CN103920154A - 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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- CN103920154A CN103920154A CN201410147858.0A CN201410147858A CN103920154A CN 103920154 A CN103920154 A CN 103920154A CN 201410147858 A CN201410147858 A CN 201410147858A CN 103920154 A CN103920154 A CN 103920154A
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- pharmaceutical composition
- injection
- tartaric acid
- butethanol
- tetracaine hydrochloride
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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 90
- 229960002494 tetracaine hydrochloride Drugs 0.000 title claims abstract description 53
- 238000002360 preparation method Methods 0.000 title claims abstract description 48
- 239000007924 injection Substances 0.000 title claims abstract description 44
- 238000002347 injection Methods 0.000 title claims abstract description 44
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 43
- 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 47
- 239000011975 tartaric acid Substances 0.000 claims abstract description 47
- 235000002906 tartaric acid Nutrition 0.000 claims abstract description 47
- 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
- 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
- 238000004108 freeze drying Methods 0.000 claims description 24
- 239000012528 membrane Substances 0.000 claims description 24
- 238000010792 warming Methods 0.000 claims description 24
- 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
- VNWKTOKETHGBQD-AKLPVKDBSA-N carbane Chemical compound [15CH4] VNWKTOKETHGBQD-AKLPVKDBSA-N 0.000 claims description 12
- 238000005056 compaction Methods 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 12
- 238000007689 inspection Methods 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 239000011265 semifinished product Substances 0.000 claims description 12
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- 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
- 239000000203 mixture Substances 0.000 description 28
- 238000012360 testing method Methods 0.000 description 27
- 230000000052 comparative effect Effects 0.000 description 26
- 238000009472 formulation Methods 0.000 description 26
- 238000005516 engineering process Methods 0.000 description 14
- 239000000126 substance Substances 0.000 description 13
- 238000013019 agitation Methods 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 230000008859 change Effects 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
- 238000012546 transfer Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 230000004520 agglutination Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 210000004204 blood vessel 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
- 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
- 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
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 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
- 210000004027 cell Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 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
- 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
- 230000001537 neural effect Effects 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
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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 technical field.
Background technology
Butethanol of injection, as a kind of local anaesthetics, acts on peripheral nervous, stablizes nervous tissue's cell membrane, 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 clinically retardance in surperficial local anaesthesia, nerve block and canalis spinalis.Listing product forms has injection and injection freeze-dried powder.Because tetracaine hydrochloride injection is unstable, standing time, slightly precipitation can be decomposed or separate out to length just, and therefore developing a kind of stay-in-grade butethanol of injection freeze-dried powder seems particularly important.
Application number is 97110524.6 Chinese patent, discloses a kind of butethanol of injection lyophilized injectable powder, by tetracaine hydrochloride is dissolved in water for injection, adds activated carbon filtration, and subpackage postlyophilization makes.The quality research data of the unexposed obtained product of this patent, product effect is unknown.
Application number is 98110524.6 Chinese patent, discloses a kind of preparation method of butethanol of injection.By preparing certain density Tetracaine Hydrochloride Solution, joined solution successively after overcharging nitrogen, sterilization, filtration, subpackage, is made to butethanol of injection through vacuum freeze-drying technique.But because nitrogen technique is filled in this patent use, to having relatively high expectations of equipment, and the nitrogen colorless and odorless being filled with, whether enough from judging in appearance the nitrogen being filled with, if there is equipment fault in preparation process, stop filling nitrogen, can not discover rapidly, product quality is difficult to ensure.
For the problems referred to above, a kind of tetracaine hydrochloride steady quality of guaranteeing need to be found in this area, and evident in efficacy, toxic and side effects is few, simple new compositions and the technique of technique, and 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, technique easy operating, and the constant product quality preparing, safe and reliable.
For achieving the above object, butethanol of injection pharmaceutical composition provided by the invention, is comprised 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.
