CN102525963A - Netilmicin sulfate lyophiled powder injection and preparation method thereof - Google Patents
Netilmicin sulfate lyophiled powder injection and preparation method thereof Download PDFInfo
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- CN102525963A CN102525963A CN2012100272596A CN201210027259A CN102525963A CN 102525963 A CN102525963 A CN 102525963A CN 2012100272596 A CN2012100272596 A CN 2012100272596A CN 201210027259 A CN201210027259 A CN 201210027259A CN 102525963 A CN102525963 A CN 102525963A
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- netilmicin sulfate
- freeze
- temperature
- netilmicin
- dried powder
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- CZPLANDPABRVHX-UHFFFAOYSA-N cascade blue Chemical compound C=1C2=CC=CC=C2C(NCC)=CC=1C(C=1C=CC(=CC=1)N(CC)CC)=C1C=CC(=[N+](CC)CC)C=C1 CZPLANDPABRVHX-UHFFFAOYSA-N 0.000 title claims abstract description 61
- 229960004832 netilmicin sulfate Drugs 0.000 title claims abstract description 61
- 239000000843 powder Substances 0.000 title claims abstract description 18
- 238000002347 injection Methods 0.000 title claims abstract description 16
- 239000007924 injection Substances 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000004108 freeze drying Methods 0.000 claims abstract description 19
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000000654 additive Substances 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 6
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims abstract description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000004202 carbamide Substances 0.000 claims abstract description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims abstract description 3
- 229920002472 Starch Polymers 0.000 claims abstract description 3
- 229960003964 deoxycholic acid Drugs 0.000 claims abstract description 3
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 claims abstract description 3
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000008107 starch Substances 0.000 claims abstract description 3
- 235000019698 starch Nutrition 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 25
- 239000007788 liquid Substances 0.000 claims description 24
- 239000003814 drug Substances 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 18
- 238000012856 packing Methods 0.000 claims description 17
- 239000008215 water for injection Substances 0.000 claims description 12
- 239000000725 suspension Substances 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- 239000003610 charcoal Substances 0.000 claims description 7
- 229940105082 medicinal charcoal Drugs 0.000 claims description 7
- 239000012528 membrane Substances 0.000 claims description 7
- 238000005292 vacuum distillation Methods 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 6
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 235000013877 carbamide Nutrition 0.000 claims description 4
- 239000001117 sulphuric acid Substances 0.000 claims description 4
- 235000011149 sulphuric acid Nutrition 0.000 claims description 4
- 238000010521 absorption reaction Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- 238000003556 assay Methods 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 210000004907 gland Anatomy 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000000859 sublimation Methods 0.000 claims description 2
- 230000008022 sublimation Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000000463 material Substances 0.000 abstract description 4
- 230000003750 conditioning effect Effects 0.000 abstract 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 abstract 1
- 241001313857 Bletilla striata Species 0.000 abstract 1
- 229920000858 Cyclodextrin Polymers 0.000 abstract 1
- 239000001116 FEMA 4028 Substances 0.000 abstract 1
- 235000011114 ammonium hydroxide Nutrition 0.000 abstract 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 abstract 1
- 229960004853 betadex Drugs 0.000 abstract 1
- 150000004676 glycans Chemical class 0.000 abstract 1
- 229940102213 injectable suspension Drugs 0.000 abstract 1
- 229920001282 polysaccharide Polymers 0.000 abstract 1
- 239000005017 polysaccharide Substances 0.000 abstract 1
- 235000017550 sodium carbonate Nutrition 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 7
- 239000002671 adjuvant Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000007689 inspection Methods 0.000 description 6
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 5
- 238000004140 cleaning Methods 0.000 description 5
- 239000000693 micelle Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000005070 sampling Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 229940126575 aminoglycoside Drugs 0.000 description 2
- 230000003064 anti-oxidating effect Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 229960000808 netilmicin Drugs 0.000 description 2
- ZBGPYVZLYBDXKO-HILBYHGXSA-N netilmycin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@]([C@H](NC)[C@@H](O)CO1)(C)O)NCC)[C@H]1OC(CN)=CC[C@H]1N ZBGPYVZLYBDXKO-HILBYHGXSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- 241000588724 Escherichia coli Species 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
