CN103494769B - A kind of compound long-acting in-situ gel injection agent for the treatment of chronic viral hepatitis B and preparation method thereof - Google Patents
A kind of compound long-acting in-situ gel injection agent for the treatment of chronic viral hepatitis B and preparation method thereof Download PDFInfo
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- CN103494769B CN103494769B CN201310467495.4A CN201310467495A CN103494769B CN 103494769 B CN103494769 B CN 103494769B CN 201310467495 A CN201310467495 A CN 201310467495A CN 103494769 B CN103494769 B CN 103494769B
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- 238000011065 in-situ storage Methods 0.000 title claims abstract description 54
- 238000002347 injection Methods 0.000 title claims abstract description 37
- 239000007924 injection Substances 0.000 title claims abstract description 37
- 239000003795 chemical substances by application Substances 0.000 title claims abstract description 34
- 150000001875 compounds Chemical class 0.000 title claims abstract description 31
- 208000002672 hepatitis B Diseases 0.000 title claims abstract description 19
- 230000001684 chronic effect Effects 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 108010050904 Interferons Proteins 0.000 claims abstract description 74
- 102000014150 Interferons Human genes 0.000 claims abstract description 74
- 229940079322 interferon Drugs 0.000 claims abstract description 74
- 239000000463 material Substances 0.000 claims abstract description 55
- 108010078233 Thymalfasin Proteins 0.000 claims abstract description 38
- 229960004231 thymalfasin Drugs 0.000 claims abstract description 38
- NZVYCXVTEHPMHE-ZSUJOUNUSA-N thymalfasin Chemical compound CC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O NZVYCXVTEHPMHE-ZSUJOUNUSA-N 0.000 claims abstract description 36
- 150000003751 zinc Chemical class 0.000 claims abstract description 33
- 159000000003 magnesium salts Chemical class 0.000 claims abstract description 27
- 239000002904 solvent Substances 0.000 claims abstract description 26
- 230000001954 sterilising effect Effects 0.000 claims description 21
- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 claims description 14
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 claims description 14
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- -1 dimethyl sulfoxine Chemical compound 0.000 claims description 8
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 8
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 claims description 8
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims description 7
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- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical group CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 4
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical group OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 4
- 229920002125 Sokalan® Polymers 0.000 claims description 4
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- 238000000034 method Methods 0.000 claims description 4
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- JKJWYKGYGWOAHT-UHFFFAOYSA-N bis(prop-2-enyl) carbonate Chemical compound C=CCOC(=O)OCC=C JKJWYKGYGWOAHT-UHFFFAOYSA-N 0.000 claims 2
- 208000000419 Chronic Hepatitis B Diseases 0.000 abstract description 6
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- 229960003507 interferon alfa-2b Drugs 0.000 description 17
- MIXCUJKCXRNYFM-UHFFFAOYSA-M sodium;diiodomethanesulfonate;n-propyl-n-[2-(2,4,6-trichlorophenoxy)ethyl]imidazole-1-carboxamide Chemical compound [Na+].[O-]S(=O)(=O)C(I)I.C1=CN=CN1C(=O)N(CCC)CCOC1=C(Cl)C=C(Cl)C=C1Cl MIXCUJKCXRNYFM-UHFFFAOYSA-M 0.000 description 17
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- 238000004090 dissolution Methods 0.000 description 10
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- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 229920000642 polymer Polymers 0.000 description 10
- 239000008227 sterile water for injection Substances 0.000 description 10
- 238000004659 sterilization and disinfection Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 229920001983 poloxamer Polymers 0.000 description 9
- 230000005855 radiation Effects 0.000 description 9
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 8
- QNILTEGFHQSKFF-UHFFFAOYSA-N n-propan-2-ylprop-2-enamide Chemical compound CC(C)NC(=O)C=C QNILTEGFHQSKFF-UHFFFAOYSA-N 0.000 description 6
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 6
- 229940007718 zinc hydroxide Drugs 0.000 description 6
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 6
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 5
- 241000700721 Hepatitis B virus Species 0.000 description 5
- 229920001993 poloxamer 188 Polymers 0.000 description 5
- 229940044519 poloxamer 188 Drugs 0.000 description 5
- 229920001661 Chitosan Chemical class 0.000 description 4
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical class C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 4
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 4
- 239000001866 hydroxypropyl methyl cellulose Chemical class 0.000 description 4
- 229920003088 hydroxypropyl methyl cellulose Chemical class 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- 229960003943 hypromellose Drugs 0.000 description 4
- 229960000502 poloxamer Drugs 0.000 description 4
- 239000011592 zinc chloride Substances 0.000 description 4
- 235000005074 zinc chloride Nutrition 0.000 description 4
