CN101934067B - Preparation method of polygeline injection - Google Patents
Preparation method of polygeline injection Download PDFInfo
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- CN101934067B CN101934067B CN 201010271416 CN201010271416A CN101934067B CN 101934067 B CN101934067 B CN 101934067B CN 201010271416 CN201010271416 CN 201010271416 CN 201010271416 A CN201010271416 A CN 201010271416A CN 101934067 B CN101934067 B CN 101934067B
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- 238000002347 injection Methods 0.000 title claims abstract description 34
- 239000007924 injection Substances 0.000 title claims abstract description 34
- 108010002885 Polygeline Proteins 0.000 title abstract description 10
- 229960004250 polygeline Drugs 0.000 title abstract description 10
- 238000002360 preparation method Methods 0.000 title abstract description 7
- 239000000243 solution Substances 0.000 claims abstract description 75
- 108010010803 Gelatin Proteins 0.000 claims abstract description 46
- 239000008273 gelatin Substances 0.000 claims abstract description 46
- 229920000159 gelatin Polymers 0.000 claims abstract description 46
- 235000019322 gelatine Nutrition 0.000 claims abstract description 46
- 235000011852 gelatine desserts Nutrition 0.000 claims abstract description 46
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 34
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 27
- 238000003756 stirring Methods 0.000 claims abstract description 26
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims abstract description 22
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 22
- 239000008215 water for injection Substances 0.000 claims abstract description 22
- 238000004132 cross linking Methods 0.000 claims abstract description 21
- 230000015556 catabolic process Effects 0.000 claims abstract description 19
- 238000006731 degradation reaction Methods 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 19
- 230000001954 sterilising effect Effects 0.000 claims abstract description 12
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims abstract description 11
- 239000001110 calcium chloride Substances 0.000 claims abstract description 11
- 229910001628 calcium chloride Inorganic materials 0.000 claims abstract description 11
- 239000001103 potassium chloride Substances 0.000 claims abstract description 11
- 235000011164 potassium chloride Nutrition 0.000 claims abstract description 11
- 239000011780 sodium chloride Substances 0.000 claims abstract description 11
- 238000010438 heat treatment Methods 0.000 claims abstract description 10
- 230000001105 regulatory effect Effects 0.000 claims abstract description 9
- 238000004821 distillation Methods 0.000 claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- OMRDSWJXRLDPBB-UHFFFAOYSA-N N=C=O.N=C=O.C1CCCCC1 Chemical compound N=C=O.N=C=O.C1CCCCC1 OMRDSWJXRLDPBB-UHFFFAOYSA-N 0.000 claims description 15
- 239000003431 cross linking reagent Substances 0.000 claims description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 14
- 238000010792 warming Methods 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 238000012856 packing Methods 0.000 claims description 12
- 238000012545 processing Methods 0.000 claims description 12
- 238000004659 sterilization and disinfection Methods 0.000 claims description 11
- AKABKVXLWWIVIW-UHFFFAOYSA-N 1,1-diisocyanatohexane Chemical compound CCCCCC(N=C=O)N=C=O AKABKVXLWWIVIW-UHFFFAOYSA-N 0.000 claims description 9
- 241000282894 Sus scrofa domesticus Species 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 238000007689 inspection Methods 0.000 claims description 7
- 238000010521 absorption reaction Methods 0.000 claims description 6
- 230000008021 deposition Effects 0.000 claims description 6
- 238000005374 membrane filtration Methods 0.000 claims description 6
- 230000001186 cumulative effect Effects 0.000 claims description 4
- 239000003643 water by type Substances 0.000 claims description 2
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 11
- 238000001816 cooling Methods 0.000 abstract description 6
- 230000007062 hydrolysis Effects 0.000 abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000007788 liquid Substances 0.000 abstract description 2
- 238000004806 packaging method and process Methods 0.000 abstract description 2
- 229920001184 polypeptide Polymers 0.000 abstract 2
