CN103920154B - Tetracaine hydrochloride pharmaceutical composition for injection and preparation method of pharmaceutical composition - Google Patents
Tetracaine hydrochloride pharmaceutical composition for injection and preparation method of pharmaceutical composition Download PDFInfo
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- CN103920154B CN103920154B CN201410147858.0A CN201410147858A CN103920154B CN 103920154 B CN103920154 B CN 103920154B CN 201410147858 A CN201410147858 A CN 201410147858A CN 103920154 B CN103920154 B CN 103920154B
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- pharmaceutical composition
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- tartaric acid
- tetracaine hydrochloride
- butethanol
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- PPWHTZKZQNXVAE-UHFFFAOYSA-N Tetracaine hydrochloride Chemical compound Cl.CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 PPWHTZKZQNXVAE-UHFFFAOYSA-N 0.000 title claims abstract description 87
- 229960002494 tetracaine hydrochloride Drugs 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 48
- 239000007924 injection Substances 0.000 title claims abstract description 42
- 238000002347 injection Methods 0.000 title claims abstract description 42
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 40
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 46
- 235000002906 tartaric acid Nutrition 0.000 claims abstract description 46
- 239000011975 tartaric acid Substances 0.000 claims abstract description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 49
- 239000000243 solution Substances 0.000 claims description 35
- 239000008215 water for injection Substances 0.000 claims description 35
- 239000000203 mixture Substances 0.000 claims description 29
- 239000000047 product Substances 0.000 claims description 25
- 238000003756 stirring Methods 0.000 claims description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- 239000012528 membrane Substances 0.000 claims description 24
- 238000010792 warming Methods 0.000 claims description 24
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 14
- 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 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 238000005056 compaction Methods 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 12
- 238000004108 freeze drying Methods 0.000 claims description 12
- 238000007689 inspection Methods 0.000 claims description 12
- 239000011265 semifinished product Substances 0.000 claims description 12
- 229910000831 Steel Inorganic materials 0.000 claims description 2
- 239000010959 steel Substances 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 20
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 10
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000003860 storage Methods 0.000 abstract description 3
- 230000002035 prolonged effect Effects 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 26
- 238000009472 formulation Methods 0.000 description 26
- 238000012360 testing method Methods 0.000 description 25
- 238000005516 engineering process Methods 0.000 description 14
- 239000000126 substance Substances 0.000 description 13
- 238000000034 method Methods 0.000 description 11
- 238000013019 agitation Methods 0.000 description 10
- 230000008859 change Effects 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000008354 sodium chloride injection Substances 0.000 description 8
- 206010018910 Haemolysis Diseases 0.000 description 7
- 230000008588 hemolysis Effects 0.000 description 7
- 210000003743 erythrocyte Anatomy 0.000 description 6
- 238000005286 illumination Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 230000004520 agglutination Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000003511 endothelial effect Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 240000007711 Peperomia pellucida Species 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 230000003118 histopathologic effect Effects 0.000 description 1
- 230000036540 impulse transmission Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 230000028161 membrane depolarization Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000009781 safety test method Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
Abstract
The invention provides a novel tetracaine hydrochloride pharmaceutical composition for injection and a preparation method of the pharmaceutical composition. A small amount of tartaric acid is used in a prescription, so that the stability of the product is remarkably improved, the product can be further stored stable for a long time under the condition of high temperature, high humidity and light, and the storage time is prolonged. The preparation process is simple and free from nitrogen charge operation, and the demand on the production equipment is reduced, so that the invention is more suitable for production on a large scale.
Description
Technical field
The present invention relates to a kind of medicinal composition for injections and preparation technology thereof, particularly a kind of butethanol of injection pharmaceutical composition and preparation method thereof, belongs to medical art.
Background technology
Butethanol of injection, as a kind of local anaesthetics, acts on peripheral nervous, stablizes neural tissue cell film, reduces sodium ion inflow, and normal polarization is alternately obstructed with depolarization, and neural impulse transmission cannot be carried out, and plays analgesic effect.Be mainly used in surperficial local anaesthesia, nerve block and block inside vertebral canal clinically.Commercialized product dosage form has injection and injection freeze-dried powder.Because tetracaine hydrochloride injection is unstable, standing time, slightly precipitation be decomposed or be separated out to length just can, therefore develops a kind of stay-in-grade butethanol of injection freeze-dried powder and seem particularly important.
