CN103494769A - Compound in-situ gel long-acting injection for treating chronic hepatitis and preparation method thereof - Google Patents
Compound in-situ gel long-acting injection for treating chronic hepatitis and preparation method thereof Download PDFInfo
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Abstract
The invention relates to the technical field of medicine, and discloses a compound in-situ gel long-acting injection for treating chronic hepatitis and a preparation method thereof. The compound in-situ gel long-acting injection for treating chronic hepatitis, disclosed by the invention, is prepared from 5-24 parts of zinc salt interferon a or magnesium salt interferon a, 150-800 parts of thymalfasin, 1800-12000 parts of in-situ gel materials, and 8000-100000 parts of solvent. The compound in-situ gel long-acting injection disclosed by the invention is prepared from the thymalfasin, the interferons and proper in-situ gel materials. Thus, the administration frequency is reduced; the medicine effect can be stably and lastingly released for a long period of time; the compound in-situ gel long-acting injection is free of obvious toxic and side effects, and high in medicine concentration and encapsulation efficiency; the product quality is superior to the specified standard; the compound in-situ gel long-acting injection is suitable for popularization and application in treatment of the chronic hepatitis.
Description
Technical field
The present invention relates to medical technical field, be specifically related to a kind of compound long-acting situ-gel injection 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 approximately has 300,000,000, and most of in Asia, in population of China, the Chronic HBV carrier accounts for 10%～15%.In chronic hepatitis B (CHB) patient, annual generation hepatitis interstitialis chronica and hepatocarcinoma person account for respectively 2% and 1%, and this numeral is still in ascendant trend.90% the people treatment of going to see a doctor is arranged in hepatitis B morbidity patient, and on average approximately have 40% Patients on Recurrence to be hospitalized for treatment.
Studies have shown that in a large number, interferon is current both at home and abroad accepted treatment viral hepatitis active drug, but it can only inhibition HBV replication, and can not in human body, thoroughly remove HBV, so after drug withdrawal, relapse rate is high.Thymalfasin is the highly purified polypeptide be comprised of 28 aminoacid of synthetic, it can increase the body anti-infection ability, alleviate hepatocellular immunopathogenesis damage, promote the hepatocyte function reparation, and the effect of virus sweep still can continue to increase after finishing the course for the treatment of of treatment hepatitis B, there is curative effect lasting, use safe characteristics.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 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 of injection and one week 2 times subcutaneous injection thymalfasins next day of general, the problem that this easily brings compliance and forget administration the patient, finally affect the treatment, so develop a kind of be necessary containing the compound long-acting injection of interferon and thymalfasin for chronic hepatitis B and feasible, interferon and thymalfasin compound long-acting injection not yet have relevant report at present.
Summary of the invention
In view of this, the object of the present invention is to provide a kind of compound long-acting situ-gel injection for the treatment of chronic viral hepatitis B and preparation method thereof, make the present invention prepared compound long-acting situ-gel injection quality, medicament contg and envelop rate higher, and can be administered once and stablize the sustained release drug effect and reach about 30 days.
For achieving the above object, the invention provides following technical scheme:
A kind of compound long-acting situ-gel injection for the treatment of chronic viral hepatitis B, is characterized in that, in weight portion, 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 one or more of biodegradable polymers for removal of solvents type situ-gel, thermosensitive in situ gel material, pH sensitive in situ gels research material, ionic strength sensitive in situ gels research material;
The described biodegradable polymers for removal of solvents type situ-gel is selected from polyoxyethylene polyoxypropylene block copolymer, polylactic acid, PLGA, one or more in polylactic acid-polyethylene glycol block copolymer, polylactic-co-glycolic acid-polyethyleneglycol block copolymer, PLA-PEG-PLA block copolymer, polylactic-co-glycolic acid-Polyethylene Glycol embedding-polylactic-co-glycolic acid section copolymer, poly-N-isopropyl propylene phthalein amine, acetic acid-isopropylformic acid. sucrose vinegar;
Described thermosensitive in situ gel material be selected from poloxamer, methylcellulose, hypromellose, chitosan derivatives, polylactic acid-polyethylene glycol block copolymer, polylactic acid through guanidine-acetic acid-polyethyleneglycol block copolymer, second one or more in base ethyl cellulose, polycaprolactone-polyethylene glycol block copolymer, poly-N-isopropyl acrylamide;
Described pH sensitive in situ gels research material is selected from CAP, and the hypromellose phthalandione is cruel, one or more in carbomer, chitosan;
Described ionic strength sensitive in situ gels research material is selected from one or both in alginate, gellan gum;
Described solvent is selected from the 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 make through interferon a and zinc salt or magnesium salt hybrid reaction.