- 102000004196 processed proteins & peptides Human genes 0.000 abstract 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 abstract 1
- 125000005442 diisocyanate group Chemical group 0.000 abstract 1
- 230000000007 visual effect Effects 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- PWKHSTCASLCOJJ-UHFFFAOYSA-N CC(C)=O.N=C=O.N=C=O.C1CCCCC1 Chemical compound CC(C)=O.N=C=O.N=C=O.C1CCCCC1 PWKHSTCASLCOJJ-UHFFFAOYSA-N 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 239000003792 electrolyte Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 230000036772 blood pressure Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000002253 acid Substances 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000008279 sol Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 239000004971 Cross linker Substances 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000032456 Hemorrhagic Shock Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010049771 Shock haemorrhagic Diseases 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- SYUXAJSOZXEFPP-UHFFFAOYSA-N glutin Natural products COc1c(O)cc2OC(=CC(=O)c2c1O)c3ccccc3OC4OC(CO)C(O)C(O)C4O SYUXAJSOZXEFPP-UHFFFAOYSA-N 0.000 description 1
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical group O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000012634 optical imaging Methods 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- RINCXYDBBGOEEQ-UHFFFAOYSA-N succinic anhydride Chemical class O=C1CCC(=O)O1 RINCXYDBBGOEEQ-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
Images
Abstract
The invention discloses a prescription of polygeline injection and a preparation method thereof. The preparation method comprises the following steps: a. dissolving gelatin with water for injection, regulating the pH value of the gelatin solution to be 4.5-6.0, heating to 116-131 DEG C, keeping the temperature constant for 2-3 hours, stopping heating, and cooling to 25-40 DEG C; b. regulating the pH value of degradation liquid to be 8.0-9.0, adding cyclohexyl diisocyanate acetone solution, and stirring and crosslinking for 1.5-2.5 hours; c. carrying out reduced pressure distillation to obtain acetone; d. adding water for injection, potassium chloride, sodium chloride and calcium chloride in the remaining solution after distillation, and regulating the pH value to be 6.5-7.5; d. adsorbing and filtering; and e. sterilizing, carrying out visual check and packaging. The degradation condition controllability of the method is good; the weight-average molecular weight of polypeptide obtained by hydrolysis is 5000-18500, which can satisfy the optimum conditional requirements of the crosslinking reaction; the crosslinking degree is high; the crosslinking product polypeptide is globular molecule; and the prepared polygeline injection conforms to the National Drug Standards. The clinical use result proves that the product is safe and effective.
Description
Technical field
The present invention relates to the poly gelatin peptide injection method for preparing, be specifically related to a kind of prescription and preparation technology with Os Bovis seu Bubali or Os Sus domestica manufacturing of gelatin poly gelatin peptide injection.
Background technology
Poly gelatin peptide injection is widely used in diseases such as the hemorrhagic shock that a variety of causes causes, indecorous fluidity shock clinically, has rapid replenishment of blood content, keeps the effect of blood pressure, has substituted blood plasma.At present; There is different preparation in this product; Like publication number is " preparation technology of poly gelatin peptide injection " application for a patent for invention of CN1387912A, and this application discloses following technical method: 1, colloidal sol: with injection hot water dissolving Os Bovis seu Bubali, Os Sus domestica or other gelatin; 2, thermal degradation: transfer Os Bovis seu Bubali, Os Sus domestica or other aqueous gelatin solution pH value between 5.0 ~ 6.0, be warming up to 110 ~ 125 ℃, keep this temperature, measure relative viscosity, reach at 2.0 ~ 2.5 o'clock to relative viscosity, stop heating, be quickly cooled to 30 ~ 37 ℃; 3, crosslinked: degradation solution is transferred pH to 6.5 ~ 7.5,25 ~ 35 ℃ of holding temperatures, and adding glutin content is 0.7 ~ 1.2% cross-linking agent, stirs crosslinked 1 ~ 3 hour; 4, add electrolyte: adjust pH 7.4 ~ 7.6, add sodium chloride, calcium