2.5 the mensuration of release in vitro degree is undertaken by Chinese Pharmacopoeia version drug release determination in 2010 method.Select for use the 1000ml normal saline as release medium, temperature is located at (37 ± 0.5) ℃, and rotating speed is 50r/min, because implant density is littler than normal saline, so select the basket method of changeing for use, the assurance preparation immerses in the release medium fully.The design sample time is 2,4,6,8,12,24h, sampling every day afterwards once, after the 10d, every 3d sampling once, after obvious swelling set takes place in the medicine profile, once every the 1d sampling.Each sampling 5ml replenishes the normal saline with volume simultaneously.It is stable that cetrorelix acetate solution all keeps in 10d, higher for preventing because of release medium Chinese medicine concentration, and influences the release of medicine, and preceding 10 days, every 1d changed release medium, and behind the 10d, every 3d changes release medium one time.Discharge liquid and filter through 0.22 μ m microporous filter membrane, get subsequent filtrate 20 μ L by chromatographic condition sample introduction under " 2.1 " item, measure peak area, substitution standard curve calculating concentration draws per stage release amount, the results are shown in Table 2-2.
In 600h, cetrorelix discharges fully in the implant.
Per stage release amount (μ g) of cetrorelix in the table 2-2 implant
2.6 the research of external release rule adopts various math equations that release profiles is carried out match respectively for the rule that cetrorelix in the explanation cetrorelix acetate implant discharges, and the results are shown in Table 2-3.2-3 can find out by table: cetrorelix is inequality at different time period release behaviors in this preparation.At preceding 10 days that discharge, use the Higuchi equation model, good relationship, after the 10d, release profiles is better with the zero level equation model, and the release that this time period medicine is described is with more stable speed constant release, behind the 600h, the release of medicine almost completely, the dependency of Mt/M ∞ t good (r=0.9953, P=0.000).And the release behavior of whole implant is than Higuchi equation.
3 kinds of fit equation of cetrorelix release profiles in the table 2-3 cetrorelix acetate implant
The dispose procedure of implant: after implant runs into release medium,, make substrate PLCG swelling at first at moistened surface, the surface drug stripping, this process belongs to the rapid release process, and the swelling of top layer substrate does not have influence to the release of surface drug.Therefore the phase relation number average after the preceding 10 days release behavior match is not high; After the 10d, the swollen PLCG in top layer continues aquation swelling under the effect of release medium, the stripping substantially of surface drug this moment, form a large amount of ducts, release medium is continued to the implant internal penetration, and the dissolving internal drug makes its outside stripping, this stage is exactly the controlled release stage of implantation slow releasing preparation, is subjected to the influence and the restriction of substrate swelling rate.Constant swelling rate makes medicine, and dissolution rate is relatively stable from inside to outside, can guarantee to keep constant drug level; Along with the increase of medicine stripping, increasing duct has appearred, and release medium enters the inside of substrate in a large number, makes the abundant swelling degraded of PLCG, and medicine discharges fully.
Embodiment 3:
20% cetrorelix acetate, 80%PLA.Its preparation technology is as follows:
Precision weighing cetrorelix acetate 1200mg adds 300ml acetone and makes it dissolving in tool plug conical flask; Precision weighing PLA4800mg adds the 100ml acetone solution, above-mentioned two solution is mixed kept at room temperature overnight.It is sticky shape transparency liquid that the vortex concussion makes its abundant mix homogeneously, solution.Divide several to be poured on the horizontal glass template of a cleaning it, heating in water bath reaches 24h for 40 ℃, and acetone is fully volatilized, and forms thickness and is about the certain elastic white pastille PLA thin film of having of 1mm.Thin film is intactly taken off, put into mould, be pressed into column type in 50 ℃ water-bath, room temperature is placed 2d, more than the lyophilization 24h.After the packing, with boring
60Sterilization.The implant of gained is cylindric, and diameter is 0.2cm, and length is 1.0cm.
Make 400 of the sustained-release implants of cetrorelix acetate injection by present embodiment, every contains principal agent 3mg.By the mensuration of release, its slow release effect and clinical drug safety are investigated.
