CN110063932A - A kind of slow releasing composition preparation of polypeptide protein class drug and preparation method thereof - Google Patents
A kind of slow releasing composition preparation of polypeptide protein class drug and preparation method thereof Download PDFInfo
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- CN110063932A CN110063932A CN201910292036.4A CN201910292036A CN110063932A CN 110063932 A CN110063932 A CN 110063932A CN 201910292036 A CN201910292036 A CN 201910292036A CN 110063932 A CN110063932 A CN 110063932A
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- Prior art keywords
- slow releasing
- polypeptide protein
- protein class
- releasing composition
- preparation
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- 239000003814 drug Substances 0.000 title claims abstract description 87
- 239000000203 mixture Substances 0.000 title claims abstract description 87
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 73
- 229940079593 drug Drugs 0.000 title claims abstract description 71
- 229920001184 polypeptide Polymers 0.000 title claims abstract description 70
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 70
- 102000004169 proteins and genes Human genes 0.000 title claims abstract description 68
- 108090000623 proteins and genes Proteins 0.000 title claims abstract description 68
- 238000002360 preparation method Methods 0.000 title claims abstract description 55
- 239000007864 aqueous solution Substances 0.000 claims abstract description 66
- 108010016290 deoxyribonucleoprotamine Proteins 0.000 claims abstract description 54
- 229920000642 polymer Polymers 0.000 claims abstract description 47
- 229910052751 metal Inorganic materials 0.000 claims abstract description 21
- 239000002184 metal Substances 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 8
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 claims description 19
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims description 18
- 239000004246 zinc acetate Substances 0.000 claims description 18
- 239000000725 suspension Substances 0.000 claims description 17
- 102000002265 Human Growth Hormone Human genes 0.000 claims description 14
- 108010000521 Human Growth Hormone Proteins 0.000 claims description 14
- 239000000854 Human Growth Hormone Substances 0.000 claims description 14
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 10
- 238000009472 formulation Methods 0.000 claims description 9
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 claims description 7
- 239000006228 supernatant Substances 0.000 claims description 6
- 108010058846 Ovalbumin Proteins 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 229940092253 ovalbumin Drugs 0.000 claims description 5
- 102000004877 Insulin Human genes 0.000 claims description 4
- 108090001061 Insulin Proteins 0.000 claims description 4
- 229940125396 insulin Drugs 0.000 claims description 4
- 108010088406 Glucagon-Like Peptides Proteins 0.000 claims description 3
- 102000014150 Interferons Human genes 0.000 claims description 3
- 108010050904 Interferons Proteins 0.000 claims description 3
- 239000011557 critical solution Substances 0.000 claims description 3
- 235000013601 eggs Nutrition 0.000 claims description 3
- 229940079322 interferon Drugs 0.000 claims description 3
- QCVGEOXPDFCNHA-UHFFFAOYSA-N 5,5-dimethyl-2,4-dioxo-1,3-oxazolidine-3-carboxamide Chemical compound CC1(C)OC(=O)N(C(N)=O)C1=O QCVGEOXPDFCNHA-UHFFFAOYSA-N 0.000 claims description 2
- 108060003951 Immunoglobulin Proteins 0.000 claims description 2
- 238000005119 centrifugation Methods 0.000 claims description 2
- 238000004108 freeze drying Methods 0.000 claims description 2
- 102000018358 immunoglobulin Human genes 0.000 claims description 2
- 239000004026 insulin derivative Substances 0.000 claims description 2
- 239000003446 ligand Substances 0.000 claims description 2
- 108010000912 Egg Proteins Proteins 0.000 claims 1
- 102000002322 Egg Proteins Human genes 0.000 claims 1
- 102400000321 Glucagon Human genes 0.000 claims 1
- 108060003199 Glucagon Proteins 0.000 claims 1
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical class C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 claims 1
- 229920000436 Poly(lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly(lactide-co-glycolide) Polymers 0.000 claims 1
- 229920000432 Polylactide-block-poly(ethylene glycol)-block-polylactide Polymers 0.000 claims 1
- 108091007744 Programmed cell death receptors Proteins 0.000 claims 1
- 150000001768 cations Chemical class 0.000 claims 1
- 235000014103 egg white Nutrition 0.000 claims 1
- 210000000969 egg white Anatomy 0.000 claims 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 claims 1
- 229960004666 glucagon Drugs 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 27
- 230000000694 effects Effects 0.000 abstract description 15
- 238000013268 sustained release Methods 0.000 abstract description 15
- 239000012730 sustained-release form Substances 0.000 abstract description 15
- 238000002347 injection Methods 0.000 abstract description 10
- 239000007924 injection Substances 0.000 abstract description 10
- 238000001647 drug administration Methods 0.000 abstract description 3
- 239000002131 composite material Substances 0.000 abstract description 2
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- 230000000052 comparative effect Effects 0.000 description 31
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- 230000002195 synergetic effect Effects 0.000 description 10
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- 239000003795 chemical substances by application Substances 0.000 description 7
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- 238000003756 stirring Methods 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 230000036760 body temperature Effects 0.000 description 4
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- 238000002242 deionisation method Methods 0.000 description 4
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- 239000008363 phosphate buffer Substances 0.000 description 3
- -1 poly(N-isopropylacrylamide) Polymers 0.000 description 3
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- 229920001661 Chitosan Polymers 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
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- 229920003213 poly(N-isopropyl acrylamide) Polymers 0.000 description 2
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- 229920000573 polyethylene Polymers 0.000 description 2
- 239000004626 polylactic acid Substances 0.000 description 2
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- 239000000843 powder Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
