CN114601916B - Pegylated hippocampus peptide injection and preparation method thereof - Google Patents
Pegylated hippocampus peptide injection and preparation method thereof Download PDFInfo
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- CN114601916B CN114601916B CN202210381804.5A CN202210381804A CN114601916B CN 114601916 B CN114601916 B CN 114601916B CN 202210381804 A CN202210381804 A CN 202210381804A CN 114601916 B CN114601916 B CN 114601916B
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- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 43
- 210000001320 hippocampus Anatomy 0.000 title claims abstract description 32
- 238000002347 injection Methods 0.000 title claims abstract description 17
- 239000007924 injection Substances 0.000 title claims abstract description 17
- 230000000971 hippocampal effect Effects 0.000 claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims description 106
- 239000007788 liquid Substances 0.000 claims description 65
- 238000003756 stirring Methods 0.000 claims description 59
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 58
- 239000000243 solution Substances 0.000 claims description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 42
- 239000000203 mixture Substances 0.000 claims description 39
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 38
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 38
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 38
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical group [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 36
- 239000011780 sodium chloride Substances 0.000 claims description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 230000003204 osmotic effect Effects 0.000 claims description 14
- 239000000337 buffer salt Substances 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 6
- 241001478425 Hippocampus japonicus Species 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 229940071643 prefilled syringe Drugs 0.000 claims description 5
- 241000246150 Cercis Species 0.000 claims description 4
- 235000006228 Cercis occidentalis Nutrition 0.000 claims description 4
- 229930182555 Penicillin Natural products 0.000 claims description 4
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 4
- 229940049954 penicillin Drugs 0.000 claims description 4
- 230000000505 pernicious effect Effects 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000008215 water for injection Substances 0.000 claims description 4
- 238000004806 packaging method and process Methods 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 1
- 239000000463 material Substances 0.000 abstract description 2
- 239000004480 active ingredient Substances 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- XVFMGWDSJLBXDZ-UHFFFAOYSA-O pelargonidin Chemical compound C1=CC(O)=CC=C1C(C(=C1)O)=[O+]C2=C1C(O)=CC(O)=C2 XVFMGWDSJLBXDZ-UHFFFAOYSA-O 0.000 abstract 1
- HKUHOPQRJKPJCJ-UHFFFAOYSA-N pelargonidin Natural products OC1=Cc2c(O)cc(O)cc2OC1c1ccc(O)cc1 HKUHOPQRJKPJCJ-UHFFFAOYSA-N 0.000 abstract 1
- 235000006251 pelargonidin Nutrition 0.000 abstract 1
- 239000002994 raw material Substances 0.000 description 37
- 239000008213 purified water Substances 0.000 description 19
- 238000005303 weighing Methods 0.000 description 19
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 229910019142 PO4 Inorganic materials 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- 102100031939 Erythropoietin Human genes 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 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 2
- 101000831205 Danio rerio Dynein axonemal assembly factor 11 Proteins 0.000 description 2
- 102100024282 Dynein axonemal assembly factor 11 Human genes 0.000 description 2
- 241001559542 Hippocampus hippocampus Species 0.000 description 2
- 101000831210 Homo sapiens Dynein axonemal assembly factor 11 Proteins 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 210000002960 bfu-e Anatomy 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 210000005259 peripheral blood Anatomy 0.000 description 2
- 239000011886 peripheral blood Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 210000001995 reticulocyte Anatomy 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 239000005388 borosilicate glass Substances 0.000 description 1
- 229920005557 bromobutyl Polymers 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229920005556 chlorobutyl Polymers 0.000 description 1
- 230000005757 colony formation Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229940061607 dibasic sodium phosphate Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000000925 erythroid effect Effects 0.000 description 1
- 210000003013 erythroid precursor cell Anatomy 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229940045641 monobasic sodium phosphate Drugs 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- 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
- A61K38/18—Growth factors; Growth regulators
- A61K38/1816—Erythropoietin [EPO]
-
- 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
- A61K47/02—Inorganic compounds
-
- 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
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Zoology (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Inorganic Chemistry (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dermatology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a pelargonidin hippocampal peptide injection preparation and a preparation method thereof. The invention discloses a pharmaceutical composition taking a cultivated hippocampus peptide as an active ingredient. The pharmaceutical composition contains the physiologically acceptable auxiliary materials of the pelargonidae hippocampus peptide with the pH value of 4.0-7.0. The pharmaceutical composition has good pharmaceutical stability and safety, and the preparation method is simple and convenient, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and in particular relates to a pelargonidae western Hippocampus peptide injection preparation and a preparation method thereof.