The present invention also provides a kind of preparation method of butethanol of injection pharmaceutical composition, and 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, the tetracaine hydrochloride that adds recipe quantity, stirs and makes to dissolve completely, adds 50 ℃ of insulated and stirred of 0.1% active carbon 15 minutes, use while hot 0.45 μ m microporous filter membrane coarse filtration, obtain filtrate; Inject water to nearly full dose, with 0.1mol/L hydrochloric acid solution, adjust pH to 4.8～5.1, add to the full amount of water for injection; With 0.22 μ m 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 ℃～-40 ℃ pre-freeze 1～4h, start evacuation, vacuum control, between 10～30Pa, is warming up to-25 ℃～0 ℃ and keeps 4～12h, is warming up to 20 ℃～30 ℃ and keeps 4～10h, after compaction plug, take out and roll lid, obtain aseptic lyophilization product.
The butethanol of injection of preparing by the present invention has the following advantages:
(1) in the present invention's prescription, use a small amount of tartaric acid, product stability is significantly improved, under high temperature, high humidity and illumination condition, also can keep for a long time stable, period of storage is extended;
(2) preparation technology of the present invention is simple, does not need to fill nitrogen operation, has reduced the requirement to production equipment, is more suitable for large need of production, has avoided filling the insufficient risk that causes unstable product quality of nitrogen simultaneously, more can guarantee that product quality meets the requirements.
(3) product quality is better.The butethanol of injection that adopts prescription of the present invention and technique to prepare, is all being better than prior art aspect the clarity of outward appearance, redissolution speed, solution and color, moisture and related substance; 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.
The specific embodiment
Below in conjunction with embodiment, the present invention is described in further detail, but limitation of the present invention not, all any this areas of doing according to the disclosure of invention be equal to replacement, all belong to protection scope of the present invention.
Embodiment 1: and butethanol of injection (in 1000 bottles, unit: g)
| Tetracaine hydrochloride | 25g |
| Tartaric acid | 0.5g |
| Water for injection adds to | 1000ml |
Preparation technology: inject the water for injection of 800ml in Agitation Tank, first add 0.5g tartaric acid, after stirring and dissolving, add 25g tetracaine hydrochloride, stir and make to dissolve completely, add 50 ℃ of insulated and stirred of 0.1% active carbon 15 minutes, use while hot 0.45 μ m microporous filter membrane coarse filtration, obtain filtrate; Inject water to nearly full dose, with 0.1mol/L hydrochloric acid solution, adjust pH to 4.8, add to the full amount of water for injection; With 0.22 μ m 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 ℃ of pre-freeze 4h, start evacuation, and vacuum control, between 10～30Pa, is warming up to-25 ℃ and keeps 12h, is warming up to 30 ℃ and keeps 4h, after compaction plug, takes out and rolls lid, obtains aseptic lyophilization product.
Embodiment 2: and butethanol of injection (in 1000 bottles, unit: g)
| Tetracaine hydrochloride | 25g |
| Tartaric acid | 2.5g |
| Water for injection adds to | 1000ml |
Preparation technology: inject the water for injection of 800ml in Agitation Tank, first add 2.5g tartaric acid, after stirring and dissolving, add 25g tetracaine hydrochloride, stir and make to dissolve completely, add 50 ℃ of insulated and stirred of 0.1% active carbon 15 minutes, use while hot 0.45 μ m microporous filter membrane coarse filtration, obtain filtrate; Inject water to nearly full dose, with 0.1mol/L hydrochloric acid solution, adjust pH to 5.1, add to the full amount of water for injection; With 0.22 μ m 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 ℃ of pre-freeze 1h, start evacuation, and vacuum control, between 10～30Pa, is warming up to 0 ℃ and keeps 4h, is warming up to 20 ℃ and keeps 10h, after compaction plug, takes out and rolls lid, obtains aseptic lyophilization product.
Embodiment 3: and butethanol of injection prescription (in 1000 bottles, unit: g)
| Tetracaine hydrochloride | 25g |
| Tartaric acid | 1.0g |
| Water for injection adds to | 1000ml |
Preparation technology: inject the water for injection of 800ml in Agitation Tank, first add 1.0g tartaric acid, after stirring and dissolving, add 25g tetracaine hydrochloride, stir and make to dissolve completely, add 50 ℃ of insulated and stirred of 0.1% active carbon 15 minutes, use while hot 0.45 μ m microporous filter membrane coarse filtration, obtain filtrate; Inject water to nearly full dose, with 0.1mol/L hydrochloric acid solution, adjust pH to 4.9, add to the full amount of water for injection; With 0.22 μ m 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 ℃ of pre-freeze 3h, start evacuation, and vacuum control, between 10～30Pa, is warming up to-15 ℃ and keeps 6h, is warming up to 20 ℃ and keeps 6h, after compaction plug, takes out and rolls lid, obtains aseptic lyophilization product.