Application number is the Chinese patent of 97110524.6, disclosing a kind of butethanol of injection lyophilized injectable powder, by being dissolved in water for injection by tetracaine hydrochloride, adding activated carbon filtration, and subpackage postlyophilization obtains.The quality research data of the unexposed obtained product of this patent, product effect is unknown.
Application number is the Chinese patent of 98110524.6, discloses a kind of preparation method of butethanol of injection.By preparing certain density Tetracaine Hydrochloride Solution, by joined solution successively after overcharging nitrogen, sterilization, filtration, subpackage, make butethanol of injection through vacuum freeze-drying technique.But fill nitrogen technique because this patent uses, higher to the requirement of equipment, and the nitrogen colorless and odorless be filled with, whether enough from the nitrogen that cannot judge in appearance to be filled with, if equipment fault occur in preparation process and stop filling nitrogen, can not discover rapidly, product quality is difficult to ensure.
For the problems referred to above, this area needs to find one and guarantees tetracaine hydrochloride steady quality, and evident in efficacy, toxic and side effects is few, and the compositions that technique is simply new and technique, the present invention meets such demand.
Summary of the invention
The invention provides a kind of new butethanol of injection pharmaceutical composition and preparation method thereof, prescription is simple, and technique is easy to operation, and the constant product quality prepared is safe and reliable.
For achieving the above object, butethanol of injection pharmaceutical composition provided by the invention, is made up of tetracaine hydrochloride, tartaric acid.
Preferably, the pharmaceutical composition of per unit preparation is composed of the following components: tetracaine hydrochloride 25mg ~ 50mg, tartaric acid 0.5mg ~ 2.5mg.
Preferred, the pharmaceutical composition of per unit preparation is composed of the following components: tetracaine hydrochloride 25mg ~ 50mg, tartaric acid 1.0mg ~ 2.0mg.
Wherein, the pharmaceutical composition of per unit preparation is composed of the following components: tetracaine hydrochloride 25mg, tartaric acid 0.5mg.
Or the pharmaceutical composition of per unit preparation is composed of the following components: tetracaine hydrochloride 25mg, tartaric acid 2.5mg.
Or the pharmaceutical composition of per unit preparation is composed of the following components: tetracaine hydrochloride 25mg, tartaric acid 1.0mg.
Or the pharmaceutical composition of per unit preparation is composed of the following components: tetracaine hydrochloride 25mg, tartaric acid 1.5mg.
Or the pharmaceutical composition of per unit preparation is composed of the following components: tetracaine hydrochloride 25mg, tartaric acid 2.0mg.
Or the pharmaceutical composition of per unit preparation is composed of the following components: tetracaine hydrochloride 50mg, tartaric acid 0.5mg.
Or the pharmaceutical composition of per unit preparation is composed of the following components: tetracaine hydrochloride 50mg, tartaric acid 2.5mg.
Or the pharmaceutical composition of per unit preparation is composed of the following components: tetracaine hydrochloride 50mg, tartaric acid 1.0mg.
Or the pharmaceutical composition of per unit preparation is composed of the following components: tetracaine hydrochloride 50mg, tartaric acid 1.5mg.
Or the pharmaceutical composition of per unit preparation is composed of the following components: tetracaine hydrochloride 50mg, tartaric acid 2.0mg.
Present invention also offers a kind of preparation method of butethanol of injection pharmaceutical composition, the method comprises the following steps:
Add preparation total amount 80% water for injection in rustless steel container, first add the tartaric acid of recipe quantity, after stirring and dissolving, add the tetracaine hydrochloride of recipe quantity, stir and make to dissolve completely, add 0.1% active carbon, 50 DEG C of insulated and stirred 15 minutes, use 0.45 μm of microporous filter membrane coarse filtration while hot, obtain filtrate; Inject water to nearly full dose, adjust pH to 4.8 ~ 5.1 with 0.1mol/L hydrochloric acid solution, add to the full amount of water for injection; With 0.22 μm of microporous filter membrane fine straining, carry out the inspection of semifinished product, after qualified with every bottled 1.0ml fill in 3ml cillin bottle; Be placed in freeze drying box ,-50 DEG C ~-40 DEG C pre-freeze 1 ~ 4h, start evacuation, vacuum control, between 10 ~ 30Pa, is warming up to-25 DEG C ~ 0 DEG C and keeps 4 ~ 12h, is warming up to 20 DEG C ~ 30 DEG C and keeps 4 ~ 10h, take out after compaction plug and roll lid, obtain sterile cryo dry product.