Background
The cultivated Hippocampus japonicus peptide is artificially synthesized PEG erythropoietin mimetic peptide, and can promote proliferation of bone marrow erythroid directional progenitor cells (BFU-E, CFU-E) and differentiation of precursor cells with identifiable morphology by combining with specific EPO receptor on the cell surface, and can also accelerate proliferation and differentiation of precursor cells and promote release of reticulocytes by bone marrow and promote generation of erythrocytes.
The cultivated hippocampal peptide obviously stimulates proliferation of EPO-dependent blood cells (UT 7/EPO cells) in vitro, inhibits apoptosis and stimulates phosphorylation of cell Stat 5; BFU-E colony formation was stimulated (> 50 cells). EPO-018B significantly stimulated peripheral blood reticulocyte production in vivo, with a significant increase in peripheral blood RBC, hgb, HCT%.
The cultivated Hippocampus japonicus peptide is unstable under alkaline condition, and the fluctuation range of pH value can be greatly reduced by using buffer salt solution as pH regulator, meanwhile, the optimal buffer salt proportion is screened out by research, and the pH environment of the solution after the raw material medicine is added is further ensured, so that the stability of the product is ensured, and the clinical use safety is further improved.
The active carbon is a heat source removing component commonly used in injection, and the raw material sources and the production processes are various, so that the active carbon possibly contains different element impurities, and part of the elements are toxic, including neurotoxicity, nephrotoxicity and the like. Activated carbon is also a potential risk source for insoluble particles in injections, increasing the risk of insoluble particle incorporation. Meanwhile, the activated carbon has a certain adsorption effect on the medicine, and particularly has a great influence on the content of the medicine with low dosage.
The preparation process avoids using active carbon, and can ensure product stability and liquid medicine dissolving speed.
Disclosure of Invention
In view of the above, the invention provides a preparation method of a cultivated Hippocampus peptide injection preparation with simple and convenient process, strong stability and high safety, and the preparation method thereof, which can solve the problems of unstable alkali and low content of main medicine after liquid preparation in the liquid preparation process by enhancing the control of endotoxin in raw materials and auxiliary materials without using active carbon in the preparation process, and reduce the clinical application risk.
The invention provides a cercis hippocampal peptide injection preparation which is characterized by comprising cercis hippocampal peptide or pharmaceutically acceptable buffer salt thereof, an osmotic pressure regulator and a solvent.
The preparation of the pernicious western sea horse peptide is characterized in that the buffer salt is dibasic phosphate and monobasic phosphate, preferably dibasic sodium phosphate and monobasic sodium phosphate.
The pernicious western sea horse peptide preparation is characterized in that the osmotic pressure regulator is one or more of sodium chloride, mannitol, glucose, sorbitol or glycerol, preferably mannitol or sodium chloride.
The preparation of the cultivated hippocampal peptide is characterized in that the phosphate proportion of the buffer solution is disodium hydrogen phosphate: the ratio of the sodium dihydrogen phosphate is 1:10 to 30, preferably 1:10 to 20, more preferably 1:17 to 18.
The solvent is water for injection.
The injection preparation comprises 0.05% -3.0% (W/V) of the cultivated Hippocampus peptide, preferably 0.1% -1.0% (W/V).
The injection preparation of the invention contains 0.05 to 5.0 percent (W/V) of buffer salt, preferably 0.5 to 1.5 percent (W/V).
The injection preparation of the invention contains 0.05 to 4.0 percent (W/V) of isotonic regulator, preferably 0.1 to 1.0 percent (W/V).
