CN103446043A - In-situ gel injection implant - Google Patents
In-situ gel injection implant Download PDFInfo
- Publication number
- CN103446043A CN103446043A CN2012101721465A CN201210172146A CN103446043A CN 103446043 A CN103446043 A CN 103446043A CN 2012101721465 A CN2012101721465 A CN 2012101721465A CN 201210172146 A CN201210172146 A CN 201210172146A CN 103446043 A CN103446043 A CN 103446043A
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- Prior art keywords
- situ
- implant
- gel
- gel injection
- copolymer
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- 239000007943 implant Substances 0.000 title claims abstract description 84
- 238000002347 injection Methods 0.000 title claims abstract description 65
- 239000007924 injection Substances 0.000 title claims abstract description 65
- 238000011065 in-situ storage Methods 0.000 title abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 57
- 229920001577 copolymer Polymers 0.000 claims abstract description 35
- 239000000178 monomer Substances 0.000 claims abstract description 21
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229920001519 homopolymer Polymers 0.000 claims abstract description 14
- 239000003960 organic solvent Substances 0.000 claims abstract description 14
- YFHICDDUDORKJB-UHFFFAOYSA-N trimethylene carbonate Chemical compound O=C1OCCCO1 YFHICDDUDORKJB-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000013270 controlled release Methods 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229920000642 polymer Polymers 0.000 claims description 34
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical group CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 22
- WWYNJERNGUHSAO-XUDSTZEESA-N (+)-Norgestrel Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 WWYNJERNGUHSAO-XUDSTZEESA-N 0.000 claims description 15
- 229960004400 levonorgestrel Drugs 0.000 claims description 14
- 229960000746 testosterone undecanoate Drugs 0.000 claims description 14
- UDSFVOAUHKGBEK-CNQKSJKFSA-N testosterone undecanoate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCCCCCCCC)[C@@]1(C)CC2 UDSFVOAUHKGBEK-CNQKSJKFSA-N 0.000 claims description 14
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](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)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 claims description 10
- 229960004338 leuprorelin Drugs 0.000 claims description 10
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 claims description 9
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 9
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 9
- 229960004316 cisplatin Drugs 0.000 claims description 9
- 229960005309 estradiol Drugs 0.000 claims description 9
- 229930182833 estradiol Natural products 0.000 claims description 9
- 229960001680 ibuprofen Drugs 0.000 claims description 9
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 claims description 8
- -1 analgesic Substances 0.000 claims description 7
- 238000013268 sustained release Methods 0.000 claims description 6
- 230000002459 sustained effect Effects 0.000 claims description 5
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 claims description 5
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 claims description 4
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 claims description 4
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 claims description 4
- 239000003607 modifier Substances 0.000 claims description 4
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 4
- 239000011148 porous material Substances 0.000 claims description 4
- 229960003604 testosterone Drugs 0.000 claims description 4
- 108010000817 Leuprolide Proteins 0.000 claims description 3
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 claims description 2
- UOACKFBJUYNSLK-XRKIENNPSA-N Estradiol Cypionate Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H](C4=CC=C(O)C=C4CC3)CC[C@@]21C)C(=O)CCC1CCCC1 UOACKFBJUYNSLK-XRKIENNPSA-N 0.000 claims description 2
- RSEPBGGWRJCQGY-RBRWEJTLSA-N Estradiol valerate Chemical compound C1CC2=CC(O)=CC=C2[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCC)[C@@]1(C)CC2 RSEPBGGWRJCQGY-RBRWEJTLSA-N 0.000 claims description 2
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 claims description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 2
- 108010069236 Goserelin Proteins 0.000 claims description 2
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 claims description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 2
- 230000000202 analgesic effect Effects 0.000 claims description 2
- 239000003098 androgen Substances 0.000 claims description 2
- 229940030486 androgens Drugs 0.000 claims description 2
- 229940046836 anti-estrogen Drugs 0.000 claims description 2
- 230000001833 anti-estrogenic effect Effects 0.000 claims description 2
- 229940034982 antineoplastic agent Drugs 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 229960004126 codeine Drugs 0.000 claims description 2
- 229960004976 desogestrel Drugs 0.000 claims description 2
- RPLCPCMSCLEKRS-BPIQYHPVSA-N desogestrel Chemical compound C1CC[C@@H]2[C@H]3C(=C)C[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 RPLCPCMSCLEKRS-BPIQYHPVSA-N 0.000 claims description 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 2
- 238000012377 drug delivery Methods 0.000 claims description 2