- 241000588748 Klebsiella Species 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 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
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000284 endotoxic Toxicity 0.000 description 1
- 230000002346 endotoxic effect Effects 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000004482 other powder Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000009781 safety test method Methods 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 210000002229 urogenital system Anatomy 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses netilmicin sulfate lyophiled powder injection and a preparation method of the netilmicin sulfate lyophiled powder injection. Netilmicin sulfate and additives are added with water to be prepared into netilmicin sulfate injectable suspension, and the netilmicin sulfate lyophiled powder injection is obtained through freeze drying, wherein the additives are inclusion molecules and pH conditioning agents, the inclusion molecules are selected from bletilla striata polysaccharide, beta-cyclodextrin, urea, thiourea, beta-cyclodextrin derivatives, deoxycholic acid and starch, and the pH conditioning agents are selected from sodium carbonate, sodium bicarbonate, ammonia water, sulfuric acid and phosphoric acid. Required auxiliary materials are few, the preparation process is simple, the freeze drying process is particularly screened and optimized, and the netilmicin sulfate lyophiled powder injection and the preparation method has the characteristics that the stability is high, the biological availability is high, the production cost is low, the quality is safe and reliable, and the like.
Description
Technical field
The invention belongs to a kind of pharmaceutical preparation, be specifically related to a kind of inclusion technique that utilizes and prepare antibiotics injection netilmicin sulfate freeze-dried powder and preparation method thereof.
Background technology
Netilmicin sulfate Netilmicin Sulfate, NTM are the of new generation semi-synthetic aminoglycoside antibioticss of introducing in 1994, synthesize through the normal protein matter that suppresses sensitive microbial and work.Be mainly used in respiratory tract due to the gram-negative bacterias such as escherichia coli, klebsiella spp, Bacillus proteus, Enterobacter, digestive tract, genito-urinary system, skin and soft tissue, bone and site infections such as joint, abdominal cavity; Its main feature is strong to fastbacteria and the effect of beta-lactam fastbacteria, becomes the clinical choice drug that the aminoglycoside applicating finger syndrome is arranged.The oral difficult absorption of netilmicin sulfate, intramuscular injection absorb rapidly fully, and the main dosage form of this medicine is an injection.But descend because the aqueous solution of netilmicin, is prone to variable color and content to thermally labile, must add more antioxidant, be unfavorable for clinical use.
That Chinese patent CN101461783B discloses is a kind of " can intravenous netilmicin sulfate nano-micelle preparations and preparation method thereof ".This patent nano-micelle is wrapped in netilmicin sulfate in the hydrophobic core; Mode intravenously administrable with the nano-micelle lyophilized formulations; Though increased stability of formulation, the supplementary product consumption that in preparation process, adds is excessive, has brought potential safety hazard to injecting drug use.On the other hand, this patent system Preparation Method is comparatively complicated, and preparation cost is high, and solution proportion does not meet the requirements, and reaches 4310g like the total amount that adds among the embodiment 2, and the quantity of solvent that needs is excessive, according to the material total of its adding, be can't dissolve freeze dried.According to the lyophilizing principle, the method also can not obtain target product in suitability for industrialized production, be not suitable for large-scale industrial production, and micelle itself belongs to micelle shape material simultaneously, belongs to macromolecular substances, is unfavorable for effective utilization of medicine.State Food and Drug Administration put into effect state's food medicine prison and has annotated [2008] No. 7 files on January 10th, 2008; Kind and the consumption of wherein stipulating the used adjuvant of injection should be the least possible, are directed against the untoward reaction incident that the heavy addition adjuvant causes on the market exactly and the associated documents of putting into effect.
Summary of the invention
The objective of the invention is to overcome the deficiency of prior art and provide a kind of supplementary product consumption little, preparation technology is simple, preparation cost is low, but does not have a kind of netilmicin sulfate freeze-dried powder of the large-scale industrial production that antioxidant adds.