The preparation of the cultivated hippocampal peptide is characterized in that the pH adjustment range is selected from 4-7, preferably 5-6.
The invention also provides a method for preparing the injection preparation of the cultivated hippocampal peptide, which comprises the following steps:
1) Adding the osmotic pressure regulator with the prescription amount into water for injection, stirring and dissolving;
2) Adding a prescribed amount of buffer salt into the solution in the step 1), and stirring for dissolution;
3) Adding the cultivated Hippocampus japonicus peptide into the solution in the step 2), stirring for dissolution, and measuring the pH value of the solution;
4) Filtering the liquid medicine in the step 3), sub-packaging the filtered liquid medicine into a penicillin bottle or a clip type bottle or a prefilled syringe, filling nitrogen and plugging;
the preparation method of the pernicious Hippocampus peptide preparation is characterized in that sodium chloride is added first, then disodium hydrogen phosphate is added, and then sodium dihydrogen phosphate is added in the preparation process.
The preparation of the cultivated hippocampus peptide is characterized in that the preparation temperature is 10-50 ℃, preferably 15-25 ℃.
The preparation of the cultivated Hippocampus peptide is characterized in that the temperature needs to be suddenly reduced from 30-50 ℃ to 10-25 ℃ when the preparation is prepared; preferably 30℃is suddenly reduced to 25 ℃.
The preparation is characterized in that the pharmaceutical composition is packaged by a penicillin bottle, a cartridge bottle or a prefilled syringe.
The preparation is characterized in that the split charging container of the pharmaceutical composition is made of medium borosilicate glass.
The invention relates to a cerHippocampus peptide preparation, which is characterized in that the rubber plug used is a chlorinated butyl rubber plug or a brominated butyl rubber plug.
The preparation of the cultivated hippocampal peptide is characterized in that an injection pen device is adopted for administration.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) The injection preparation provided by the invention has the advantages that the preparation process is simple, the active carbon adsorption process is not needed, the safety of the product is further ensured, the active carbon treatment is not needed, the production cost is reduced, the environment is not polluted, the active carbon is prevented from introducing new impurities, and the safety risk and the environmental protection pressure are avoided.
(2) Meanwhile, the research shows that the impurity A component is alkali sensitive impurity and temperature sensitive impurity, and the free polyethylene glycol (20 KD,40 KD) is sensitive to the ion concentration change of the liquid medicine system. The phosphate proportion screening and preparation process is examined to find a stable and proper pH environment and preparation process, so that the stability of the product can be effectively ensured.
Detailed Description
The present invention will be described in more detail with reference to examples, but the present invention is not limited to the examples.
Example 1:
(1) weighing 70% of the prescribed amount (100 ml') of purified water into a beaker, wherein the water temperature is less than or equal to 25 ℃;
(2) 59mg of disodium hydrogen phosphate and 1032mg of sodium dihydrogen phosphate are added into the solution, and the mixture is stirred until the mixture is completely dissolved;
(3) adding 400mg (calculated as the cultivated Hippocampus peptide) of the raw material medicine, and magnetically stirring until the raw material medicine is completely dissolved;
(4) and (3) fixing the volume to 100ml, stirring for 45min after fixing the volume, and measuring the pH of the liquid medicine to 5-6.
And measuring the osmotic pressure of the liquid medicine after the volume is fixed.
Example 2:
(1) weighing 70% of the prescribed amount (100 ml') of purified water into a beaker, wherein the water temperature is less than or equal to 25 ℃;
(2) 200mg of sodium chloride is added and stirred magnetically until the sodium chloride is completely dissolved;
(3) 59mg of disodium hydrogen phosphate and 1032mg of sodium dihydrogen phosphate are added into the solution, and the mixture is stirred until the mixture is completely dissolved;
(4) adding 400mg (calculated as the cultivated Hippocampus peptide) of the raw material medicine, and magnetically stirring until the raw material medicine is completely dissolved;
(5) and (3) fixing the volume to 100ml, stirring for 45min after fixing the volume, and measuring the pH of the liquid medicine to 5-6.
And measuring the osmotic pressure of the liquid medicine after the volume is fixed.