3.1 the chromatographic condition chromatographic column is Zorbax SB-Aq C
18(4.6mm * 15cm, P.N); Mobile phase is acetonitrile-phosphate buffer (pH5.8) (40: 60); Flow velocity is 1.0ml/min; The detection wavelength is 254nm; Sample size is 20 μ L.
3.2 homemade work reference substance is got in the preparation of standard curve, being made into mass concentration is the cetrorelix acetate series standard solution of 0.01-5mg/ml.Drawing concentration respectively is each 20 μ L injecting chromatograph of solution of 0.01mg/ml, 0.05mg/ml, 0.25mg/ml, 0.50mg/ml, 1.25mg/ml, 2.50mg/ml, 5.00mg/ml, measures peak area by above-mentioned chromatographic condition.With the peak area is vertical coordinate, and the concentration of cetrorelix acetate is abscissa, the drawing standard curve, record cetrorelix acetate in 0.01～5mg/ml scope, peak area and drug level are good linear relationship, and regression equation is Y=50.35X-1.08, r=0.9995.
3.3 the recovery test precision is measured each 9 parts of a certain amount of self-control work reference substances, add the 10ml normal saline, get this solution 100 μ L and be diluted to 100ml with purified water, 0.22 μ m microporous filter membrane filters, both got need testing solution,, drawn 20 μ L sample introductions by the chromatographic condition under " 3.1 " item, measure it and indicate content and calculate recovery rate, result such as following table.
Table 3-1 recovery test result
3.4 stability test is got the cetrorelix acetate implant, add 50ml DMF and make its dissolving, add the extraction of 10ml normal saline, by the method preparation under " 3.3 " item, respectively 1,2,4,8,12,24h, each draws 20 μ L sample introductions, measures its peak area, and the RSD of cetrorelix acetate solution in 24h is 1.72% (n=5) as a result.Show that need testing solution is stable in 24h.
3.5 the mensuration of release in vitro degree is undertaken by Chinese Pharmacopoeia version drug release determination in 2010 method.Select for use the 1000ml normal saline as release medium, temperature is located at (37 ± 0.5) ℃, and rotating speed is 50r/min, because implant density is littler than normal saline, so select the basket method of changeing for use, the assurance preparation immerses in the release medium fully.The design sample time is 2,4,6,8,12,24h, sampling every day afterwards once, after the 10d, every 3d sampling once, after obvious swelling set takes place in the medicine profile, once every the 1d sampling.Each sampling 5ml replenishes the normal saline with volume simultaneously.It is stable that cetrorelix acetate solution all keeps in 10d, higher for preventing because of release medium Chinese medicine concentration, and influences the release of medicine, and preceding 10 days, every 1d changed release medium, and behind the 10d, every 3d changes release medium one time.Discharge liquid and filter through 0.22 μ m microporous filter membrane, get subsequent filtrate 20 μ L by chromatographic condition sample introduction under " 3.1 " item, measure peak area, substitution standard curve calculating concentration draws per stage release amount, the results are shown in Table 3-2.
In 600h, cetrorelix discharges fully in the implant.
Per stage release amount (μ g) of cetrorelix in the table 3-2 implant
3.6 the research of external release rule adopts various math equations that release profiles is carried out match respectively for the rule that cetrorelix in the explanation cetrorelix acetate implant discharges, and the results are shown in Table 3-3.3-3 can find out by table: cetrorelix is inequality at different time period release behaviors in this preparation.At preceding 10 days that discharge, use the Higuchi equation model, good relationship, after the 10d, release profiles is better with the zero level equation model, and the release that this time period medicine is described is with more stable speed constant release, behind the 600h, the release of medicine almost completely, the dependency of Mt/M ∞ t good (r=0.9913, P=0.000).And the release behavior of whole implant is than Higuchi equation.
3 kinds of fit equation of cetrorelix release profiles in the table 3-3 cetrorelix acetate implant
The dispose procedure of implant: after implant runs into release medium,, make substrate PLA swelling at first at moistened surface, the surface drug stripping, this process belongs to the rapid release process, and the swelling of top layer substrate does not have influence to the release of surface drug.Therefore the phase relation number average after the preceding 10 days release behavior match is not high; After the 10d, the swollen PLA in top layer continues aquation swelling under the effect of release medium, the stripping substantially of surface drug this moment, form a large amount of ducts, release medium is continued to the implant internal penetration, and the dissolving internal drug makes its outside stripping, this stage is exactly the controlled release stage of implantation slow releasing preparation, is subjected to the influence and the restriction of substrate swelling rate.Constant swelling rate makes medicine, and dissolution rate is relatively stable from inside to outside, can guarantee to keep constant drug level; Along with the increase of medicine stripping, increasing duct has appearred, and release medium enters the inside of substrate in a large number, makes the abundant swelling degraded of PLA, and medicine discharges fully.