Embodiment 4: and butethanol of injection (in 1000 bottles, unit: g)
| Tetracaine hydrochloride | 25g |
| Tartaric acid | 1.5g |
| Water for injection adds to | 1000ml |
Preparation technology: inject the water for injection of 800ml in Agitation Tank, first add 1.5g tartaric acid, after stirring and dissolving, add 25g tetracaine hydrochloride, stir and make to dissolve completely, add 50 ℃ of insulated and stirred of 0.1% active carbon 15 minutes, use while hot 0.45 μ m microporous filter membrane coarse filtration, obtain filtrate; Inject water to nearly full dose, with 0.1mol/L hydrochloric acid solution, adjust pH to 5.0, add to the full amount of water for injection; With 0.22 μ m 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 ℃ of pre-freeze 4h, start evacuation, and vacuum control, between 10～30Pa, is warming up to-10 ℃ and keeps 9h, is warming up to 25 ℃ and keeps 5h, after compaction plug, takes out and rolls lid, obtains aseptic lyophilization product.
Embodiment 5: and butethanol of injection (in 1000 bottles, unit: g)
| Tetracaine hydrochloride | 25g |
| Tartaric acid | 2.0g |
| Water for injection adds to | 1000ml |
Preparation technology: inject the water for injection of 800ml in Agitation Tank, first add 2.0g tartaric acid, after stirring and dissolving, add 25g tetracaine hydrochloride, stir and make to dissolve completely, add 50 ℃ of insulated and stirred of 0.1% active carbon 15 minutes, use while hot 0.45 μ m microporous filter membrane coarse filtration, obtain filtrate; Inject water to nearly full dose, with 0.1mol/L hydrochloric acid solution, adjust pH to 4.8, add to the full amount of water for injection; With 0.22 μ m 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 ℃ of pre-freeze 2h, start evacuation, and vacuum control, between 10～30Pa, is warming up to-5 ℃ and keeps 8h, is warming up to 25 ℃ and keeps 8h, after compaction plug, takes out and rolls lid, obtains aseptic lyophilization product.
Embodiment 6: and butethanol of injection (in 1000 bottles, unit: g)
| Tetracaine hydrochloride | 50g |
| Tartaric acid | 0.5g |
| Water for injection adds to | 1000ml |
Preparation technology: inject the water for injection of 800ml in Agitation Tank, first add 0.5g tartaric acid, after stirring and dissolving, add 50g tetracaine hydrochloride, stir and make to dissolve completely, add 50 ℃ of insulated and stirred of 0.1% active carbon 15 minutes, use while hot 0.45 μ m microporous filter membrane coarse filtration, obtain filtrate; Inject water to nearly full dose, with 0.1mol/L hydrochloric acid solution, adjust pH to 4.9, add to the full amount of water for injection; With 0.22 μ m 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 ℃ of pre-freeze 3h, start evacuation, and vacuum control, between 10～30Pa, is warming up to-20 ℃ and keeps 10h, is warming up to 25 ℃ and keeps 6h, after compaction plug, takes out and rolls lid, obtains aseptic lyophilization product.
Embodiment 7: and butethanol of injection (in 1000 bottles, unit: g)
| Tetracaine hydrochloride | 50g |
| Tartaric acid | 2.5g |
| Water for injection adds to | 1000ml |
Preparation technology: inject the water for injection of 800ml in Agitation Tank, first add 2.5g tartaric acid, after stirring and dissolving, add 50g tetracaine hydrochloride, stir and make to dissolve completely, add 50 ℃ of insulated and stirred of 0.1% active carbon 15 minutes, use while hot 0.45 μ m microporous filter membrane coarse filtration, obtain filtrate; Inject water to nearly full dose, with 0.1mol/L hydrochloric acid solution, adjust pH to 5.0, add to the full amount of water for injection; With 0.22 μ m 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 ℃ of pre-freeze 2h, start evacuation, and vacuum control, between 10～30Pa, is warming up to-25 ℃ and keeps 4h, is warming up to 30 ℃ and keeps 10h, after compaction plug, takes out and rolls lid, obtains aseptic lyophilization product.