The situ-gel injection can adopt different situ-gel materials according to the difference of principal agent, the selection of situ-gel material is improper can't realize long-acting, and the quality of injection also can descend, particularly, in the situation that principal agent is more than a kind of, the selection of situ-gel material is more crucial.The situ-gel injection agent component formula that is applicable to all principal agents is not arranged in the art, situ-gel injection agent component formula, particularly interferon and thymalfasin compound recipe for compound recipe are not more arranged.For solving the 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 stablize for a long time lasting drug effect, the injection that quality, medicament contg and envelop rate are higher.
As preferably, on the technical scheme basis provided in the claims in the present invention 1, described compound long-acting situ-gel injection, is characterized in that, in weight portion, 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 provided in the claims in the present invention 1, a kind of in thermosensitive in situ gel material, pH sensitive in situ gels research material, ionic strength sensitive in situ gels research material of described situ-gel material and forming for the biodegradable polymers of removal of solvents type situ-gel; 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 in situ gels research material with 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 biodegradable polymers or the thermosensitive in situ gel material for removal of solvents type situ-gel, for example polylactic acid, PLGA, poloxamer, poly-N-isopropyl acrylamide separately.
As preferably, on the technical scheme basis provided in the claims in the present invention 1, the described biodegradable polymers for removal of solvents type situ-gel is that weight average molecular weight is 5000-50000Da, the polylactic acid that intrinsic viscosity is 0.1dl/g-0.5dl/g, or by the lactic acid units of 25%≤molar percentage<100% and the PLGA that the hydroxyacetic acid unit forms, weight average molecular weight is 2000-50000Da, intrinsic viscosity is 0.1dl/g-0.5dl/g of 0<molar percentage≤75%.
As preferably, on the technical scheme basis provided in the claims in the present invention 1, 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 provided in the claims in the present invention 1, 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 provided in the claims in the present invention 1, 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 provided in the claims in the present invention 1, described interferon a is selected from one or more of interferon a-2a type, Interferon a-1b type, interferon a-2b type.
As preferably, on the technical scheme basis provided in the claims in the present invention 1, described zinc salt is selected from one or both in zinc hydroxide, zinc chloride, and described magnesium salt is selected from one or both in magnesium hydroxide, magnesium oxide.
As preferably, on the technical scheme basis provided in the claims in the present invention 7, described solvent is N-Methyl pyrrolidone, ethyl lactate, glycerol formal, and 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 situ-gel injection of chronic viral hepatitis B, in weight portion, take 1800-12000 part situ-gel material and 8000-100000 part solvent mixes, 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 one or more of biodegradable polymers for removal of solvents type situ-gel, thermosensitive in situ gel material, pH sensitive in situ gels research material, ionic strength sensitive in situ gels research material;
The described biodegradable polymers for removal of solvents type situ-gel is selected from polyoxyethylene polyoxypropylene block copolymer, polylactic acid, PLGA, one or more in polylactic acid-polyethylene glycol block copolymer, polylactic-co-glycolic acid-polyethyleneglycol block copolymer, PLA-PEG-PLA block copolymer, polylactic-co-glycolic acid-Polyethylene Glycol embedding-polylactic-co-glycolic acid section copolymer, poly-N-isopropyl propylene phthalein amine, acetic acid-isopropylformic acid. sucrose vinegar;
Described thermosensitive in situ gel material be selected from poloxamer, methylcellulose, hypromellose, chitosan derivatives, polylactic acid-polyethylene glycol block copolymer, polylactic acid through guanidine-acetic acid-polyethyleneglycol block copolymer, second one or more in base ethyl cellulose, polycaprolactone-polyethylene glycol block copolymer, poly-N-isopropyl acrylamide;
Described pH sensitive in situ gels research material is selected from CAP, and the hypromellose phthalandione is cruel, one or more in carbomer, chitosan;
Described ionic strength sensitive in situ gels research material is selected from one or both in alginate, gellan gum;
Described solvent is selected from the 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 make through interferon a and zinc salt or magnesium salt hybrid reaction.