chloride and potassium chloride electrolyte, electrolyte is dissolved fully; 5, adsorption clarification: 0.1 ~ 1% kieselguhr after the adding activation, stir while adding, be warming up to 115 ℃ and insulation, sealed reactor, cooling is cooled to 35 ℃, leaves standstill; 6, the liquid after above-mentioned the leaving standstill is forwarded in the sterile chamber with aseptic siphon, 0.1% ~ 1% kieselguhr and active carbon after the adding activation detect and also regulate pH7.0 ~ 7.6, stirring and adsorbing, and then through 4 grades of filtrations, packing; 7, sterilization; 8, lamp inspection packing.This method for preparing exists technological parameter imprecise, poor controllability, and there is certain potential safety hazard in unstable product quality, and major defect is: 1, extent of thermal degradation is poor.When palliating degradation degree is controlled to be 2.0 ~ 2.5 with relative density, the weight average molecular weight of catabolite surpasses 20000 dalton, is not suitable for the reaction requirement of cyclohexane diisocyanate cross-linking agent.2, crosslinked operation poor operability.Three kinds of cross-linking agent (succinic anhydrides, Biformyl or cyclohexane diisocyanate) character is different, and reaction condition has nothing in common with each other.Cyclohexane diisocyanate is water insoluble, must be the cross-linking reaction of cross-linking agent so above-mentioned crosslinked operation can not be suitable for the cyclohexane diisocyanate can add after the appropriate solvent dissolving.3, the degree of cross linking is low.Because the molecular weight of catabolite amino or amide active low on 20000 peptide chains when above increased crosslinked difficulty, causes the degree of cross linking low, and cross-linking products is chain molecule, and weight average molecular weight is greater than 40000 dalton's (see figure 1)s.4, because product is mainly chain molecule, clinical replenishment of blood content, the effect of keeping blood pressure are relatively poor, are difficult to guarantee curative effect and safety.
Summary of the invention
The object of the present invention is to provide a kind of with Os Bovis seu Bubali or Os Sus domestica manufacturing of gelatin poly gelatin peptide injection and preparation method thereof.
Poly gelatin peptide injection fabricating technology scheme of the present invention is:
A kind of poly gelatin peptide injection method for preparing, this method may further comprise the steps:
A kind of poly gelatin peptide injection method for preparing, this method may further comprise the steps:
The thermal degradation of a, gelatin: Os Bovis seu Bubali or Os Sus domestica gelatin are dissolved with 40 ~ 90 ℃ of waters for injection; The pH value of regulating gelatin solution is 4.5～6.0; Be warming up to 116 ~ 131 ℃; Reach 1.30 ~ 1.85 when (preferred relative viscositys 1.5 ~ 1.7) to relative viscosity, stop heating, and be cooled to 20 ~ 40 ℃ and obtain degradation solution;
B, crosslinked: the pH value of regulating degradation solution is 8.0 ~ 9.0; Under 25 ~ 40 ℃ of temperature conditions, add crosslinker concentration and be acetone soln or the acetone soln of 6-hexylidene diisocyanate of the cyclohexane diisocyanate of 4 ~ 15% (v/v); Constantly stir crosslinked 1.5 ~ 2.5 hours;
C, distillation: with cross-linking products heat temperature raising to 45 ~ 65 of step b ℃, distilling under reduced pressure 45 ~ 180 minutes steams acetone;
D, electrolytical adjusting: in the remaining solution in step c distillation back, add the injection water, add potassium chloride, sodium chloride and calcium chloride, after the dissolving, add hydrochloric acid solution adjust pH to 6.5 ~ 7.5;
E, absorption, filtration;
F, embedding, sterilization, lamp inspection, packing;
The amount ratio of above-mentioned gelatin, cross-linking agent, sodium chloride, potassium chloride, calcium chloride and water for injection is 3.2kg:0.25-0.50L:3.6-3.8kg:0.09-0.12kg:0.05-0.06kg:490-5 00L (consumption units wherein and L are merely clear and definite its proportionate relationship and do not limit its concrete consumption, that is to say amplify in proportion or dwindle all should be within the scope of the present invention); Wherein gelatin is to contain the N amount, and cross-linking agent is in the amount of cyclohexane diisocyanate or 6-hexylidene diisocyanate.
