CN108774285A - A kind of preparation method and its pharmaceutical composition of growth hormone release inhibiting hormone - Google Patents
A kind of preparation method and its pharmaceutical composition of growth hormone release inhibiting hormone Download PDFInfo
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- CN108774285A CN108774285A CN201810707150.4A CN201810707150A CN108774285A CN 108774285 A CN108774285 A CN 108774285A CN 201810707150 A CN201810707150 A CN 201810707150A CN 108774285 A CN108774285 A CN 108774285A
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- growth hormone
- release inhibiting
- hormone release
- preparation
- hormone
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- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 97
- 239000005556 hormone Substances 0.000 title claims abstract description 96
- 229940088597 hormone Drugs 0.000 title claims abstract description 96
- 102000018997 Growth Hormone Human genes 0.000 title claims abstract description 95
- 108010051696 Growth Hormone Proteins 0.000 title claims abstract description 95
- 239000000122 growth hormone Substances 0.000 title claims abstract description 95
- 238000002360 preparation method Methods 0.000 title claims abstract description 43
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
- 238000004108 freeze drying Methods 0.000 claims abstract description 23
- 238000002347 injection Methods 0.000 claims abstract description 22
- 239000007924 injection Substances 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000000203 mixture Substances 0.000 claims abstract description 17
- 239000000843 powder Substances 0.000 claims abstract description 10
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000003957 anion exchange resin Substances 0.000 claims abstract description 5
- 239000003729 cation exchange resin Substances 0.000 claims abstract description 5
- 239000007853 buffer solution Substances 0.000 claims description 39
- 239000000243 solution Substances 0.000 claims description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 24
- 239000007788 liquid Substances 0.000 claims description 19
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 18
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 18
- 239000003480 eluent Substances 0.000 claims description 17
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 14
- 239000012043 crude product Substances 0.000 claims description 13
- 239000008215 water for injection Substances 0.000 claims description 11
- 239000011347 resin Substances 0.000 claims description 10
- 229920005989 resin Polymers 0.000 claims description 10
- 239000007974 sodium acetate buffer Substances 0.000 claims description 10
- 238000011068 loading method Methods 0.000 claims description 9
- 229920002684 Sepharose Polymers 0.000 claims description 8
- 150000003625 trehaloses Chemical class 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- 239000011780 sodium chloride Substances 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 239000008363 phosphate buffer Substances 0.000 claims description 6
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 5
- 239000012064 sodium phosphate buffer Substances 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 239000011543 agarose gel Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000000872 buffer Substances 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 239000000047 product Substances 0.000 description 15
- 238000012360 testing method Methods 0.000 description 13
- 239000000126 substance Substances 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000000825 pharmaceutical preparation Substances 0.000 description 6
- 238000004140 cleaning Methods 0.000 description 5
- 239000012982 microporous membrane Substances 0.000 description 5
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 238000012856 packing Methods 0.000 description 4
- 238000012216 screening Methods 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical class [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000011067 equilibration Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 235000011091 sodium acetates Nutrition 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 2
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 235000011008 sodium phosphates Nutrition 0.000 description 2
- 125000000647 trehalose group Chemical group 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical class [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- 238000000825 ultraviolet detection Methods 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 1
- -1 GHRIH Substances 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 108060003100 Magainin Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 102100028255 Renin Human genes 0.000 description 1
- 108090000783 Renin Proteins 0.000 description 1
- 102000005157 Somatostatin Human genes 0.000 description 1
- 108010056088 Somatostatin Proteins 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- 239000003629 gastrointestinal hormone Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229960002163 hydrogen peroxide Drugs 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000000297 inotrophic effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 1
- 229960000553 somatostatin Drugs 0.000 description 1
- 210000002325 somatostatin-secreting cell Anatomy 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/655—Somatostatins
-
- 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
- A61K38/31—Somatostatins
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Endocrinology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Dermatology (AREA)
- Toxicology (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to biomedicine technical fields, and in particular to a kind of preparation method and its pharmaceutical composition of growth hormone release inhibiting hormone, this method obtain growth hormone release inhibiting hormone using the method that cation exchange resin column, anion-exchange resin column elute；Operation is simple for purified growth chalone method provided by the invention, and the growth hormone release inhibiting hormone purity of acquisition is up to 99.7%, yield up to 60% or more.Freeze drying powder injection dissolubility made from composition of the present invention is good, stability is good, solubility is good；The freeze drying powder injection made from the composition is easy to use, is conducive to storing, preparation method is simple, is easy to industrialized production, and production cost is low.