As preferably, on the technical scheme basis provided in the claims in the present invention 7, described compound long-acting situ-gel injection, is characterized in that, in weight portion, 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 provided in the claims in the present invention 7, a kind of in thermosensitive in situ gel material, pH sensitive in situ gels research material, ionic strength sensitive in situ gels research material of described situ-gel material and forming for the biodegradable polymers of removal of solvents type situ-gel; 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 in situ gels research material with 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 biodegradable polymers or the thermosensitive in situ gel material for removal of solvents type situ-gel, for example polylactic acid, PLGA, poloxamer, poly-N-isopropyl acrylamide separately.
As preferably, on the technical scheme basis provided in the claims in the present invention 7, the described biodegradable polymers for removal of solvents type situ-gel is that weight average molecular weight is 5000-50000Da, the polylactic acid that intrinsic viscosity is 0.1dl/g-0.5dl/g, or by the lactic acid units of 25%≤molar percentage<100% and the PLGA that the hydroxyacetic acid unit forms, weight average molecular weight is 2000-50000Da, intrinsic viscosity is 0.1dl/g-0.5dl/g of 0<molar percentage≤75%.
As preferably, on the technical scheme basis provided in the claims in the present invention 7, 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 provided in the claims in the present invention 7, 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 provided in the claims in the present invention 7, 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 provided in the claims in the present invention 7, described interferon a is selected from one or more in interferon a-2a type, Interferon a-1b type, interferon a-2b type.
As preferably, on the technical scheme basis provided in the claims in the present invention 7, described zinc salt is selected from one or both in zinc hydroxide, zinc chloride, and described magnesium salt is selected from one or both in magnesium hydroxide, magnesium oxide.
As preferably, on the technical scheme basis provided in the claims in the present invention 7, described solvent is N-Methyl pyrrolidone, ethyl lactate, glycerol formal, ethanol, and 2-Pyrrolidone more preferably, is N-Methyl pyrrolidone.
The compound long-acting situ-gel injection prepared by the present invention, product quality is better than required standard, and without obvious toxic-side effects, the thymalfasin content of dispersion is more than 96%, interferon content is more than 90%, whole both envelop rates are all more than 90%, and after testing, compound long-acting situ-gel injection release in vitro of the present invention is steady, persistent period reached about 30 days, release in vitro curve linear degree is better, is tending towards straight line, the drug effect larger fluctuation do not occur.
From above technical scheme, compound long-acting situ-gel injection of the present invention is made by thymalfasin and interferon and suitable situ-gel material, reduced administration frequency, can stablize for a long time the sustained release drug effect, without obvious toxic-side effects, content of dispersion and envelop rate are higher, and product quality is better than required standard, are adapted at applying in treating chronic hepatitis B.
The 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 charts;
Fig. 3 is the embodiment of the present invention 3 vitro release curve charts;
Fig. 4 is the embodiment of the present invention 4 vitro release curve charts;
Fig. 5 is the embodiment of the present invention 5 vitro release curve charts;
Fig. 6 is the embodiment of the present invention 6 vitro release curve charts;
Fig. 7 is the embodiment of the present invention 7 vitro release curve charts;
Fig. 8 is the embodiment of the present invention 8 vitro release curve charts;
Fig. 9 is the embodiment of the present invention 9 vitro release curve charts;
Figure 10 is the embodiment of the present invention 10 vitro release curve charts.
The specific embodiment
The invention discloses a kind of compound long-acting situ-gel injection for the treatment of chronic viral hepatitis B and preparation method thereof, those skilled in the art can use for reference this paper content, suitably improve technological parameter and realize.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they all are deemed to be included in the present invention.Product of the present invention and method are described by preferred embodiment, the related personnel obviously can be within not breaking away from content of the present invention, spirit and scope to compound as herein described with preparation method is changed or suitably change and combination, realize and apply the technology of the present invention.
Below in conjunction with embodiment, further set forth the present invention.