The water for injection consumption is 35% ~ 45% of a water for injection cumulative volume amount among the above-mentioned steps a.
Among the above-mentioned steps c, the vacuum of distilling under reduced pressure is-0.08Mpa.
Among the above-mentioned steps d, the injection water yield of adding is 35% ~ 45% of a water for injection cumulative volume amount; Among the step e, absorption is meant: add 0.1 ~ 0.5% kieselguhr of activated processing, stir while adding, be warming up to 115 ~ 125 ℃, be incubated 45～90 minutes; Be cooled to 60 ~ 80 ℃ rapidly, placed at least 8 hours, discard deposition mud; Solution is transferred in another container, adds 0.1 ~ 0.5% kieselguhr and 0.1 ~ 0.5% active carbon of activated processing, add the water for injection of surplus; Adjust pH to 6.5 ~ 7.5, stirring and adsorbing 1.5～2.5 hours; Filtration is: the membrane filtration that refers to use successively 10 μ m, 0.45 μ m and 0.22 μ m.
Among the above-mentioned steps f, sterilization process is: adopt 115 ℃ of sterilizations 30 minutes.
The specification of the poly gelatin peptide injection of said method Production and Packaging can be: 250ml:1.6g (in nitrogen content), 500ml:3.2g (in nitrogen content).
The present invention has following characteristics:
1, thermal degradation condition is easy to control.Molecular weight is big more, and the relative viscosity of solution is big more, and extent of thermal degradation can be controlled with relative viscosity.If the relative viscosity of solution is greater than 2.0, the weight average molecular weight of catabolite surpasses 20000 dalton, and this not only will increase crosslinked difficulty, and the weight average molecular weight of cross-linking products will cause product defective above 40000 dalton.The applicant finds; The relative viscosity of solution is in 1.30 ~ 1.85 scopes the time; The weight average molecular weight of catabolite is between 5000 ~ 18500 dalton; Meeting the optimum response requirement of cyclohexane diisocyanate (or 6-hexylidene diisocyanate) cross-linking agent, help next step cross-linking reaction, is that globular molecule and molecular weight meet the requirements to guarantee gained cross-linking reaction product.
2, the cross-linking reaction condition can accurately be controlled, and the degree of cross linking is high.Cross-linking agent is mixed with 5% ~ 15% cyclohexane diisocyanate (or 6-hexylidene diisocyanate) acetone soln, and it is complete to help improving the stability of cross-linking agent, the dispersion that helps cross-linking agent and cross-linking reaction.Cross-linking agent cyclohexane diisocyanate and 6-hexylidene diisocyanate are all water insoluble, and character is all unstable, reacts like alcohol, acid, amine, water, alkali etc. with the chemical compound that includes reactive hydrogen atom easily.The applicant finds to add acetone at cyclohexane diisocyanate or 6-hexylidene diisocyanate, can play sealing process to improve its stability; And reduction viscosity increases dispersibility, serves as the media of oiliness base and aqueous base simultaneously, and the dispersion and the cross-linking reaction that help cross-linking agent are complete, and the degree of cross linking is high.
The applicant finds that also the present invention helps the generation of cross-linking reaction in weakly alkaline solution, and is but very slow at acid solution.Be converted into the alkalescence urea groups when alkaline amino in the reaction, and carboxyl is when forming salt, the pH value of solution will diminish.It is preferable that the pH value of cross-linking reaction of the present invention is controlled at 8.0 ~ 9.0 o'clock cross-linking effects.
3, distillation condition can accurately be controlled, and solvent recovery is complete.The boiling point of acetone is low, be easy to reclaim, and adopts the heating distilling under reduced pressure, can guarantee that organic solvent-free is residual in the product.
4, can accurately control potassium, sodium, the calcium ion concentration of product, make it to equate with blood electrolyte.