- 229940046085 endocrine therapy drug gonadotropin releasing hormone analogues Drugs 0.000 claims description 2
- 229960005416 estradiol cypionate Drugs 0.000 claims description 2
- 229960004766 estradiol valerate Drugs 0.000 claims description 2
- 229940011871 estrogen Drugs 0.000 claims description 2
- 239000000262 estrogen Substances 0.000 claims description 2
- 239000000328 estrogen antagonist Substances 0.000 claims description 2
- 229960002568 ethinylestradiol Drugs 0.000 claims description 2
- 229960002941 etonogestrel Drugs 0.000 claims description 2
- GCKFUYQCUCGESZ-BPIQYHPVSA-N etonogestrel Chemical compound O=C1CC[C@@H]2[C@H]3C(=C)C[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 GCKFUYQCUCGESZ-BPIQYHPVSA-N 0.000 claims description 2
- 229930195729 fatty acid Natural products 0.000 claims description 2
- 239000000194 fatty acid Substances 0.000 claims description 2
- 150000004665 fatty acids Chemical class 0.000 claims description 2
- 229960002949 fluorouracil Drugs 0.000 claims description 2
- 229960005352 gestodene Drugs 0.000 claims description 2
- SIGSPDASOTUPFS-XUDSTZEESA-N gestodene Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](C=C4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 SIGSPDASOTUPFS-XUDSTZEESA-N 0.000 claims description 2
- 125000005456 glyceride group Chemical group 0.000 claims description 2
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical class 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 claims description 2
- 229960002913 goserelin Drugs 0.000 claims description 2
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 claims description 2
- 229960000485 methotrexate Drugs 0.000 claims description 2
- 229960005181 morphine Drugs 0.000 claims description 2
- 229960004719 nandrolone Drugs 0.000 claims description 2
- 238000006116 polymerization reaction Methods 0.000 claims description 2
- 229960003387 progesterone Drugs 0.000 claims description 2
- 239000000186 progesterone Substances 0.000 claims description 2
- 239000000583 progesterone congener Substances 0.000 claims description 2
- 229940095055 progestogen systemic hormonal contraceptives Drugs 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 229960001603 tamoxifen Drugs 0.000 claims description 2
- 229960005026 toremifene Drugs 0.000 claims description 2
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 claims description 2
- 229920003169 water-soluble polymer Polymers 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 20
- 239000000203 mixture Substances 0.000 abstract description 10
- 239000002904 solvent Substances 0.000 abstract description 7
- 239000007787 solid Substances 0.000 abstract description 2
- 230000005540 biological transmission Effects 0.000 abstract 1
- 210000003205 muscle Anatomy 0.000 abstract 1
- 238000007920 subcutaneous administration Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 33
- 238000002360 preparation method Methods 0.000 description 20
- 230000015556 catabolic process Effects 0.000 description 16
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- 229920001610 polycaprolactone Polymers 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
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- 238000001727 in vivo Methods 0.000 description 9
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- 230000001954 sterilising effect Effects 0.000 description 8
- 238000004659 sterilization and disinfection Methods 0.000 description 8
- IWEQQRMGNVVKQW-OQKDUQJOSA-N Toremifene citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 IWEQQRMGNVVKQW-OQKDUQJOSA-N 0.000 description 7
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- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
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- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
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- 231100000252 nontoxic Toxicity 0.000 description 2
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- 229920000166 polytrimethylene carbonate Polymers 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- PTNZGHXUZDHMIQ-UHFFFAOYSA-N 4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1=CC=C2C(C)C(C(O)C3C(C(O)=C(C(N)=O)C(=O)C3N(C)C)(O)C3=O)C3=C(O)C2=C1O PTNZGHXUZDHMIQ-UHFFFAOYSA-N 0.000 description 1
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- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention mainly provides an in-situ gel injection implant. The implant is mainly composed of drugs, homopolymers or copolymers taking lactide, caprolactone or trimethylene carbonate as the monomers, and an organic solvent, which is mutually soluble with water. The drug transmission system can be injected into the subcutaneous parts, muscles, or diseased regions, and then a solid, namely an in-situ controlled-release implant, is formed through the solvent exchange. Through adjusting the ratios and molecular weights of each monomer and the prescription composition, the drugs can be released from one month to one year.
Description
Technical field
The invention belongs to slow controlled release pharmaceutical formulation art, prepare specifically a kind of situ-gel injection implant that homopolymer that lactide, caprolactone, trimethylene carbonate be monomer or copolymer be substrate of take.