Embodiment 1:
Take 15mg interferon a-2b and be dissolved in sterile water for injection, add the 35mg zinc hydroxide after micronization and sterilization treatment, vortex mixed 10min, form 1g zinc salt interferon a-2b solution.
Take 2.6g PLGA(weight average molecular weight 10000, intrinsic viscosity is 0.10dl/g-0.20dl/g, LA:GA=75:25), 0.9g poloxamer188 and 18g NMP, mix, be mixed with polymer solution, then add thymalfasin crude drug 0.30g, ultrasonic dissolution, add until completely dissolved 1g zinc salt interferon a-2b solution, (30 ℃ of temperature, 10000rpm) 5min form the medicine carrying sol system containing granule to the heated at constant temperature high-speed stirred, through the electron beam ray sterilizing, obtain compound long-acting situ-gel injection.Detecting the interferon drug loading through HPLC is 0.37%, and envelop rate is 95%.The thymalfasin drug loading is 7.18%, and envelop rate is 92%.Quality testing is in Table 1, and the vitro release curve is shown in Fig. 1.
Table 1 product quality testing result
Embodiment 2:
Take 20mg interferon a-2a and be dissolved in sterile water for injection, add the 55mg zinc chloride after micronization and sterilization treatment, vortex mixed 10min, form 1g zinc salt interferon a-2a solution.
Take 4.0g PLGA(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, mix, be mixed with polymer solution, then add thymalfasin crude drug 0.80g, ultrasonic dissolution, add until completely dissolved 1g zinc salt interferon a-2a solution, (30 ℃ of temperature, 10000rpm) 7min form the medicine carrying sol system containing granule to the heated at constant temperature high-speed stirred, through the electron beam ray sterilizing, obtain compound long-acting situ-gel injection.Detecting the interferon drug loading through HPLC is 0.33%, and envelop rate is 97%.The thymalfasin drug loading is 12.53%, and envelop rate is 92%.Quality testing is in Table 2, and the vitro release curve is shown in Fig. 2.
Table 2 product quality testing result
Embodiment 3:
Take the 25mg Interferon a-1b and be dissolved in sterile water for injection, add the 55mg magnesium hydroxide after micronization and sterilization treatment, vortex mixed 10min, form 1g magnesium salt Interferon a-1b solution.
Take 3.75g PLA(weight average molecular weight 15000, intrinsic viscosity is 0.10dl/g-0.25dl/g), 3.75g carbomer 934 and 35g acetone, mix, be mixed with polymer solution, then add thymalfasin crude drug 0.75g, ultrasonic dissolution, add 1g magnesium salt Interferon a-1b solution until completely dissolved, heated at constant temperature high-speed stirred (30 ℃ of temperature, 10000rpm) 5min, form the medicine carrying sol system containing granule, through the electron beam ray sterilizing, obtain compound long-acting situ-gel injection.Detecting the interferon drug loading through HPLC is 0.28%, and envelop rate is 98%.The thymalfasin drug loading is 12.44%, and envelop rate is 91%.Quality testing is in Table 3, and the vitro release curve is shown in Fig. 3.
Table 3 product quality testing result
Embodiment 4:
Take 15mg interferon a-2b and be dissolved in sterile water for injection, add the 40mg magnesium oxide after micronization and sterilization treatment, vortex mixed 10min, form 1g magnesium salt interferon a-2b solution.
Take 4.0g PLGA(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, mix, be mixed with polymer solution, then add thymalfasin crude drug 0.40g, ultrasonic dissolution, add 1g magnesium salt interferon a-2b solution, heated at constant temperature high-speed stirred (30 ℃ of temperature until completely dissolved, 10000rpm) 8min, form the medicine carrying sol system containing granule.Detecting the interferon drug loading through HPLC is 0.26%, and envelop rate is 98%.The thymalfasin drug loading is 6.79%, and envelop rate is 96%.Quality testing is in Table 4, and the vitro release curve is shown in Fig. 4.
Table 4 product quality testing result
Embodiment 5:
Take 40mg interferon a-2b and be dissolved in sterile water for injection, add the 80mg zinc hydroxide after micronization and sterilization treatment, vortex mixed 10min, form 1g zinc salt interferon a-2b solution.