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- 241000251468 Actinopterygii Species 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical group OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- 244000134336 Malus baccata Species 0.000 description 1
- 235000005079 Malus baccata Nutrition 0.000 description 1
- 101100519207 Mus musculus Pdcd1 gene Proteins 0.000 description 1
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- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
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- 238000012377 drug delivery Methods 0.000 description 1
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- 238000005516 engineering process Methods 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical group CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
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- 210000004279 orbit Anatomy 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229940048914 protamine Drugs 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
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- 230000001105 regulatory effect Effects 0.000 description 1
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- 238000012827 research and development Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
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- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000013269 sustained drug release Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
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- 230000010148 water-pollination Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/26—Glucagons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/38—Albumins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Endocrinology (AREA)
- Inorganic Chemistry (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Dermatology (AREA)
- Diabetes (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention discloses a kind of slow releasing composition preparation and preparation method thereof of polypeptide protein class drug.The slow releasing composition preparation is made of polypeptide protein class drug, complex reagent and temperature sensitive polymer aqueous solution；The complex reagent is the composition of nucleoprotamine or nucleoprotamine and metal salt；The controlled-release preparation composite can realize the controllable precise sustained release of polypeptide protein class drug under the premise of not influencing polypeptide protein class medicine effect, the drug administration by injection number of drug be effectively reduced, to improve the compliance of patient.All steps of preparation method of the slow releasing composition preparation carry out in water phase, effectively maintain the structure and bioactivity of polypeptide protein class drug.
Description
Technical field
The invention belongs to polypeptide protein class field of pharmaceutical preparations, and in particular to a kind of controlled release composition of polypeptide protein class drug
Object preparation and preparation method thereof.
Background technique
Compared with the traditional small-molecule drug for dominating entire pharmaceutical market all the time, polypeptide protein class drug has higher
Specificity, it is higher activity and lower toxicity, can be used for tumour, chronic metabolic diseases, central nervous system, siberian crabapple
The treatment of the diseases such as system, angiocarpy.However, most polypeptide protein drugs need repeatedly even long term administration, using normal injection
Agent treatment, the compliance of patient are very poor.Therefore, by medicament slow release technology extend pharmaceutical release time with reduce administration number of times,
Improve the key that medication compliance is always polypeptide protein class medicament research and development.The polypeptide protein sustained release preparation listed at present is all made of
Microballoon makes drug slow release 1 week~4 weeks as carrier, significantly improves the medication compliance of such drug, but microballoon system
There are preparation process complexity, influence pharmaceutical activity, drug releases to control the problems such as difficult for agent.In recent years, thermo-sensitive gel note in situ
It penetrates agent and is increasingly becoming a kind of novel polypeptide protein medicament slow release dosage form.
Thermo-sensitive gel injection in situ is using temperature sensitive polymer as carrier, and it is water-soluble that drug is dispersed or dissolved in temperature sensitive polymer
The injection being prepared in liquid, the temperature-responsive phase transition occurred using temperature sensitive polymer aqueous solution in medicine-feeding part, note
It penetrates agent and is transformed into semisolid hydrogel from liquid, to make drug slow release.Thermo-sensitive gel injection in situ, which has, carries medicine work
Skill is simple, keeps medicine stability, the advantages that histocompatbility is good, and long in the residence time of medicine-feeding part, plays medicine
The effect of object storage cavern can delay drug release.If the temperature sensitive polymer for polypeptide protein class medicament slow release reported at present has
Dry type, including natural polymer subsystem (such as hydroxypropyl methyl cellulose (HMPC) and chitosan polysaccharide and its with the group of salt
Close) and synthesis Polymer Systems (including non-degradables polymer and the polylactic acid-such as poly(N-isopropylacrylamide) (PNIPAM)
Polyethylene glycol-polylactic acid (PLA-PEG-PLA), poly(lactic-co-glycolic acid)-polyethylene glycol-poly lactic-co-glycolic acid are total
The degradable polymers such as polymers (PLGA-PEG-PLGA)).
Although polysaccharide/salt system preparation process is relatively easy, cost is relatively low, there are the problem of mainly skeleton polymerize
Object hydrophily is poor, and polymer concentration is lower in solution, therefore the gel skeleton intensity formed is low, and moisture is easy to run off, and degrades
Comparatively fast, it is not able to satisfy the long-acting demand of medicament slow release.The prior art, the one kind announced such as Chinese patent application CN108653197A
Carboxymethyl chitosan quaternary ammonium salt thermo-sensitive gel and preparation method, gelling temperature and the human body temperature phase of obtained thermo-sensitive gel
Together, gelation time is extremely short and anti-microbial property is significant, but its medicament slow release performance is poor, thus application range is confined to skin wound
The positions such as face.
