CN104434901B - A kind of pharmaceutical composition of Flurbiprofen axetil - Google Patents
A kind of pharmaceutical composition of Flurbiprofen axetil Download PDFInfo
- Publication number
- CN104434901B CN104434901B CN201410633307.5A CN201410633307A CN104434901B CN 104434901 B CN104434901 B CN 104434901B CN 201410633307 A CN201410633307 A CN 201410633307A CN 104434901 B CN104434901 B CN 104434901B
- Authority
- CN
- China
- Prior art keywords
- injection
- pharmaceutical composition
- flurbiprofen axetil
- fat emulsion
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
Abstract
The invention belongs to medical art, specifically, relate to a kind of pharmaceutical composition of Flurbiprofen axetil, wherein, described pharmaceutical composition is fat emulsion injection, and it is composed as follows: Flurbiprofen axetil 0.005 ~ 0.015g/ml, soybean oil 0.1 ~ 0.12g/ml, lecithin 0.01 ~ 0.02g/ml, vitamin E 0.001 ~ 0.002g/ml, glycerol 0.01 ~ 0.03g/ml and pH adjusting agent are appropriate.The uniform particle sizes of fat emulsion injection of the present invention, has good stability, greatly alleviates the degraded of Flurbiprofen axetil, thus decreases the generation of other impurity, reduces potential safety hazard.Meanwhile, fat emulsion injection compatibility dilution stability of the present invention is good.
Description
Technical field
The present invention relates to technical field of pharmaceuticals, specifically, relate to a kind of pharmaceutical composition of Flurbiprofen axetil.
Background technology
Flurbiprofen axetil belongs to nonsteroidal antiinflammatory drug, and mechanism of action mainly suppresses the activity of cyclooxygenase in arachidonic acid cascade waterfall, thus suppresses the synthesis causing the prostaglandin of pain and inflammatory reaction, plays analgesic effect.Its analgesia effect is better than aspirin, has even exceeded pentazocine.
Flurbiprofen axetil, its chemical name is: (±) 2-(the fluoro-4-xenyl of 2-) propanoic acid-1-acetoxyethyl, molecular formula: C
19h
19fO
4, molecular weight: 330.36, its structural formula is:
Flurbiprofen axetil is water insoluble, need make applicable intravenous liquid emulsion.Flurbiprofen axetil fat milk injection (trade name Furbiprofen axetil) take fat milk as pharmaceutical carrier according to the exploitation of drug delivery system conceptual approach, and the preparation of encapsulating Flurbiprofen axetil, during its injection, zest is little, and analgesic effect is rapid-action.The advantage of Flurbiprofen axetil microsphere injection liquid mainly contains following several respects: 1) targeting, the medicine of parcel is assembled at lesions position and strengthens drug effect; 2) control the release of packaging medicine, duration of efficacy is extended; 3) be easy to transmembrane transport, promote the absorption of medicine, shorten onset time further; 4) can intravenous injection, avoid the oral damage to alimentary canal mucous membrane.
But, existing Flurbiprofen axetil Emulsion can be subject to process conditions in preparation, storage process, (national drug standards YBH15412004 requires 0 ~ 20 DEG C of airtight preservation to holding conditions, avoid freezing, 18 months effect duration) etc. the impact of factor and existence and stability problem, such as may there is the phenomenons such as breakdown of emulsion (oil floats in water), layering in this injection emulsion in high temperature sterilize or put procedure, breakdown of emulsion rear section mainly enters in water and causes content significantly to reduce, and affects stability.
For solving the problem, " research of Flurbiprofen axetil lipid microsphere injection " discloses a kind of Flurbiprofen axetil lipid microsphere injection comprising Flurbiprofen axetil, soybean oil, lecithin, F68, glycerol, enuatrol and sodium hydrogen phosphate, is intended to the quality being improved product by interpolation F68 and enuatrol.But consider from injection security standpoint, the kind increasing adjuvant, while raising agent in vitro stability, too increases the potential safety hazard in body.
For this reason, CN102988291A under existing preparation prescription condition, by optimizing existing preparation method to improve the quality of products.