Take 8.0g PLGA(weight average molecular weight 25000, intrinsic viscosity is 0.20dl/g-0.30dl/g, LA:GA=55:45), 2.5g alginate and 80g2-ketopyrrolidine, mix, be mixed with polymer solution, then add thymalfasin crude drug 1.5g, ultrasonic dissolution, add until completely dissolved 1g magnesium salt interferon a-2b solution, (30 ℃ of temperature, 10000rpm) 7min form the medicine carrying sol system containing granule to the heated at constant temperature high-speed stirred, through the electron beam ray sterilizing, obtain compound long-acting situ-gel injection.Detecting the interferon drug loading through HPLC is 0.33%, and envelop rate is 99%.The thymalfasin drug loading is 11.51%, and envelop rate is 93%.Quality testing is in Table 5, and the vitro release curve is shown in Fig. 5.
Table 5 product quality testing result
Embodiment 6:
Take 20mg interferon a-2a and be dissolved in sterile water for injection, add the 20mg zinc chloride after micronization and sterilization treatment, vortex mixed 10min, form 1g zinc salt interferon a-2a solution.
Take 2.5g PLA(weight average molecular weight 40000, intrinsic viscosity is 0.35dl/g-0.45dl/g), 1.5g gellan gum and 65gNMP, mix, be mixed with polymer solution, then add thymalfasin crude drug 0.4g, ultrasonic dissolution, add until completely dissolved 1g magnesium salt interferon a-2a solution, (30 ℃ of temperature, 10000rpm) 5min form the medicine carrying sol system containing granule to the heated at constant temperature high-speed stirred, through the electron beam ray sterilizing, obtain compound long-acting situ-gel injection.Detecting the interferon drug loading through HPLC is 0.41%, and envelop rate is 92%.The thymalfasin drug loading is 8.20%, and envelop rate 91 is %.Quality testing is in Table 6, and the vitro release curve is shown in Fig. 6.
Table 6 product quality testing result
Embodiment 7:
Take 25mg interferon a-2a and be dissolved in sterile water for injection, add the 30mg zinc hydroxide after micronization and sterilization treatment, vortex mixed 10min, form 1g zinc salt interferon a-2a solution.
Take 3.5g PLGA(weight average molecular weight 40000, intrinsic viscosity is 0.35dl/g-0.45dl/g, LA:GA=50:50), 1.4g PLURONICS F87 and 50gNMP, mix, be mixed with polymer solution, then add thymalfasin crude drug 1.4g, ultrasonic dissolution, add until completely dissolved 1g magnesium salt interferon a-2a solution, (30 ℃ of temperature, 10000rpm) 8min form the medicine carrying sol system containing granule to the heated at constant temperature high-speed stirred, through the electron beam ray sterilizing, obtain compound long-acting situ-gel injection.Detecting the interferon drug loading through HPLC is 0.38%, and envelop rate is 97%.The thymalfasin drug loading is 19.83%, and envelop rate is 90%.Quality testing is in Table 7, and the vitro release curve is shown in Fig. 7.
Table 7 product quality testing result
Embodiment 8
Take 45mg interferon a-2b and be dissolved in sterile water for injection, add the 95mg zinc hydroxide after micronization and sterilization treatment, vortex mixed 10min, form 1g zinc salt interferon a-2b solution.
Take 11.5g PLA(weight average molecular weight 10000, intrinsic viscosity is 0.10dl/g-0.20dl/g, LA:GA=75:25) and 81g NMP, mix, be mixed with polymer solution, then add thymalfasin crude drug 1.3g, ultrasonic dissolution, add 1g zinc salt interferon a-2b solution, heated at constant temperature high-speed stirred (30 ℃ of temperature until completely dissolved, 10000rpm) 8min, form the medicine carrying sol system containing granule, through the electron beam ray sterilizing, obtain compound long-acting situ-gel injection, detecting the 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 the vitro release curve is shown in Fig. 8.
Table 8 product quality testing result
Embodiment 9
Take the 50mg Interferon a-1b and be dissolved in sterile water for injection, add the 60mg zinc oxide after micronization and sterilization treatment, vortex mixed 10min, form 1g zinc salt Interferon a-1b solution.