Description
Technical field
The invention belongs to biomedicine technical fields, and in particular to the preparation method of growth hormone release inhibiting hormone and contain growth hormone release inhibiting hormone
Pharmaceutical composition.
Background technology
Growth hormone release inhibiting hormone (growth hormone release-inhibiting hormone, GHRIH, growth hormone release-inlease-
Inhibiting hormone or somatostatin) it is tetradecapeptide from the macromolecular peptide cracking of 116 amino acid,
It has divided structure annular in shape, and there are one disulfide bond between the 3rd and the 14th cysteine, and chemical constitution is as follows, molecule
Formula is C76H104N18O19S2, relative molecular mass 1637.89 are white powder.
Growth hormone release inhibiting hormone is a kind of inhibiting hormone of growth, is initially found from hypothalamus of animals by Brazen etc. 1973, main
There are 14 and 28 amino acid, two kinds of active forms.It is distributed widely in maincenter and peripheral neverous system and gastrointestinal tract, also
It is present in rat and human heart, gastrointestinal tract mucous interior, growth hormone release inhibiting hormone is discharged by D cells, and content is with antrum and stomach
Body portion highest.Growth hormone release inhibiting hormone can inhibit the secretion of Magainin, α-deoxyglucose etc., reduce renin activity, generate pressure reduction effect；
Growth hormone release inhibiting hormone has negative inotropic action to isolated guinea pig heart, it can further decrease its heart and refer in the presence of furosemide
Number and arterial pressure；It can be by adjusting intestinal hormone secretion, and stabilizing cell membrane plays a protective role to it.In addition, raw
Long chalone has inhibiting effect to the secretion of whole gastrointestinal tracts.
The purity and yield of the growth hormone release inhibiting hormone prepared at present are all relatively low, cannot meet the needs of industrialized production, special
Be not can not large scale purification growth hormone release inhibiting hormone, constrain the application of growth hormone release inhibiting hormone.Therefore it provides a kind of side of purified growth chalone
Method is of great significance.
Invention content
For solve it is above-mentioned the problems of in the prior art, We conducted a large amount of experimental explorations, find a kind of new
Growth hormone release inhibiting hormone purification process, the growth hormone release inhibiting hormone purity higher that the present invention obtains.It is another object of the present invention to provide
A kind of growth hormone release inhibiting hormone pharmaceutical composition and preparation method thereof.
Specifically, the present invention provides：
A kind of purification process of growth hormone release inhibiting hormone, includes the following steps：
Step 1, after washing cation exchange resin column with the first buffer solution, it is thick with the first buffer solution growth hormone release inhibiting hormone
Product, and by≤50g growth hormone release inhibiting hormones crude product/L resins/cycle loading；It is eluted with the second buffer solution, obtains the first eluate；It is described
First and second buffer solution is sodium phosphate buffer；
Step 2：With phosphate buffer by the pH value of eluent to 4.5~6.5, solution is obtained；
Step 3：It is washed after anion-exchange resin column pre-equilibrated with third buffer solution, is walked with third buffer solution
Rapid 2 products therefrom, and carry out loading by 30g growth hormone release inhibiting hormones crude product/L resins/cycle；It is eluted, is obtained with the 4th buffer solution
Second eluate is concentrated and dried up to growth hormone release inhibiting hormone；Third and fourth described buffer solution is sodium-acetate buffer.
The cation exchange resin is Carboxymethyl Sepharose column；The anion exchange resin is agarose Gel column.
The pH value of phosphate buffer in the step 2 is 5.0~7.0.
Described first, second, three, the pH value of four buffer solutions be 4.0~6.0.
Described second, contain sodium chloride in four buffer solutions.
A kind of pharmaceutical composition containing growth hormone release inhibiting hormone includes growth hormone release inhibiting hormone, excipient, the excipient be trehalose,
The mixture of galactolipin composition.
The composition includes the ingredient of following parts by weight：0.8~1 parts by weight growth hormone release inhibiting hormone, 30~50 parts by weight figurations
Agent.
Trehalose is α, the bis- carboxylic trehaloses of α-, β in the excipient, in the bis- carboxylic isotrehaloses of β-or the bis- carboxylic trehaloses of α, β-
One or more.
Trehalose in the excipient：The weight ratio of galactolipin is (0.5~0.9)：1.