Example 3:
(1) weighing 70% of the prescribed amount (100 ml') of purified water into a beaker, wherein the water temperature is less than or equal to 25 ℃;
(2) 350mg of sodium chloride is added and stirred magnetically until the mixture is completely dissolved;
(3) 59mg of disodium hydrogen phosphate and 1032mg of sodium dihydrogen phosphate are added into the solution, and the mixture is stirred until the mixture is completely dissolved;
(4) adding 400mg (calculated as the cultivated Hippocampus peptide) of the raw material medicine, and magnetically stirring until the raw material medicine is completely dissolved;
(5) and (3) fixing the volume to 100ml, stirring for 45min after fixing the volume, and measuring the pH of the liquid medicine to 5-6.
And measuring the osmotic pressure of the liquid medicine after the volume is fixed.
Example 4:
(1) weighing 70% of the prescribed amount (100 ml') of purified water into a beaker, wherein the water temperature is less than or equal to 25 ℃;
(2) 425mg of sodium chloride is added and stirred magnetically until the mixture is completely dissolved;
(3) 59mg of disodium hydrogen phosphate and 1032mg of sodium dihydrogen phosphate are added into the solution, and the mixture is stirred until the mixture is completely dissolved;
(4) adding 400mg (calculated as the cultivated Hippocampus peptide) of the raw material medicine, and magnetically stirring until the raw material medicine is completely dissolved;
(5) and (3) fixing the volume to 100ml, stirring for 45min after fixing the volume, and measuring the pH of the liquid medicine to 5-6.
And measuring the osmotic pressure of the liquid medicine after the volume is fixed.
Study of influence of sodium chloride consumption on osmotic pressure
| Sodium chloride dosage (g) | Sodium chloride concentration (mg/ml) | Osmotic pressure (mOsm/Kg) |
| 0 | 0 | 159 |
| 0.2 | 2 | 226 |
| 0.35 | 3.5 | 277 |
| 0.425 | 4.25 | 297 |
Conclusion: the dosage of sodium chloride as osmotic regulator in the prescription is 4.25mg/ml, which can ensure the quality of the product and meet the clinical administration requirement.
Example 5:
(1) weighing 70% of the prescribed amount (100 ml') of purified water into a beaker, wherein the water temperature is less than or equal to 25 ℃;
(2) 425mg of sodium chloride is added and stirred magnetically until the mixture is completely dissolved;
(3) 59mg of disodium hydrogen phosphate and 295mg of sodium dihydrogen phosphate are added into the solution in the step (2), and the proportion is 1:5, stirring until the mixture is completely dissolved;
(4) adding 400mg (calculated as the cultivated Hippocampus peptide) of the raw material medicine, and magnetically stirring until the raw material medicine is completely dissolved;
(5) adjusting the pH value of the solution to 5.0-6.0 by using 1% sodium dihydrogen phosphate;
(6) and (3) fixing the volume to 100ml, stirring for 45min after fixing the volume, and measuring the pH of the liquid medicine to 5-6.
And (5) placing the liquid medicine with the constant volume at the temperature of less than or equal to 25 ℃ to determine the stability of the liquid medicine within 12 hours.
Example 6:
(1) weighing 70% of the prescribed amount (100 ml') of purified water into a beaker, wherein the water temperature is less than or equal to 25 ℃;
(2) 425mg of sodium chloride is added and stirred magnetically until the mixture is completely dissolved;
(3) 59mg of disodium hydrogen phosphate and 590mg of sodium dihydrogen phosphate are added into the solution in the step (2), and the proportion is 1:10, stirring until the mixture is completely dissolved;
(4) adding 400mg (calculated as the cultivated Hippocampus peptide) of the raw material medicine, and magnetically stirring until the raw material medicine is completely dissolved;
(5) adjusting the pH value of the solution to 5.0-6.0 by using 1% sodium dihydrogen phosphate;
(6) and (3) fixing the volume to 100ml, stirring for 45min after fixing the volume, and measuring the pH of the liquid medicine to 5-6.