Background technology
The chemosynthetic organism degradation polymer common are aliphatic polyester, paracyanogen base, acrylate, poe, poly-epsilon-caprolactone, polyureas alkane, polyamino acid etc.Most widely used in this base polymer is α-polyesters, as polylactide (PLA), poly lactic coglycolic acid (PLGA) and lactide caprolactone copolymer (P (CL/DL-LA)) etc.They have good biocompatibility, after implant into body is interior, can become lactic acid monomer through biodegradation, finally become CO after tricarboxylic acid cycle
2and H
2o, through lung, kidney, skin excretion.So according to the treatment needs, select the polymer of different size to make product, degradation in vivo speed is controlled, is also safe to body after use.The biological degradation polyalcohol goods are existing much enters medical market, as is prepared into surgical sutures, orthopedic fixation devices, microsphere or heeling-in type sustained-release preparation.
In the medicine of clinical use, there is a class medicine to need long-term (some months is the several years even) stably administration, such as cancer therapy drug, anti-additive medicament, cardiovascular drugs, contraceptive and vaccine etc.To this class medicine, exist many problem demanding prompt solutions when adopting conventional drug-supplying system: needs of patients is frequently taken medicine or is accepted injection, discontinues medication and will cause Relapse rate, to the patient, brings very large inconvenience; Be subject to the impacts such as gastroenteric environment, liver " first pass effect ", the bioavailability of medicine is low, and individual variation is large; Blood drug level that can not stable for extended periods of time, reduced the therapeutic effect of medicine, increased side effect; For some polypeptide, gene class medicine, due to the absorption resistance of small intestinal, conventional oral formulations can't be realized administration.Such as contraceptive mostly is hormonal medicaments, long-term short time interval is taken medicine and is easily missed, thereby causes contraceptive failure.Therefore, be prepared into slow releasing preparation and there is unique advantage, as Norplant
tMimplant.But existing implant need to carry out heeling-in after surgical incision under local anesthesia, if implant is biological non-degradable type, also needs similar program to be removed.This has brought great inconvenience to use.
In-situ forming gel implant is the study hotspot that delays in recent years control type injection field, and it is that medicine and polymer are dissolved in suitable solvent, local subcutaneous injection, and at medicine-feeding part, polymer solidifies and forms semisolid or solid drugs storage storehouse under physiological condition.Situ-gel has overcome the shortcoming of emulsion, liposome, microsphere and micelle, the relative advantage such as simple of misery, the preparation technology who have the topical that can be used for diseased region, extend the release cycle, reduce dosage and adverse effect, avoids implant to operate on while implanting.The preparation process of α-polyester based copolymer situ-gel is: polymer and medicine are dissolved in the organic solvent that (medicine also can be scattered in) can dissolve each other with water, be injected in vivo, solvent diffuse enters physiological fluid, polymer deposits after losing dissolve medium, at the injection site embedding medicinal, forms the semisolid implant.Got permission to comprise N-Methyl pyrrolidone (NMP), glyceryl triacetate, benzyl benzoate, glycerol alditol and glycerol formal for the preparation of the solvent of injection-type In-situ forming gel implant.The concentration of solvent species and polymer and molecular mass are the deciding factors that affects drug release.
Summary of the invention
Due to the special benefits of In-situ forming gel implant, caused at present widely and paid close attention to, the focus of research concentrates on PLA and PLGA polymer.The commodity that gone on the market have
said preparation contains 10% doxycycline hydrochloride, and the substrate of implant is comprised of PLA.Before use, by drug gel, in syringe needle injects patient's periodontal pocket, medicine can be local sustained release 1 week.
U.S. Durect company has also successfully developed take the thin excellent implants of injectable that PLGA is skeleton, for luteinizing hormone releasing hormone (LHRH) analog such as leuprorelin, Gao She Rayleigh injections implants, also can be used as the slow releasing injection of many hydrophilic, hydrophobic drugs except successfully.This dosage form can effectively reduce the burst effect of the rear medicine of injection, and can reach 6 months by the zero mode release in vivo.
Polylactide (PLA) has good biocompatibility and biological degradability, catabolite can participate in the metabolism of human body, and its performance can be by adjusted with other monomer copolymerizations on a large scale, become in current biomedical sector one of the most valued material.The PLA degradation speed is very fast, and after body corrodes, intensity descends very soon, is not suitable for the application of long period drug release, surgical cable and organizational project aspect.Aspect mechanical property, PLA has higher hot strength, modulus of compressibility, but matter is hard, toughness is poor, lacks flexibility and elasticity, very easily flexural deformation, thereby limited its application.