The pH value of the composition is 4.5~6.5.
A method of the pharmaceutical composition containing growth hormone release inhibiting hormone prepares freeze-dried powder, includes the following steps：
1) it weighs excipient by recipe quantity to be dissolved in the water for injection of 2/3 recipe quantity, stir evenly；
2) it waits for that above-mentioned preparation liquid is cooled to room temperature, recipe quantity growth hormone release inhibiting hormone is added, survey pH value, adjust pH to 4.5~6.0,
Water for injection is added to full dose, with miillpore filter refined filtration, freeze-drying obtains freeze-dried powder.
Compared with the prior art, the present invention has the following advantages and good effect：
1, operation is simple for purified growth chalone method provided by the invention, and the growth hormone release inhibiting hormone purity of acquisition is reachable
99.7%, yield is up to 60% or more.
2, the freeze drying powder injection made from the composition has good stability, and solubility is good；It is lyophilized made from the composition
Powder-injection is easy to use, is conducive to storing, preparation method is simple, is easy to industrialized production, and production cost is low.
Specific implementation mode
The following describes the present invention further through the description of specific embodiments, but this is not the limit to the present invention
System, those skilled in the art's basic thought according to the present invention can make various modifications or improvements, but without departing from this
The basic thought of invention, is all within the scope of the present invention.
Growth hormone release inhibiting hormone crude product is purchased from the Hangzhou bio tech ltd Tai Jia, its HPLC purity is 93.02% after testing.
Embodiment 1
Step 1：Carboxymethyl Sepharose column, which is washed, with the 25mM sodium phosphate buffers (the first buffer solution) of pH6.0 carries out pre- put down
After weighing apparatus, with the first buffer solution growth hormone release inhibiting hormone crude product, loading is carried out by 40g growth hormone release inhibiting hormones crude product/L resins/cycle；Use 10-
60% the second buffer solution of gradient (20mM sodium phosphates, 110mM sodium chloride, pH6.5) is through 20 times of column volumes；Flow velocity is 7mL/ minutes,
And eluent is monitored by being detected at 215nm, collects characteristic peak eluent；
Step 2：It is that 7.0 phosphate buffers adjust the pH of eluent to 5.0 with pH value, obtains solution；
Step 3：Phenyl Sepharose HP columns are washed with the 20mM sodium-acetate buffers (third buffer solution) of pH4.0 to carry out
After pre-equilibration, with third buffer solution step 2 acquired solution, carried out according to 30g growth hormone release inhibiting hormones crude product/L resins/cycle
Sample；It is eluted through 25 times of column volumes with the gradient of the 4th buffer solutions of 0-20% (20mM sodium acetates, 1M sodium chloride, pH7.5)；Flow velocity is
5mL/ minutes and eluent by 215nm UV detections monitor；Characteristic peak eluent is collected, is concentrated and dried, obtains purity
For 99.93% growth hormone release inhibiting hormone 25.73g, purifying total recovery is 64.32%.
Embodiment 2
Step 1：Carboxymethyl Sepharose column, which is washed, with the 25mM sodium phosphate buffers (the first buffer solution) of pH6.0 carries out pre- put down
After weighing apparatus, with the first buffer solution growth hormone release inhibiting hormone crude product, loading is carried out by 100g growth hormone release inhibiting hormones crude product crude product/L resins/cycle；
The second buffer solution of 0-40% gradients is washed through 20 times of column volumes, then gradient of the second buffer solutions of 40-80% through 3 times of column volumes
It is de-；Flow velocity is 7mL/ minutes, and eluent is monitored by being detected at 215nm；Collect characteristic peak eluent；
Step 2：With pH value be 7.0 phosphate buffers by the pH value of eluent to 6.0, obtain solution；
Step 3：Phenyl Sepharose HP columns are washed with the 20mM sodium-acetate buffers (third buffer solution) of pH4.0 to carry out
After pre-equilibration, with third buffer solution step 2 products therefrom, loading is carried out by 20g growth hormone release inhibiting hormones crude product/L resins/cycle；
It is eluted through 25 times of column volumes with the gradient of the 4th buffer solutions of 0-20% (20mM sodium acetates, 1M sodium chloride, pH4.5)；Flow velocity is
5mL/ minutes and eluent by 215nm UV detections monitor；The pure eluent of characteristic peak is collected, is concentrated and dried, obtains pure
Degree is 99.81% growth hormone release inhibiting hormone 63.21g, and purifying total recovery is 63.21%.