Embodiment 4:
30% cetrorelix acetate, 70%PCL.Preparation technology is as follows for base:
Precision weighing cetrorelix acetate 1800mg adds 450ml acetone and makes it dissolving in tool plug conical flask; Precision weighing PCL 4200mg adds the 50ml acetone solution, above-mentioned two solution is mixed kept at room temperature overnight.It is sticky shape transparency liquid that the vortex concussion makes its abundant mix homogeneously, solution.Divide several to be poured on the horizontal glass template of a cleaning it, heating in water bath reaches 24h for 40 ℃, and acetone is fully volatilized, and forms thickness and is about the certain elastic white pastille PCL thin film of having of 1mm.Thin film is intactly taken off, put into mould, be pressed into column type on 50 ℃ water-soluble, room temperature is placed 2d, more than the lyophilization 24h.After the packing, use cobalt
60Sterilization.The implant of gained is cylindric, and diameter is 0.2cm, and length is 1.0cm.
Make 600 of the sustained-release implants of cetrorelix acetate injection by present embodiment, every contains principal agent 3mg.By the mensuration of release, its slow release effect and clinical drug safety are investigated.
4.1 the chromatographic condition chromatographic column is Zorbax SB-Aq C
18(4.6mm * 15cm, P.N); Mobile phase is acetonitrile-phosphate buffer (pH5.8) (40: 60); Flow velocity is 1.0ml/min; The detection wavelength is 254nm; Sample size is 20 μ L.
4.2 homemade work reference substance is got in the preparation of standard curve, being made into mass concentration is the cetrorelix acetate series standard solution of 0.01-5mg/ml.Drawing concentration respectively is each 20 μ L injecting chromatograph of solution of 0.01mg/ml, 0.05mg/ml, 0.25mg/ml, 0.50mg/ml, 1.25mg/ml, 2.50mg/ml, 5.00mg/ml, measures peak area by above-mentioned chromatographic condition.With the peak area is vertical coordinate, and the concentration of cetrorelix acetate is abscissa, the drawing standard curve, record cetrorelix acetate in 0.01～5mg/ml scope, peak area and drug level are good linear relationship, and regression equation is Y=50.35X-1.08, r=0.9995.
4.3 the recovery test precision is measured each 9 parts of a certain amount of self-control work reference substances, add the 10ml normal saline, get this solution 100 μ L and be diluted to 100ml with purified water, 0.22 μ m microporous filter membrane filters, both got need testing solution,, drawn 20 μ L sample introductions by the chromatographic condition under " 4.1 " item, measure it and indicate content and calculate recovery rate, result such as following table.
Table 4-1 recovery test result
4.4 stability test is got the cetrorelix acetate implant, add 50ml DMF and make its dissolving, add the extraction of 10ml normal saline, by the method preparation under " 4.3 " item, respectively 1,2,4,8,12,24h, each draws 20 μ L sample introductions, measures its peak area, and the RSD of cetrorelix acetate solution in 24h is 2.03% (n=5) as a result.Show that need testing solution is stable in 24h.
4.5 the mensuration of release in vitro degree is undertaken by Chinese Pharmacopoeia version drug release determination in 2010 method.Select for use the 1000ml normal saline as release medium, temperature is located at (37 ± 0.5) ℃, and rotating speed is 50r/min, because implant density is littler than normal saline, so select the basket method of changeing for use, the assurance preparation immerses in the release medium fully.The design sample time is 2,4,6,8,12,24h, sampling every day afterwards once, after the 10d, every 3d sampling once, after obvious swelling set takes place in the medicine profile, once every the 1d sampling.Each sampling 5ml replenishes the normal saline with volume simultaneously.It is stable that cetrorelix acetate solution all keeps in 10d, higher for preventing because of release medium Chinese medicine concentration, and influences the release of medicine, and preceding 10 days, every 1d changed release medium, and behind the 10d, every 3d changes release medium one time.Discharge liquid and filter through 0.22 μ m microporous filter membrane, get subsequent filtrate 20 μ L by chromatographic condition sample introduction under " 4.1 " item, measure peak area, substitution standard curve calculating concentration draws per stage release amount, the results are shown in Table 4-2.