And (5) placing the liquid medicine with the constant volume at the temperature of less than or equal to 25 ℃ to determine the stability of the liquid medicine within 12 hours.
Example 7:
(1) weighing 70% of the prescribed amount (100 ml') of purified water into a beaker, wherein the water temperature is less than or equal to 25 ℃;
(2) 425mg of sodium chloride is added and stirred magnetically until the mixture is completely dissolved;
(3) 59mg of disodium hydrogen phosphate and 885mg of sodium dihydrogen phosphate are added into the solution in the step (2), and the proportion is 1:15, stirring until the mixture is completely dissolved;
(4) adding 400mg (calculated as the cultivated Hippocampus peptide) of the raw material medicine, and magnetically stirring until the raw material medicine is completely dissolved;
(5) adjusting the pH value of the solution to 5.0-6.0 by using 1% sodium dihydrogen phosphate;
(6) and (3) fixing the volume to 100ml, stirring for 45min after fixing the volume, and measuring the pH of the liquid medicine to 5-6.
And (5) placing the liquid medicine with the constant volume at the temperature of less than or equal to 25 ℃ to determine the stability of the liquid medicine within 12 hours.
Example 8:
(1) weighing 70% of the prescribed amount (100 ml') of purified water into a beaker, wherein the water temperature is less than or equal to 25 ℃;
(2) 425mg of sodium chloride is added and stirred magnetically until the mixture is completely dissolved;
(3) 59mg of disodium hydrogen phosphate and 1180mg of sodium dihydrogen phosphate are added into the solution in the step (2), and the proportion is 1:20, stirring until the mixture is completely dissolved;
(4) adding 400mg (calculated as the cultivated Hippocampus peptide) of the raw material medicine, and magnetically stirring until the raw material medicine is completely dissolved;
(5) adjusting the pH value of the solution to 5.0-6.0 by using 1% disodium hydrogen phosphate;
(6) and (3) fixing the volume to 100ml, stirring for 45min after fixing the volume, and measuring the pH of the liquid medicine to 5-6.
And (5) placing the liquid medicine with the constant volume at the temperature of less than or equal to 25 ℃ to determine the stability of the liquid medicine within 12 hours.
Example 9:
(1) weighing 70% of the prescribed amount (100 ml') of purified water into a beaker, wherein the water temperature is less than or equal to 25 ℃;
(2) 425mg of sodium chloride is added and stirred magnetically until the mixture is completely dissolved;
(3) 59mg of disodium hydrogen phosphate and 1023mg of sodium dihydrogen phosphate are added into the solution in the step (2), and the proportion is 1:17.5, stirring until the mixture is completely dissolved;
(4) adding 400mg (calculated as the cultivated Hippocampus peptide) of the raw material medicine, and magnetically stirring until the raw material medicine is completely dissolved;
(5) measuring the pH of the solution to be in the range of 5.0-6.0;
(6) and (3) fixing the volume to 100ml, stirring for 45min after fixing the volume, and measuring the pH of the liquid medicine to 5-6.
And (5) placing the liquid medicine with the constant volume at the temperature of less than or equal to 25 ℃ to determine the stability of the liquid medicine within 12 hours.
Conclusion(s)
The ratio of disodium hydrogen phosphate to sodium dihydrogen phosphate is 1: at 17.5, the intermediate liquid medicine has the best stability.
Example 10:
(1) weighing 70% of the prescribed amount (100 ml') of purified water into a beaker, wherein the water temperature is less than or equal to 25 ℃;
(2) 425mg of sodium chloride is added and stirred magnetically until the mixture is completely dissolved;
(3) 59mg of disodium hydrogen phosphate and 1023mg of sodium dihydrogen phosphate are added into the solution in the step (2), and the proportion is 1:17.5, stirring until the mixture is completely dissolved;
(4) adding 400mg (calculated as the cultivated Hippocampus peptide) of the raw material medicine, and magnetically stirring until the raw material medicine is completely dissolved;
(5) adjusting the pH value of the solution to 5.0-6.0 by using 1% sodium dihydrogen phosphate or 1% disodium hydrogen phosphate;
(6) and (3) fixing the volume to 100ml, stirring for 45min after fixing the volume, and measuring the pH of the liquid medicine to 5-6.