Block copolymer is one of widest thermo-sensitive gel material of research.The block copolymer delivered at present is temperature sensitive solidifying
Colloid system is more than 30 kinds, wherein based on ABA type triblock copolymer.It is advantageous that polymer solution concentration is higher, gel
Skeleton structure intensity is preferable, and Thermo-sensitive, degradability and lowest critical solution temperature (LCST) of material etc. can according to need
Regulated and controled.Be MacroMed company exploitation temperature sensing in situ gel rubber product, used in thermo-sensitive gel material be
The PLGA-PEG-PLGA of low molecular weight；1 week~6 weeks slow-release functions may be implemented in the gel systems, have exploitation and infuse at sustained release
Penetrate the basis of agent.However, the study found thatThere is also burst releases and gel to adjust the problems such as limited.Chinese patent
ZL200910049664.6 discloses the mixed gel tool being made of two or more PLGA-PEG-PLGA block copolymer
The temperature-sensing property for having single polymers gel not have can adjust the property such as LCST, degradation speed of gel more flexiblely
Matter.But due to the aqueous environments of thermo-sensitive gel, the water soluble drugs such as polypeptide protein are easy to spread by inner passage, to make
At burst release, limit its application.The Chinese patent of notification number CN103622902B discloses a kind of thermo-sensitive gel pharmaceutical preparation,
It is reduced using by one of metal salt, glucide and the medicinal hydrophilic polymer of injection or a variety of auxiliary materials formed
The burst release of water soluble drug reaches sustained release purpose.It uses at least two temperature sensitive polymers to be blended and by multiple auxiliary materials
Addition realizes that the fine tuning discharged to gel, the design of preparation are relative complex.
Summary of the invention
The purpose of the present invention is to provide slow releasing composition preparations of a kind of polypeptide protein class drug and preparation method thereof, should
Polypeptide protein class burst drug release can be effectively reduced in slow releasing composition preparation, realizes that the controllable precise of polypeptide protein class drug is slow
It releases, to reduce drug administration by injection number, improves the medication compliance of patient.
Present invention discover that temperature sensitive polymer and nucleoprotamine have a synergistic function, temperature sensitive polymer and nucleoprotamine,
Zinc ion also has synergistic function, can significantly improve the slow release effect of polypeptide protein class medicament slow release preparation, sustained release speed
Rate is steady, maintains effective treatment concentration for a long time, to realize the controllable precise sustained release of polypeptide protein class drug.
A kind of slow releasing composition preparation of polypeptide protein class drug, by polypeptide protein class drug, complex reagent and temperature sensitive poly-
Close object aqueous solution composition；The complex reagent is the composition of nucleoprotamine or nucleoprotamine and metal salt；
The metal salt is the metal salt that divalent metal is dissociated into pharmaceutically acceptable and aqueous solution；It is described
Divalent metal be zinc ion；
The temperature sensitive polymer is one or more of PLA-PEG-PLA, PLGA-PEG-PLGA.
In order to reach better invention effect, progress is following preferred:
The dosage of the nucleoprotamine is the 0.1%~5% of slow releasing composition weight of formulation, further preferably 0.1%
~1%, it is more significant with the synergistic function of temperature sensitive polymer.
The dosage of the metal salt is the 0.1%~10% of slow releasing composition weight of formulation.
The metal salt selects zinc acetate；The dosage of the metal salt be slow releasing composition weight of formulation 0.1%~
3%, further preferably 0.1%~0.5%.The amount ranges can guarantee the completely multiple of zinc acetate and polypeptide protein class drug
It closes, and synergistic function is stronger.
The dosage of the polypeptide protein class drug is the 0.1%~5% of slow releasing composition weight of formulation, further preferably
0.1%~0.5%.Guarantee the blood concentration of polypeptide protein class drug when slow releasing composition formulation application within the scope of therapeutic window
It maintains, while reducing high concentration medicine and causing side reaction possibility to body.
The polypeptide protein class drug includes insulin (insulin), insulin analog, interferon
(interferon), ovalbumin (OVA), human growth hormone recombinant (rhGH), glucagon-like peptide (GLP), pancreas hyperglycemia
Plain sample peptide analogues, immunoglobulin (IgG), programmed death receptor 1 (PD-1), apoptosis-ligand (PD-L1) etc.
One or more of.
Preferably, the number-average molecular weight of PEG block is 1000~2000 in the temperature sensitive polymer, and weight percent is
The number-average molecular weight of 20%~40%, PLA or PLGA block is 1000~2000, and weight percent is 60%~80%, PLGA
The molar ratio of lactic acid units (LA) and glycolic acid units (GA) are 1~3:1 in block.Molecular weight ranges that the present invention selects,
The lowest critical solution temperature of the aqueous solution of the temperature sensitive polymer of block ratio is 20 DEG C~35 DEG C, can be realized temperature-sensitive hydrogel
Room temperature preparation and body temperature under quick-gelatinizing.The temperature-responsive phase transition of this kind of temperature sensitive polymer, in body temperature item
Hydrogel is automatically converted under part, and more significant with complex reagent synergy, slow release drug reduces administration number of times, mentions
The medication compliance of high patient.Further preferably, the temperature sensitive polymer is PLGA-PEG-PLGA, and wherein the number of PEG block is equal
Molecular weight is 1000~1450, weight percent be the number-average molecular weight of 29.4%~32.6%, PLGA block be 1200~
1500, the molar ratio that weight percent is LA and GA in 67.4%~70.6%, PLGA block is 3:1.
The concentration expressed in percentage by weight of the temperature sensitive polymer aqueous solution is 10%~30%, further preferably 20%.