In 600h, cetrorelix discharges fully in the implant.
Per stage release amount (μ g) of cetrorelix in the table 4-2 implant
4.6 the research of external release rule adopts various math equations that release profiles is carried out match respectively for the rule that cetrorelix in the explanation cetrorelix acetate implant discharges, and the results are shown in Table 4-3.4-3 can find out by table: cetrorelix is inequality at different time period release behaviors in this preparation.At preceding 10 days that discharge, use the Higuchi equation model, good relationship, after the 10d, release profiles is better with the zero level equation model, and the release that this time period medicine is described is with more stable speed constant release, behind the 600h, the release of medicine almost completely, the dependency of Mt/M ∞ t good (r=0.9924, P=0.000).And the release behavior of whole implant is than Higuchi equation.
3 kinds of fit equation of cetrorelix release profiles in the table 4-3 cetrorelix acetate implant
The dispose procedure of implant: after implant runs into release medium,, make substrate PCL swelling at first at moistened surface, the surface drug stripping, this process belongs to the rapid release process, and the swelling of top layer substrate does not have influence to the release of surface drug.Therefore the phase relation number average after the preceding 10 days release behavior match is not high; After the 10d, the swollen PCL in top layer continues aquation swelling under the effect of release medium, the stripping substantially of surface drug this moment, form a large amount of ducts, release medium is continued to the implant internal penetration, and the dissolving internal drug makes its outside stripping, this stage is exactly the controlled release stage of implantation slow releasing preparation, is subjected to the influence and the restriction of substrate swelling rate.Constant swelling rate makes medicine, and dissolution rate is relatively stable from inside to outside, can guarantee to keep constant drug level; Along with the increase of medicine stripping, increasing duct has appearred, and release medium enters the inside of substrate in a large number, makes the abundant swelling degraded of PCL, and medicine discharges fully.
Claims (10)
1. the slow release implantation preparation of a lhrh antagonist injection is characterized in that the lhrh antagonist cetrorelix acetate is loaded in the polymeric carrier material of being made up of certain proportion, is compressed into the implant of definite shape, for implantable injection; Described preparation is made up of the cetrorelix acetate and the slow-release auxiliary material of effective anticancer, and slow-release auxiliary material is mainly biodegradable and has the high-molecular copolymer of biocompatibility.
2. the described preparation of claim 1, the shape of its implant are selected from graininess, spherical, block, needle-like, bar-shaped, column, membranaceous etc., and be preferably cylindric; Implantable injections such as its route of administration is selected from vein, subcutaneous, Intradermal, muscle, intracavity, the tumor, tumor week are in the preferred tumor or all implantable injections of tumor.
3. the described preparation of claim 1, the percentage by weight of its effective anticancer cetrorelix acetate is 5-30%, the percentage by weight of high-molecular copolymer slow-release auxiliary material is 50%-95%.
4. it is that lactic acid-ethanol copolymer (PLGA), polylactide Acetic acid, hydroxy-, bimol. cyclic ester (PLCG), polylactic acid (PLA), poly-own propyl ester (PCL), poly hydroxybutyric acid (PHB) or natural polymer are one of gelatin, glucosan, albumin, chitin etc. or its combination that the described preparation of claim 1, its high-molecular copolymer slow-release auxiliary material are selected from synthetic polymer.
5. the described preparation of claim 4, the preferred PLGA of its high-molecular copolymer slow-release auxiliary material (1: 1), PLCG (3: 1), PLA, PCL.
6. claim 3 or 5 described preparations, its prescription consists of: 5-30% cetrorelix acetate, 70-95%PLGA.
7. claim 3 or 5 described preparations, its prescription consists of: 10-35% cetrorelix acetate, 65-90%PLCG.