Embodiment 8: and butethanol of injection (in 1000 bottles, unit: g)
| Tetracaine hydrochloride | 50g |
| Tartaric acid | 1.0g |
| Water for injection adds to | 1000ml |
Preparation technology: inject the water for injection of 800ml in Agitation Tank, first add 1.0g tartaric acid, after stirring and dissolving, add 50g tetracaine hydrochloride, stir and make to dissolve completely, add 50 ℃ of insulated and stirred of 0.1% active carbon 15 minutes, use while hot 0.45 μ m microporous filter membrane coarse filtration, obtain filtrate; Inject water to nearly full dose, with 0.1mol/L hydrochloric acid solution, adjust pH to 5.1, add to the full amount of water for injection; With 0.22 μ m 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 ℃ of pre-freeze 3h, start evacuation, and vacuum control, between 10～30Pa, is warming up to-10 ℃ and keeps 7h, is warming up to 20 ℃ and keeps 4h, after compaction plug, takes out and rolls lid, obtains aseptic lyophilization product.
Embodiment 9: and butethanol of injection (in 1000 bottles, unit: g)
| Tetracaine hydrochloride | 50g |
| Tartaric acid | 1.5g |
| Water for injection adds to | 1000ml |
Preparation technology: inject the water for injection of 800ml in Agitation Tank, first add 1.5g tartaric acid, after stirring and dissolving, add 50g tetracaine hydrochloride, stir and make to dissolve completely, add 50 ℃ of insulated and stirred of 0.1% active carbon 15 minutes, use while hot 0.45 μ m microporous filter membrane coarse filtration, obtain filtrate; Inject water to nearly full dose, with 0.1mol/L hydrochloric acid solution, adjust pH to 4.8, add to the full amount of water for injection; With 0.22 μ m 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 ℃ of pre-freeze 1h, start evacuation, and vacuum control, between 10～30Pa, is warming up to 0 ℃ and keeps 12h, is warming up to 28 ℃ and keeps 5h, after compaction plug, takes out and rolls lid, obtains aseptic lyophilization product.
Embodiment 10: and butethanol of injection (in 1000 bottles, unit: g)
| Tetracaine hydrochloride | 50g |
| Tartaric acid | 2.0g |
| Water for injection adds to | 1000ml |
Preparation technology: inject the water for injection of 800ml in Agitation Tank, first add 2.0g tartaric acid, after stirring and dissolving, add 50g tetracaine hydrochloride, stir and make to dissolve completely, add 50 ℃ of insulated and stirred of 0.1% active carbon 15 minutes, use while hot 0.45 μ m microporous filter membrane coarse filtration, obtain filtrate; Inject water to nearly full dose, with 0.1mol/L hydrochloric acid solution, adjust pH to 5.1, add to the full amount of water for injection; With 0.22 μ m 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 ℃ of pre-freeze 2h, start evacuation, and vacuum control, between 10～30Pa, is warming up to-18 ℃ and keeps 11h, is warming up to 24 ℃ and keeps 9h, after compaction plug, takes out and rolls lid, obtains aseptic lyophilization product.
Comparative formulation 1: in the Chinese patent that is 97109821.2 according to application number, the prescription of embodiment 1 and technique prepare, specification: every bottle of 50mg;
Comparative formulation 2: the method that is 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 test
Get each 20, the sample of the embodiment of the present invention 1,3,7,10 preparation and Comparative formulation 1, Comparative formulation 2 samples, respectively at high temperature (60 ℃), illumination (4500lx, 25 ℃), (25 ℃ of high humiditys, RH92.5%) under condition, place 10 days, respectively at sampling in the 0th day, 5 days, 10 days, carry out the mensuration of the clarity of outward appearance, redissolution speed, solution and color, moisture, related substance, wherein with 0.9% sodium chloride injection, measure redissolution speed, result of the test is as shown in table 1.
Table 1 embodiment of the present invention and Comparative formulation mass ratio are
Result shows, in the time of 0 day, embodiment of the present invention sample and the equal outward appearance of Comparative formulation 1,2 sample are full, the loose block that is white in color, and solution is colourless clear liquid, and content, related substance are all up to specification, each other no significant difference; But the moisture of embodiment of the present invention sample is significantly less than Comparative formulation 1,2 samples, and redissolution speed is obviously faster than Comparative formulation 1,2 samples.