The preparation method of the slow releasing composition preparation of the polypeptide protein class drug, comprising the following steps:
(1) nucleoprotamine aqueous solution or nucleoprotamine aqueous solution and metal salt are added dropwise into polypeptide protein class pharmaceutical aqueous solution
Aqueous solution is uniformly mixed, and obtains polypeptide protein class medicinal composition suspension, and centrifugation removal supernatant or freeze-drying obtain polypeptide egg
White class medicinal composition；
(2) temperature sensitive polymer aqueous solution is uniformly mixed with the polypeptide protein class medicinal composition in step (1), is obtained more
The slow releasing composition preparation of peptide protein medicaments.
The temperature sensitive sustained-release composite preparation that the present invention contains polypeptide protein class drug can be used as thermo-sensitive gel injection in situ
Agent.
Compared with prior art, present invention has an advantage that
(1) present invention, can be with using temperature sensitive polymer aqueous solution and polypeptide protein class pharmaceutical composition with suitable LCST
It realizes locally injecting administration, and passes through the temperature-responsive phase transition of temperature sensitive polymer, be automatically converted to water under body temperature
Gel, slow release drug reduce administration number of times, improve the medication compliance of patient.
(2) present invention is using nucleoprotamine or nucleoprotamine and metal salt compositions as complex reagent complex polypeptide albumen
Class drug, temperature sensitive polymer and nucleoprotamine have synergistic function, and temperature sensitive polymer also has with nucleoprotamine, zinc ion
Synergistic function can be effectively reduced polypeptide protein class burst drug release, further significantly improve sustained drug release effect, and keep
The stability of polypeptide protein class drug, sustained release rate is steady, maintains effective treatment concentration for a long time, to realize polypeptide protein
The controllable precise of class drug is sustained.
(3) preparation method that uses of the present invention is simple, content of dispersion with higher, and all steps in water phase into
Row, effectively maintains the structure and bioactivity of polypeptide protein class drug, is suitable for industrial application.
(4) the equal non-immunogenicity of raw material that the present invention uses, good biocompatibility.
Detailed description of the invention
Fig. 1 is the In-vitro release curves of rhGH in comparative example 1 of the present invention and comparative example 2.
Fig. 2 is comparative example 3 of the present invention, comparative example 5 and embodiment 1, embodiment 3, embodiment 4, embodiment 5 and embodiment 7
The In-vitro release curves of middle rhGH.
Fig. 3 be comparative example 4 of the present invention, comparative example 6 and embodiment 2, in embodiment 6 rhGH In-vitro release curves.
Fig. 4 be the embodiment of the present invention 1, in embodiment 3 and comparative example 5 rhGH Drug-time curve.
Specific embodiment
Below with reference to the embodiment in the present invention, technical solution of the present invention is described in detail, it is described
Embodiment is a part of the embodiments of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, this field skill
Art personnel all other embodiment obtained in the case where not making creative work condition, belongs to protection of the present invention
Range.
Embodiment 1
It (is number-average molecular weight, the weight hundred of PEG block that precision, which weighs 200mgPLGA1500-PEG1450-PLGA1500,
The weight percent than being 32.6%, PLGA block is divided to be 67.4%, the molar ratio of LA/GA is 3:1), add 0.80ml deionization
Water dissolves under room temperature magnetic agitation, obtains the temperature sensitive polymer aqueous solution that concentration is 20% (w/w), and LCST is 32 DEG C.Precision claims
1mg human growth hormone recombinant (rhGH) is taken, adds 0.3ml water to dissolve, obtains rhGH aqueous solution；Precision weighs 1mg nucleoprotamine, adds
The dissolution of 0.3ml water, obtains nucleoprotamine aqueous solution；Under the conditions of magnetic agitation, nucleoprotamine aqueous solution is added dropwise to
In rhGH aqueous solution, it is uniformly mixed, obtains the suspension of rhGH compound；The suspension of rhGH compound is centrifuged, in removal
Clear liquid to get arrive rhGH compound.RhGH compound is uniformly mixed with temperature sensitive polymer aqueous solution up to rhGH controlled release composition
Object, it is respectively 0.1%:0.1% that wherein rhGH and nucleoprotamine, which account for rhGH slow releasing composition weight ratio,.
Embodiment 2
The PLGA1200-PEG1000-PLGA1200 that precision weighs 200mg (is number-average molecular weight, the weight of PEG block
Percentage 29.4%, it is 3:1 that the weight percent of PLGA block, which is 70.6%, LA/GA molar ratio), add the deionization of 0.80ml
Water dissolves under 15 DEG C of magnetic agitations, obtains the temperature sensitive polymer aqueous solution that concentration is 20% (w/w), and LCST is 20 DEG C.Precision claims
The human growth hormone recombinant for taking 1mg adds 0.3ml water to dissolve, obtains rhGH aqueous solution；Precision weighs the nucleoprotamine of 1mg, adds
The water of 0.3ml dissolves, and obtains nucleoprotamine aqueous solution；Nucleoprotamine aqueous solution is added dropwise to the rhGH aqueous solution under stirring
In, it is uniformly mixed, obtains the suspension of rhGH compound；The suspension of rhGH compound is centrifuged, removes supernatant to get arriving
RhGH compound.RhGH compound is uniformly mixed to rhGH slow releasing composition to obtain the final product with temperature sensitive polymer aqueous solution, wherein rhGH
Accounting for rhGH slow releasing composition weight ratio with nucleoprotamine is respectively 0.1%:0.1%.