But the particle diameter of the Flurbiprofen axetil fat emulsion injection adopting above-mentioned prescription or preparation method to obtain, all at about 200nm, is easy to breakdown of emulsion.In addition, common fats emulsion injection is heterogeneous liquid preparation, belong to thermodynamics and kinetics Unstable Systems, in long-term put procedure, emulsion droplet particle is easy to merge, there is the phenomenons such as particle diameter increase, emulsion droplet reunion, not easily store, limit stability and the safety of Flurbiprofen axetil fat emulsion injection.And, oil and phospholipid are all easily oxidized, be hydrolyzed in preparation and storage process, and the reduction of grease emulsifying effect, medicine also can be made to be wrapped completely, and then increase the degraded of principal agent Flurbiprofen axetil, and Flurbiprofen axetil degraded generates flurbiprofen (A) and 1-hydroxyethyl (B), 1-hydroxyethyl is degraded into acetic acid (C) and formaldehyde (D) further, wherein flurbiprofen is active metabolite, impurity C and D is then the impurity causing safety risks, needs strictly to control.
In view of this, special proposition the present invention.
Summary of the invention
The object of the invention is to the defect overcoming prior art, the Flurbiprofen axetil pharmaceutical composition that a kind of uniform particle sizes, stability better, are not easily degraded is provided.
For realizing object of the present invention, the present invention adopts following technical scheme:
A pharmaceutical composition for Flurbiprofen axetil, wherein, described pharmaceutical composition is fat emulsion injection, and it is composed as follows:
Preferably, described fat emulsion injection composed as follows:
More preferably, described fat emulsion injection composed as follows:
Most preferably, described fat emulsion injection composed as follows:
The present invention is surprised to find that, uniform particle sizes, the stability of the Flurbiprofen axetil fat emulsion injection obtained increase the vitamin E of minute quantity in prescription after are better, and not easily degrade.The probability that impurity C and impurity D generates is also corresponding to be decreased, thus potential safety hazard is reduced greatly.
Flurbiprofen axetil fat emulsion injection is intravenous formulations, and before administration, use after often needing to carry out compatibility dilution according to clinical application, therefore, the stability after compatibility dilution is extremely important.Desirable infatmul requires to use ultra-pure water, normal saline, glucose or blank plasma infinite dilution within the specific limits, without layering, breakdown of emulsion, does not also occur the phenomenons such as particle diameter becomes large, medicine precipitation.
The present inventor has investigated the compatibility dilution stability of the Flurbiprofen axetil fat emulsion injection of the present invention and prior art.Surprisingly find that Flurbiprofen axetil fat emulsion injection of the present invention is after with 0.9%NaCl solution dilution, injection size after placement certain hour of each extension rate does not have significant change substantially, and oil droplet and lamination do not appear in liquid level yet.And the Flurbiprofen axetil fat emulsion injection adopting the method for prior art obtained is after with 0.9%NaCl solution dilution, injection change of size after placement certain hour of each extension rate is larger, and after placement 36h, all there is oil droplet, lamination in liquid level.
In pharmaceutical composition of the present invention, wherein, described pH adjusting agent is sodium hydrogen phosphate and citrate buffer, and its consumption is for making described injection pH=4.5 ~ 6.5, and wherein the mol ratio of sodium hydrogen phosphate and citric acid is 4:1.
The present invention also provides the preparation method of described pharmaceutical composition, and the method comprises the steps:
1) under nitrogen protection, soybean oil and lecithin are heated to 70-75 DEG C, add Flurbiprofen axetil and vitamin E while stirring, dissolve, obtain oil phase;
2) under nitrogen protection, in partial syringe water, add glycerol, dissolve, obtain aqueous phase;
3) under nitrogen protection, by step 1) oil phase add step 2) aqueous phase in, high speed shear disperse, regulate pH=4.5 ~ 6.5 by pH adjusting agent, add water for injection standardize solution, stir, obtain colostrum;
4) under nitrogen protection, colostrum is added in high pressure homogenizer, high pressure homogenize, obtain Emulsion;
5) Emulsion is crossed filtering with microporous membrane, inflated with nitrogen, embedding, sterilizing, obtain described fat emulsion injection.
In above-mentioned preparation method, wherein, step 3) described in high speed shear jitter time be 20 ~ 30 minutes, shear rate is 6000 ~ 8000rpm.
Step 4) described in high pressure homogenize pressure be 600 ~ 1000bar, homogenization cycles is 3 ~ 5 times, preferably 3 times.
Step 4) described in high pressure homogenize process in, regulate condensate flow, control emulsion temperature be no more than 30 DEG C.
Step 5) described in sterilizing be 121 DEG C of sterilizings 15 minutes.
Compared with prior art, the uniform particle sizes of Flurbiprofen axetil fat emulsion injection of the present invention, stability better, are not easily degraded; Meanwhile, Flurbiprofen axetil fat emulsion injection compatibility dilution of the present invention is stablized.
Detailed description of the invention
Be below the specific embodiment of the present invention, described embodiment is to further describe the present invention, instead of restriction the present invention.