Take 12g PLA(weight average molecular weight 15000, intrinsic viscosity is 0.10dl/g-0.20dl/g, LA:GA=75:25) and 82g NMP, mix, be mixed with polymer solution, then add thymalfasin crude drug 1.5g, ultrasonic dissolution, add 1g zinc salt Interferon a-1b solution until completely dissolved, heated at constant temperature high-speed stirred (30 ℃ of temperature, 10000rpm) 6min, form the medicine carrying sol system containing granule, through the electron beam ray sterilizing, obtain compound long-acting situ-gel injection, detecting the interferon drug loading through HPLC is 0.35%, and envelop rate is 94%.The thymalfasin drug loading is 10.00%, and envelop rate is 91%.Quality testing is in Table 9, and the vitro release curve is shown in Fig. 9.
Table 9 product quality testing result
Take 60mg interferon a-2b and be dissolved in sterile water for injection, add the 80mg zinc oxide after micronization and sterilization treatment, vortex mixed 10min, form 1g zinc salt interferon a-2b solution.
Take 14.0g PLGA(weight average molecular weight 20000, intrinsic viscosity is 0.15dl/g-0.25dl/g, LA:GA=50:50) and 68g NMP, mix, be mixed with polymer solution, then add thymalfasin crude drug 2.5g, ultrasonic dissolution, add 1g zinc salt interferon a-2b solution, heated at constant temperature high-speed stirred (30 ℃ of temperature until completely dissolved, 10000rpm) 9min, form the medicine carrying sol system containing granule, through the electron beam ray sterilizing, obtain compound long-acting situ-gel injection, detecting the interferon drug loading through HPLC is 0.35%, and envelop rate is 97%.The thymalfasin drug loading is 14.00%, and envelop rate is 93%.Quality testing is in Table 10, and the 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 (11)
1. a compound long-acting situ-gel injection for the treatment of chronic viral hepatitis B, is characterized in that, in weight portion, 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 one or more of biodegradable polymers for removal of solvents type situ-gel, thermosensitive in situ gel material, pH sensitive in situ gels research material, ionic strength sensitive in situ gels research material;
The described biodegradable polymers for removal of solvents type situ-gel is selected from polyoxyethylene polyoxypropylene block copolymer, polylactic acid, PLGA, one or more in polylactic acid-polyethylene glycol block copolymer, polylactic-co-glycolic acid-polyethyleneglycol block copolymer, PLA-PEG-PLA block copolymer, polylactic-co-glycolic acid-Polyethylene Glycol embedding-polylactic-co-glycolic acid section copolymer, poly-N-isopropyl propylene phthalein amine, acetic acid-isopropylformic acid. sucrose vinegar;
Described thermosensitive in situ gel material be selected from poloxamer, methylcellulose, hypromellose, chitosan derivatives, polylactic acid-polyethylene glycol block copolymer, polylactic acid through guanidine-acetic acid-polyethyleneglycol block copolymer, second one or more in base ethyl cellulose, polycaprolactone-polyethylene glycol block copolymer, poly-N-isopropyl acrylamide;
Described pH sensitive in situ gels research material is selected from CAP, and the hypromellose phthalandione is cruel, one or more in carbomer, chitosan;
Described ionic strength sensitive in situ gels research material is selected from one or both in alginate, gellan gum;
Described solvent is selected from the 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 make through interferon a and zinc salt or magnesium salt hybrid reaction.
2. compound long-acting situ-gel injection according to claim 1, is characterized in that, in weight portion, 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. compound long-acting situ-gel injection according to claim 1, it is characterized in that a kind of in thermosensitive in situ gel material, pH sensitive in situ gels research material, ionic strength sensitive in situ gels research material of described situ-gel material and forming for the biodegradable polymers of removal of solvents type situ-gel.
4. compound long-acting situ-gel injection according to claim 1, it is characterized in that, the described biodegradable polymers for removal of solvents type situ-gel is that weight average molecular weight is 5000-50000Da, the polylactic acid that intrinsic viscosity is 0.1dl/g-0.5dl/g, or by the lactic acid units of 25%≤molar percentage<100% and the PLGA that the hydroxyacetic acid unit forms, weight average molecular weight is 2000-50000Da, intrinsic viscosity is 0.1dl/g-0.5dl/g of 0<molar percentage≤75%.