Another object of the present invention provides a kind of method of utilizing inclusion technique to prepare the netilmicin sulfate freeze-dried powder.
The objective of the invention is to realize like this: a kind of netilmicin sulfate freeze-dried powder; It is characterized in that comprising that netilmicin sulfate and additives process through the method that comprises following steps: additives are added the water wiring solution-forming; Fully add the netilmicin sulfate stirring and dissolving behind the mixing and get the netilmicin sulfate suspension; The filtration of netilmicin sulfate suspension, packing, lyophilization are got the netilmicin sulfate freeze-dried powder; Wherein said additives are enclose molecule and pH regulator agent, and wherein netilmicin sulfate 100g, enclose molecule 75-120g, pH regulator agent 0.5-1.0g adjust pH are 4.8-5.8; Described enclose molecule is selected from Pseudobulbus Bletillae polysaccharose, beta-schardinger dextrin-, carbamide, thiourea, beta-cyclodextrin derivative, deoxycholic acid and starch; Described regulator is selected from sodium carbonate, sodium bicarbonate, ammonia, sulphuric acid and phosphoric acid.
A kind of method for preparing of netilmicin sulfate freeze-dried powder is characterized in that comprising following steps:
1. the enclose molecule is added the injection water and be made into 40～50% solution; Add the netilmicin sulfate stirring and dissolving and add to the full amount of water for injection, stir the netilmicin sulfate suspension, the medicinal charcoal that adds overall solution volume 0.1 ~ 0.3% stirs; Absorption is more than 30 minutes; Solution temperature is controlled at below 33 ℃, and taking liquid detects, and regulating pH value is 4.8-5.8 and mensuration solution content;
2. after the assay was approved, the coarse filtration carbon removal, with the aseptic filtration of 0.22um microporous filter membrane, the sterile liquid medicine fill in vial, lyophilization, gland, label, pack netilmicin sulfate freeze-dried powder finished product.
Said freeze drying process comprises the steps:
1. pre-freeze.Products temperature was reduced to-35～-45 ℃ of pre-freezes 2 hours, and went up to-10～-20 ℃ to freeze again 1 hour;
2. sublimation drying.Reduce at condenser temperature-50 ℃ stable after, baffle temperature rises to-15 ℃, dry 8-10 hour of low-temperature distillation;
3. dry again.Baffle temperature is set at 30 ℃, and products temperature maintains 26～28 ℃, dry again 5-7 hour of vacuum heat-preserving.
Compared with prior art, beneficial effect of the present invention is:
1, the present invention's no too many adjuvant in whole freeze-dry process process adds, and is guaranteeing the preparation single while of composition, has prevented various more because adjuvant adds the untoward reaction that causes.In order to improve stability of drug, the present invention adopts the state-of-the-art inclusion technique of formulation art in recent years, has increased the dissolubility of medicine greatly, has regulated rate of release, has improved bioavailability of medicament, has reduced the zest and the toxic and side effects of medicine.
2, the Pseudobulbus Bletillae polysaccharose that uses among the present invention has the antioxidation that other enclose molecules do not have, and designs to the netilmicin sulfate that is prone to oxidation especially.Pseudobulbus Bletillae polysaccharose (BSPS) is formed by mannose and glucose polymerisation, can form helical structure, has the effect that forms enclose content medicine; Simultaneously; That Pseudobulbus Bletillae polysaccharose has is nontoxic, antioxidation and stable properties, in application process, have safe and effective, the characteristics that have no side effect.Its its specific structure can substitute the lyophilizing skeleton in freeze-drying process simultaneously, reduces adjuvant and adds.Find that through repetitious test the enclose effect of Pseudobulbus Bletillae polysaccharose is for the pointed solution of easy oxidation shortcoming of netilmicin sulfate.