The butethanol of injection prepared by the present invention is had the following advantages:
(1) use a small amount of tartaric acid in prescription of the present invention, product stability is significantly improved, under high temperature, high humidity and illumination condition, also can keep stable for a long time, period of storage is extended;
(2) preparation technology of the present invention is simple, does not need to carry out filling nitrogen operation, reduces the requirement to production equipment, is more suitable for large need of production, avoid simultaneously and fill the insufficient risk causing unstable product quality of nitrogen, more can guarantee that product quality meets the requirements.
(3) product quality is better.Adopt butethanol of injection prepared by prescription of the present invention and technique, in the clarity and color, moisture and related substance of outward appearance, redissolution speed, solution, be all better than prior art; In addition, with 0.9% sodium chloride injection compatibility after in 24 hours the quality of sample be better than the prior art under the same terms.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in further detail, but not limitation of the present invention, and the equivalent replacement of all any this areas done according to the disclosure of invention, all belongs to protection scope of the present invention.
Embodiment 1: butethanol of injection (in 1000 bottles, unit: g)
| Tetracaine hydrochloride | 25g |
| Tartaric acid | 0.5g |
| Water for injection adds to | 1000ml |
Preparation technology: the water for injection injecting 800ml in Agitation Tank, first adds 0.5g tartaric acid, after stirring and dissolving, add 25g tetracaine hydrochloride, stir and make to dissolve completely, add 0.1% active carbon, 50 DEG C of insulated and stirred 15 minutes, use 0.45 μm of microporous filter membrane coarse filtration while hot, obtain filtrate; Inject water to nearly full dose, adjust pH to 4.8 with 0.1mol/L hydrochloric acid solution, add to the full amount of water for injection; With 0.22 μm of microporous filter membrane fine straining, carry out the inspection of semifinished product, after qualified with every bottled 1.0ml fill in 3ml cillin bottle; Be placed in freeze drying box ,-40 DEG C of pre-freeze 4h, start evacuation, vacuum control, between 10 ~ 30Pa, is warming up to-25 DEG C and keeps 12h, is warming up to 30 DEG C and keeps 4h, takes out and rolls lid, obtain sterile cryo dry product after compaction plug.
Embodiment 2: butethanol of injection (in 1000 bottles, unit: g)
| Tetracaine hydrochloride | 25g |
| Tartaric acid | 2.5g |
| Water for injection adds to | 1000ml |
Preparation technology: the water for injection injecting 800ml in Agitation Tank, first adds 2.5g tartaric acid, after stirring and dissolving, add 25g tetracaine hydrochloride, stir and make to dissolve completely, add 0.1% active carbon, 50 DEG C of insulated and stirred 15 minutes, use 0.45 μm of microporous filter membrane coarse filtration while hot, obtain filtrate; Inject water to nearly full dose, adjust pH to 5.1 with 0.1mol/L hydrochloric acid solution, add to the full amount of water for injection; With 0.22 μm of microporous filter membrane fine straining, carry out the inspection of semifinished product, after qualified with every bottled 1.0ml fill in 3ml cillin bottle; Be placed in freeze drying box ,-50 DEG C of pre-freeze 1h, start evacuation, vacuum control, between 10 ~ 30Pa, is warming up to 0 DEG C and keeps 4h, is warming up to 20 DEG C and keeps 10h, takes out and rolls lid, obtain sterile cryo dry product after compaction plug.
Embodiment 3: butethanol of injection prescription (in 1000 bottles, unit: g)
| Tetracaine hydrochloride | 25g |
| Tartaric acid | 1.0g |
| Water for injection adds to | 1000ml |
Preparation technology: the water for injection injecting 800ml in Agitation Tank, first adds 1.0g tartaric acid, after stirring and dissolving, add 25g tetracaine hydrochloride, stir and make to dissolve completely, add 0.1% active carbon, 50 DEG C of insulated and stirred 15 minutes, use 0.45 μm of microporous filter membrane coarse filtration while hot, obtain filtrate; Inject water to nearly full dose, adjust pH to 4.9 with 0.1mol/L hydrochloric acid solution, add to the full amount of water for injection; With 0.22 μm of microporous filter membrane fine straining, carry out the inspection of semifinished product, after qualified with every bottled 1.0ml fill in 3ml cillin bottle; Be placed in freeze drying box ,-40 DEG C of pre-freeze 3h, start evacuation, vacuum control, between 10 ~ 30Pa, is warming up to-15 DEG C and keeps 6h, is warming up to 20 DEG C and keeps 6h, takes out and rolls lid, obtain sterile cryo dry product after compaction plug.