Embodiment 3
The PLGA1500-PEG1450-PLGA1500 that precision weighs 200mg (is number-average molecular weight, the weight of PEG block
Percentage is that the molar ratio that the weight percent of 32.6%, PLGA block is 67.4%, LA/GA is 3:1), add going for 0.80ml
Ionized water dissolves under 15 DEG C of magnetic agitations, obtains the temperature sensitive polymer aqueous solution that concentration is 20% (w/w).Precision weighs 1mg's
Human growth hormone recombinant adds 0.3ml water to dissolve, obtains rhGH aqueous solution；Precision weighs the zinc acetate of 1mg, adds that 0.3ml's is water-soluble
Solution, obtains zinc acetate aqueous solution；Precision weighs the nucleoprotamine of 1mg, adds the water of 0.3ml to dissolve, obtains nucleoprotamine aqueous solution；
Zinc acetate aqueous solution and nucleoprotamine aqueous solution are added dropwise in the rhGH aqueous solution under stirring respectively, are uniformly mixed, obtain
To the suspension of rhGH compound；The suspension of rhGH compound is centrifuged, removes supernatant to get rhGH compound is arrived.It will
RhGH compound is uniformly mixed rhGH slow releasing composition to obtain the final product with temperature sensitive polymer aqueous solution, wherein rhGH, nucleoprotamine and vinegar
It is respectively 0.1%:0.1%:0.1% that sour zinc, which accounts for rhGH slow releasing composition weight ratio,.
Embodiment 4
Other than the dosage of nucleoprotamine is 5mg, remaining operation obtains rhGH slow releasing composition with embodiment 1, wherein
It is respectively 0.1%:0.5% that rhGH and nucleoprotamine, which account for rhGH slow releasing composition weight ratio,.
Embodiment 5
Other than the dosage of nucleoprotamine is 10mg, remaining operation obtains rhGH slow releasing composition with embodiment 1,
It is respectively 0.1%:1.0% that middle rhGH and nucleoprotamine, which account for rhGH slow releasing composition weight ratio,.
Embodiment 6
In addition to (being number-average molecular weight, the weight hundred of PEG block with the PLGA1200-PEG1000-PLGA1200 of 200mg
Divide ratio 29.4%, it is 3:1 that the weight percent of PLGA block, which is 70.6%, LA/GA molar ratio), replace 200mg's
PLGA1500-PEG1450-PLGA1500 (is number-average molecular weight, the weight percent of PEG block is 32.6%, PLGA block
Weight percent be 67.4%, LA/GA molar ratio be 3:1) except, remaining operation with embodiment 3, obtain rhGH sustained release group
Object is closed, it is respectively 0.1%:0.1%:0.1% that wherein rhGH, nucleoprotamine and zinc acetate, which account for rhGH slow releasing composition weight ratio,.
Embodiment 7
In addition to the dosage of rhGH is 5mg, the dosage of nucleoprotamine is 5mg, and the dosage of zinc acetate is remaining behaviour except 5mg
Make to obtain rhGH slow releasing composition, wherein rhGH, nucleoprotamine and zinc acetate account for rhGH slow releasing composition weight with embodiment 3
Than being respectively 0.5%:0.5%:0.5%.
Embodiment 8
Other than changing rhGH into insulin, remaining operation obtains rhGH slow releasing composition, wherein pancreas with embodiment 3
It is respectively 0.1%:0.1%:0.1% that island element, nucleoprotamine and zinc acetate, which account for rhGH slow releasing composition weight ratio,.
Embodiment 9
Other than changing rhGH into OVA, remaining operation obtains rhGH slow releasing composition, wherein OVA, fish with embodiment 3
It is respectively 0.1%:0.1%:0.1% that protamine and zinc acetate, which account for rhGH slow releasing composition weight ratio,.
Embodiment 10
The PLGA1500-PEG1450-PLGA1500 that precision weighs 200mg (is number-average molecular weight, the weight of PEG block
Percentage is that the molar ratio that the weight percent of 32.6%, PLGA block is 67.4%, LA/GA is 3:1), add going for 0.80ml
Ionized water dissolves under 15 DEG C of magnetic agitations, obtains the temperature sensitive polymer aqueous solution that concentration is 20% (w/w).Precision weighs 5mg's
Human growth hormone recombinant adds 0.30ml water to dissolve, obtains rhGH aqueous solution；Precision weighs the nucleoprotamine of 1mg, adds 0.30ml's
Water dissolution, obtains nucleoprotamine aqueous solution；Nucleoprotamine aqueous solution is added dropwise in the rhGH aqueous solution under stirring, mixing
Uniformly, the suspension of rhGH compound is obtained；The suspension of rhGH compound is lyophilized to obtain rhGH compound freeze-dried powder.It will
RhGH compound freeze-dried powder is uniformly mixed to obtain rhGH slow releasing composition with temperature sensitive polymer aqueous solution, wherein rhGH and milt egg
The white rhGH slow releasing composition weight ratio that accounts for is respectively 0.5%:0.1%.
Comparative example 1
Precision weighs the human growth hormone recombinant of 5mg, adds 0.50ml water to dissolve, obtains rhGH aqueous solution；Precision weighs 1mg
Nucleoprotamine, add the water of 0.50ml to dissolve, obtain nucleoprotamine aqueous solution；Nucleoprotamine aqueous solution is added dropwise to stirring
Under rhGH aqueous solution in, be uniformly mixed, obtain the suspension of rhGH compound；The suspension of rhGH compound is centrifuged, is moved
Except supernatant to get arrive rhGH compound.The weight ratio that rhGH and nucleoprotamine account for the suspension of rhGH compound is 0.5%:
0.1%.