Embodiment 3
Step 1：Carboxymethyl Sepharose column, which is washed, with the 25mM sodium phosphate buffers (the first buffer solution) of pH6.0 carries out pre- put down
After weighing apparatus, with the first buffer solution growth hormone release inhibiting hormone, loading is carried out by 50g growth hormone release inhibiting hormones/L resins/cycle；With 10-60% second
The gradient of buffer solution (20mM sodium phosphates, 110mM sodium chloride, pH6.5) is through 20 times of column volumes；Flow velocity is 7mL/ minutes, and is washed
De- liquid is monitored by being detected at 215nm；Collect characteristic peak eluent；
Step 2：With pH value be 6.0 phosphate buffers by the pH value of eluent to 4.5, obtain solution；
Step 3：Phenyl Sepharose HP columns are washed with the 20mM sodium-acetate buffers (third buffer solution) of pH4.0 to carry out
After pre-equilibration, with third buffer solution step 2 products therefrom, loading is carried out by 30g growth hormone release inhibiting hormones/L resins/cycle；Use 0-
The gradient of 20% the 4th buffer solution (20mM sodium acetates, 1M sodium chloride, pH4.5) is eluted through 25 times of column volumes；Flow velocity is 5mL/
Minute and eluent by 215nm at UV detect and monitor；The pure eluent of characteristic peak is collected, is concentrated and dried, obtaining purity is
99.81% growth hormone release inhibiting hormone 31.89g, purifying total recovery are 63.78%.
Test case 1：
Related substance takes this product, is dissolved in water and the solution containing 0.5mg in every 1ml is made, as test solution；It is accurate
2ml is measured, sets in 100ml measuring bottles, is diluted with water to scale, shake up, as a contrast solution, according to high performance liquid chromatography (2015
Version pharmacopeia) it measures, it is filler with octadecylsilane chemically bonded silica, (takes phosphatase 11 1ml with phosphoric acid solution, add water 800ml, use
Triethylamine adjusts pH value to 2.3, is diluted with water to 1000ml) it is mobile phase A, acetonitrile is Mobile phase B；Flow velocity is per minute
1.5ml；Detection wavelength is 215nm.Gradient elution is carried out by table 1；Growth hormone release inhibiting hormone reference substance about 10mg is taken, is set in 20ml measuring bottles,
Add 30% hydrogenperoxide steam generator 1ml, be placed at room temperature for 1 hour, be diluted with water to scale, shake up, filter, take subsequent filtrate 50ml, notes
Enter liquid chromatograph, number of theoretical plate is calculated by growth hormone release inhibiting hormone peak is not less than 2000, growth hormone release inhibiting hormone main peak retention time corresponding thereto
The separating degree at about 1.1 oxidative degradation object peak should be not less than 2.0.It takes contrast solution 50ml to inject liquid chromatograph, adjusts inspection
Sensitivity is surveyed, it is about the 20% of full scale to make principal component chromatography peak height.Precision measures test solution and each 50ml of contrast solution,
It is injected separately into liquid chromatograph, records chromatogram.
1 gradient elution of table
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 79 | 21 |
| 18 | 60 | 40 |
| 20 | 60 | 40 |
| 21 | 79 | 21 |
| 26 | 79 | 21 |
Assay is measured according to high performance liquid chromatography (2015 editions pharmacopeia).
Chromatographic condition is filler with octadecylsilane chemically bonded silica with system suitability；It (is taken with phosphoric acid solution
Phosphatase 11 1ml adds water 800ml, with triethylamine adjust pH value to 2.3, be diluted with water to 1000ml)-acetonitrile (75: 25) be flowing
Phase；Flow velocity is 1.5ml per minute；Detection wavelength is 215nm.Number of theoretical plate is calculated by growth hormone release inhibiting hormone peak is not less than 1500.
Measuring method takes this product appropriate, accurately weighed, and being dissolved in water and quantifying dilution is made the solution containing 0.1mg in every 1ml,
Precision measures 20ml and injects liquid chromatograph, records chromatogram；It separately takes growth hormone release inhibiting hormone reference substance appropriate, is measured in the same method.By external standard
Method with calculated by peak area to get.As a result table 2.