Embodiment 4: butethanol of injection (in 1000 bottles, unit: g)
| Tetracaine hydrochloride | 25g |
| Tartaric acid | 1.5g |
| Water for injection adds to | 1000ml |
Preparation technology: the water for injection injecting 800ml in Agitation Tank, first adds 1.5g tartaric acid, after stirring and dissolving, add 25g tetracaine hydrochloride, stir and make to dissolve completely, add 0.1% active carbon, 50 DEG C of insulated and stirred 15 minutes, use 0.45 μm of microporous filter membrane coarse filtration while hot, obtain filtrate; Inject water to nearly full dose, adjust pH to 5.0 with 0.1mol/L hydrochloric acid solution, add to the full amount of water for injection; With 0.22 μm of microporous filter membrane fine straining, carry out the inspection of semifinished product, after qualified with every bottled 1.0ml fill in 3ml cillin bottle; Be placed in freeze drying box ,-40 DEG C of pre-freeze 4h, start evacuation, vacuum control, between 10 ~ 30Pa, is warming up to-10 DEG C and keeps 9h, is warming up to 25 DEG C and keeps 5h, takes out and rolls lid, obtain sterile cryo dry product after compaction plug.
Embodiment 5: butethanol of injection (in 1000 bottles, unit: g)
| Tetracaine hydrochloride | 25g |
| Tartaric acid | 2.0g |
| Water for injection adds to | 1000ml |
Preparation technology: the water for injection injecting 800ml in Agitation Tank, first adds 2.0g tartaric acid, after stirring and dissolving, add 25g tetracaine hydrochloride, stir and make to dissolve completely, add 0.1% active carbon, 50 DEG C of insulated and stirred 15 minutes, use 0.45 μm of microporous filter membrane coarse filtration while hot, obtain filtrate; Inject water to nearly full dose, adjust pH to 4.8 with 0.1mol/L hydrochloric acid solution, add to the full amount of water for injection; With 0.22 μm of microporous filter membrane fine straining, carry out the inspection of semifinished product, after qualified with every bottled 1.0ml fill in 3ml cillin bottle; Be placed in freeze drying box ,-45 DEG C of pre-freeze 2h, start evacuation, vacuum control, between 10 ~ 30Pa, is warming up to-5 DEG C and keeps 8h, is warming up to 25 DEG C and keeps 8h, takes out and rolls lid, obtain sterile cryo dry product after compaction plug.
Embodiment 6: butethanol of injection (in 1000 bottles, unit: g)
| Tetracaine hydrochloride | 50g |
| Tartaric acid | 0.5g |
| Water for injection adds to | 1000ml |
Preparation technology: the water for injection injecting 800ml in Agitation Tank, first adds 0.5g tartaric acid, after stirring and dissolving, add 50g tetracaine hydrochloride, stir and make to dissolve completely, add 0.1% active carbon, 50 DEG C of insulated and stirred 15 minutes, use 0.45 μm of microporous filter membrane coarse filtration while hot, obtain filtrate; Inject water to nearly full dose, adjust pH to 4.9 with 0.1mol/L hydrochloric acid solution, add to the full amount of water for injection; With 0.22 μm of microporous filter membrane fine straining, carry out the inspection of semifinished product, after qualified with every bottled 1.0ml fill in 3ml cillin bottle; Be placed in freeze drying box ,-45 DEG C of pre-freeze 3h, start evacuation, vacuum control, between 10 ~ 30Pa, is warming up to-20 DEG C and keeps 10h, is warming up to 25 DEG C and keeps 6h, takes out and rolls lid, obtain sterile cryo dry product after compaction plug.