High humidity (25 ℃, RH92.5%) under condition, place after 10 days, embodiment of the present invention sample is compared with 0 day with Comparative formulation 1,2 sample indices, and significant change does not all occur.
Under high temperature (60 ℃) and illumination (4500lx, 25 ℃) condition, placing after 10 days, 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 samples, significant variation has all occurred all the other indices.Comparative formulation 1 sample appearance becomes off-white color atrophy block from white loose block, and Comparative formulation 2 samples become the loose block of off-white color; In addition, both redissolution speed is obviously slack-off, solution colour by colourless become faint yellow.And Comparative formulation 1 sample related substance exceeds prescribed limit, Comparative formulation 2 samples are transferred postpone related substance in hot conditions and are exceeded prescribed limit, transfer postpone related substance approach prescribed limit at illumination condition.
From the above results, can find out, under influence factor's condition, place after 10 days, embodiment of the present invention sample indices is all highly stable, and significant change does not occur; And there is significant change in Comparative formulation 1,2 samples on outward appearance, clarity of solution, redissolution speed index.Comparative formulation 1 sample related substance has exceeded prescribed limit, and Comparative formulation 2 samples are transferred postpone related substance in hot conditions and exceeded prescribed limit, transfer postpone related substance approach prescribed limit at illumination condition.As can be seen here, embodiment of the present invention sample is all being better than Comparative formulation 1, Comparative formulation 2 samples aspect the clarity of outward appearance, redissolution speed, solution and color, moisture, related substance, and product quality and stability are better.
Test example 2 compatibility tests
According to the usage and dosage of stipulating in the butethanol of injection description of State Food and Drug Administration's approval, respectively the embodiment of the present invention 1,3,7,10 samples and Comparative formulation 1,2 samples being mixed with to tetracaine hydrochloride concentration with 0.9% sodium chloride injection is 0.1%(g/ml) solution, investigate it and after compatibility, in room temperature, transfer the situation of change of character while setting to 0 h, 12h, 24h, content and related substance.Result of the test sees the following form 2.
Table 2 compatibility result of the test
Result shows: after embodiment 1,3,7,10 sample compatibilities, character, content and the related substance of medicinal liquid all do not occur obviously to change, solution colour generation significant change when medicinal liquid is placed 24h after Comparative formulation 1,2 sample compatibilities, Comparative formulation 1 sample compatibility solution is from the colourless yellow that becomes, Comparative formulation 2 sample compatibility solution from colourless become faint yellow; In addition, both slightly reduce by content, and related substance all exceeds standard prescribed limit.With 0.9% sodium chloride injection compatibility and place in 24h process, the embodiment of the present invention 1,3,7,10 sample qualities are stable as can be seen from the test results, are significantly better than Comparative formulation 1 and Comparative formulation 2 samples under the same terms.
Test example 3 safety testings
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 samples being mixed with respectively to tetracaine hydrochloride concentration is 0.1%(g/ml) solution, as need testing solution, standby.
(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, make into defibrinated blood.Add approximately 10 times of amounts of 0.9% sodium chloride solution, shake up, per minute 1000～1500 leave the heart 15 minutes, remove supernatant, and the erythrocyte of precipitation washs 2～3 times as stated above with 0.9% sodium chloride solution again, till the not aobvious redness of supernatant.The erythrocyte of gained is made to 2% suspension with 0.9% sodium chloride solution, be for experiment.