8. claim 3 or 5 described preparations, its prescription consists of: 15-40% cetrorelix acetate, 60-85%PLA.
9. claim 3 or 5 described preparations, its prescription consists of: 20-45% cetrorelix acetate, 55-80%PCL.
10. the described preparation of claim 1, its method for preparing sustained-release implant is selected from dissolution method, promptly the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, drying.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100540735A CN102145160A (en) | 2011-03-07 | 2011-03-07 | Controlled-release implanting preparation used for injecting LHRH (luteinizing hormone releasing hormone) antagonist |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100540735A CN102145160A (en) | 2011-03-07 | 2011-03-07 | Controlled-release implanting preparation used for injecting LHRH (luteinizing hormone releasing hormone) antagonist |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102145160A true CN102145160A (en) | 2011-08-10 |
Family
ID=44419761
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011100540735A Pending CN102145160A (en) | 2011-03-07 | 2011-03-07 | Controlled-release implanting preparation used for injecting LHRH (luteinizing hormone releasing hormone) antagonist |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102145160A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107773528A (en) * | 2016-08-24 | 2018-03-09 | 南京星银药业集团有限公司 | A kind of acetic acid Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2 injection-type sustained-release implant |
| WO2018144603A1 (en) * | 2017-01-31 | 2018-08-09 | Veru Inc. | COMPOSITIONS AND METHODS FOR LONG TERM RELEASE OF GANADOTROPIN-RELEASING HORMONE (GnRH) ANTAGONISTS |
| CN111714442A (en) * | 2019-03-04 | 2020-09-29 | 广州铂思雅生物医药科技有限公司 | Preparation of implants |
| CN113116830A (en) * | 2019-12-31 | 2021-07-16 | 广州铂思雅生物医药科技有限公司 | Preparation of sustained-release granules |
| RU2789057C2 (en) * | 2017-01-31 | 2023-01-27 | Веру Инк. | COMPOSITIONS AND METHODS FOR LONG-TERM RELEASE OF ANTAGONISTS OF GONADOTROPIN-RELEASING HORMONE (GnRH) |
| WO2024131788A1 (en) * | 2022-12-23 | 2024-06-27 | 长春金赛药业有限责任公司 | Injectable composition of gnrh antagonist, preparation method therefor and use thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1301172A (en) * | 1998-03-20 | 2001-06-27 | 武田药品工业株式会社 | Sustained-release physiologically active polypeptide and production thereof |
| CN101001640A (en) * | 2004-05-31 | 2007-07-18 | 斯玛特药物系统公司 | Sustained release composition |
| US20070196416A1 (en) * | 2006-01-18 | 2007-08-23 | Quest Pharmaceutical Services | Pharmaceutical compositions with enhanced stability |
-
2011
- 2011-03-07 CN CN2011100540735A patent/CN102145160A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1301172A (en) * | 1998-03-20 | 2001-06-27 | 武田药品工业株式会社 | Sustained-release physiologically active polypeptide and production thereof |
| CN101001640A (en) * | 2004-05-31 | 2007-07-18 | 斯玛特药物系统公司 | Sustained release composition |
| US20070196416A1 (en) * | 2006-01-18 | 2007-08-23 | Quest Pharmaceutical Services | Pharmaceutical compositions with enhanced stability |
Non-Patent Citations (1)
| Title |
|---|
| 《European Journal of Pharmaceutics and Biopharmaceutics》 20031130 Grégoire Schwach Biodegradable microparticles for sustained release of a new GnRH antagonist - part I: screening commercial PLGA and formulation technologies 327-336 1-10 第56卷, 第3期 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107773528A (en) * | 2016-08-24 | 2018-03-09 | 南京星银药业集团有限公司 | A kind of acetic acid Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2 injection-type sustained-release implant |
| WO2018144603A1 (en) * | 2017-01-31 | 2018-08-09 | Veru Inc. | COMPOSITIONS AND METHODS FOR LONG TERM RELEASE OF GANADOTROPIN-RELEASING HORMONE (GnRH) ANTAGONISTS |
| CN110234336A (en) * | 2017-01-31 | 2019-09-13 | 维鲁公司 | The composition and method of sustained release for gonadotropin-releasing hormone (GRH) (GnRH) antagonist |