5, product quality is easy to control, and qualification rate is high, and good stability has no side effect, drug safety.Can prolong RT in blood, increase alternately strike and press, thereby play replenishment of blood content, keep the therapeutical effect of blood pressure.
Description of drawings
The polygeline molecular shape photo that Fig. 1 makes for prior art;
The polygeline molecular shape photo that Fig. 2 ~ 4 make for the present invention.
Polygeline molecular shape system adopts patented technology " a kind of object external outline nonlinear multi-stage amplification optical imaging know-why, device and image capture method " (application number/patent No.: 200910060951) take among the figure.
The specific embodiment
One, the prescription of poly gelatin peptide injection:
| Gelatin (to contain the N amount) | 3.2kg |
| Cyclohexane diisocyanate | 0.34L |
| Sodium hydroxide | 0.36kg |
| Sodium chloride | 3.71kg |
| Potassium chloride | 0.11kg |
| Calcium chloride | 55.5g |
| Hydrochloric acid | In right amount |
| Water for injection | In right amount |
| ? | 500L (pH value 6.5～7.5) |
Two, produce poly gelatin peptide injection by prescription composition and technical scheme requirement:
1, colloidal sol: getting Os Bovis seu Bubali or Os Sus domestica gelatin is 42 ℃ by the temperature that recipe quantity drops into water for injection.
2, the thermal degradation of gelatin: the pH value (pH value preferred 5.5～5.8) in 4.5～6.0 scopes of regulating gelatin solution with hydrochloric acid or sodium hydroxide solution; Be warming up to 116 ~ 131 ℃ (preferred 120 ~ 125 ℃); Kept temperature 2 ~ 3 hours; When the relative viscosity of solution reaches in 1.30～1.85 (25 ℃ of mensuration) scope (preferred relative viscosity 1.5 ~ 1.7), stop heating immediately, make solution be cooled to 25 ~ 40 ℃ rapidly.
3, peptide chain is crosslinked: pH value to 8.0 ~ 9.0 (preferred pH value 8.5) of regulating degradation solution with NaOH solution; Keep 25 ~ 40 ℃ of solution temperatures; Slowly add 4% ~ 15% (v/v) cyclohexane diisocyanate acetone (or 6-hexylidene diisocyanate) solution 3.4L (preferred 10% cyclohexane diisocyanate acetone soln), and constantly stirred 1.5 ~ 2.5 hours.
4, distillation: heat temperature raising to 45 ~ 65 ℃, distilling under reduced pressure 45 ~ 180 minutes steams acetone.
5, electrolytical adjusting: in distilling the remaining solution in back, add 70% ~ 90% of injection water to total amount, mixing is pressed recipe quantity and is added potassium chloride, sodium chloride and calcium chloride, after stirring makes dissolving, adds hydrochloric acid solution adjust pH to 6.5 ~ 7.5.
6, absorption, filtration: add 0.1 ~ 0.5% kieselguhr of activated processing, stir while adding, be warming up to 115 ~ 125 ℃, be incubated 45～90 minutes, the relative viscosity of measuring solution should be in 1.85～2.20 (25 ℃ of mensuration) scope.Cooling was placed 8 hours at least rapidly, discarded deposition mud; Supernatant is transferred in another container, adds 0.1 ~ 0.5% kieselguhr and 0.1 ~ 0.5% active carbon of activated processing, add water for injection to the total amount of writing out a prescription; Adjust pH to 6.5 ~ 7.5; Stirring and adsorbing 1.5～2.5 hours is used the membrane filtration of 10 μ m, 0.45 μ m and 0.22 μ m, embedding successively.
7, sterilization: sterilized 30 minutes for 115 ℃.
8, lamp inspection, packing.
The specification of complying with the poly gelatin peptide injection of above-mentioned explained hereafter packing has: 250ml:1.6g (in nitrogen content), 500ml:3.2 g (in nitrogen content).