The different samples of table 2
| Sample | Total related substance (%) | Single maximum contaminant (%) | Impurity number |
| Embodiment 1 | 0.11 | 0.02 | 3 |
| Embodiment 2 | 0.10 | 0.03 | 3 |
| Embodiment 3 | 0.09 | 0.03 | 4 |
| Raw material | 4.67 | 1.32 | 24 |
Conclusion：The above results show that total related substance of growth hormone release inhibiting hormone prepared by the present invention is respectively less than 0.1%, single maximum
Impurity is less than 0.05%, is superior to raw material.
Embodiment 4
Under conditions of cleaning, 18.5g α in the bis- carboxylic trehaloses of α-and 26.5g galactolipins input liquid dispenser tool, are added
Stirring and dissolving in water for injection 700ml, is cooled to room temperature, and waits for that above-mentioned preparation liquid is cooled to room temperature, and 1g growth hormone release inhibiting hormones are added (by real
1 the method for example is applied to be made), pH value is surveyed, pH to 5.2 is adjusted with Acetic acid-sodium acetate buffer solution (0.1M, pH=4.5), note is added
It penetrates and obtains growth hormone release inhibiting hormone filtrate through 0.22 μm of filtering with microporous membrane with water to full dose.3ml is dispensed in ampere bottle, freeze-drying
Aseptic freeze-dried powder-injection is made within 72 hours.
Embodiment 5
Under conditions of cleaning, by 18g α, in the bis- carboxylic trehaloses of β-and 22g galactolipins input liquid dispenser tool, injection is added
It with stirring and dissolving in water 700ml, waits for that above-mentioned preparation liquid is cooled to room temperature, 1.0g growth hormone release inhibiting hormones is added and (press 3 the method for embodiment
It is made), pH value is surveyed, pH to 5.1 is adjusted with Acetic acid-sodium acetate buffer solution (0.1M, pH=4.5), water for injection is added to full dose,
Through 0.22 μm of filtering with microporous membrane, growth hormone release inhibiting hormone filtrate is obtained.3ml is dispensed in ampere bottle, nothing is made in 72 hours in freeze-drying
Bacterium freeze drying powder injection.
Embodiment 6
Under conditions of cleaning, 23.7g β in the bis- carboxylic isotrehaloses of β-and 26.3g galactolipins input liquid dispenser tool, add
Enter stirring and dissolving in water for injection 700ml, wait for that above-mentioned preparation liquid is cooled to room temperature, 1.0g growth hormone release inhibiting hormones are added and (press 2 institute of embodiment
Method is stated to be made), pH value is surveyed, with Acetic acid-sodium acetate buffer solution (0.1M, pH=4.5) to 5.0, water for injection is added to full dose,
Through 0.22 μm of filtering with microporous membrane, growth hormone release inhibiting hormone filtrate is obtained.3ml is dispensed in ampere bottle, nothing is made in 72 hours in freeze-drying
Bacterium freeze drying powder injection.
Embodiment 7
Under conditions of cleaning, by 5g α, the bis- carboxylic trehaloses of α-, the bis- carboxylic isotrehaloses of 5g β, β-and 20g galactolipins input are matched
In liquid utensil, stirring and dissolving in water for injection 700ml is added, waits for that above-mentioned preparation liquid is cooled to room temperature, 1.0g growth hormone release inhibiting hormones are added
(being made by 1 the method for embodiment), surveys pH value, and pH to 4.9 is adjusted with Acetic acid-sodium acetate buffer solution (0.1M, pH=4.5),
Water for injection is added and obtains growth hormone release inhibiting hormone filtrate through 0.22 μm of filtering with microporous membrane to full dose.3ml is dispensed in ampere bottle, it is cold
It is lyophilized dry 72 hours and aseptic freeze-dried powder-injection is made.
Embodiment 8
Under conditions of cleaning, by 3g α, the bis- carboxylic trehaloses of α-, the bis- carboxylic isotrehaloses of 7g β, β-, the bis- carboxylic trehaloses of 8g α, β-
In 20g galactolipins input liquid dispenser tool, stirring and dissolving in water for injection 700ml is added, waits for that above-mentioned preparation liquid is cooled to room temperature,
1.0g growth hormone release inhibiting hormones are added, survey pH value, adjusts pH to 4.9 with Acetic acid-sodium acetate buffer solution (0.1M, pH=4.5), injection is added
With water to full dose growth hormone release inhibiting hormone filtrate is obtained through 0.22 μm of filtering with microporous membrane.3ml is dispensed in ampere bottle, freeze-drying 72
Aseptic freeze-dried powder-injection is made in hour.