3, the present invention improves on production technology, particularly freeze-drying time and freeze temperature, strict control freeze-drying curve; Taked the lyophilizing mode of multigelation; Not only improve medicine stability, also guaranteed the unicity of medicine, reduced the generation of untoward reaction; Medicine becomes the micromolecule state, has improved bioavailability.Simultaneously, method for preparing of the present invention is the result who obtains through the test of suitability for industrialized production repeatedly, is suitable for large-area suitability for industrialized production, with respect to existing lyophilizing mode, has shortened freeze-drying time, has practiced thrift the lyophilizing cost and the energy, has reduced waste discharge.
The specific embodiment
Applicant of the present invention finds Pseudobulbus Bletillae polysaccharose as the enclose molecular material unexpectedly through studying repeatedly and testing, and this wherein also comprises the selection of dosing and freeze drying process in the method for preparing; Not only make preparation in freeze-drying process, need not too many adjuvant and add, guarantee the preparation single while of composition, also improved stability of drug greatly; Increased the dissolubility of medicine; Regulate rate of release, improved bioavailability of medicament, reduced the zest and the toxic and side effects of medicine.
Further describe the present invention with embodiment below, but said embodiment only is used to explain the present invention rather than restriction the present invention.
Embodiment 1:
Prescription: netilmicin sulfate 100g
Pseudobulbus Bletillae polysaccharose 75g
Sodium carbonate 0.5g
Method for preparing:
(1) prepares: behind the used pipeline of conventional treatment dosing, the vessel, with water for injection washing cleaning; Cillin bottle, plug are slightly washed post rinse earlier, dry, sterilize, cool off subsequent use then.
(2) dosing: take by weighing the Pseudobulbus Bletillae polysaccharose of recipe quantity earlier, add injection water 800ml and be made into 40% solution, add netilmicin sulfate and add water for injection 1200ml and stir to full dose and make it dissolving.
(3) decolouring: the medicinal charcoal of adding overall solution volume 0.1%, stirring and adsorbing gets the netilmicin sulfate suspension under the room temperature more than 30 minutes, sampling, the pH value of mensuration medicinal liquid, adding sodium carbonate adjusting pH is 4.8, mensuration content is 49.2mg/ml.
(4) filter packing: after institute's vehicle pH value and content are qualified; Warp 0.22
degerming of microporous filter membrane fine straining; Get the netilmicin sulfate settled solution; Medicinal liquid is filtered to aseptic liquid containing bottle, after inspection medicinal liquid clarity and visible foreign matters are qualified, and packing false add plug.
(5) lyophilization.Products temperature was reduced to-35 ℃ of pre-freezes 2 hours, and went up to-10 ℃ to freeze again 1 hour; Reduce at condenser temperature-50 ℃ stable after, baffle temperature rises to-15 ℃, dry 8 hours of low-temperature distillation; Baffle temperature is set at 30 ℃, and products temperature maintains 26 ℃, vacuum heat-preserving dry 5 hours again.
(6) tamponade, roll lid, packing, check, warehouse-in.
Embodiment 2:
Prescription: netilmicin sulfate 100g
Beta-schardinger dextrin-85g
Sodium bicarbonate 0.6g
Method for preparing:
(1) prepares: behind the used pipeline of conventional treatment dosing, the vessel, with water for injection washing cleaning; Cillin bottle, plug are slightly washed post rinse earlier, dry, sterilize, cool off subsequent use then.
(2) dosing: take by weighing the beta-schardinger dextrin-of recipe quantity earlier, add injection water 800ml and be made into 40% solution, add netilmicin sulfate and add water for injection 1200ml and stir to full dose and make it dissolving.
(3) decolouring: the medicinal charcoal of adding overall solution volume 0.1%, stirring and adsorbing gets the netilmicin sulfate suspension under the room temperature more than 30 minutes, sampling, the pH value of mensuration medicinal liquid, adding sodium bicarbonate adjusting pH is 5.0, mensuration content is 48.7mg/ml.
(4) filter packing: after institute's vehicle pH value and content are qualified; Warp 0.22
degerming of microporous filter membrane fine straining; Get the netilmicin sulfate settled solution; Medicinal liquid is filtered to aseptic liquid containing bottle, after inspection medicinal liquid clarity and visible foreign matters are qualified, and packing false add plug.