Embodiment 1
Prescription:
Preparation technology:
1) under nitrogen protection, soybean oil and lecithin are heated to 70 DEG C, add Flurbiprofen axetil and vitamin E dissolving while stirring, obtain oil phase;
2) under nitrogen protection, in partial syringe water, add glycerol, dissolve, obtain aqueous phase;
3) under nitrogen protection, by step 1) oil phase add step 2) aqueous phase in, high speed shear disperses 20 minutes, shear rate is 6000rpm, then regulates pH=4.5 by pH adjusting agent, adds water for injection and is settled to 1000ml, stir, obtain colostrum;
4) under nitrogen protection, added by colostrum in high pressure homogenizer, setting high pressure homogenize pressure is 800bar, and high pressure homogenize 3 times, in high pressure homogenize process, regulates condensate flow, controls emulsion temperature and is no more than 30 DEG C, obtain Emulsion;
5) Emulsion is crossed filtering with microporous membrane, inflated with nitrogen, fill is in 7ml cillin bottle; To in sterilizing cabinet, sterilizing 15 minutes at 121 DEG C, obtains described Flurbiprofen axetil fat emulsion injection.
By Flurbiprofen axetil fat emulsion injection centrifugal 30min in DT5-3 centrifuge of preparation, fat milk is still clear, does not produce precipitation, does not occur layering, turbid phenomenon.This illustrates that its physical stability is good, still can keep good stability after the side light naturally standing long period.
Embodiment 2
Prescription:
Preparation technology:
1) under nitrogen protection, soybean oil and lecithin are heated to 75 DEG C, add Flurbiprofen axetil and vitamin E dissolving while stirring, obtain oil phase;
2) under nitrogen protection, in partial syringe water, add glycerol, dissolve, obtain aqueous phase;
3) under nitrogen protection, by step 1) oil phase add step 2) aqueous phase in, high speed shear disperses 30 minutes, shear rate is 8000rpm, then regulates pH=6.5 by pH adjusting agent, adds water for injection and is settled to 1000ml, stir, obtain colostrum; Described pH adjusting agent is sodium hydrogen phosphate and citrate buffer, and its consumption is for making described injection pH=6.5, and wherein the mol ratio of sodium hydrogen phosphate and citric acid is 4:1;
4) under nitrogen protection, added by colostrum in high pressure homogenizer, setting high pressure homogenize pressure is 800bar, and high pressure homogenize 6 times, in high pressure homogenize process, regulates condensate flow, controls emulsion temperature and is no more than 30 DEG C, obtain Emulsion;
5) Emulsion is crossed filtering with microporous membrane, inflated with nitrogen, fill is in 7ml cillin bottle; To in sterilizing cabinet, sterilizing 15 minutes at 121 DEG C, obtains described Flurbiprofen axetil fat emulsion injection.
By Flurbiprofen axetil fat emulsion injection centrifugal 30min in DT5-3 centrifuge of preparation, fat milk is still clear, does not produce precipitation, does not occur layering, turbid phenomenon.This illustrates that its physical stability is good, still can keep good stability after the side light naturally standing long period.
Embodiment 3
Prescription:
Preparation technology:
1) under nitrogen protection, soybean oil and lecithin are heated to 72 DEG C, add Flurbiprofen axetil and vitamin E dissolving while stirring, obtain oil phase;
2) under nitrogen protection, in partial syringe water, add glycerol, dissolve, obtain aqueous phase;
3) under nitrogen protection, by step 1) oil phase add step 2) aqueous phase in, high speed shear disperses 25 minutes, shear rate is 7000rpm, then regulates pH=5.5 by pH adjusting agent, adds water for injection and is settled to 1000ml, stir, obtain colostrum;
4) under nitrogen protection, added by colostrum in high pressure homogenizer, setting high pressure homogenize pressure is 800bar, and high pressure homogenize 4 times, in high pressure homogenize process, regulates condensate flow, controls emulsion temperature and is no more than 30 DEG C, obtain Emulsion;
5) Emulsion is crossed filtering with microporous membrane, inflated with nitrogen, fill is in 7ml cillin bottle; To in sterilizing cabinet, sterilizing 15 minutes at 121 DEG C, obtains described Flurbiprofen axetil fat emulsion injection.
By Flurbiprofen axetil fat emulsion injection centrifugal 30min in DT5-3 centrifuge of preparation, fat milk is still clear, does not produce precipitation, does not occur layering, turbid phenomenon.This illustrates that its physical stability is good, still can keep good stability after the side light naturally standing long period.