Prescription screening is tested
1, in preparation solution excipients screening (one)
Contain growth hormone release inhibiting hormone 1mg/ml.And contain mannitol, trehalose and the galactolipin (weight ratio 3 of 4% (W/V) respectively:
1) composition, trehalose, galactolipin are as excipients.It is positioned over 37 DEG C of incubators and incubates bath, detect each time point growth from solution
The stability of chalone.And be lyophilized (freeze-drying program be：- 40 DEG C of pre-freezes 4 hours；It is evacuated to 300mT；Temperature program is set
1 DEG C/min, rise to -20 DEG C；Freeze-drying 12 hours；1 DEG C/min of temperature program is set, rises to 30 DEG C；It is 4 hours dry；Tamponade is simultaneously
Roll lid.), observe the appearance of its lyophilized form preparation, test result such as table 3.Judge from stability and freeze-drying appearance angle, preparation
The preferred mannitol of solution or the composition of trehalose and galactolipin are as excipients.
3 growth hormone release inhibiting hormone of table is containing the purity (%) and freeze-drying appearance in excipient formulation solution
2, in preparation solution excipients screening (two)
Contain 0,0.1,0.25,0.5,1.0,2.0,3.2 or 6.0mg/ml of growth hormone release inhibiting hormone.And contain 4% (W/V's) respectively
Mannitol, the composition of trehalose and galactolipin, trehalose, galactolipin are as excipients.It is prepared simultaneously without containing excipients
Preparation solution.Vial is taken, by the 1ml/ bottles of above-mentioned preparation solutions of packing, freeze-drying.The pharmaceutical preparation for investigating lyophilized form redissolves feelings
Condition.Test result such as table 4.
Lyophilized preparation when containing different excipients in 4 preparation solution of table, the clarity of preparation after redissolution
Note：<1, which refers to turbidity, is less than No. 1 titer；>1, which refers to turbidity, is more than No. 1 titer
This test result is shown, introduces the composition (weight ratio 3 of mannitol, trehalose and galactolipin:1), trehalose, half
The solute molecules such as the excipients such as lactose will only prepare the concentration model for the pharmaceutical preparation growth from solution chalone that can dissolve lyophilized preparation
It encloses and 0~0.25mg/ml is increased to by 0~0.1mg/ml, slightly increase after freeze-drying that can to redissolve growth hormone release inhibiting hormone in pharmaceutical preparation dense
Degree；Some excipients are introduced into after raising is lyophilized in (such as galactolipin) influence that can redissolve growth hormone release inhibiting hormone concentration in pharmaceutical preparation
Less.
3, in preparation solution excipients screening (three)
Formulated solution, wherein different weight are than trehalose and gala sugar composite, growth hormone release inhibiting hormone 1mg/ml, with water tune
With into.Using PB-10 types pH meter (Sartorius companies of the U.S.), according to《Pharmacopoeia of People's Republic of China 2015 editions》It is related
The requirement of pH value detection is detected.Detect the solubility of growth hormone release inhibiting hormone in preparation solution.Preparation solution is packed into 2ml glass to freeze
Dry bottle, moves into low-temperature freeze-drying machine (Supermodulyo types, 0.4m by 1ml/ bottles2, E-CApparatus companies) and product bin jelly
It is dry.The preparation that freeze-drying is redissolved with 1ml waters for injection, the pharmaceutical preparation for investigating lyophilized form redissolve situation.The preparation of freeze-drying is put into
37 DEG C of incubators are incubated and are redissolved with 1ml waters for injection for every bottle after bathing 8 weeks, detect the purity of growth hormone release inhibiting hormone in preparation solution.Different weight
The appearance of lyophilized form preparation and redissolution situation after the trehalose of ratio and the preparation solution pH value of galactolipin, freeze-drying, and freeze-drying
The purity of growth hormone release inhibiting hormone is as shown in table 5 after the preparation of form is placed 8 weeks at 37 DEG C, and growth hormone release inhibiting hormone is pure after each preparation solution freeze-drying
Degree detection is 99.86%.By the stability comprehensive descision of preparation solution pH, lyophilized form preparation shape and lyophilized preparation,
It is preferred that trehalose and galactolipin weight ratio are (0.5~0.9)：1.The pharmaceutical preparation of lyophilized form can be used 1ml to 5ml injections
Water redissolves, and liquid pharmaceutical formulation is made again.