Comparative example 2
Precision weighs the human growth hormone recombinant of 5mg, adds 0.30ml water to dissolve, obtains rhGH aqueous solution；Precision weighs 1mg
Zinc acetate, add the water of 0.30ml to dissolve, obtain zinc acetate aqueous solution；Precision weighs the nucleoprotamine of 1mg, adds the water of 0.3ml
Dissolution, obtains nucleoprotamine aqueous solution；Zinc acetate aqueous solution and nucleoprotamine aqueous solution are added dropwise to respectively under stirring
In rhGH aqueous solution, it is uniformly mixed, obtains the suspension of rhGH compound；The suspension of rhGH compound is centrifuged, in removal
Clear liquid to get arrive rhGH compound.
Comparative example 3
The PLGA1500-PEG1450-PLGA1500 that precision weighs 200mg (is number-average molecular weight, the weight of PEG block
Percentage is that the molar ratio that the weight percent of 32.6%, PLGA block is 67.4%, LA/GA is 3:1), add going for 0.80ml
Ionized water dissolves under 15 DEG C of magnetic agitations, obtains the temperature sensitive polymer aqueous solution that concentration is 20% (w/w).Precision weighs 5mg's
Human growth hormone recombinant is uniformly mixed with temperature sensitive polymer aqueous solution, is configured to rhGH and accounts for slow releasing composition weight ratio be 0.5%
Slow releasing composition.
Comparative example 4
The PLGA1200-PEG1000-PLGA1200 that precision weighs 200mg (is number-average molecular weight, the weight of PEG block
Percentage 29.4%, it is 3:1 that the weight percent of PLGA block, which is 70.6%, LA/GA molar ratio), add the deionization of 0.80ml
Water dissolves under 15 DEG C of magnetic agitations, obtains the temperature sensitive polymer aqueous solution that concentration is 20% (w/w).Precision weighs the recombination of 5mg
Human growth hormone (HGH) is uniformly mixed with temperature sensitive polymer aqueous solution, be configured to rhGH account for slow releasing composition weight ratio be 0.5% it is slow
Release composition.
Comparative example 5
It (is number-average molecular weight, the weight hundred of PEG block that precision, which weighs 200mgPLGA1500-PEG1450-PLGA1500,
The weight percent than being 32.6%, PLGA block is divided to be 67.4%, the molar ratio of LA/GA is 3:1), add 0.80ml deionization
Water dissolves under room temperature magnetic agitation, obtains the temperature sensitive polymer aqueous solution that concentration is 20% (w/w), and LCST is 32 DEG C.Precision claims
1mg human growth hormone recombinant is taken, adds 0.3ml water to dissolve, obtains rhGH aqueous solution；Precision weighs 1mg zinc acetate, adds 0.3ml water
Dissolution, obtains zinc acetate aqueous solution；Under the conditions of magnetic agitation, zinc acetate aqueous solution is added dropwise in rhGH aqueous solution,
It is uniformly mixed, obtains the suspension of rhGH compound；The suspension of rhGH compound is centrifuged, removes supernatant to get arriving
RhGH compound.RhGH compound is uniformly mixed to slow releasing composition to obtain the final product with temperature sensitive polymer aqueous solution, wherein rhGH and vinegar
The weight ratio that sour zinc accounts for slow releasing composition is respectively 0.1%:0.1%.
Comparative example 6
In addition to (being number-average molecular weight, the weight hundred of PEG block with the PLGA1200-PEG1000-PLGA1200 of 200mg
Divide ratio 29.4%, it is 3:1 that the weight percent of PLGA block, which is 70.6%, LA/GA molar ratio), replace 200mg's
PLGA1500-PEG1450-PLGA1500 (is number-average molecular weight, the weight percent of PEG block is 32.6%, PLGA block
Weight percent be 67.4%, LA/GA molar ratio be 3:1) except, remaining operation with comparative example 5, obtain controlled release composition
Object, it is respectively 0.1%:0.1% that wherein rhGH and zinc acetate, which account for slow releasing composition weight ratio,.
1 embodiment of table and comparative example preparation composition summarize
Drug release test: it is released using the drug that dialysis investigates each sample of embodiment 1-10 and comparative example 1-6 preparation
Clearance is that steps are as follows: weighing appropriate amount of sample in Spectra/Por dialysis tubing (MWCO100KDa), drug release medium is
7.4 phosphate buffer of 10mL pH, dialysis tubing is placed in constant-temperature table, constant-temperature table parameter setting: 37 DEG C of temperature, revolving speed
100rpm.Phosphate buffer 2ml is accurately drawn from drug delivery system respectively at different time points, then to delivery systme
In add the phosphate buffer dissolution medium of same volume.Polypeptide protein drug concentration high-efficient liquid phase technique in samples taken
(Chinese Pharmacopoeia 2015 editions) detection, experimental result is shown in Fig. 1-Fig. 3 and table 2.
2 embodiment of table summarizes with comparative example drug release data
In table, * indicates that 0.01 < P < 0.05, # indicate P < 0.01；0.01 < P < 0.05 indicates that otherness is significant；The table of P < 0.01
Show that otherness is extremely significant.