Poly-epsilon-caprolactone (PCL) is that a kind of degree of crystallinity is 45% left and right, has the semi-crystalline polymer of good biocompatibility.The ester group that five nonpolar methylene and a polarity are arranged on the construction unit that PCL repeats; existence with ester group of hydrolytic instability; can cause the biodegradation of PCL; yet; because PCL has higher degree of crystallinity; the existence of nonpolar methylene makes again the PCL hydrophilic poor, so its biological degradability is very slow.The important specially good effect of PCL is that small-molecule drug is had to fabulous permeability, is better than other polyester, so PCL useful as drug release vehicle.
PTMC (PTMC) be a kind of nontoxic, there is good biocompatibility, unordered or there is the biomaterial of a little crystallization, be a Recent study class fatty poly-ester carbonate the most widely.PTMC hydrolysis rate in vitro is lower 20 times than PCL, but degradation rate in vivo is more much higher than PCL.PTMC has compliance preferably, and its tensile stress and modular ratio PCL are low, and extension at break is higher than PCL.Because PTMC has very submissive engineering properties and unique degradability, therefore can be incorporated in the main chain of polymer, to change the engineering properties of polymer, regulate degradation rate.
In sum, the homopolymer of three kinds of monomers respectively has characteristic, up to the present, people have carried out careful research to these homopolymer, and have delivered a large amount of about its structure, physicochemical property, degraded and stability, toxicity and article and the patent at field of medicaments, applied.Yet, apply maximum various copolymers that are polymerized according to a certain percentage by different monomers that are actually in the medicine sustained and controlled release field, because on the one hand in the medicine sustained and controlled release field, to different medicines, require its carrier material to there is different drug release rates, only rely on the molecular weight and molecualr weight distribution adjusting degradation speed of homopolymer to have significant limitation, independent homopolymer can not meet all requirements; On the other hand, in order further to improve physical strength, drug permeability and the hydrophilic of carrier material, also usually the homopolymer skeleton is modified, introduce other degradable high polymer materials and make each analog copolymer, improve the performance of carrier material, to better meet the requirement of medicine sustained and controlled release.For example, in order to improve the biodegradation rate of polycaprolactone, by caprolactone and lactide or trimethylene carbonate copolymerization, the copolymer degradation speed obtained is greatly accelerated.And by lactide and the formed block copolymer of polytrimethylene carbonate monomer except the biocompatibility that has retained polylactide PLA better, mechanism of degradation is diffused, the degradation speed good characteristic such as very fast, also can, by adjusting the content of two monomers, regulate the consistency and elasticity of block copolymer.When adding a small amount of polytrimethylene carbonate in the PLA chain, the copolymer moderate strength and more tough and tensile that can become, if when the former content further increases, can become soft and flexible.
At present the homopolymer of lactide, caprolactone, trimethylene carbonate or copolymer in slow controlled release field for the preparation of microcapsule, microgranule, implant, class Emulsion, nanoparticle and eye drops system etc., but only PLA application to some extent on the gel injection implant in position, homopolymer PLC, PTMC and lactide caprolactone copolymer P(CL-DLLA), trimethylene carbonate-lactide copolymer P(TMC-LLA) and trimethylene carbonate-caprolactone copolymer P(TMC-CL) also do not studied and be applied in situ-gel and inject in the preparation of implant.The present invention take first the homopolymer of lactide, caprolactone, trimethylene carbonate or copolymer as prepared by carrier material multiple biodegradable situ-gel injection implant.
Another key of situ-gel injection implant is to select suitable organic solvent, guarantee that solvent is nontoxic, polymer dissolubility therein is good, form the low-viscosity implant solution that is beneficial to injection.Simultaneously, the gel form formed in the polymer precipitation process also depends on the character of organic solvent, the form of its implant of organic solvent that hydrophilic is poor mostly is intensive spongiosis, and hydrophilic organic solvent becomes to have the open mesh structure of a lot of spaces and passage as the NMP multiform.These forms have great impact to prominent releasing with slow release kinetics of the initial stage of gel.Based on conclusions, the present invention selects the solvent of N-Methyl pyrrolidone (NMP) as polymer and medicine, is prepared into the injection solution that a kind of toxicity is little, viscosity is low, syringeability is good.