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 3
- 229920002148 Gellan gum Polymers 0.000 description 3
- 229940082484 carbomer-934 Drugs 0.000 description 3
- 239000000216 gellan gum Substances 0.000 description 3
- 235000010492 gellan gum Nutrition 0.000 description 3
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 3
- 239000000347 magnesium hydroxide Substances 0.000 description 3
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 3
- 239000000395 magnesium oxide Substances 0.000 description 3
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 3
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 3
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical group CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
- JVTIXNMXDLQEJE-UHFFFAOYSA-N 2-decanoyloxypropyl decanoate 2-octanoyloxypropyl octanoate Chemical compound C(CCCCCCC)(=O)OCC(C)OC(CCCCCCC)=O.C(=O)(CCCCCCCCC)OCC(C)OC(=O)CCCCCCCCC JVTIXNMXDLQEJE-UHFFFAOYSA-N 0.000 description 2
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- 229920000432 Polylactide-block-poly(ethylene glycol)-block-polylactide Polymers 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- QXNIBPDSSDVBQP-UHFFFAOYSA-N acetic acid;2-methylpropanoic acid Chemical compound CC(O)=O.CC(C)C(O)=O QXNIBPDSSDVBQP-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229910052785 arsenic Inorganic materials 0.000 description 2
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- LGRFSURHDFAFJT-UHFFFAOYSA-N phthalic anhydride Chemical compound C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 2
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- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to medical art, disclose compound long-acting in-situ gel injection agent for the treatment of chronic viral hepatitis B and preparation method thereof.The compound long-acting in-situ gel injection agent for the treatment of chronic viral hepatitis B of the present invention by 5-24 part zinc salt interferon a or magnesium salt interferon a, 150-800 part thymalfasin, 1800-12000 part situ-gel material, 8000-100000 part solvent composition.Compound long-acting in-situ gel injection of the present invention agent is made up of thymalfasin and interferon and suitable situ-gel material, reduce administration frequency, can long-time stable sustained release drug effect, without obvious toxic-side effects, content of dispersion and envelop rate higher, product quality is better than required standard, is adapted at applying in treating chronic hepatitis B.
Description
Technical field
The present invention relates to medical art, be specifically related to a kind of compound long-acting in-situ gel injection agent for the treatment of chronic viral hepatitis B and preparation method thereof.
Background technology
It is one of modal viral infection of the mankind that hepatitis B virus (HBV) infects, and whole world Patients with Chronic HBV Infection about has 300,000,000, and major part is in Asia, and in population of China, Chronic HBV carriers accounts for 10% ~ 15%.In chronic hepatitis B (CHB) patient, annual generation hepatitis interstitialis chronica and hepatocarcinoma person account for 2% and 1% respectively, and this numeral is still in ascendant trend.In hepatitis B morbidity patient, there is the people of 90% to go to see a doctor treatment, and on average about have the Patients on Recurrence of 40% to be hospitalized for treatment.
Large quantity research proves, interferon is current both at home and abroad accepted treatment viral hepatitis active drug, but it can only inhibition HBV replication, and in human body, thoroughly can not remove HBV, and therefore after drug withdrawal, relapse rate is high.Thymalfasin is the highly purified polypeptide be made up of 28 aminoacid of synthetic, it can increase body anti-infection ability, alleviate the damage of hepatocellular immunopathogenesis, promote hepatocyte function reparation, and the effect of virus sweep still can continue to increase after terminating the course for the treatment of of treatment hepatitis B, there is curative effect lasting, the feature of use safety.Thymalfasin can improve chronic hepatitis B patient to the biochemical of interferon and serology response rate, reduces its drug resistance incidence rate, and the two is combined is a kind of Anti-HBV activity Therapeutic Method preferably.
But on market, interferon and thymalfasin all only have common injection, treatment cycle long (average more than 1 year), need frequent and long-term administration, 1 interferon and one week 2 times subcutaneous injection thymalfasins are injected the next day of general, this is easily to the problem that patient brings compliance and forgets administration, finally affect the treatment, so develop a kind of to be necessary containing the compound long-acting injection of interferon and thymalfasin for chronic hepatitis B and feasible, current interferon and thymalfasin compound long-acting injection not yet have relevant report.
Summary of the invention
In view of this, the object of the present invention is to provide a kind of compound long-acting in-situ gel injection agent for the treatment of chronic viral hepatitis B and preparation method thereof, make compound long-acting in-situ gel injection agent quality, medicament contg and envelop rate prepared by the present invention higher, and the stable sustained release drug effect that can be administered once reach about 30 days.