Embodiment 7: butethanol of injection (in 1000 bottles, unit: g)
| Tetracaine hydrochloride | 50g |
| Tartaric acid | 2.5g |
| Water for injection adds to | 1000ml |
Preparation technology: the water for injection injecting 800ml in Agitation Tank, first adds 2.5g tartaric acid, after stirring and dissolving, add 50g tetracaine hydrochloride, stir and make to dissolve completely, add 0.1% active carbon, 50 DEG C of insulated and stirred 15 minutes, use 0.45 μm of microporous filter membrane coarse filtration while hot, obtain filtrate; Inject water to nearly full dose, adjust pH to 5.0 with 0.1mol/L hydrochloric acid solution, add to the full amount of water for injection; With 0.22 μm of microporous filter membrane fine straining, carry out the inspection of semifinished product, after qualified with every bottled 1.0ml fill in 3ml cillin bottle; Be placed in freeze drying box ,-50 DEG C of pre-freeze 2h, start evacuation, vacuum control, between 10 ~ 30Pa, is warming up to-25 DEG C and keeps 4h, is warming up to 30 DEG C and keeps 10h, takes out and rolls lid, obtain sterile cryo dry product after compaction plug.
Embodiment 8: butethanol of injection (in 1000 bottles, unit: g)
| Tetracaine hydrochloride | 50g |
| Tartaric acid | 1.0g |
| Water for injection adds to | 1000ml |
Preparation technology: the water for injection injecting 800ml in Agitation Tank, first adds 1.0g tartaric acid, after stirring and dissolving, add 50g tetracaine hydrochloride, stir and make to dissolve completely, add 0.1% active carbon, 50 DEG C of insulated and stirred 15 minutes, use 0.45 μm of microporous filter membrane coarse filtration while hot, obtain filtrate; Inject water to nearly full dose, adjust pH to 5.1 with 0.1mol/L hydrochloric acid solution, add to the full amount of water for injection; With 0.22 μm of microporous filter membrane fine straining, carry out the inspection of semifinished product, after qualified with every bottled 1.0ml fill in 3ml cillin bottle; Be placed in freeze drying box ,-50 DEG C of pre-freeze 3h, start evacuation, vacuum control, between 10 ~ 30Pa, is warming up to-10 DEG C and keeps 7h, is warming up to 20 DEG C and keeps 4h, takes out and rolls lid, obtain sterile cryo dry product after compaction plug.
Embodiment 9: butethanol of injection (in 1000 bottles, unit: g)
| Tetracaine hydrochloride | 50g |
| Tartaric acid | 1.5g |
| Water for injection adds to | 1000ml |
Preparation technology: the water for injection injecting 800ml in Agitation Tank, first adds 1.5g tartaric acid, after stirring and dissolving, add 50g tetracaine hydrochloride, stir and make to dissolve completely, add 0.1% active carbon, 50 DEG C of insulated and stirred 15 minutes, use 0.45 μm of microporous filter membrane coarse filtration while hot, obtain filtrate; Inject water to nearly full dose, adjust pH to 4.8 with 0.1mol/L hydrochloric acid solution, add to the full amount of water for injection; With 0.22 μm of microporous filter membrane fine straining, carry out the inspection of semifinished product, after qualified with every bottled 1.0ml fill in 3ml cillin bottle; Be placed in freeze drying box ,-46 DEG C of pre-freeze 1h, start evacuation, vacuum control, between 10 ~ 30Pa, is warming up to 0 DEG C and keeps 12h, is warming up to 28 DEG C and keeps 5h, takes out and rolls lid, obtain sterile cryo dry product after compaction plug.
Embodiment 10: butethanol of injection (in 1000 bottles, unit: g)
| Tetracaine hydrochloride | 50g |
| Tartaric acid | 2.0g |
| Water for injection adds to | 1000ml |
Preparation technology: the water for injection injecting 800ml in Agitation Tank, first adds 2.0g tartaric acid, after stirring and dissolving, add 50g tetracaine hydrochloride, stir and make to dissolve completely, add 0.1% active carbon, 50 DEG C of insulated and stirred 15 minutes, use 0.45 μm of microporous filter membrane coarse filtration while hot, obtain filtrate; Inject water to nearly full dose, adjust pH to 5.1 with 0.1mol/L hydrochloric acid solution, add to the full amount of water for injection; With 0.22 μm of microporous filter membrane fine straining, carry out the inspection of semifinished product, after qualified with every bottled 1.0ml fill in 3ml cillin bottle; Be placed in freeze drying box ,-43 DEG C of pre-freeze 2h, start evacuation, vacuum control, between 10 ~ 30Pa, is warming up to-18 DEG C and keeps 11h, is warming up to 24 DEG C and keeps 9h, takes out and rolls lid, obtain sterile cryo dry product after compaction plug.