By can be seen that this with the comparison of the release profiles of polypeptide protein compound and polypeptide protein thermo-sensitive gel mixture
Embodiment slow releasing composition preparation in invention is without phenomenon of burst release, and slow release effect is excellent, and sustained release rate is steady, 6 days and 20 days
Cumulative release amount is significantly lower than its corresponding comparative example preparation；The identical embodiment 1 of temperature sensitive polymer material, embodiment 3, reality
Example 4, embodiment 5, embodiment 7, embodiment 8, embodiment 9 and embodiment 10 are applied compared with comparative example 3, comparative example 5, embodiment system
The Cumulative release amount (long-acting slow-release) of agent 20 days is substantially less than comparative example preparation (P < 0.05)；Temperature sensitive polymer material is identical
Embodiment 2 and embodiment 6 compared with comparative example 4, comparative example 6,20 days Cumulative release amounts of embodiment preparation be substantially less than pair
Ratio preparation (P < 0.05).Wherein the Cumulative release amount of comparative example 1 and comparative example 2 in 1 day is more than 80%, comparative example 3, right
Ratio 4, comparative example 5 and comparative example 6 are able to extend the release of albumen, but sustained release rate is not flat enough due to foring thermo-sensitive gel
Surely.And the present invention is added nucleoprotamine and carries out the compound embodiment 1-10 slow releasing composition preparation being prepared and comparative example preparation
It compares, slow release effect is more excellent, can significantly improve the slow release effect of polypeptide protein class medicament slow release preparation, and sustained release rate is flat
Surely, be mainly based upon temperature sensitive polymer and nucleoprotamine synergistic function and temperature sensitive polymer and nucleoprotamine, zinc from
The synergistic function of son to realize the controllable precise sustained release of polypeptide protein class drug, and can be effectively reduced burst release.
Zoopery: using 200g-250g female sd inbred rats as experimental animal, the controlled release composition of subcutaneous injection embodiment preparation
300 μ l of object, certain time point carry out eye socket and take blood, and blood sample is centrifuged to obtain serum.Drug concentration in serum is with ab190811 people
Growth hormone ELISA kit is tested, and Drug-time curve is obtained.Control group is slow releasing composition prepared by comparative example 5, subcutaneously
300 μ l of injection dosage.Experimental result is shown in Fig. 4.
Document and clinical data show that the blood concentration (Cp) of growth hormone is maintained at the level of 5ng/ml and can be only achieved
Clinical therapeutic efficacy (Cleland, Jeffrey L., et al. " Recombinant human the growth hormone of effect
poly(lactic-co-glycolic acid)(PLGA)microspheres provide a long lasting
effect."Journal of Controlled Release 49.2-3(1997):193-205.).The experimental results showed that this hair
Bright example composition can be realized the controllable sustained-release of growth hormone in animal body, and optimal slow release effect is 3 He of embodiment
Embodiment 4 can maintain blood concentration, up to 14 days, can maintain effective treatment concentration for a long time more than 5ng/ml level,
Effective clinical therapeutic efficacy can be reached.Embodiment 1,2,5,6,7 and 10 can maintain blood concentration 5ng/ml level with
On number of days at -10 days 7 days, can also maintain effective treatment concentration for a long time, effective clinical therapeutic efficacy can be reached.Make
For control, comparative example 5 (thermo-sensitive gel and the combination of growth hormone/zinc complexes) maintains to discharge in the intracorporal effective concentration of rat
Just treatment concentration is reduced to after 2-3 days hereinafter, effective treatment concentration cannot be maintained for a long time.Polypeptide protein class drug is in animal
Intracorporal release is influenced by gel aperture and complex stabilities, and the present invention uses the combination of nucleoprotamine and growth hormone
The dissociation behavior that growth hormone can be changed, since the interaction between its albumen is better than the compound work of zinc ion and growth hormone
With, it is thus possible to it is significant to extend the slow release effect of human growth hormone (HGH) in animal body.
Embodiment 8 and 9 can maintain effective treatment concentration at one week or more, can reach effective clinical treatment effect
Fruit.
In the present invention, the combination of nucleoprotamine and polypeptide protein class drug can change the dissociation row of polypeptide protein class drug
For, since the interaction between albumen is better than the compound action of zinc ion Yu polypeptide protein class drug, while temperature sensitive polymer with
The synergistic function of the synergistic function and temperature sensitive polymer of nucleoprotamine and nucleoprotamine, zinc ion, it is thus possible to
Significant to extend the slow release effect of polypeptide protein class drug in animal body, sustained release rate is steady.Do not influencing polypeptide protein class medicine
The controllable precise sustained release that polypeptide protein class drug is realized under the premise of object drug effect, is effectively reduced the drug administration by injection number of drug, mentions
The compliance of high patient, and effective treatment concentration is maintained for a long time.The variation of parameter not shadow in preparation method of the present invention
Ring polypeptide protein class drug slow releasing composition preparation preparation, therefore in preparation method of the present invention arbitrary parameter combination
Realize the preparation of the slow releasing composition preparation of polypeptide protein class drug.Details are not described herein.
Claims (10)
1. a kind of slow releasing composition preparation of polypeptide protein class drug, which is characterized in that by polypeptide protein class drug, complex reagent
It is formed with temperature sensitive polymer aqueous solution；The complex reagent is the composition of nucleoprotamine or nucleoprotamine and metal salt；
The metal salt is the metal salt that divalent metal is dissociated into pharmaceutically acceptable and aqueous solution；Described two
Valence metal cation is zinc ion；
The temperature sensitive polymer is one or more of PLA-PEG-PLA, PLGA-PEG-PLGA.