PH, freeze-drying appearance, weight molten time under the different excipient of table 5 and 8 peripheral stabilities
Note：<1, which refers to turbidity, is less than No. 1 titer；>1, which refers to turbidity, is more than No. 1 titer
Conclusion (of pressure testing)：It is above-mentioned experiments have shown that, use weight ratio for (0.5~0.9)：1 trehalose：The excipient of galactolipin,
The excipient of preparation as growth hormone release inhibiting hormone, product quality are more outstanding.
Injection growth hormone release inhibiting hormone test example
1, instrument and drug
High performance liquid chromatograph (HP1100 types, hewlette-packard), DAD detectors, AgilentChemstation colors
Compose work station：YB-2 type clarity test instrument (Precision Instrument Factory, Tianjin Univ.)；DU640 types UV detector (U.S. shellfish
Gram Mann)；PHS-3C types digital ph (Shanghai Lei Ci instrument plants)；WS/08-0l types temperature and humidity regulator (Hangzhou blue sky instrument
Device production Co., Ltd)；METYLER.AE200 type analysis balance (Switzerland)；Injection growth hormone release inhibiting hormone is (according to embodiment 4-8 institutes
State the sample of preparation).
2, method
Acidity takes this product, is dissolved in water and the solution containing 0.5mg in every 1ml is made, and mixing measures (VI H of annex) in accordance with the law,
PH value should be 4.5~6.5.
Assay takes 10 bottles of this product, respectively plus appropriate amount of water, make contents melting and quantify dilution be made in every 1ml containing about
The solution of 0.1mg is measured as test solution according to the method under growth hormone release inhibiting hormone item, is calculated every bottle of content, is found out 10 bottles
Average content to get.
2.3 influence factors are tested
Under marketed products terms of packing, three batches of 5 samples of embodiment (lot number 160321,160407,160610) are existed
Investigated 5,10 days under high temperature (60 DEG C), strong light (4500lx), super-humid conditions, to the indexs such as its acidity, content and related substance into
Row is investigated, and indices meet regulation.Measurement result is shown in Table 6.
6 influence factor test result of table
A, B, C represent three batches of samples of embodiment 5, the sample of lot number 160321,160407,160610.
2.6 Acceleration study
Under marketed products terms of packing, three batches of 5 samples of embodiment (lot number 160321,160407,160610) are existed
It stores under the conditions of temperature (40 ± 2) DEG C, 75% soil 5% of relative humidity, is sampled respectively at 0,1,2,3,6 the end of month, measured every
Index.Each batch of sample property is white loose block.Acidity the results are shown in Table 7 in relation to substance and assay.
2.7 long-term experiment
Under marketed products terms of packing, three batches of 5 samples of embodiment (lot number 160321,160407,160610) are existed
It stores under the conditions of temperature (25 ± 2) DEG C, relative humidity 60% ± 10%, is sampled respectively at 0,3,6,12,18,24 the end of month, surveyed
Determine indices.Each batch of sample property is white loose block, and acidity the results are shown in Table 7 in relation to substance and assay.
7 accelerated test of table and long term test investigate result
A, B, C represent three batches of samples of embodiment 5, the sample of lot number 160321,160407,160610.
Conclusion：Influence factor experiment, accelerated test are the results show that injection growth hormone release inhibiting hormone items testing index becomes without apparent
Change, has good stability；24 months every quality index of injection growth hormone release inhibiting hormone are placed under the conditions of long-term room-temperature without significant change, production
Product have good stability.
Stability Determination after injection growth hormone release inhibiting hormone redissolves is tested
After 160321,160407,160610 sample is redissolved with water for injection 250ml, it is placed in 4 DEG C of refrigerators, daily
Primary, METHOD FOR CONTINUOUS DETERMINATION 14 days is measured, linear regression analysis is carried out to the time (X) with measured value (Y).The results are shown in Table 8.
Stability after the redissolution of 8 injection growth hormone release inhibiting hormone of table
P>0.05 illustrates that the concentration of growth hormone release inhibiting hormone is basicly stable within the time measured.
Conclusion：As known from Table 8, for METHOD FOR CONTINUOUS DETERMINATION after 14 days, growth hormone release inhibiting hormone keeps content steady after three batches of products of the present invention redissolve
It is fixed.Property is stablized after illustrating injection growth hormone release inhibiting hormone redissolution prepared by method shown in the present invention.