In addition, the inventor has investigated the release rule of degradation rule and the medicine of macromolecular material by test.There is following rule in this kind of situ-gel injection implant:
(1) three kind of monomer-polymer degradation speed in vivo by the speed sequence is: PCL<PTMC<PLA; In general, the content of caprolactone in copolymer (CL) monomer is more, and the degradation in vivo time limit is longer; The content of lactide in copolymer (LA) monomer is more, and the sample degradation in vivo time limit is shorter, whereby the length in adjustment release cycle;
(2) various polymer degraded mode in vivo has two kinds: erodible degraded, and as PTMC, the volume of implant constantly diminishes with the prolongation of Implantation Time; Bulk degradation, as P(CL-DLLA), the initial stage degraded shows as molecular weight and molecular weight, and material breakage just appears in the degraded later stage;
(3) similar polymers, with the increase of molecular weight, drug release rate is slack-off; In polymer, the ratio of two kinds of monomers is little on the drug release rate impact, larger on the degradation speed impact; Molecular weight is larger, and the viscosity of formulation soln is larger;
(4) prescription Chinese medicine proportion is fewer, and every day, burst size was less.
Utilize above-mentioned rule, by adjusting molecular weight and the monomer ratio of polymer, the present invention can prepare and discharge the time limit at one month to 1 year, and can discharge the implant of different doses every day.
The invention provides following technical scheme:
1, a kind of situ-gel injection implant, wherein, this situ-gel injection implant comprises:
(a) medicine;
(b) organic solvent that can dissolve each other with water;
(c) the immiscible high molecular polymer with biocompatibility and biodegradability of water;
Wherein, described high molecular polymer is for take homopolymer or the copolymer that lactide, caprolactone, trimethylene carbonate be monomer, and described medicine and described high molecular polymer dissolve, disperse or be suspended in described organic solvent.
2, according to above-mentioned situ-gel injection implant, wherein, described high molecular polymer is to be selected from more than one in lactide caprolactone copolymer, trimethylene carbonate homopolymer, trimethylene carbonate-lactide copolymer and trimethylene carbonate-caprolactone copolymer, and the weight average molecular weight of described high molecular polymer is 5000 ~ 500000.
3, according to above-mentioned situ-gel injection implant, wherein, the mol ratio that forms the monomer polymerization of lactide caprolactone copolymer, trimethylene carbonate-lactide copolymer and trimethylene carbonate-caprolactone copolymer is 95: 5 ~ 5: 95.
4, according to above-mentioned situ-gel injection implant, wherein, described organic solvent is N-Methyl pyrrolidone, and the percentage by weight of described high molecular polymer in described organic solvent is 10 ~ 50%.
5, according to above-mentioned situ-gel injection implant, wherein, this drug delivery system also comprises pore former and/or release rate modifier.
6, according to above-mentioned situ-gel injection implant, wherein, described pore former is more than one in sugar, salt and water-soluble polymer, and described release rate modifier is glyceride and/or fatty acid.
7,, according to above-mentioned situ-gel injection implant, wherein, described medicine is to be selected from more than one in progestogens, estrogens, anti-estrogens, androgens, gonadotropin releasing hormone analogues, analgesic, antineoplastic agent.
8, according to above-mentioned situ-gel injection implant, wherein, described medicine is to be selected from more than one in desogestrel, etonogestrel, levonorgestrel, gestodene, promise first time progesterone, estradiol, ethinylestradiol, estradiol valerate, estradiol cypionate, testosterone, testosterone undecanoate, 7 Alpha-Methyls-19-nortestosterone, tamoxifen, toremifene, goserelin, music score of Chinese operas Rayleigh, leuprorelin, ibuprofen, codeine, morphine, 5-fluorouracil, cisplatin and methotrexate.
9,, according to above-mentioned situ-gel injection implant, wherein, the described medicine percentage by weight in the gel injection implant in position is 0.1 ~ 50%.
10, the above-mentioned application of situ-gel injection implant in preparing sustained and controlled release medicament.
Concrete preparation process of the present invention is: polymer mixes with certain proportion with N-Methyl pyrrolidone, and 37 ℃ of stirrings are spent the night, until obtain the solution of transparent homogeneous.Solution 65 degree are added to heat extraction bubble wherein.Powder after medicine pulverizes and sieves adds dissolving or disperses, and stirs.In preparation process sterile working or preparation complete after sterilization.Under the cold drying condition, preserve.
The present invention is simple except possessing the preparation of situ-gel injection implant, outside the advantage such as easy to use, the situ-gel injection implant prepared with PLGA with existing PLA is compared, used more advanced high molecular polymer, molecular weight and monomer ratio by telomerized polymer, can meet the more burst size requirement of multiple medicines thing, reach different slow release durations, there is more diversified slow release effect and the regulatable advantage of medicament slow release concentration.