2. the slow releasing composition preparation of polypeptide protein class drug according to claim 1, which is characterized in that the milt egg
White dosage is the 0.1%~5% of slow releasing composition weight of formulation.
3. the slow releasing composition preparation of polypeptide protein class drug according to claim 1, which is characterized in that the metal salt
Dosage be slow releasing composition weight of formulation 0.1%~10%.
4. the slow releasing composition preparation of polypeptide protein class drug according to claim 1, which is characterized in that the metal salt
For zinc acetate；The dosage of the metal salt is the 0.1%~3% of slow releasing composition weight of formulation.
5. the slow releasing composition preparation of polypeptide protein class drug according to claim 1, which is characterized in that the polypeptide egg
The dosage of white class drug is the 0.1%~5% of slow releasing composition weight of formulation.
6. the slow releasing composition preparation of polypeptide protein class drug according to claim 1 or 5, which is characterized in that described more
Peptide protein medicaments include insulin, insulin analog, interferon, ovalbumin, human growth hormone recombinant, glucagon
Sample peptide, glucagon-like peptide-1 analogs, immunoglobulin, programmed death receptor 1, one in apoptosis-ligand
Kind is two or more.
7. the slow releasing composition preparation of polypeptide protein class drug according to claim 1, which is characterized in that described temperature sensitive poly-
The lowest critical solution temperature for closing object aqueous solution is 20 DEG C~35 DEG C.
8. the slow releasing composition preparation of polypeptide protein class drug according to claim 1, which is characterized in that described temperature sensitive poly-
The concentration expressed in percentage by weight for closing object aqueous solution is 10%~30%.
9. the slow releasing composition preparation of polypeptide protein class drug according to claim 1, which is characterized in that described temperature sensitive poly-
The number-average molecular weight for closing PEG block in object is 1000~2000, and weight percent is 20%~40%, PLA or PLGA block
Number-average molecular weight is 1000~2000, and the molar ratio that weight percent is LA and GA in 60%~80%, PLGA block is 1~3:
1。
10. the preparation method of the slow releasing composition preparation of described in any item polypeptide protein class drugs according to claim 1~9,
Characterized by comprising the following steps:
(1) nucleoprotamine aqueous solution or nucleoprotamine aqueous solution is added dropwise into polypeptide protein class pharmaceutical aqueous solution and metal salt is water-soluble
Liquid is uniformly mixed, and obtains polypeptide protein class medicinal composition suspension, and centrifugation removal supernatant or freeze-drying obtain polypeptide protein class
Medicinal composition；
(2) temperature sensitive polymer aqueous solution is uniformly mixed with the polypeptide protein class medicinal composition in step (1), obtains polypeptide egg
The slow releasing composition preparation of white class drug.
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| US5461031A (en) * | 1994-06-16 | 1995-10-24 | Eli Lilly And Company | Monomeric insulin analog formulations |
| PE79099A1 (en) * | 1997-06-13 | 1999-08-24 | Lilly Co Eli | STABLE INSULIN FORMULATIONS |
| CN1276731A (en) * | 1997-10-24 | 2000-12-13 | 伊莱利利公司 | Insoluble insulin compositions |
| US7534763B2 (en) * | 2004-07-02 | 2009-05-19 | Bristol-Myers Squibb Company | Sustained release GLP-1 receptor modulators |
| KR100746962B1 (en) * | 2006-04-04 | 2007-08-07 | 한국과학기술연구원 | Thermosensitive polyphosphazene-bioactive molecule conjugates, preparation method thereof and use thereof |
| CN1973901B (en) * | 2006-12-07 | 2010-05-19 | 浙江大学 | Composite microsphere preparation of lactic acid-hydroxyacetic acid copolymer and its preparation process |
| CN101361963A (en) * | 2008-09-16 | 2009-02-11 | 哈尔滨工业大学 | Preparation method of protein and peptide drugs slow-release microcapsules |
| CN101845120B (en) * | 2010-03-25 | 2011-11-16 | 淮阴师范学院 | Method for synthesizing temperature-sensitive and biodegradable in situ gel |
| CN102370611B (en) * | 2010-08-17 | 2013-09-18 | 东莞太力生物工程有限公司 | Temperature-sensitive hydrogel containing exendin-4 and injection thereof |
| WO2013185032A1 (en) * | 2012-06-07 | 2013-12-12 | President And Fellows Of Harvard College | Nanotherapeutics for drug targeting |
| CN103622902B (en) * | 2012-08-24 | 2016-12-21 | 上海现代药物制剂工程研究中心有限公司 | A kind of thermosensitive hydrogel pharmaceutical preparation and preparation method thereof |
| CN103637978B (en) * | 2013-12-13 | 2015-03-11 | 北京诺康达医药科技有限公司 | Stable gel containing bromelain |
| CN108201622A (en) * | 2016-12-16 | 2018-06-26 | 宁波宁融生物医药有限公司 | A kind of bortezomib pharmaceutical composition and its application |
| CN108210461A (en) * | 2016-12-16 | 2018-06-29 | 中国科学院上海药物研究所 | A kind of Talazoparib pharmaceutical compositions and its application |
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