5. compound long-acting situ-gel injection according to claim 1, is characterized in that, described thermosensitive in situ gel material is poloxamer188, PLURONICS F87 or methylcellulose.
6. compound long-acting situ-gel injection according to claim 1, is characterized in that, described pH sensitive in situ gels research material is selected from one or more in CAP, carbomer 934, Acritamer 940, Carbopol 941.
7. a preparation method for the treatment of the compound long-acting situ-gel injection of chronic viral hepatitis B, it is characterized in that, in weight portion, take 1800-12000 part situ-gel material and 8000-100000 part solvent mixes, 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 one or more of biodegradable polymers for removal of solvents type situ-gel, thermosensitive in situ gel material, pH sensitive in situ gels research material, ionic strength sensitive in situ gels research material;
The described biodegradable polymers for removal of solvents type situ-gel is selected from polyoxyethylene polyoxypropylene block copolymer, polylactic acid, PLGA, one or more in polylactic acid-polyethylene glycol block copolymer, polylactic-co-glycolic acid-polyethyleneglycol block copolymer, PLA-PEG-PLA block copolymer, polylactic-co-glycolic acid-Polyethylene Glycol embedding-polylactic-co-glycolic acid section copolymer, poly-N-isopropyl propylene phthalein amine, acetic acid-isopropylformic acid. sucrose vinegar;
Described thermosensitive in situ gel material be selected from poloxamer, methylcellulose, hypromellose, chitosan derivatives, polylactic acid-polyethylene glycol block copolymer, polylactic acid through guanidine-acetic acid-polyethyleneglycol block copolymer, second one or more in base ethyl cellulose, polycaprolactone-polyethylene glycol block copolymer, poly-N-isopropyl acrylamide;
Described pH sensitive in situ gels research material is selected from CAP, and the hypromellose phthalandione is cruel, one or more in carbomer, chitosan;
Described ionic strength sensitive in situ gels research material is selected from one or both in alginate, gellan gum;
Described solvent is selected from the 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 make through interferon a and zinc salt or magnesium salt hybrid reaction.
8. preparation method according to claim 7, it is characterized in that a kind of in thermosensitive in situ gel material, pH sensitive in situ gels research material, ionic strength sensitive in situ gels research material of described situ-gel material and forming for the biodegradable polymers of removal of solvents type situ-gel.
9. preparation method according to claim 7, it is characterized in that, the described biodegradable polymers for removal of solvents type situ-gel is that weight average molecular weight is 5000-50000Da, the polylactic acid that intrinsic viscosity is 0.1dl/g-0.5dl/g, or by the lactic acid units of 25%≤molar percentage<100% and the PLGA that the hydroxyacetic acid unit forms, weight average molecular weight is 2000-50000Da, intrinsic viscosity is 0.1dl/g-0.5dl/g of 0<molar percentage≤75%.
10. preparation method according to claim 7, is characterized in that, described thermosensitive in situ gel material is poloxamer188, PLURONICS F87 or methylcellulose.
11. preparation method, is characterized in that according to claim 7, described pH sensitive in situ gels research material is selected from one or more in CAP, carbomer 934, Acritamer 940, Carbopol 941.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115554237A (en) * | 2022-12-08 | 2023-01-03 | 山东则正医药技术有限公司 | Lomepilon in-situ gel long-acting injection and preparation method and application thereof |
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| CN1634570A (en) * | 2004-09-29 | 2005-07-06 | 中国人民解放军第二军医大学 | Method for preparing 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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| CN1087829A (en) * | 1992-07-13 | 1994-06-15 | 肯尼思·E·舍曼 | The compositions and the method thereof of treatment hepatitis B |
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| CN102525884A (en) * | 2010-12-19 | 2012-07-04 | 复旦大学 | Thermosensitive in-situ gel preparation for vaginal administration |
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| CN115554237A (en) * | 2022-12-08 | 2023-01-03 | 山东则正医药技术有限公司 | Lomepilon in-situ gel long-acting injection and preparation method and application thereof |
| CN115554237B (en) * | 2022-12-08 | 2023-09-12 | 山东则正医药技术有限公司 | Rumex-pirone in-situ gel long-acting injection and preparation method and application thereof |
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