For achieving the above object, the invention provides following technical scheme:
Treat a compound long-acting in-situ gel injection agent for chronic viral hepatitis B, it is characterized in that, with parts by weight, composed of the following components:
5-24 part zinc salt interferon a or magnesium salt interferon a, 150-800 part thymalfasin, 1800-12000 part situ-gel material, 8000-100000 part solvent;
Wherein, described situ-gel material is for one or more in the biodegradable polymers of removal of solvents type situ-gel, thermosensitive in situ gel material, pH sensitive in situ gels research material, ionic strength sensitive type situ-gel material;
The described biodegradable polymers for removal of solvents type situ-gel is selected from polyoxyethylene polyoxypropylene block copolymer, polylactic acid, PLGA, polylactic acid-polyethylene glycol block copolymer, polylactic-co-glycolic acid-polyethyleneglycol block copolymer, PLA-PEG-PLA block copolymer, polylactic-co-glycolic acid-Polyethylene Glycol be embedding-polylactic-co-glycolic acid section copolymer, poly-N-isopropyl propylene phthalein amine, one or more in acetic acid-isopropylformic acid. sucrose vinegar;
Described thermosensitive in situ gel material is selected from poloxamer, methylcellulose, hypromellose, chitosan derivatives, polylactic acid-polyethylene glycol block copolymer, polylactic acid through one or more in base ethyl cellulose, polycaprolactone-polyethylene glycol block copolymer, poly-N-isopropyl acrylamide of guanidine-acetic acid-polyethyleneglycol block copolymer, second;
Described pH sensitive in situ gels research material is selected from CAP, and hypromellose phthalandione is cruel, one or more in carbomer, chitosan;
Described ionic strength sensitive type situ-gel material be selected from alginate, gellan gum one or both;
Described solvent is selected from N-methyl and adjoins pyrrolidone, triacetin, ethyl lactate, glycerol formal, benzyl benzoate, dimethyl sulfoxine, acetone, one or both during 2-arsenic pyrrolidone, propylene carbonate are cruel;
Described zinc salt interferon a or magnesium salt interferon a obtains through interferon a and zinc salt or magnesium salt hybrid reaction.
In-situ gel injection agent can adopt different situ-gel materials according to the difference of principal agent, situ-gel Material selec-tion is improper, cannot realize long-acting, and the quality of injection also can decline, particularly when principal agent is incessantly a kind of, the selection of situ-gel material is more crucial.There is not the in-situ gel injection agent component formula of applicable all principal agents in the art, do not have in-situ gel injection the agent component formula, particularly interferon for compound recipe and thymalfasin compound recipe.For solving needs of patients injection repeatedly, the problems such as poor compliance, the present invention selects suitable situ-gel material fit interferon and thymalfasin preparation can long-time stable constant drug effect, the injection that quality, medicament contg and envelop rate are higher.
As preferably, on the technical scheme basis that the claims in the present invention 1 provide, the agent of described compound long-acting in-situ gel injection, is characterized in that, with parts by weight, composed of the following components:
10-20 part zinc salt interferon a or magnesium salt interferon a, 170-300 part thymalfasin, 3500-4500 part situ-gel material, 30000-50000 part solvent.
As preferably, on the technical scheme basis that the claims in the present invention 1 provide, described situ-gel material is made up of a kind of and for removal of solvents type situ-gel the biodegradable polymers in thermosensitive in situ gel material, pH sensitive in situ gels research material, ionic strength sensitive type situ-gel material; More preferably, described situ-gel material is 1:0.5-4 by thermosensitive in situ gel material, pH sensitive in situ gels research material or ionic strength sensitive type situ-gel material and the weight ratio for the biodegradable polymers of removal of solvents type situ-gel.
In addition, in some embodiments of the present invention, described situ-gel material is separately biodegradable polymers for removal of solvents type situ-gel or thermosensitive in situ gel material, such as polylactic acid, PLGA, poloxamer, poly-N-isopropyl acrylamide.
As preferably, on the technical scheme basis that the claims in the present invention 1 provide, the described biodegradable polymers for removal of solvents type situ-gel is weight average molecular weight is 5000-50000Da, intrinsic viscosity is the polylactic acid of 0.1dl/g-0.5dl/g, or by the lactic acid units of 25%≤molar percentage < 100% with the glycolic acid units of 0 < molar percentage≤75% forms, weight average molecular weight is 2000-50000Da, intrinsic viscosity is the PLGA of 0.1dl/g-0.5dl/g.
As preferably, on the technical scheme basis that the claims in the present invention 1 provide, described thermosensitive in situ gel material is one or more in poloxamer188, PLURONICS F87, methylcellulose, polylactic acid-polyethylene glycol block copolymer, polylactic-co-glycolic acid-polyethyleneglycol block copolymer, polycaprolactone-polyethylene glycol block copolymer, poly-N-isopropyl acrylamide, more preferably, described thermosensitive in situ gel material is poloxamer188, PLURONICS F87 or methylcellulose.
As preferably, on the technical scheme basis that the claims in the present invention 1 provide, described pH sensitive in situ gels research material is one or more in CAP, carbomer 934, Acritamer 940, Carbopol 941.
As preferably, described alginate is sodium alginate.