And (5) placing the liquid medicine with the constant volume at 35 ℃ to determine the stability of the liquid medicine within 12 hours.
Example 11:
(1) weighing 70% of the prescribed amount (100 ml') of purified water into a beaker, wherein the water temperature is less than or equal to 25 ℃;
(2) 425mg of sodium chloride is added and stirred magnetically until the mixture is completely dissolved;
(3) 59mg of disodium hydrogen phosphate and 1023mg of sodium dihydrogen phosphate are added into the solution in the step (2), and the proportion is 1:17.5, stirring until the mixture is completely dissolved;
(4) adding 400mg (calculated as the cultivated Hippocampus peptide) of the raw material medicine, and magnetically stirring until the raw material medicine is completely dissolved;
(5) adjusting the pH value of the solution to 5.0-6.0 by using 1% sodium dihydrogen phosphate or 1% disodium hydrogen phosphate;
(6) and (3) fixing the volume to 100ml, stirring for 45min after fixing the volume, and measuring the pH of the liquid medicine to 5-6.
And (5) placing the liquid medicine with the constant volume at 30 ℃ to determine the stability of the liquid medicine within 12 hours.
Example 12:
(1) weighing 70% of the prescribed amount (100 ml') of purified water into a beaker, wherein the water temperature is less than or equal to 25 ℃;
(2) 425mg of sodium chloride is added and stirred magnetically until the mixture is completely dissolved;
(3) 59mg of disodium hydrogen phosphate and 1023mg of sodium dihydrogen phosphate are added into the solution in the step (2), and the proportion is 1:17.5, stirring until the mixture is completely dissolved;
(4) adding 400mg (calculated as the cultivated Hippocampus peptide) of the raw material medicine, and magnetically stirring until the raw material medicine is completely dissolved;
(5) adjusting the pH value of the solution to 5.0-6.0 by using 1% sodium dihydrogen phosphate or 1% disodium hydrogen phosphate;
(6) and (3) fixing the volume to 100ml, stirring for 45min after fixing the volume, and measuring the pH of the liquid medicine to 5-6.
And (5) placing the liquid medicine with the constant volume at 25 ℃ to determine the stability of the liquid medicine within 12 hours.
Example 13:
(1) weighing 70% of the prescribed amount (100 ml') of purified water into a beaker, wherein the water temperature is less than or equal to 25 ℃;
(2) 425mg of sodium chloride is added and stirred magnetically until the mixture is completely dissolved;
(3) 59mg of disodium hydrogen phosphate and 1023mg of sodium dihydrogen phosphate are added into the solution in the step (2), and the proportion is 1:17.5, stirring until the mixture is completely dissolved;
(4) adding 400mg (calculated as the cultivated Hippocampus peptide) of the raw material medicine, and magnetically stirring until the raw material medicine is completely dissolved;
(5) adjusting the pH value of the solution to 5.0-6.0 by using 1% sodium dihydrogen phosphate or 1% disodium hydrogen phosphate;
(6) and (3) fixing the volume to 100ml, stirring for 45min after fixing the volume, and measuring the pH of the liquid medicine to 5-6.
And (5) placing the liquid medicine with the constant volume at 20 ℃ to determine the stability of the liquid medicine within 12 hours.
Conclusion: the intermediate liquid medicine is sensitive to temperature, and the preparation temperature is stable below 25 ℃.
Meanwhile, the research on the destruction experiments of the bulk drugs is carried out by the company, the results are shown in the following table, and the cultivated Hippocampus japonicus peptide is sensitive to alkali, high temperature and oxygen.
Note that: (1) N/D represents undetected.