According to the poly gelatin peptide injection of above-mentioned explained hereafter, press the check of the poly gelatin peptide injection national drug standards, the equal National standard of result.And the polygeline molecule that makes is the globular molecule (see figure 2).
Embodiment 1:
1, gets Os Sus domestica gelatin 200g, add temperature and be 40 ℃ water for injection 1750ml, stir and make dissolving.Regulate the pH value to 4.5 of gelatin solution with hydrochloric acid or sodium hydroxide solution; Be warming up to 116 ℃; Kept temperature 3 hours, and reached 1.85 to the relative viscosity of solution, the weight average molecular weight that makes hydrolysis gained peptide chain is 16000-18500; Stop heating immediately, (the cold circulation as adopting routine is cooled off) makes solution be cooled to 25 ℃ rapidly.
2, regulate the pH value to 8.0 of above-mentioned degradation solution with NaOH solution; Keep 25 ℃ of solution temperatures; Slowly (with 28ml/ hour speed) adds cyclohexane diisocyanate acetone soln (be dissolved in obtain the cyclohexane diisocyanate acetone soln in the 68ml acetone by the 3.4ml cyclohexane diisocyanate), constantly stirs 2.5 hours, and is every at a distance from 20 minutes; Measure the pH value of solution, and the pH value that uses NaOH solution to regulate to keep solution is 8.0.
3, with above-mentioned solution under vacuum-0.08Mpa, 50 ℃ of conditions of temperature, distilling under reduced pressure 180 minutes is steamed to no longer including acetone.
4, in distilling the remaining solution in back, add injection water 2250ml, mixing adds potassium chloride 1.1g, sodium chloride 37.1g and calcium chloride 555mg, after stirring makes dissolving, adds hydrochloric acid solution adjust pH to 6.5.
6, add 0.1% kieselguhr of activated processing, stir while adding, be warming up to 115 ℃, be incubated 90 minutes, the relative viscosity of measuring solution is 1.85, and the weight average molecular weight of gained polygeline is 29006, and it is shaped as globular molecule, sees Fig. 2.Cooling was placed 8 hours rapidly, discarded deposition mud; Supernatant is transferred in another container, adds 0.5% kieselguhr and 0.1% active carbon of activated processing, add water for injection 1000ml; About adjust pH to 6.8; Stirring and adsorbing 1.5 hours is used the membrane filtration of 10 μ m, 0.45 μ m and 0.22 μ m, embedding successively.
7, sterilization: sterilized 30 minutes for 115 ℃.
8, lamp inspection, packing.The packing specification is: 500ml:3.2g (in nitrogen content).
Embodiment 2:
1, gets Os Bovis seu Bubali gelatin 200g, add temperature and be 65 ℃ water for injection 1900ml, stir and make dissolving.PH value to 5.5 with hydrochloric acid or sodium hydroxide solution adjusting gelatin solution is warming up to 121 ℃, keeps temperature 2.5 hours; Relative viscosity to solution reaches 1.60; The weight average molecular weight that makes hydrolysis gained peptide chain is 10000-15500, stops heating immediately, makes solution be cooled to 35 ℃ rapidly.
2, regulate the pH value to 8.5 of above-mentioned degradation solution with NaOH solution; Keep 35 ℃ of solution temperatures; Slowly add cyclohexane diisocyanate acetone soln (be dissolved in 34ml acetone obtain by the 3.4ml cyclohexane diisocyanate), constantly stirred 2 hours, every at a distance from 20 minutes; Measure the pH value of solution, and the pH value that uses NaOH solution to regulate to keep solution is 8.5.
3, with above-mentioned solution under vacuum-0.08Mpa, 65 ℃ of conditions of temperature, distilling under reduced pressure 45 minutes is steamed to no longer including acetone.
4, in distilling the remaining solution in back, add injection water 2750ml, mixing adds potassium chloride 1.1g, sodium chloride 37.1g and calcium chloride 555mg, after stirring makes dissolving, adds hydrochloric acid solution adjust pH to 7.0.