Comparative formulation 1: be that prescription and the technique of embodiment 1 in the Chinese patent of 97109821.2 prepares according to application number, specification: every bottle of 50mg;
Comparative formulation 2: the method being embodiment 2 in 98110524.6 Chinese patents according to application number prepares Comparative formulation 2, tetracaine hydrochloride concentration is 2%(g/ml).
Test example 1 quality research is tested
Get sample and Comparative formulation 1, each 20 of Comparative formulation 2 sample of the embodiment of the present invention 1,3,7,10 preparation, respectively at high temperature (60 DEG C), illumination (4500lx, 25 DEG C), high humidity (25 DEG C, RH92.5%) place 10 days under condition, the mensuration of outward appearance, redissolution speed, the clarity of solution and color, moisture, related substance is carried out respectively at sampling in the 0th day, 5 days, 10 days, wherein measure redissolution speed with 0.9% sodium chloride injection, result of the test is as shown in table 1.
Table 1 embodiment of the present invention and Comparative formulation quality comparation
Result shows, 0 day time, embodiment of the present invention sample and the equal outward appearance of Comparative formulation 1,2 sample full, in white loose block, solution is colourless clear liquid, and content, related substance all conform with the regulations, each other no significant difference; But the moisture of embodiment of the present invention sample is significantly less than Comparative formulation 1,2 sample, and the speed of redissolution is obviously faster than Comparative formulation 1,2 sample.
Placing after 10 days under high humidity (25 DEG C, RH92.5%) condition, compared with 0 day, all there is not significant change in embodiment of the present invention sample and Comparative formulation 1,2 sample indices.
Place 10 days under high temperature (60 DEG C) with illumination (4500lx, 25 DEG C) condition after, all there is not significant change in embodiment of the present invention sample indices; There is not significant change in the moisture of Comparative formulation 1,2 sample, all the other indices all there occurs significant change.Comparative formulation 1 sample appearance becomes off-white color atrophy block from white loose block, and Comparative formulation 2 sample then becomes off-white color and to loosen block; In addition, it is obviously slack-off that both redissolve speed, solution colour by colourless become faint yellow.And Comparative formulation 1 sample related substance exceeds prescribed limit, Comparative formulation 2 sample is placed rear related substance under the high temperature conditions and is exceeded prescribed limit, transfers postpone related substance close to prescribed limit at illumination condition.
As can be seen from the above results, place after 10 days under influence factor's condition, embodiment of the present invention sample indices is all highly stable, and significant change does not occur; And Comparative formulation 1,2 sample there occurs significant change on outward appearance, clarity of solution, redissolution speed index.Comparative formulation 1 sample related substance is beyond prescribed limit, and Comparative formulation 2 sample is placed rear related substance under the high temperature conditions and exceeded prescribed limit, transfers postpone related substance close to prescribed limit at illumination condition.As can be seen here, embodiment of the present invention sample is all better than Comparative formulation 1, Comparative formulation 2 sample in the clarity of outward appearance, redissolution speed, solution and color, moisture, related substance, product quality and stability better.
Test example 2 compatibility mechanism
The usage and dosage that butethanol of injection description according to State Food and Drug Administration's approval specifies, respectively the embodiment of the present invention 1,3,7,10 sample and Comparative formulation 1,2 sample being mixed with tetracaine hydrochloride concentration with 0.9% sodium chloride injection is 0.1%(g/ml) solution, investigate its after compatibility when ambient temperatare sets to 0 h, 12h, 24h the situation of change of character, content and related substance.Result of the test sees the following form 2.
Table 2 compatibility mechanism result
Result shows: after embodiment 1,3,7,10 sample compatibility, obvious change does not all occur for the character of medicinal liquid, content and related substance, solution colour generation significant change during medicinal liquid placement 24h after Comparative formulation 1,2 sample compatibility, Comparative formulation 1 sample compatible solution becomes yellow from colourless, Comparative formulation 2 sample compatible solution from colourless become faint yellow; In addition, both slightly reduce by content, and related substance all exceeds standard prescribed limit.Place in 24h process with 0.9% sodium chloride injection compatibility as can be seen from the test results, the embodiment of the present invention 1,3,7,10 sample quality stablizes, and is significantly better than the Comparative formulation 1 under the same terms and Comparative formulation 2 sample.
Test example 3 safety testing
By hemolytic and Local irritation study, the safety of butethanol of injection pharmaceutical composition prepared by the present invention is verified.