Example 14:
(1) weighing 70% of the prescribed amount (100 ml') of purified water into a beaker, wherein the water temperature is less than or equal to 25 ℃;
(2) 425mg of sodium chloride is added and stirred magnetically until the mixture is completely dissolved;
(3) 59mg of disodium hydrogen phosphate and 1023mg of sodium dihydrogen phosphate are added into the solution in the step (2), and the proportion is 1:17.5, stirring until the mixture is completely dissolved;
(4) adding 400mg (calculated as the cultivated Hippocampus peptide) of the raw material medicine, and magnetically stirring until the raw material medicine is completely dissolved;
(5) adjusting the pH value of the solution to 5.0-6.0 by using 1% sodium dihydrogen phosphate or 1% disodium hydrogen phosphate;
(6) and (3) fixing the volume to 100ml, stirring for 45min after fixing the volume, and measuring the pH of the liquid medicine to 5-6.
And (3) placing the liquid medicine with the constant volume at 25 ℃, and measuring the stability of the liquid medicine within 24 hours under the conditions of no light shielding and no nitrogen charging.
Example 15:
(1) weighing 70% of the prescribed amount (100 ml') of purified water into a beaker, wherein the water temperature is less than or equal to 25 ℃;
(2) 425mg of sodium chloride is added and stirred magnetically until the mixture is completely dissolved;
(3) 59mg of disodium hydrogen phosphate and 1023mg of sodium dihydrogen phosphate are added into the solution in the step (2), and the proportion is 1:17.5, stirring until the mixture is completely dissolved;
(4) adding 400mg (calculated as the cultivated Hippocampus peptide) of the raw material medicine, and magnetically stirring until the raw material medicine is completely dissolved;
(5) adjusting the pH value of the solution to 5.0-6.0 by using 1% sodium dihydrogen phosphate or 1% disodium hydrogen phosphate;
(6) and (3) fixing the volume to 100ml, stirring for 45min after fixing the volume, and measuring the pH of the liquid medicine to 5-6.
And (3) placing the liquid medicine with the constant volume at 25 ℃, and measuring the stability of the liquid medicine within 24 hours under the condition of no light shielding and nitrogen charging.
Example 16:
(1) weighing 70% of the prescribed amount (100 ml') of purified water into a beaker, wherein the water temperature is less than or equal to 25 ℃;
(2) 425mg of sodium chloride is added and stirred magnetically until the mixture is completely dissolved;
(3) 59mg of disodium hydrogen phosphate and 1023mg of sodium dihydrogen phosphate are added into the solution in the step (2), and the proportion is 1:17.5, stirring until the mixture is completely dissolved;
(4) adding 400mg (calculated as the cultivated Hippocampus peptide) of the raw material medicine, and magnetically stirring until the raw material medicine is completely dissolved;
(5) adjusting the pH value of the solution to 5.0-6.0 by using 1% sodium dihydrogen phosphate or 1% disodium hydrogen phosphate;
(6) and (3) fixing the volume to 100ml, stirring for 45min after fixing the volume, and measuring the pH of the liquid medicine to 5-6.
And (3) placing the liquid medicine with the constant volume at 25 ℃, avoiding light, and measuring the stability of the liquid medicine within 24 hours under the condition of no nitrogen filling.
Example 17:
(1) weighing 70% of the prescribed amount (100 ml') of purified water into a beaker, wherein the water temperature is less than or equal to 25 ℃;
(2) 425mg of sodium chloride is added and stirred magnetically until the mixture is completely dissolved;
(3) 59mg of disodium hydrogen phosphate and 1023mg of sodium dihydrogen phosphate are added into the solution in the step (2), and the proportion is 1:17.5, stirring until the mixture is completely dissolved;
(4) adding 400mg (calculated as the cultivated Hippocampus peptide) of the raw material medicine, and magnetically stirring until the raw material medicine is completely dissolved;
(5) adjusting the pH value of the solution to 5.0-6.0 by using 1% sodium dihydrogen phosphate or 1% disodium hydrogen phosphate;
(6) and (3) fixing the volume to 100ml, stirring for 45min after fixing the volume, and measuring the pH of the liquid medicine to 5-6.
And (3) placing the liquid medicine with the constant volume at 25 ℃, and measuring the stability of the liquid medicine within 24 hours under the condition of light shielding and nitrogen charging.
Natural light, temperature and nitrogen influence result on liquid medicine stability
Conclusion: the intermediate liquid medicine is stable under 24 hours, and the short-time influence of light and oxygen on the intermediate liquid medicine is small.