Get 14 of clean teat glasses numbering, wherein 1, No. 2 pipe is embodiment 1 sample test sample pipe, 3, No. 4 pipes are embodiment 3 sample test sample pipes, 5, No. 6 pipes are embodiment 7 sample test sample pipes, 7, No. 8 pipes are embodiment 10 sample test sample pipes, manage negative control tube No. 9, manage positive control tube No. 10, 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.Shown according to the form below, add successively 2% red cell suspension, 0.9% sodium chloride solution, distilled water, after mixing, put immediately in the calorstat of 37 ℃ ± 0.5 ℃ 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, positive control pipe (No. 10 pipe) adds after distilled water and occurs haemolysis in 15 minutes; 11～No. 14 pipe is colourless clear liquid, and 1～No. 9 pipe erythrocyte sinks, and supernatant achromatism and clarity and is managed almost zero difference 11～No. 14, shows that the embodiment of the present invention 1,3,7,10 samples all occur without haemolysis; 1～No. 9 pipe is reversed 3 times gently, and 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 30 of health, ear edge not damaged rabbit, be divided at random A, B, C, D, five groups of E, 6 every group.Wherein, A group: embodiment 1 sample need testing solution, B group: embodiment 3 sample need testing solutions, C group: embodiment 7 sample need testing solutions, D group: embodiment 10 sample need testing solutions, E group: 0.9% sodium chloride injection matched group.Respectively with aseptic manipulation the be in above-mentioned A of rabbit ear edge intravenous drip, B, C, D, five groups of injection of E.Through multiple dosing, perusal phenomenon is: when vein slowly instils, animal is without the reaction of struggling, and medication part 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 that other are abnormal, with 0.9% sodium chloride injection group no significant difference relatively.Result shows, butethanol of injection pharmaceutical composition of the present invention is to blood vessel nonirritant.
Known by above-mentioned result of the test, the butethanol of injection pharmaceutical composition that adopts prescription of the present invention and technique to prepare, prescription is simple, only use a small amount of tartaric acid, just make product stability significantly improve, under high temperature, high humidity and illumination condition, can keep for a long time stable, 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 fill nitrogen operation, has reduced the requirement to production equipment, is more suitable for large need of production, has avoided filling the insufficient risk that causes unstable product quality of nitrogen simultaneously, more can guarantee that product quality meets the requirements.
Claims (10)
1. a butethanol of injection pharmaceutical composition, is characterized in that, this pharmaceutical composition is comprised of tetracaine hydrochloride, tartaric acid.
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 0.5mg～2.5mg.
3. butethanol of injection pharmaceutical composition according to claim 2, 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.
4. butethanol of injection pharmaceutical composition according to claim 2, is characterized in that, the pharmaceutical composition of per unit preparation is composed of the following components: tetracaine hydrochloride 25mg, tartaric acid 0.5mg.
5. butethanol of injection pharmaceutical composition according to claim 2, is characterized in that, the pharmaceutical composition of per unit preparation is composed of the following components: tetracaine hydrochloride 25mg, tartaric acid 1.0mg.
6. butethanol of injection pharmaceutical composition according to claim 2, is characterized in that, the pharmaceutical composition of per unit preparation is composed of the following components: tetracaine hydrochloride 50mg, tartaric acid 2.0mg.
7. butethanol of injection pharmaceutical composition according to claim 2, is characterized in that, the pharmaceutical composition of per unit preparation is composed of the following components: tetracaine hydrochloride 50mg, tartaric acid 2.5mg.
8. butethanol of injection pharmaceutical composition according to claim 2, is characterized in that, the pharmaceutical composition of per unit preparation is composed of the following components: tetracaine hydrochloride 25mg, tartaric acid 1.5mg.
9. butethanol of injection pharmaceutical composition according to claim 2, is characterized in that, the pharmaceutical composition of per unit preparation is composed of the following components: tetracaine hydrochloride 50mg, tartaric acid 1.5mg.
10. a preparation method for the butethanol of injection pharmaceutical composition described in claim 1～9 any one, is characterized in that, 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, the tetracaine hydrochloride that adds recipe quantity, stirs and makes to dissolve completely, adds 50 ℃ of insulated and stirred of 0.1% active carbon 15 minutes, use while hot 0.45 μ m microporous filter membrane coarse filtration, obtain filtrate; Inject water to nearly full dose, with 0.1mol/L hydrochloric acid solution, adjust pH to 4.8～5.1, add to the full amount of water for injection; With 0.22 μ m 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 ℃～-40 ℃ pre-freeze 1～4h, start evacuation, vacuum control, between 10～30Pa, is warming up to-25 ℃～0 ℃ and keeps 4～12h, is warming up to 20 ℃～30 ℃ and keeps 4～10h, after compaction plug, take out and roll lid, obtain aseptic lyophilization product.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
-
2014
- 2014-04-11 CN CN201410147858.0A patent/CN103920154B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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