As preferably, on the technical scheme basis that the claims in the present invention 1 provide, the mol ratio of described interferon a and zinc salt is 1:1-3, and the mol ratio of described interferon a and magnesium salt is 1:1-3.
As preferably, on the technical scheme basis that the claims in the present invention 1 provide, described interferon a be selected from interferon a-2a type, Interferon a-1b type, Interferon Alfa-2b type one or more.
As preferably, on the technical scheme basis that the claims in the present invention 1 provide, described zinc salt be selected from zinc hydroxide, zinc chloride one or both, described magnesium salt be selected from magnesium hydroxide, magnesium oxide one or both.
As preferably, on the technical scheme basis that the claims in the present invention 7 provide, described solvent is N-Methyl pyrrolidone, ethyl lactate, glycerol formal, 2-Pyrrolidone, more preferably, is N-Methyl pyrrolidone.
In addition, the present invention also provides a kind of preparation method for the treatment of the compound long-acting in-situ gel injection agent of chronic viral hepatitis B, with parts by weight, take 1800-12000 part situ-gel material and the mixing of 8000-100000 part solvent, add 150-800 part thymalfasin, supersound process, then add 5-24 part zinc salt interferon a or magnesium salt interferon a, heated at constant temperature 10000rpm-20000rpm stirs 5min-10min, sterilizing and get final product;
Wherein, described situ-gel material is for one or more in the biodegradable polymers of removal of solvents type situ-gel, thermosensitive in situ gel material, pH sensitive in situ gels research material, ionic strength sensitive type situ-gel material;
The described biodegradable polymers for removal of solvents type situ-gel is selected from polyoxyethylene polyoxypropylene block copolymer, polylactic acid, PLGA, polylactic acid-polyethylene glycol block copolymer, polylactic-co-glycolic acid-polyethyleneglycol block copolymer, PLA-PEG-PLA block copolymer, polylactic-co-glycolic acid-Polyethylene Glycol be embedding-polylactic-co-glycolic acid section copolymer, poly-N-isopropyl propylene phthalein amine, one or more in acetic acid-isopropylformic acid. sucrose vinegar;
Described thermosensitive in situ gel material is selected from poloxamer, methylcellulose, hypromellose, chitosan derivatives, polylactic acid-polyethylene glycol block copolymer, polylactic acid through one or more in base ethyl cellulose, polycaprolactone-polyethylene glycol block copolymer, poly-N-isopropyl acrylamide of guanidine-acetic acid-polyethyleneglycol block copolymer, second;
Described pH sensitive in situ gels research material is selected from CAP, and hypromellose phthalandione is cruel, one or more in carbomer, chitosan;
Described ionic strength sensitive type situ-gel material be selected from alginate, gellan gum one or both;
Described solvent is selected from N-methyl and adjoins pyrrolidone, triacetin, ethyl lactate, glycerol formal, benzyl benzoate, dimethyl sulfoxine, acetone, ethanol, one or both during 2-arsenic pyrrolidone, propylene carbonate are cruel;
Described zinc salt interferon a or magnesium salt interferon a obtains through interferon a and zinc salt or magnesium salt hybrid reaction.
As preferably, on the technical scheme basis that the claims in the present invention 7 provide, the agent of described compound long-acting in-situ gel injection, is characterized in that, with parts by weight, composed of the following components:
10-20 part zinc salt interferon a or magnesium salt interferon a, 170-300 part thymalfasin, 3500-4500 part situ-gel material, 30000-50000 part solvent.
As preferably, on the technical scheme basis that the claims in the present invention 7 provide, described situ-gel material is made up of a kind of and for removal of solvents type situ-gel the biodegradable polymers in thermosensitive in situ gel material, pH sensitive in situ gels research material, ionic strength sensitive type situ-gel material; More preferably, described situ-gel material is 1:0.5-4 by thermosensitive in situ gel material, pH sensitive in situ gels research material or ionic strength sensitive type situ-gel material and the weight ratio for the biodegradable polymers of removal of solvents type situ-gel.
In addition, in some embodiments of the present invention, described situ-gel material is separately in the biodegradable polymers of removal of solvents type situ-gel or thermosensitive in situ gel material, such as polylactic acid, PLGA, poloxamer, poly-N-isopropyl acrylamide.
As preferably, on the technical scheme basis that the claims in the present invention 7 provide, the described biodegradable polymers for removal of solvents type situ-gel is weight average molecular weight is 5000-50000Da, intrinsic viscosity is the polylactic acid of 0.1dl/g-0.5dl/g, or by the lactic acid units of 25%≤molar percentage < 100% with the glycolic acid units of 0 < molar percentage≤75% forms, weight average molecular weight is 2000-50000Da, intrinsic viscosity is the PLGA of 0.1dl/g-0.5dl/g.