(5) lyophilization.Products temperature was reduced to-35 ℃ of pre-freezes 2 hours, and went up to-10 ℃ to freeze again 1 hour; Reduce at condenser temperature-50 ℃ stable after, baffle temperature rises to-15 ℃, dry 10 hours of low-temperature distillation; Baffle temperature is set 30 ℃, and products temperature maintains 26 ℃, vacuum heat-preserving dry 6 hours again.
(6) tamponade, roll lid, packing, check, warehouse-in.
Embodiment 3:
Prescription: netilmicin sulfate 100g
Carbamide 90g
Ammonia 0.8g
Method for preparing:
(1) prepares: behind the used pipeline of conventional treatment dosing, the vessel, with water for injection washing cleaning; Cillin bottle, plug are slightly washed post rinse earlier, dry, sterilize, cool off subsequent use then.
(2) dosing: take by weighing the carbamide of recipe quantity earlier, add injection water 900ml and be made into 45% solution, add netilmicin sulfate and add water for injection 1100ml and stir to full dose and make it dissolving.
(3) decolouring: the medicinal charcoal of adding overall solution volume 0.3%, stirring and adsorbing gets the netilmicin sulfate suspension under the room temperature more than 30 minutes, sampling, the pH value of mensuration medicinal liquid, adding ammonia adjusting pH is 5.3, mensuration content is 49.2mg/ml.
(4) filter packing: after institute's vehicle pH value and content are qualified; Warp 0.22
degerming of microporous filter membrane fine straining; Get the netilmicin sulfate settled solution; Medicinal liquid is filtered to aseptic liquid containing bottle, after inspection medicinal liquid clarity and visible foreign matters are qualified, and packing false add plug.
(5) lyophilization.Products temperature was reduced to-45 ℃ of pre-freezes 2 hours, and went up to-15 ℃ to freeze again 1 hour; Reduce at condenser temperature-50 ℃ stable after, baffle temperature rises to-15 ℃, dry 10 hours of low-temperature distillation; Baffle temperature is set 30 ℃, and products temperature maintains 28 ℃, vacuum heat-preserving dry 5 hours again.
(6) tamponade, roll lid, packing, check, warehouse-in.
Embodiment 4:
Prescription: netilmicin sulfate 100g
Pseudobulbus Bletillae polysaccharose 100g
Sulphuric acid 0.9g
Method for preparing:
(1) prepares: behind the used pipeline of conventional treatment dosing, the vessel, with water for injection washing cleaning; Cillin bottle, plug are slightly washed post rinse earlier, dry, sterilize, cool off subsequent use then.
(2) dosing: take by weighing the Pseudobulbus Bletillae polysaccharose of recipe quantity earlier, add injection water 1000ml and be made into 50% solution, add netilmicin sulfate and add water for injection 1000ml and stir to full dose and make it dissolving.
(3) decolouring: the medicinal charcoal of adding overall solution volume 0.2%, stirring and adsorbing gets the netilmicin sulfate suspension under the room temperature more than 30 minutes, sampling, the pH value of mensuration medicinal liquid, adding sulphuric acid adjusting pH is 5.5, mensuration content is 50.1mg/ml.
(4) filter packing: after institute's vehicle pH value and content are qualified; Warp 0.22
degerming of microporous filter membrane fine straining; Get the netilmicin sulfate settled solution; Medicinal liquid is filtered to aseptic liquid containing bottle, after inspection medicinal liquid clarity and visible foreign matters are qualified, and packing false add plug.
(5) lyophilization.Products temperature was reduced to-40 ℃ of pre-freezes 2 hours, and went up to-20 ℃ to freeze again 1 hour; Reduce at condenser temperature-50 ℃ stable after, baffle temperature rises to-15 ℃, dry 9 hours of low-temperature distillation; Baffle temperature is set 30 ℃, and products temperature maintains 27 ℃, vacuum heat-preserving dry 6 hours again.
(6) tamponade, roll lid, packing, check, warehouse-in.