6, add 0.3 % kieselguhr of activated processing, stir while adding, be warming up to 115 ℃, be incubated 70 minutes, the relative viscosity of measuring solution is 2.20, and the weight average molecular weight of gained polygeline is 33924, and it is shaped as globular molecule, sees Fig. 3.Cooling was placed 12 hours rapidly, discarded deposition mud; Supernatant is transferred in another container, adds 0.1% kieselguhr and the 0.3 % active carbon of activated processing, add water for injection 350ml; About adjust pH to 7.0; Stirring and adsorbing 2 hours is used the membrane filtration of 10 μ m, 0.45 μ m and 0.22 μ m, embedding successively.
7, sterilization: sterilized 30 minutes for 115 ℃.
8, lamp inspection, packing.The packing specification is: 250ml:1.6 g (in nitrogen content).
Embodiment 3:
1, gets Os Sus domestica gelatin 200g, add temperature and be 90 ℃ water for injection 2000ml, stir and make dissolving.PH value to 6.0 with hydrochloric acid or sodium hydroxide solution adjusting gelatin solution is warming up to 131 ℃, keeps temperature 2 hours; Relative viscosity to solution reaches 1.3; The weight average molecular weight that makes hydrolysis gained peptide chain is 5500-9000, stops heating immediately, makes solution be cooled to 40 ℃ rapidly.
2, regulate the pH value to 9.0 of above-mentioned degradation solution with NaOH solution; Keep 40 ℃ of solution temperatures; Slowly add cyclohexane diisocyanate acetone soln (be dissolved in 24ml acetone obtain by the 3.4ml cyclohexane diisocyanate), constantly stirred 1.5 hours, every at a distance from 20 minutes; Measure the pH value of solution, and the pH value that uses NaOH solution to regulate to keep solution is 9.0.
3, with above-mentioned solution under vacuum-0.08Mpa, 45 ℃ of conditions of temperature, distilling under reduced pressure 100 minutes is steamed to no longer including acetone.
4, in distilling the remaining solution in back, add injection water 2500ml, mixing adds potassium chloride 1.1g, sodium chloride 37.1g and calcium chloride 555mg, after stirring makes dissolving, adds hydrochloric acid solution adjust pH to 6.5.
6, absorption, filtration: add 0.5 % kieselguhr of activated processing, stir while adding, be warming up to 125 ℃; Be incubated 45 minutes, the relative viscosity of measuring solution should be 2.0, and the weight average molecular weight of gained polygeline is 31783; It is shaped as globular molecule, sees Fig. 4.Cooling was placed 16 hours rapidly, discarded deposition mud; Supernatant is transferred in another container, adds 0.3% kieselguhr and 0.3% active carbon of activated processing, add water for injection 500ml; About adjust pH to 7.3; Stirring and adsorbing 2.5 hours is used the membrane filtration of 10 μ m, 0.45 μ m and 0.22 μ m, embedding successively.
7, sterilization: sterilized 30 minutes for 115 ℃.
8, lamp inspection, packing.The packing specification is: 500ml:3.2g (in nitrogen content).