As preferably, on the technical scheme basis that the claims in the present invention 7 provide, described thermosensitive in situ gel material is one or more in poloxamer188, PLURONICS F87, methylcellulose, polylactic acid-polyethylene glycol block copolymer, polylactic-co-glycolic acid-polyethyleneglycol block copolymer, polycaprolactone-polyethylene glycol block copolymer, poly-N-isopropyl acrylamide, more preferably, be poloxamer188, PLURONICS F87 or methylcellulose.
As preferably, on the technical scheme basis that the claims in the present invention 7 provide, described pH sensitive in situ gels research material is one or more in CAP, carbomer 934, Acritamer 940, Carbopol 941.
As preferably, described alginate is sodium alginate.
As preferably, on the technical scheme basis that the claims in the present invention 7 provide, the mol ratio of described interferon a and zinc salt is 1:1-3, and the mol ratio of described interferon a and magnesium salt is 1:1-3.
As preferably, on the technical scheme basis that the claims in the present invention 7 provide, described interferon a be selected from interferon a-2a type, Interferon a-1b type, Interferon Alfa-2b type one or more.
As preferably, on the technical scheme basis that the claims in the present invention 7 provide, described zinc salt be selected from zinc hydroxide, zinc chloride one or both, described magnesium salt be selected from magnesium hydroxide, magnesium oxide one or both.
As preferably, on the technical scheme basis that the claims in the present invention 7 provide, described solvent is N-Methyl pyrrolidone, ethyl lactate, glycerol formal, ethanol, 2-Pyrrolidone, more preferably, is N-Methyl pyrrolidone.
The compound long-acting in-situ gel injection agent prepared by the present invention, product quality is better than required standard, and without obvious toxic-side effects, thymalfasin content of dispersion is more than 96%, interferon content is more than 90%, both entirety envelop rate is all more than 90%, and after testing, compound long-acting in-situ gel injection agent release in vitro of the present invention is steady, persistent period reaches about 30 days, the In-vitro release curves linearity is better, is tending towards straight line, does not occur drug effect larger fluctuation.
From above technical scheme, compound long-acting in-situ gel injection of the present invention agent is made up of thymalfasin and interferon and suitable situ-gel material, reduce administration frequency, can long-time stable sustained release drug effect, without obvious toxic-side effects, content of dispersion and envelop rate higher, product quality is better than required standard, is adapted at applying in treating chronic hepatitis B.
Accompanying drawing explanation
Fig. 1 is the embodiment of the present invention 1 vitro release curve chart;
Fig. 2 is the embodiment of the present invention 2 vitro release curve chart;
Fig. 3 is the embodiment of the present invention 3 vitro release curve chart;
Fig. 4 is the embodiment of the present invention 4 vitro release curve chart;
Fig. 5 is the embodiment of the present invention 5 vitro release curve chart;
Fig. 6 is the embodiment of the present invention 6 vitro release curve chart;
Fig. 7 is the embodiment of the present invention 7 vitro release curve chart;
Fig. 8 is the embodiment of the present invention 8 vitro release curve chart;
Fig. 9 is the embodiment of the present invention 9 vitro release curve chart;
Figure 10 is the embodiment of the present invention 10 vitro release curve chart.
Detailed description of the invention
The invention discloses a kind of compound long-acting in-situ gel injection agent for the treatment of chronic viral hepatitis B and preparation method thereof, those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.Product of the present invention and method are described by preferred embodiment, related personnel obviously can not depart from content of the present invention, spirit and scope compound as herein described and preparation method are changed or suitably change with combination, realize and apply the technology of the present invention.
Below in conjunction with embodiment, set forth the present invention further.
Embodiment 1:
Taking 15mg Interferon Alfa-2b is dissolved in sterile water for injection, adds the 35mg zinc hydroxide after micronization and sterilization treatment, vortex mixed 10min, forms 1g zinc salt Interferon Alfa-2b solution.
Take 2.6gPLGA(weight average molecular weight 10000, intrinsic viscosity is 0.10dl/g-0.20dl/g, LA:GA=75:25), 0.9g poloxamer188 and 18gNMP, mixing, be mixed with polymer solution, then thymalfasin crude drug 0.30g is added, ultrasonic dissolution, add 1g zinc salt Interferon Alfa-2b solution until completely dissolved, heated at constant temperature high-speed stirred (temperature 30 DEG C, 10000rpm) 5min, forms the medicine carrying sol system containing granule, through beam radiation sterilizing, obtain the agent of compound long-acting in-situ gel injection.Detecting interferon drug loading through HPLC is 0.37%, and envelop rate is 95%.Thymalfasin drug loading is 7.18%, and envelop rate is 92%.Quality testing is in table 1, and vitro release curve is shown in Fig. 1.