Example 18:
(1) weighing 70% of the prescription amount (2L) of purified water into a beaker, wherein the water temperature is less than or equal to 25 ℃;
(2) 8.5g of sodium chloride is added and stirred magnetically until the sodium chloride is completely dissolved;
(3) 1.18g of disodium hydrogen phosphate and 20.46g of sodium dihydrogen phosphate are added into the solution in the step (2), and the proportion is 1:17.5, stirring until the mixture is completely dissolved;
(4) adding 8.0g (calculated as the cultivated Hippocampus peptide) of the crude drug, and magnetically stirring until the crude drug is completely dissolved;
(5) adjusting the pH value of the solution to 5.0-6.0 by using 1% sodium dihydrogen phosphate or 1% disodium hydrogen phosphate;
(6) constant volume to 2L, stirring for 45min after constant volume, and measuring the pH of the liquid medicine to 5-6.
Filtering the liquid medicine with a 0.22 μm filter membrane, filling 1.5ml into a prefilled syringe after filtering, and respectively performing nitrogen filling protection and plugging.
And (5) respectively carrying out lofting investigation on the split-packed samples to the conditions of the influencing factors. The results are shown in Table 1.
Example 19:
(1) weighing 70% of the prescription amount (2L) of purified water into a beaker, wherein the water temperature is less than or equal to 25 ℃;
(2) 8.5g of sodium chloride is added and stirred magnetically until the sodium chloride is completely dissolved;
(3) 1.18g of disodium hydrogen phosphate and 20.46g of sodium dihydrogen phosphate are added into the solution in the step (2), and the proportion is 1:17.5, stirring until the mixture is completely dissolved;
(4) adding 8.0g (calculated as the cultivated Hippocampus peptide) of the crude drug, and magnetically stirring until the crude drug is completely dissolved;
(5) adjusting the pH value of the solution to 5.0-6.0 by using 1% sodium dihydrogen phosphate or 1% disodium hydrogen phosphate;
(6) constant volume to 2L, stirring for 45min after constant volume, and measuring the pH of the liquid medicine to 5-6.
The liquid medicine after volume fixing was filtered with a 0.22 μm filter membrane, and 1.5ml (6.0 mg specification) was filled into a prefilled syringe after filtration.
And (5) respectively carrying out lofting investigation on the conditions of the influencing factors. The results are shown in Table 2.
Claims (4)
1. An injection preparation of the cercis hippocampus peptide is characterized by comprising the cercis hippocampus peptide, buffer salt, osmotic pressure regulator and solvent;
the injection preparation comprises 0.1 to 1.0 percent (W/V) of the cultivated hippocampus peptide, 0.5 to 1.5 percent (W/V) of buffer salt and 0.1 to 1.0 percent (W/V) of osmotic pressure regulator;
the osmotic pressure regulator is sodium chloride, and the solvent is water for injection;
the pH range of the pharmaceutical composition is 5.0-6.0;
the buffer salt is selected from disodium hydrogen phosphate and sodium dihydrogen phosphate, and the ratio of the disodium hydrogen phosphate to the sodium dihydrogen phosphate is 1:17-18.
2. A method of preparing the pernicious western hippocampal peptide injection formulation of claim 1, comprising the steps of:
1) Adding the osmotic pressure regulator with the prescription amount into water for injection, stirring and dissolving;
2) Adding a prescribed amount of buffer salt into the solution in the step 1), and stirring for dissolution;
3) Adding the cultivated Hippocampus japonicus peptide into the solution in the step 2), stirring for dissolution, and measuring the pH value of the solution;
4) Filtering the liquid medicine in the step 3), sub-packaging the filtered liquid medicine into a penicillin bottle or a card bottle or a prefilled syringe, and plugging.
3. The method according to claim 2, wherein the preparation temperature is 10-30 ℃, and the liquid medicine is packaged into penicillin bottles or card bottles or prefilled syringes and is protected by nitrogen filling.
4. A method according to claim 3, characterized in that the preparation temperature is 10-25 ℃.
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