Embodiment 5:
Prescription: netilmicin sulfate 100g
Beta-cyclodextrin derivative 120g
Phosphatase 11 .0g
processes 1000 bottles
Method for preparing:
(1) prepares: behind the used pipeline of conventional treatment dosing, the vessel, with water for injection washing cleaning; Cillin bottle, plug are slightly washed post rinse earlier, dry, sterilize, cool off subsequent use then.
(2) dosing: take by weighing the beta-cyclodextrin derivative of recipe quantity earlier, add injection water 1000ml and be made into 50% solution, add netilmicin sulfate and add water for injection 1000ml and stir to full dose and make it dissolving.
(3) decolouring: the medicinal charcoal of adding overall solution volume 0.2%, stirring and adsorbing gets the netilmicin sulfate suspension under the room temperature more than 30 minutes, sampling, the pH value of mensuration medicinal liquid, adding phosphoric acid adjusting pH is 5.8, mensuration content is 49.9mg/ml.
(4) filter packing: after institute's vehicle pH value and content are qualified; Warp 0.22
degerming of microporous filter membrane fine straining; Get the netilmicin sulfate settled solution; Medicinal liquid is filtered to aseptic liquid containing bottle, after inspection medicinal liquid clarity and visible foreign matters are qualified, and packing false add plug.
(5) lyophilization.Products temperature was reduced to-40 ℃ of pre-freezes 2 hours, and went up to-20 ℃ to freeze again 1 hour; Reduce at condenser temperature-50 ℃ stable after, baffle temperature rises to-15 ℃, dry 10 hours of low-temperature distillation; Baffle temperature is set 30 ℃, and products temperature maintains 27 ℃, vacuum heat-preserving dry 5 hours again.
(6) tamponade, roll lid, packing, check, warehouse-in.
Table one: the embodiment investigation result that writes out a prescription
In sum, each item index of embodiment is all better, in conjunction with cost of supplementary product with produce man-hour, embodiment 4 is an optimum formula.
Quality stability is investigated.The sample of above embodiment 4 preparations and other powder pin goods of listing are put in carry out long-term 18 months test under the condition of 25 ℃ of temperature, relative humidity 60% ± 10% and investigate; Be put in the test of quickening 6 months under the condition of 40 ℃ of temperature, relative humidity 75% ± 10% and investigate result of the test such as following table:
Table two: long-term test results
Table three: accelerated test result
Above result shows the test investigation that the embodiment sample quickened 6 months under the condition of carrying out long-term 18 months test investigation and 40 ℃ of temperature, relative humidity 75% ± 10% under the condition of 25 ℃ of temperature, relative humidity 60% ± 10%; Character, pH value, clarity, related substance, content detection have no significant change; The equal conformance with standard requirement of each item index, constant product quality.
Safety testing.Bacterial endotoxin is investigated the inspection according to two appendix XI of Chinese Pharmacopoeia version in 2010 E, contains endotoxic amount all less than 1.2EU in every 1mg netilmicin.Meet standards of pharmacopoeia.
Claims (3)
1. netilmicin sulfate freeze-dried powder; It is characterized in that comprising that netilmicin sulfate and additives process through the method that comprises following steps: additives are added injection water wiring solution-forming; Fully add the netilmicin sulfate stirring and dissolving behind the mixing and get the netilmicin sulfate suspension; The filtration of netilmicin sulfate suspension, packing, lyophilization are got the netilmicin sulfate freeze-dried powder; Wherein said additives are enclose molecule and pH regulator agent, and wherein netilmicin sulfate 100g, enclose molecule 75-120g, pH regulator agent 0.5-1.0g adjust pH are 4.8-5.8; Described enclose molecule is selected from Pseudobulbus Bletillae polysaccharose, beta-schardinger dextrin-, carbamide, thiourea, beta-cyclodextrin derivative, deoxycholic acid and starch; Described pH regulator agent is selected from sodium carbonate, sodium bicarbonate, ammonia, sulphuric acid and phosphoric acid.