Table 1 product quality testing result
Embodiment 2:
Taking 20mg interferon a-2a is dissolved in sterile water for injection, adds the 55mg zinc chloride after micronization and sterilization treatment, vortex mixed 10min, forms 1g zinc salt interferon a-2a solution.
Take 4.0gPLGA(weight average molecular weight 15000, intrinsic viscosity is 0.10dl/g-0.25dl/g, LA:GA=65:35), 2.0g methylcellulose and 45g ethyl lactate, mixing, be mixed with polymer solution, then thymalfasin crude drug 0.80g is added, ultrasonic dissolution, add 1g zinc salt interferon a-2a solution until completely dissolved, heated at constant temperature high-speed stirred (temperature 30 DEG C, 10000rpm) 7min, forms the medicine carrying sol system containing granule, through beam radiation sterilizing, obtain the agent of compound long-acting in-situ gel injection.Detecting interferon drug loading through HPLC is 0.33%, and envelop rate is 97%.Thymalfasin drug loading is 12.53%, and envelop rate is 92%.Quality testing is in table 2, and vitro release curve is shown in Fig. 2.
Table 2 product quality testing result
Embodiment 3:
Taking 25mg Interferon a-1b is dissolved in sterile water for injection, adds the 55mg magnesium hydroxide after micronization and sterilization treatment, vortex mixed 10min, forms 1g magnesium salt Interferon a-1b solution.
Take 3.75gPLA(weight average molecular weight 15000, intrinsic viscosity is 0.10dl/g-0.25dl/g), 3.75g carbomer 934 and 35g acetone, mixing, is mixed with polymer solution, then thymalfasin crude drug 0.75g is added, ultrasonic dissolution, adds 1g magnesium salt Interferon a-1b solution until completely dissolved, heated at constant temperature high-speed stirred (temperature 30 DEG C, 10000rpm) 5min, form the medicine carrying sol system containing granule, through beam radiation sterilizing, obtain the agent of compound long-acting in-situ gel injection.Detecting interferon drug loading through HPLC is 0.28%, and envelop rate is 98%.Thymalfasin drug loading is 12.44%, and envelop rate is 91%.Quality testing is in table 3, and vitro release curve is shown in Fig. 3.
Table 3 product quality testing result
Embodiment 4:
Taking 15mg Interferon Alfa-2b is dissolved in sterile water for injection, adds the 40mg magnesium oxide after micronization and sterilization treatment, vortex mixed 10min, forms 1g magnesium salt Interferon Alfa-2b solution.
Take 4.0gPLGA(weight average molecular weight 20000, intrinsic viscosity is 0.15dl/g-0.25dl/g, LA:GA=50:50), 1.2g CAP and 30g glycerol formal, mixing, is mixed with polymer solution, then thymalfasin crude drug 0.40g is added, ultrasonic dissolution, adds 1g magnesium salt Interferon Alfa-2b solution until completely dissolved, heated at constant temperature high-speed stirred (temperature 30 DEG C, 10000rpm) 8min, forms the medicine carrying sol system containing granule.Detecting interferon drug loading through HPLC is 0.26%, and envelop rate is 98%.Thymalfasin drug loading is 6.79%, and envelop rate is 96%.Quality testing is in table 4, and vitro release curve is shown in Fig. 4.
Table 4 product quality testing result
Embodiment 5:
Taking 40mg Interferon Alfa-2b is dissolved in sterile water for injection, adds the 80mg zinc hydroxide after micronization and sterilization treatment, vortex mixed 10min, forms 1g zinc salt Interferon Alfa-2b solution.
Take 8.0gPLGA(weight average molecular weight 25000, intrinsic viscosity is 0.20dl/g-0.30dl/g, LA:GA=55:45), 2.5g alginate and 80g2-ketopyrrolidine, mixing, be mixed with polymer solution, then thymalfasin crude drug 1.5g is added, ultrasonic dissolution, add 1g magnesium salt Interferon Alfa-2b solution until completely dissolved, heated at constant temperature high-speed stirred (temperature 30 DEG C, 10000rpm) 7min, forms the medicine carrying sol system containing granule, through beam radiation sterilizing, obtain the agent of compound long-acting in-situ gel injection.Detecting interferon drug loading through HPLC is 0.33%, and envelop rate is 99%.Thymalfasin drug loading is 11.51%, and envelop rate is 93%.Quality testing is in table 5, and vitro release curve is shown in Fig. 5.
Table 5 product quality testing result
Embodiment 6:
Taking 20mg interferon a-2a is dissolved in sterile water for injection, adds the 20mg zinc chloride after micronization and sterilization treatment, vortex mixed 10min, forms 1g zinc salt interferon a-2a solution.