The preparation of need testing solution: with 0.9% sodium chloride injection, embodiment 1, embodiment 3, embodiment 7, embodiment 10 sample being mixed with tetracaine hydrochloride concentration is respectively 0.1%(g/ml) solution, as need testing solution, for subsequent use.
(1) haemolysis and agglutination test
The preparation of 2% red blood cell suspension: get healthy rabbits blood, put into conical flask, stir blood with Glass rod, to remove Fibrinogen, makes into defibrinated blood.Add 0.9% sodium chloride solution about 10 times amount, shake up, per minute 1000 ~ 1500 leave the heart 15 minutes, removing supernatant, and the erythrocyte of precipitation washs 2 ~ 3 times as stated above with 0.9% sodium chloride solution again, to the not aobvious redness of supernatant.The erythrocyte of gained is made the suspension of 2% with 0.9% sodium chloride solution, be for experiment.
Get 14, cleaned glass test tube and number, wherein 1, No. 2 pipe is embodiment 1 sample test sample pipe, 3, No. 4 pipes are embodiment 3 sample test sample pipe, 5, No. 6 pipes are embodiment 7 sample test sample pipe, 7, No. 8 pipes are embodiment 10 sample test sample pipe, No. 9 pipes are negative control pipe, No. 10 pipes are positive control pipe, No. 11 pipes are embodiment 1 test sample control tube, No. 12 pipes are embodiment 3 test sample control tube, No. 13 pipes are embodiment 7 test sample control tube, and No. 14 pipes are embodiment 10 test sample control tube.Add 2% red cell suspension, 0.9% sodium chloride solution, distilled water shown according to the form below successively, after mixing, put immediately in the calorstat of 37 DEG C ± 0.5 DEG C and carry out incubation, after 3 hours, observe haemolysis and aggregation.
Table 3 haemolysis and agglutination test scheme
The haemolysis situation of each pipe of perusal, found that, namely occurs haemolysis after positive control pipe (No. 10 pipes) adds distilled water in 15 minutes; 11 ~ No. 14 pipes are colourless clear liquid, and 1 ~ No. 9 pipe erythrocyte sinks, and supernatant achromatism and clarity, manages almost zero difference with 11 ~ No. 14, shows that the embodiment of the present invention 1,3,7,10 sample all occurs without haemolysis; Reversed 3 times gently by 1 ~ No. 9 pipe, visible red cell evenly scatters, and proves without red blood cell condensation.Result shows: the butethanol of injection that the embodiment of the present invention 1,3,7,10 provides to family's rabbit erythrocyte without haemolysis and cause cohesion.
(2) irritation test
Get health, ear edge not damaged rabbit 30, be divided into A, B, C, D, E five groups at random, often organize 6.Wherein, A group: embodiment 1 sample need testing solution, B group: embodiment 3 sample need testing solution, C group: embodiment 7 sample need testing solution, D group: embodiment 10 sample need testing solution, E group: 0.9% sodium chloride injection matched group.To be in the intravenous drip of rabbit ear edge above-mentioned A, B, C, D, E five groups of injection with aseptic manipulation respectively.Through multiple dosing, perusal phenomenon is: when vein slowly instils, animal is without struggle reaction, and medication local has no the symptom such as congested, red and swollen, and blood vessel lines is very clear, and surrounding tissue is without obvious edema.Histopathologic slide's check result is visible: auricular vein is without endothelial denudation, and Endothelial Structure is complete, without thrombosis, also has no other extremely, compares no significant difference with 0.9% sodium chloride injection group.Result shows, butethanol of injection pharmaceutical composition of the present invention is to blood vessel nonirritant.
Known by above-mentioned result of the test, adopt the butethanol of injection pharmaceutical composition that prescription of the present invention and technique prepare, prescription is simple, only use a small amount of tartaric acid, just product stability is made to significantly improve, can keep stable for a long time under high temperature, high humidity and illumination condition, period of storage is extended; And, with after 0.9% sodium chloride injection compatibility in 24 hours the quality of sample be better than the prior art under the same terms.In addition, preparation technology of the present invention is simple, does not need to carry out filling nitrogen operation, reduces the requirement to production equipment, is more suitable for large need of production, avoid simultaneously and fill the insufficient risk causing unstable product quality of nitrogen, more can guarantee that product quality meets the requirements.