The assay of table 1. poly gelatin peptide injection of the present invention:
Claims (4)
1. poly gelatin peptide injection method for preparing, this method may further comprise the steps:
The thermal degradation of a, gelatin: Os Bovis seu Bubali or Os Sus domestica gelatin are dissolved with 40 ~ 90 ℃ of waters for injection; The pH value of regulating gelatin solution is 4.5～6.0, is warming up to 116 ~ 131 ℃, reaches at 1.30 ~ 1.85 o'clock to relative viscosity; Stop heating, and be cooled to 20 ~ 40 ℃ and obtain degradation solution;
B, crosslinked: the pH value of regulating degradation solution is 8.0 ~ 9.0; Acetone soln or the volumetric concentration that under 25 ~ 40 ℃ of temperature conditions, adds the cross-linking agent volumetric concentration and be 4 ~ 15% cyclohexane diisocyanate is the acetone soln of 4 ~ 15% 6-hexylidene diisocyanate; Constantly stir crosslinked 1.5 ~ 2.5 hours;
C, distillation: with cross-linking products heat temperature raising to 45 ~ 65 of step b ℃, distilling under reduced pressure 45 ~ 180 minutes steams acetone; The vacuum of distilling under reduced pressure is-0.08Mpa;
D, electrolytical adjusting: in the remaining solution in step c distillation back, add the injection water, add potassium chloride, sodium chloride and calcium chloride, after the dissolving, add hydrochloric acid solution adjust pH to 6.5 ~ 7.5;
E, absorption, filtration; Absorption is meant: add 0.1 ~ 0.5% kieselguhr of activated processing, stir while adding, be warming up to 115 ~ 125 ℃, be incubated 45～90 minutes; Be cooled to 60 ~ 80 ℃ rapidly, placed at least 8 hours, discard deposition mud; Solution is transferred in another container, adds 0.1 ~ 0.5% kieselguhr and 0.1 ~ 0.5% active carbon of activated processing, add the water for injection of surplus; Adjust pH to 6.5 ~ 7.5, stirring and adsorbing 1.5～2.5 hours; Filtration is: the membrane filtration that refers to use successively 10 μ m, 0.45 μ m and 0.22 μ m;
F, embedding, sterilization, lamp inspection, packing;
The amount ratio of above-mentioned gelatin, cross-linking agent, sodium chloride, potassium chloride, calcium chloride and water for injection is 3.2kg: (0.25-0.50L): (3.6-3.8kg): (0.09-0.12kg): (0.05-0.06kg): (490-500L); Wherein gelatin is to contain the N amount, and cross-linking agent is in the amount of cyclohexane diisocyanate or 6-hexylidene diisocyanate; The consumption of said water for injection is meant the total amount of step a-e.
2. poly gelatin peptide injection method for preparing as claimed in claim 1 is characterized in that, the water for injection consumption is 35% ~ 45% of a water for injection cumulative volume amount among the step a.
3. according to claim 1 or claim 2 poly gelatin peptide injection method for preparing is characterized in that in the steps d, the injection water yield of adding is 35% ~ 45% of a water for injection cumulative volume amount.
4. according to claim 1 or claim 2 poly gelatin peptide injection method for preparing is characterized in that among the step f, sterilization process is: adopt 115 ℃ of sterilizations 30 minutes.
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| CN 201010271416 CN101934067B (en) | 2010-09-03 | 2010-09-03 | Preparation method of polygeline injection |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2827419A (en) * | 1954-09-24 | 1958-03-18 | Charles B Knox Gelatine Co Inc | Acylated gelatins and their preparations |
| CN1387912A (en) * | 2002-06-13 | 2003-01-01 | 董道维 | Prepn of polygelatine peptide injection |
| EP1367066A2 (en) * | 2002-05-21 | 2003-12-03 | CRODA INTERNATIONAL plc | Succinylated fish gelatin |
| CN1586620A (en) * | 2004-07-14 | 2005-03-02 | 哈尔滨圣泰制药股份有限公司 | Poly gelatin peptide injection and its preparing method |
-
2010
- 2010-09-03 CN CN 201010271416 patent/CN101934067B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2827419A (en) * | 1954-09-24 | 1958-03-18 | Charles B Knox Gelatine Co Inc | Acylated gelatins and their preparations |
| EP1367066A2 (en) * | 2002-05-21 | 2003-12-03 | CRODA INTERNATIONAL plc | Succinylated fish gelatin |
| CN1387912A (en) * | 2002-06-13 | 2003-01-01 | 董道维 | Prepn of polygelatine peptide injection |
| CN1586620A (en) * | 2004-07-14 | 2005-03-02 | 哈尔滨圣泰制药股份有限公司 | Poly gelatin peptide injection and its preparing method |
Non-Patent Citations (1)
| Title |
|---|
| Peano S et al..Determination of the clearance factor for transmissible spongiform encephalophaty agents during the manufacturing process of polygeline.《Intensive Care Med》.2000,第26卷(第5期),608-12. * |
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