Take 2.5gPLA(weight average molecular weight 40000, intrinsic viscosity is 0.35dl/g-0.45dl/g), 1.5g gellan gum and 65gNMP, mixing, be mixed with polymer solution, then add thymalfasin crude drug 0.4g, ultrasonic dissolution, add 1g magnesium salt interferon a-2a solution until completely dissolved, heated at constant temperature high-speed stirred (temperature 30 DEG C, 10000rpm) 5min, forms the medicine carrying sol system containing granule, through beam radiation sterilizing, obtain the agent of compound long-acting in-situ gel injection.Detecting interferon drug loading through HPLC is 0.41%, and envelop rate is 92%.Thymalfasin drug loading is 8.20%, and envelop rate 91 is %.Quality testing is in table 6, and vitro release curve is shown in Fig. 6.
Table 6 product quality testing result
Embodiment 7:
Taking 25mg interferon a-2a is dissolved in sterile water for injection, adds the 30mg zinc hydroxide after micronization and sterilization treatment, vortex mixed 10min, forms 1g zinc salt interferon a-2a solution.
Take 3.5gPLGA(weight average molecular weight 40000, intrinsic viscosity is 0.35dl/g-0.45dl/g, LA:GA=50:50), 1.4g PLURONICS F87 and 50gNMP, mixing, be mixed with polymer solution, then thymalfasin crude drug 1.4g is added, ultrasonic dissolution, add 1g magnesium salt interferon a-2a solution until completely dissolved, heated at constant temperature high-speed stirred (temperature 30 DEG C, 10000rpm) 8min, forms the medicine carrying sol system containing granule, through beam radiation sterilizing, obtain the agent of compound long-acting in-situ gel injection.Detecting interferon drug loading through HPLC is 0.38%, and envelop rate is 97%.Thymalfasin drug loading is 19.83%, and envelop rate is 90%.Quality testing is in table 7, and vitro release curve is shown in Fig. 7.
Table 7 product quality testing result
Embodiment 8
Taking 45mg Interferon Alfa-2b is dissolved in sterile water for injection, adds the 95mg zinc hydroxide after micronization and sterilization treatment, vortex mixed 10min, forms 1g zinc salt Interferon Alfa-2b solution.
Take 11.5gPLA(weight average molecular weight 10000, intrinsic viscosity is 0.10dl/g-0.20dl/g, and 81gNMP LA:GA=75:25), mixing, be mixed with polymer solution, then thymalfasin crude drug 1.3g is added, ultrasonic dissolution, adds 1g zinc salt Interferon Alfa-2b solution until completely dissolved, heated at constant temperature high-speed stirred (temperature 30 DEG C, 10000rpm) 8min, form the medicine carrying sol system containing granule, through beam radiation sterilizing, obtain the agent of compound long-acting in-situ gel injection, detecting interferon drug loading through HPLC is 0.31%, and envelop rate is 90%.Thymalfasin drug loading 9.54 is %, and envelop rate is 95%.Quality testing is in table 8, and vitro release curve is shown in Fig. 8.
Table 8 product quality testing result
Embodiment 9
Taking 50mg Interferon a-1b is dissolved in sterile water for injection, adds the 60mg zinc oxide after micronization and sterilization treatment, vortex mixed 10min, forms 1g zinc salt Interferon a-1b solution.
Take 12gPLA(weight average molecular weight 15000, intrinsic viscosity is 0.10dl/g-0.20dl/g, and 82gNMP LA:GA=75:25), mixing, be mixed with polymer solution, then thymalfasin crude drug 1.5g is added, ultrasonic dissolution, adds 1g zinc salt Interferon a-1b solution until completely dissolved, heated at constant temperature high-speed stirred (temperature 30 DEG C, 10000rpm) 6min, form the medicine carrying sol system containing granule, through beam radiation sterilizing, obtain the agent of compound long-acting in-situ gel injection, detecting interferon drug loading through HPLC is 0.35%, and envelop rate is 94%.Thymalfasin drug loading is 10.00%, and envelop rate is 91%.Quality testing is in table 9, and vitro release curve is shown in Fig. 9.
Table 9 product quality testing result
Embodiment 10
Taking 60mg Interferon Alfa-2b is dissolved in sterile water for injection, adds the 80mg zinc oxide after micronization and sterilization treatment, vortex mixed 10min, forms 1g zinc salt Interferon Alfa-2b solution.
Take 14.0gPLGA(weight average molecular weight 20000, intrinsic viscosity is 0.15dl/g-0.25dl/g, and 68gNMP LA:GA=50:50), mixing, be mixed with polymer solution, then thymalfasin crude drug 2.5g is added, ultrasonic dissolution, adds 1g zinc salt Interferon Alfa-2b solution until completely dissolved, heated at constant temperature high-speed stirred (temperature 30 DEG C, 10000rpm) 9min, form the medicine carrying sol system containing granule, through beam radiation sterilizing, obtain the agent of compound long-acting in-situ gel injection, detecting interferon drug loading through HPLC is 0.35%, and envelop rate is 97%.Thymalfasin drug loading is 14.00%, and envelop rate is 93%.Quality testing is in table 10, and vitro release curve is shown in Figure 10.