2. the method for preparing of a netilmicin sulfate freeze-dried powder is characterized in that comprising following steps:
The enclose molecule is added the injection water be made into 40～50% solution; Add the netilmicin sulfate stirring and dissolving and add to the full amount of water for injection, stir the netilmicin sulfate suspension, the medicinal charcoal that adds overall solution volume 0.1 ~ 0.3% stirs; Absorption is more than 30 minutes; Solution temperature is controlled at below 33 ℃, and taking liquid detects, and regulating pH value is 4.8-5.8 and mensuration solution content;
After the assay was approved, the coarse filtration carbon removal, with the aseptic filtration of 0.22um microporous filter membrane, the sterile liquid medicine fill in vial, lyophilization, gland, label, pack netilmicin sulfate freeze-dried powder finished product.
3. the method for preparing of a kind of netilmicin sulfate freeze-dried powder according to claim 2 is characterized in that said freeze drying process comprises the steps:
1. pre-freeze: products temperature was reduced to-35～-45 ℃ of pre-freezes 2 hours, and went up to-10～-20 ℃ to freeze again 1 hour;
2. sublimation drying: reduce at condenser temperature-50 ℃ stable after, baffle temperature rises to-15 ℃, dry 8-10 hour of low-temperature distillation;
3. dry again: baffle temperature is set at 30 ℃, and products temperature maintains 26～28 ℃, dry again 5-7 hour of vacuum heat-preserving.
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| CN103610653A (en) * | 2013-11-27 | 2014-03-05 | 海南通用康力制药有限公司 | Preparation method of netilmicin sulfate freeze-dried powder for injection |
| CN105147599A (en) * | 2015-09-21 | 2015-12-16 | 成都天台山制药有限公司 | Netilmicin sulfate injection and preparing method |
| CN105213301A (en) * | 2015-09-21 | 2016-01-06 | 成都天台山制药有限公司 | Netilmicin sulfate inj and quality control method thereof |
| CN113171348A (en) * | 2021-04-28 | 2021-07-27 | 海南通用康力制药有限公司 | Preparation method of netilmicin sulfate sterile powder injection for injection |
| CN114146058A (en) * | 2020-09-07 | 2022-03-08 | 常州方圆制药有限公司 | Etimicin sulfate freeze-dried powder injection and preparation method thereof |
| WO2022227115A1 (en) * | 2021-04-26 | 2022-11-03 | 海南通用康力制药有限公司 | Preparation method for sisomicin sulfate sterile powder injection for injection |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103610653A (en) * | 2013-11-27 | 2014-03-05 | 海南通用康力制药有限公司 | Preparation method of netilmicin sulfate freeze-dried powder for injection |
| CN103610653B (en) * | 2013-11-27 | 2016-05-11 | 海南通用康力制药有限公司 | A kind of preparation method of injection netilmicin sulfate freeze-dried powder |
| CN105147599A (en) * | 2015-09-21 | 2015-12-16 | 成都天台山制药有限公司 | Netilmicin sulfate injection and preparing method |
| CN105213301A (en) * | 2015-09-21 | 2016-01-06 | 成都天台山制药有限公司 | Netilmicin sulfate inj and quality control method thereof |
| CN105213301B (en) * | 2015-09-21 | 2018-07-27 | 成都天台山制药有限公司 | Netilmicin sulfate injection and its quality control method |
| CN105147599B (en) * | 2015-09-21 | 2018-07-27 | 成都天台山制药有限公司 | Netilmicin sulfate injection and preparation method |
| CN114146058A (en) * | 2020-09-07 | 2022-03-08 | 常州方圆制药有限公司 | Etimicin sulfate freeze-dried powder injection and preparation method thereof |
| WO2022227115A1 (en) * | 2021-04-26 | 2022-11-03 | 海南通用康力制药有限公司 | Preparation method for sisomicin sulfate sterile powder injection for injection |
| CN113171348A (en) * | 2021-04-28 | 2021-07-27 | 海南通用康力制药有限公司 | Preparation method of netilmicin sulfate sterile powder injection for injection |
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| CN102525963B (en) | 2013-05-08 |
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