Claims (8)
1. a butethanol of injection pharmaceutical composition, is characterized in that, the pharmaceutical composition of per unit preparation is composed of the following components: tetracaine hydrochloride 25mg ~ 50mg, tartaric acid 0.5mg ~ 2.5mg; Wherein, the preparation method of said composition comprises the following steps:
Add preparation total amount 80% water for injection in rustless steel container, first add the tartaric acid of recipe quantity, after stirring and dissolving, add the tetracaine hydrochloride of recipe quantity, stir and make to dissolve completely, add 0.1% active carbon, 50 DEG C of insulated and stirred 15 minutes, use 0.45 μm of microporous filter membrane coarse filtration while hot, obtain filtrate; Inject water to nearly full dose, adjust pH to 4.8 ~ 5.1 with 0.1mol/L hydrochloric acid solution, add to the full amount of water for injection; With 0.22 μm of microporous filter membrane fine straining, carry out the inspection of semifinished product, after qualified with every bottled 1.0ml fill in 3ml cillin bottle; Be placed in freeze drying box ,-50 DEG C ~-40 DEG C pre-freeze 1 ~ 4h, start evacuation, vacuum control, between 10 ~ 30Pa, is warming up to-25 DEG C ~ 0 DEG C and keeps 4 ~ 12h, is warming up to 20 DEG C ~ 30 DEG C and keeps 4 ~ 10h, take out after compaction plug and roll lid, obtain sterile cryo dry product.
2. butethanol of injection pharmaceutical composition according to claim 1, is characterized in that, the pharmaceutical composition of per unit preparation is composed of the following components: tetracaine hydrochloride 25mg ~ 50mg, tartaric acid 1.0mg ~ 2.0mg.
3. butethanol of injection pharmaceutical composition according to claim 1, is characterized in that, the pharmaceutical composition of per unit preparation is composed of the following components: tetracaine hydrochloride 25mg, tartaric acid 0.5mg.
4. butethanol of injection pharmaceutical composition according to claim 1, is characterized in that, the pharmaceutical composition of per unit preparation is composed of the following components: tetracaine hydrochloride 25mg, tartaric acid 1.0mg.
5. butethanol of injection pharmaceutical composition according to claim 1, is characterized in that, the pharmaceutical composition of per unit preparation is composed of the following components: tetracaine hydrochloride 50mg, tartaric acid 2.0mg.
6. butethanol of injection pharmaceutical composition according to claim 1, is characterized in that, the pharmaceutical composition of per unit preparation is composed of the following components: tetracaine hydrochloride 50mg, tartaric acid 2.5mg.
7. butethanol of injection pharmaceutical composition according to claim 1, is characterized in that, the pharmaceutical composition of per unit preparation is composed of the following components: tetracaine hydrochloride 25mg, tartaric acid 1.5mg.
8. butethanol of injection pharmaceutical composition according to claim 1, is characterized in that, the pharmaceutical composition of per unit preparation is composed of the following components: tetracaine hydrochloride 50mg, tartaric acid 1.5mg.
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| CN1197636A (en) * | 1997-04-25 | 1998-11-04 | 浙江省中医院 | Freezing-dried tetracaine hydrochloride powder injection |
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| CN103494780A (en) * | 2013-10-17 | 2014-01-08 | 齐鲁动物保健品有限公司 | Gamithromycin composition lyophilized powder for injection and preparation method |
| CN103536540A (en) * | 2013-09-16 | 2014-01-29 | 南通丝乡丝绸有限公司 | Rifampin lyophilized powder and preparation method thereof |
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Patent Citations (6)
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|---|---|---|---|---|
| CN1197636A (en) * | 1997-04-25 | 1998-11-04 | 浙江省中医院 | Freezing-dried tetracaine hydrochloride powder injection |
| CN1218664A (en) * | 1997-10-24 | 1999-06-09 | 张春晓 | Method for preparing butethanol of injection |
| CN1616083A (en) * | 2004-09-01 | 2005-05-18 | 魏雪纹 | Daptomycin freeze-dried preparation for injection and preparing method |
| CN1813681A (en) * | 2005-12-12 | 2006-08-09 | 王冕 | Sodium vitamin C powder for injection and its preparing method |
| CN103536540A (en) * | 2013-09-16 | 2014-01-29 | 南通丝乡丝绸有限公司 | Rifampin lyophilized powder and preparation method thereof |
| CN103494780A (en) * | 2013-10-17 | 2014-01-08 | 齐鲁动物保健品有限公司 | Gamithromycin composition lyophilized powder for injection and preparation method |
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