Table 10 product quality testing result
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (3)
1. treat a compound long-acting in-situ gel injection agent for chronic viral hepatitis B, it is characterized in that, with parts by weight, composed of the following components:
5-24 part zinc salt interferon a or magnesium salt interferon a, 150-800 part thymalfasin, 1800-12000 part situ-gel material, 8000-100000 part solvent;
Wherein, described situ-gel material is:
CAP and PLGA;
Alginate and PLGA;
Methylcellulose and PLGA; Or
Carbomer and polylactic acid;
Described polylactic acid weight average molecular weight is 5000-50000Da, intrinsic viscosity is 0.1dl/g-0.5dl/g, and described PLGA is by the lactic acid units of 25%≤molar percentage < 100% and the glycolic acid units of 0 < molar percentage≤75% forms, weight average molecular weight is 2000-50000Da, intrinsic viscosity is 0.1dl/g-0.5dl/g;
Described solvent is selected from N-Methyl pyrrolidone, triacetin, ethyl lactate, glycerol formal, benzyl benzoate, dimethyl sulfoxine, acetone, ethanol, one or both in 2-Pyrrolidone, Allyl carbonate;
Described zinc salt interferon a or magnesium salt interferon a obtains through interferon a and zinc salt or magnesium salt hybrid reaction.
2. compound long-acting in-situ gel injection agent according to claim 1, is characterized in that, with parts by weight, composed of the following components:
10-20 part zinc salt interferon a or magnesium salt interferon a, 170-300 part thymalfasin, 3500-4500 part situ-gel material, 30000-50000 part solvent.
3. treat the preparation method of the compound long-acting in-situ gel injection agent of chronic viral hepatitis B for one kind, it is characterized in that, with parts by weight, take 1800-12000 part situ-gel material and the mixing of 8000-100000 part solvent, add 150-800 part thymalfasin, supersound process, then add 5-24 part zinc salt interferon a or magnesium salt interferon a, heated at constant temperature 10000rpm-20000rpm stirs 5min-10min, sterilizing and get final product;
Wherein, described situ-gel material is:
CAP and PLGA;
Alginate and PLGA;
Methylcellulose and PLGA; Or
Carbomer and polylactic acid;
Described polylactic acid weight average molecular weight is 5000-50000Da, intrinsic viscosity is 0.1dl/g-0.5dl/g, and described PLGA is by the lactic acid units of 25%≤molar percentage < 100% and the glycolic acid units of 0 < molar percentage≤75% forms, weight average molecular weight is 2000-50000Da, intrinsic viscosity is 0.1dl/g-0.5dl/g;
Described solvent is selected from N-Methyl pyrrolidone, triacetin, ethyl lactate, glycerol formal, benzyl benzoate, dimethyl sulfoxine, acetone, ethanol, one or both in 2-pyrroles's pyrrolidone, Allyl carbonate;
Described zinc salt interferon a or magnesium salt interferon a obtains through interferon a and zinc salt or magnesium salt hybrid reaction.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1087829A (en) * | 1992-07-13 | 1994-06-15 | 肯尼思·E·舍曼 | Compositions and methods for treating hepatitis B |
| CN1154653A (en) * | 1994-07-25 | 1997-07-16 | 阿尔克姆斯控制治疗公司 | Controlled release of metal cation-stabilized interferon |
| CN1634570A (en) * | 2004-09-29 | 2005-07-06 | 中国人民解放军第二军医大学 | A kind of preparation method of interferon long-acting injection microsphere preparation |
| CN102525884A (en) * | 2010-12-19 | 2012-07-04 | 复旦大学 | Thermosensitive in-situ gel preparation for vaginal administration |
| CN103156806A (en) * | 2013-03-27 | 2013-06-19 | 深圳翰宇药业股份有限公司 | Thymalfasin in-situ gel preparation and preparation method thereof |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1087829A (en) * | 1992-07-13 | 1994-06-15 | 肯尼思·E·舍曼 | Compositions and methods for treating hepatitis B |
| CN1154653A (en) * | 1994-07-25 | 1997-07-16 | 阿尔克姆斯控制治疗公司 | Controlled release of metal cation-stabilized interferon |
| CN1634570A (en) * | 2004-09-29 | 2005-07-06 | 中国人民解放军第二军医大学 | A kind of preparation method of interferon long-acting injection microsphere preparation |
| CN102525884A (en) * | 2010-12-19 | 2012-07-04 | 复旦大学 | Thermosensitive in-situ gel preparation for vaginal administration |
| CN103156806A (en) * | 2013-03-27 | 2013-06-19 | 深圳翰宇药业股份有限公司 | Thymalfasin in-situ gel preparation and preparation method thereof |
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