The accompanying drawing explanation
Fig. 1 is P(CL-DLLA in the present invention) polymer is at rabbit vivo degradation figure, and wherein A is PCL; B is P(CL-DLLA) (monomer mole ratio is 70: 30); C is P(CL-DLLA) (monomer mole ratio is 50: 50); D is P(CL-DLLA) (monomer mole ratio is 30: 70); E is PLA.
The release in vitro figure that Fig. 2 is levonorgestrel situ-gel injection implant.
Release graphics in the body that Fig. 3 is testosterone undecanoate situ-gel injection implant.
The specific embodiment
Below come by specific embodiment that the present invention will be described in more detail, but scope of the present invention is not limited to following examples.
The high molecular polymer used in following examples is all purchased from Mount Tai, Jinan handle of the Big Dipper bio tech ltd, and the specification of high molecular polymer refers to each example.In embodiment, levonorgestrel, estradiol are purchased from Zizhu Pharmaceutical Co., Ltd., Beijing, testosterone undecanoate, Toremifene Citrate are purchased from Wuhan Yuan Cheng Pharmacy stock Co., Ltd, leuprorelin acetate is purchased from the biochemical (Shanghai) Co., Ltd. of gill, ibuprofen is purchased from Shandong XinHua Pharmacy stock Co., Ltd, and cisplatin is purchased from Shandong Qilu Pharmaceutical Factory.
Embodiment 1
The preparation of levonorgestrel female contraception situ-gel injection implant
Prescription:
Every g levonorgestrel (LNG) situ-gel injection implant contains:
P(TMC-LLA)：174mg
LNG：6mg
NMP：820mg
Wherein P (TMC-LLA) specification is TMC: LLA=59: the 41(mol ratio), weight average molecular weight (Mw) is 346125.
After P (TMC-LLA) shreds, take recipe quantity and add a certain amount of NMP mix homogeneously, 37 ℃ of stirrings are spent the night, until obtain the solution of transparent homogeneous.The solution obtained is added to heat extraction bubble wherein under 65 ℃.After levonorgestrel was pulverized 100 mesh sieves, the levonorgestrel powder of getting recipe quantity adds and is dissolved in above-mentioned solution, stirs the solution that obtains transparent homogeneous, obtains levonorgestrel female contraception situ-gel injection implant after the gamma-ray irradiation sterilization.
Embodiment 2
The preparation of testosterone undecanoate male contraception situ-gel injection implant
Prescription:
Every g testosterone undecanoate (TU) situ-gel injection implant contains:
P(CL-DLLA)：187.5mg
TU：187.5mg
NMP：625mg
Wherein P (CL-DLLA) specification is CL: DLLA=80: the 20(mol ratio), and Mw=70357.
After P (CL-DLLA) shreds, take recipe quantity and add a certain amount of NMP mix homogeneously, 37 ℃ of stirrings are spent the night, until obtain the solution of transparent homogeneous.The solution obtained is added to heat extraction bubble wherein under 65 ℃.After testosterone undecanoate was pulverized 100 mesh sieves, the testosterone undecanoate powder of getting recipe quantity adds and is dissolved in above-mentioned solution, stirs the solution that obtains transparent homogeneous, obtains testosterone undecanoate situ-gel injection implant after the gamma-ray irradiation sterilization.
Embodiment 3
The preparation of estradiol situ-gel injection implant
Prescription:
Every g estradiol situ-gel injection implant contains:
PTMC：240mg
Estradiol: 6mg
NMP：750mg
PTMC wherein, Mw=48578.
After PTMC shreds, take recipe quantity and add a certain amount of NMP mix homogeneously, 37 ℃ of stirrings are spent the night, until obtain the solution of transparent homogeneous.The solution obtained is added to heat extraction bubble wherein under 65 ℃.After estradiol was pulverized 100 mesh sieves, the estradiol powder of getting recipe quantity adds and is dissolved in above-mentioned solution, stirs the solution that obtains transparent homogeneous, obtains estradiol situ-gel injection implant after the gamma-ray irradiation sterilization.
Embodiment 4
The preparation of leuprorelin acetate situ-gel injection implant
Prescription:
Every g leuprorelin acetate situ-gel injection implant contains:
P(CL-DLLA)：450mg
Leuprorelin acetate: 22.5mg
NMP：527.5mg
Wherein P (CL-DLLA) specification is CL: DLLA=95: the 5(mol ratio), and Mw=16253.
After P (CL-DLLA) shreds, take recipe quantity and add a certain amount of NMP mix homogeneously, 37 ℃ of stirrings are spent the night, until obtain the solution of transparent homogeneous.The solution obtained is added to heat extraction bubble wherein under 65 ℃.After leuprorelin acetate was pulverized 100 mesh sieves, the leuprorelin acetate powder of getting recipe quantity adds and is dissolved in above-mentioned solution, stirs the solution that obtains transparent homogeneous, obtains leuprorelin acetate situ-gel injection implant after the gamma-ray irradiation sterilization.