Claims (11)
1. a kind of preparation method of growth hormone release inhibiting hormone, which is characterized in that include the following steps：
Step 1, after washing cation exchange resin column with the first buffer solution, with the first buffer solution growth hormone release inhibiting hormone crude product, and
By≤50g growth hormone release inhibiting hormones crude product/L resins/cycle loading；It is eluted with the second buffer solution, obtains the first eluent；Described first,
Two buffer solutions are sodium phosphate buffer；
Step 2：With phosphate buffer by the pH value of eluent to 4.5~6.5, solution is obtained；
Step 3：It is washed after anion-exchange resin column pre-equilibrated with third buffer solution, with third buffer solution step 2
Solution, and carry out loading by 30g growth hormone release inhibiting hormones crude product/L resins/cycle；It is eluted with the 4th buffer solution, obtains second and wash
De- object, is concentrated and dried up to growth hormone release inhibiting hormone；Third and fourth described buffer solution is sodium-acetate buffer.
2. a kind of preparation method of growth hormone release inhibiting hormone according to claim 1, which is characterized in that the cation exchange resin
For Carboxymethyl Sepharose column；The anion exchange resin is agarose Gel column.
3. a kind of purification process of growth hormone release inhibiting hormone according to claim 1, which is characterized in that the phosphoric acid in the step 2
The pH value of salt buffer is 5.0~7.0.
4. a kind of preparation method of growth hormone release inhibiting hormone according to claim 1, which is characterized in that described first, second, three,
The pH value of four buffer solutions is 4.0~6.0.
5. a kind of preparation method of growth hormone release inhibiting hormone according to claim 1, which is characterized in that described second, four buffer solutions
In contain sodium chloride.
6. a kind of pharmaceutical composition containing growth hormone release inhibiting hormone, including growth hormone release inhibiting hormone, excipient, which is characterized in that the figuration
Agent is the mixture of trehalose, galactolipin composition.
7. pharmaceutical composition according to claim 6, which is characterized in that the composition include following parts by weight at
Point：0.8~1 parts by weight growth hormone release inhibiting hormone, 30~50 parts by weight excipient.
8. according to the pharmaceutical composition described in claim 6,7, which is characterized in that trehalose is α, the bis- carboxylics of α-in the excipient
Trehalose, β, one or more of the bis- carboxylic isotrehaloses of β-or the bis- carboxylic trehaloses of α, β-.
9. according to the pharmaceutical composition described in claim 6,7, which is characterized in that trehalose in the excipient：Galactolipin
Weight ratio is (0.5~0.9)：1.
10. pharmaceutical composition according to claim 6, which is characterized in that the pH value of the composition is 4.5~6.5.
11. a kind of method that the pharmaceutical composition containing growth hormone release inhibiting hormone prepares freeze-dried powder, which is characterized in that this method include with
Lower step：
1) it takes excipient to be dissolved in the water for injection of 2/3 recipe quantity, stirs evenly；
2) it waits for that above-mentioned preparation liquid is cooled to room temperature, growth hormone release inhibiting hormone is added, survey pH value, adjust pH to 4.5~6.0, injection is added
Water is to full dose, and with miillpore filter refined filtration, freeze-drying obtains freeze-dried powder.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102268073A (en) * | 2011-07-19 | 2011-12-07 | 南昌佰泰生物科技有限公司 | Method for preparing somatostatin |
| CN103265620A (en) * | 2013-05-24 | 2013-08-28 | 成都天台山制药有限公司 | Somatostatin and preparation method thereof |
| CN107698676A (en) * | 2017-11-07 | 2018-02-16 | 江西浩然生物医药有限公司 | A kind of extraction preparation method of high-purity menotropins |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102268073A (en) * | 2011-07-19 | 2011-12-07 | 南昌佰泰生物科技有限公司 | Method for preparing somatostatin |
| CN103265620A (en) * | 2013-05-24 | 2013-08-28 | 成都天台山制药有限公司 | Somatostatin and preparation method thereof |
| CN107698676A (en) * | 2017-11-07 | 2018-02-16 | 江西浩然生物医药有限公司 | A kind of extraction preparation method of high-purity menotropins |
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| ZHENG ZHU等: "Purificationand Characterization of a 43-kDa Transcription Factor Required for Rat SomatostatinGene Expression", 《THEJOURNAL OF BIOLOGICAL CHEMISTR》 * |
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