| EP4011386A1 (en) * | 2017-01-31 | 2022-06-15 | Veru Inc. | Compositions and methods for long term release of gonadotropin-releasing hormone (gnrh) antagonists |
| RU2789057C2 (en) * | 2017-01-31 | 2023-01-27 | Веру Инк. | COMPOSITIONS AND METHODS FOR LONG-TERM RELEASE OF ANTAGONISTS OF GONADOTROPIN-RELEASING HORMONE (GnRH) |
| CN111714442A (en) * | 2019-03-04 | 2020-09-29 | 广州铂思雅生物医药科技有限公司 | Preparation of implants |
| CN111714442B (en) * | 2019-03-04 | 2024-04-12 | 广州铂思雅生物医药科技有限公司 | Preparation of the implant |
| CN113116830A (en) * | 2019-12-31 | 2021-07-16 | 广州铂思雅生物医药科技有限公司 | Preparation of sustained-release granules |
| WO2024131788A1 (en) * | 2022-12-23 | 2024-06-27 | 长春金赛药业有限责任公司 | Injectable composition of gnrh antagonist, preparation method therefor and use thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Li et al. | Effective sustained release of 5-FU-loaded PLGA implant for improving therapeutic index of 5-FU in colon tumor | |
| CN102145160A (en) | Controlled-release implanting preparation used for injecting LHRH (luteinizing hormone releasing hormone) antagonist | |
| CN101336890A (en) | Anticancer sustained-release gel injection | |
| WO2022134409A1 (en) | Radioactive resin microsphere injection, preparation method, and use | |
| Yang et al. | An in situ spontaneously forming micelle-hydrogel system with programmable release for the sequential therapy of anaplastic thyroid cancer | |
| KR20220041782A (en) | Leuprolide Acetate Compositions and Methods for Use in Treatment of Breast Cancer | |
| CN111358934B (en) | Leuprorelin acetate long-acting pharmaceutical preparation combination and use method thereof | |
| CN114652865A (en) | Radioactive glass microsphere injection and preparation method and application thereof | |
| CN108066339B (en) | A kind of pharmaceutical composition of Parecoxib Sodium | |
| CN101721370A (en) | Goserelin release microsphere preparation, preparation method and detecting method thereof | |
| CN101711735A (en) | Slow-release medicament release system as well as preparation method and application thereof | |
| CN112237586A (en) | Application of rhizoma paridis saponin and sorafenib in preparation of anti-tumor combined medicine | |
| CN101219113A (en) | Compound anticancer sustained-release injection containing bendamustine | |
| CN100563711C (en) | A kind of slow-releasing anticarcinogen injection | |
| CN110856746B (en) | Freeze-dried micelle preparation containing carfilzomib and preparation method thereof | |
| CN109498547B (en) | Pingyangmycin local injection preparation and preparation method thereof | |
| CN101130057A (en) | Thymopentin long-acting implant and preparation method thereof | |
| Yi et al. | Ginsenoside RG3-loaded microneedles for in situ treatment of ovarian cancer | |
| CN109431997B (en) | Local rapamycin injection and preparation method thereof | |
| CN103040822B (en) | A kind of pharmaceutical composition containing kurarinone compound and preparation method thereof | |
| CN1311818C (en) | Pharmaceutical composition for solid tumour | |
| CN101219112A (en) | Compound anticancer sustained-release injection containing bendamustine | |
| CN1241571C (en) | Use of centella total glycoside in manufacture of medicine | |
| CN1923281B (en) | Anti-cancer slow release injection comprising plant alkaloid | |
| CN1824314A (en) | Slow release agent containing hormone kind anti cancer medicine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C53 | Correction of patent for invention or patent application | ||
| CB02 | Change of applicant information |
Address after: 518057, room 2, building ten, Shenzhen biological incubation center, No. 412, Nanshan District hi tech, Shenzhen, Guangdong Applicant after: Shenzhen City Jianyuan Pharmaceutical Technology Co., Ltd. Address before: 518000, overseas student Pioneer Building, 29 South Ring Road, Nanshan hi tech Zone, Guangdong, Shenzhen 1702 Applicant before: Shenzhen City Jianyuan Pharmaceutical Technology Co., Ltd. |
|
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20110810 |