Embodiment 5
The preparation of Toremifene Citrate situ-gel injection implant
Prescription:
Every g Toremifene Citrate situ-gel injection implant contains:
P(TMC-CL)：280mg
Toremifene Citrate: 20mg
NMP：700mg
Wherein P (TMC-CL) specification is TMC: CL=25: the 75(mol ratio), and Mw=265337
After P (TMC-CL) shreds, take recipe quantity and add a certain amount of NMP mix homogeneously, 37 ℃ of stirrings are spent the night, until obtain the solution of transparent homogeneous.The solution obtained is added to heat extraction bubble wherein under 65 ℃.After Toremifene Citrate was pulverized 100 mesh sieves, the Toremifene Citrate powder of getting recipe quantity adds and is dissolved in above-mentioned solution, stirs the solution that obtains transparent homogeneous, obtains Toremifene Citrate situ-gel injection implant after the gamma-ray irradiation sterilization.
Embodiment 6
The preparation of ibuprofen situ-gel injection implant
Prescription:
Every g ibuprofen situ-gel injection implant contains:
P(TMC-LLA)：220mg
Ibuprofen: 20mg
NMP：760mg
Wherein P (TMC-LLA) specification is TMC: LLA=81: the 19(mol ratio), and Mw=146737
After P (TMC-LLA) shreds, take recipe quantity and add a certain amount of NMP mix homogeneously, 37 ℃ of stirrings are spent the night, until obtain the solution of transparent homogeneous.The solution obtained is added to heat extraction bubble wherein under 65 ℃.After ibuprofen was pulverized 100 mesh sieves, the ibuprofen powder of getting recipe quantity adds and is dissolved in above-mentioned solution, stirs the solution that obtains transparent homogeneous, obtains ibuprofen situ-gel injection implant after the gamma-ray irradiation sterilization.
Embodiment 7
The preparation of cisplatin situ-gel injection implant
Prescription:
Every g cisplatin situ-gel injection implant contains:
P(TMC-CL)：150mg
Cisplatin: 300mg
NMP：550mg
Wherein P (TMC-CL) specification is TMC: CL=50: the 50(mol ratio), and Mw=175083.
After P (TMC-CL) shreds, take recipe quantity and add a certain amount of NMP mix homogeneously, 37 ℃ of stirrings are spent the night, until obtain the solution of transparent homogeneous.The solution obtained is added to heat extraction bubble wherein under 65 ℃.After cisplatin was pulverized 100 mesh sieves, the cisplatin powder of getting recipe quantity joins in above-mentioned solution, and dispersed with stirring is even, obtains cisplatin situ-gel injection implant after the gamma-ray irradiation sterilization.
Embodiment 8
The release in vitro of levonorgestrel situ-gel injection implant
Sample: press method preparation in embodiment 1.
0.5g levonorgestrel situ-gel injection implant solution, by No. 20 syringe needles, is injected in the 10ml distilled water, at 37 ° of C, isothermal vibration under the condition of 65rpm in 10s.Change distilled water every 24h, filter after the distilled water under changing is collected, at the 240nm place, use ultraviolet spectrophotometer to measure its trap, calculate the cumulative release amount.
Result: after levonorgestrel situ-gel injection implant discharges 90 days in vitro, the cumulative release amount is 90.54%, and its rate of release extends in time slightly and reduces, and substantially without the prominent phenomenon of releasing, exists.
Embodiment 9: in the body of testosterone undecanoate situ-gel injection implant, discharge
Sample: press the method preparation in embodiment 2, every rat dosage is 0.4g.
Male SD rat (240 ~ 260g), weigh, labelling, and grouping, after etherization, used syringe needle No. 20, back subcutaneous injection sample.All weighed before and after injector to inject, determined dosage.Respectively at the appropriate time after administration, tail venous blood sampling 0.7ml measures wherein testosterone concentration in left and right.After the blood sample sampling finishes, put to death rat, take out the residue implants, after lyophilizing, its Chinese medicine of methanol extraction, HPLC measures testosterone undecanoate content, calculates the remaining dose of implants.
Result: testosterone undecanoate male contraception situ-gel injection implant discharges stable in vivo, and in the time of 63 days, when in body, residual drug is 10.12%, 90 day, residual drug is zero substantially.After implantation, testosterone concentration rises rapidly in animal body, is approximately reaching peak value after 2 weeks, and normal value descended back in the time of 90 days.
Claims (10)
1. a situ-gel injection implant, is characterized in that, this situ-gel injection implant comprises:
(a) medicine;
(b) organic solvent that can dissolve each other with water;
(c) there is the high molecular polymer of biocompatibility and biodegradability;
Wherein, described high molecular polymer is for take homopolymer or the copolymer that lactide, caprolactone, trimethylene carbonate be monomer, and described medicine and described high molecular polymer dissolve, disperse or be suspended in described organic solvent.
2. situ-gel according to claim 1 is injected implant, wherein, described high molecular polymer is to be selected from more than one in lactide caprolactone copolymer, trimethylene carbonate homopolymer, trimethylene carbonate-lactide copolymer and trimethylene carbonate-caprolactone copolymer, and the weight average molecular weight of described high molecular polymer is 5000 ~ 500000.
3. situ-gel according to claim 2 is injected implant, and wherein, the mol ratio that forms the monomer polymerization of lactide caprolactone copolymer, trimethylene carbonate-lactide copolymer and trimethylene carbonate-caprolactone copolymer is 95: 5 ~ 5: 95.
4. according to the described situ-gel injection of any one in claim 1-3 implant, wherein, described organic solvent is N-Methyl pyrrolidone, and the percentage by weight of described high molecular polymer in described organic solvent is 10 ~ 50%.
5. situ-gel according to claim 1 is injected implant, and wherein, this drug delivery system also comprises pore former and/or release rate modifier.
6. situ-gel according to claim 5 is injected implant, and wherein, described pore former is more than one in sugar, salt and water-soluble polymer, and described release rate modifier is glyceride and/or fatty acid.
7. situ-gel according to claim 1 injection implant, wherein, described medicine is to be selected from more than one in progestogens, estrogens, anti-estrogens, androgens, gonadotropin releasing hormone analogues, analgesic, antineoplastic agent.
8. situ-gel according to claim 7 is injected implant, wherein, described medicine is to be selected from more than one in desogestrel, etonogestrel, levonorgestrel, gestodene, promise first time progesterone, estradiol, ethinylestradiol, estradiol valerate, estradiol cypionate, testosterone, testosterone undecanoate, 7 Alpha-Methyls-19-nortestosterone, tamoxifen, toremifene, goserelin, music score of Chinese operas Rayleigh, leuprorelin, ibuprofen, codeine, morphine, 5-fluorouracil, cisplatin and methotrexate.
9. situ-gel according to claim 1 injection implant, wherein, the described medicine percentage by weight in the gel injection implant in position is 0.1 ~ 50%.
10. the application of the described situ-gel injection implant of any one in preparing sustained and controlled release medicament in claim 1-9.
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| CN108619557A (en) * | 2017-03-24 | 2018-10-09 | 辽宁省计划生育科学研究院 | Application of the in-situ gel injection implant in vas deferens bolt is stifled |
| CN110475545A (en) * | 2017-03-27 | 2019-11-19 | W.L.戈尔及同仁股份有限公司 | For controlling the injectable and biodegradable polymer preparation of release bioactive agent |
| CN110475545B (en) * | 2017-03-27 | 2024-01-05 | W.L.戈尔及同仁股份有限公司 | Injectable and biodegradable polymeric formulations for the controlled release of bioactive agents |
| US11752099B2 (en) | 2017-03-27 | 2023-09-12 | W. L. Gore & Associates, Inc. | Injectable and biodegradable polymer formulations for controlled release of bioactive agents |
| RU2777534C1 (en) * | 2018-07-23 | 2022-08-05 | Чонг Кун Данг Фармасьютикал Корп. | Stable pharmaceutical composition containing testosterone undecanoate |
| CN111000798A (en) * | 2019-12-26 | 2020-04-14 | 四川恒博生物科技有限公司 | Non-operative castration injection for dogs by adopting in-situ gel technology |
| CN111000798B (en) * | 2019-12-26 | 2021-11-23 | 四川恒博生物科技有限公司 | Non-operative castration injection for dogs by adopting in-situ gel technology |
| CN113081952A (en) * | 2021-04-12 | 2021-07-09 | 山东谷雨春生物科技有限公司 | Long-acting injection gel containing entecavir |
| WO2022229402A1 (en) * | 2021-04-30 | 2022-11-03 | Medincell Sa | New formulation |
| CN113289062A (en) * | 2021-05-17 | 2021-08-24 | 辽宁省计划生育科学研究院 | Solvent precipitation type in-situ gel injection implant and application |
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