Embodiment 4
Prescription:
Preparation technology:
1) under nitrogen protection, soybean oil and lecithin are heated to 73 DEG C, add Flurbiprofen axetil and vitamin E dissolving while stirring, obtain oil phase;
2) under nitrogen protection, in partial syringe water, add glycerol, dissolve, obtain aqueous phase;
3) under nitrogen protection, by step 1) oil phase add step 2) aqueous phase in, high speed shear disperses 28 minutes, shear rate is 6500rpm, then regulates pH=5.0 by pH adjusting agent, adds water for injection and is settled to 1000ml, stir, obtain colostrum;
4) under nitrogen protection, added by colostrum in high pressure homogenizer, setting high pressure homogenize pressure is 800bar, and high pressure homogenize 5 times, in high pressure homogenize process, regulates condensate flow, controls emulsion temperature and is no more than 30 DEG C, obtain Emulsion;
5) Emulsion is crossed filtering with microporous membrane, inflated with nitrogen, fill is in 7ml cillin bottle; To in sterilizing cabinet, sterilizing 15 minutes at 121 DEG C, obtains described Flurbiprofen axetil fat emulsion injection.
By Flurbiprofen axetil fat emulsion injection centrifugal 30min in DT5-3 centrifuge of preparation, fat milk is still clear, does not produce precipitation, does not occur layering, turbid phenomenon.This illustrates that its physical stability is good, still can keep good stability after the side light naturally standing long period.
Embodiment 5
Prescription:
Preparation technology:
1) under nitrogen protection, soybean oil and soybean lecithin are heated to 74 DEG C, add Flurbiprofen axetil and vitamin E dissolving while stirring, obtain oil phase;
2) under nitrogen protection, in partial syringe water, add glycerol, dissolve, obtain aqueous phase;
3) under nitrogen protection, by step 1) oil phase add step 2) aqueous phase in, high speed shear disperses 28 minutes, shear rate is 7500rpm, then regulates pH=6.0 by pH adjusting agent, adds water for injection and is settled to 1000ml, stir, obtain colostrum; Described pH adjusting agent is sodium hydrogen phosphate and citrate buffer, and its consumption is for making described injection pH=6.0, and wherein the mol ratio of sodium hydrogen phosphate and citric acid is 4:1;
4) under nitrogen protection, added by colostrum in high pressure homogenizer, setting high pressure homogenize pressure is 600bar, and high pressure homogenize 4 times, in high pressure homogenize process, regulates condensate flow, controls emulsion temperature and is no more than 30 DEG C, obtain Emulsion;
5) Emulsion is crossed filtering with microporous membrane, inflated with nitrogen, fill is in 7ml cillin bottle; To in sterilizing cabinet, sterilizing 15 minutes at 121 DEG C, obtains described Flurbiprofen axetil fat emulsion injection.
By Flurbiprofen axetil fat emulsion injection centrifugal 30min in DT5-3 centrifuge of preparation, fat milk is still clear, does not produce precipitation, does not occur layering, turbid phenomenon.This illustrates that its physical stability is good, still can keep good stability after the side light naturally standing long period.
Embodiment 6
Prescription:
Preparation technology:
1) under nitrogen protection, soybean oil and lecithin are heated to 71 DEG C, add Flurbiprofen axetil and vitamin E dissolving while stirring, obtain oil phase;
2) under nitrogen protection, in partial syringe water, add glycerol, dissolve, obtain aqueous phase;
3) under nitrogen protection, by step 1) oil phase add step 2) aqueous phase in, high speed shear disperses 22 minutes, shear rate is 6500rpm, then regulates pH=4.8 by pH adjusting agent, adds water for injection and is settled to 1000ml, stir, obtain colostrum; Described pH adjusting agent is sodium hydrogen phosphate and citrate buffer, and its consumption is for making described injection pH=4.8, and wherein the mol ratio of sodium hydrogen phosphate and citric acid is 4:1;
4) under nitrogen protection, added by colostrum in high pressure homogenizer, setting high pressure homogenize pressure is 1000bar, and high pressure homogenize 4 times, in high pressure homogenize process, regulates condensate flow, controls emulsion temperature and is no more than 30 DEG C, obtain Emulsion;
5) Emulsion is crossed filtering with microporous membrane, inflated with nitrogen, fill is in 7ml cillin bottle; To in sterilizing cabinet, sterilizing 15 minutes at 121 DEG C, obtains described Flurbiprofen axetil fat emulsion injection.
By Flurbiprofen axetil fat emulsion injection centrifugal 30min in DT5-3 centrifuge of preparation, fat milk is still clear, does not produce precipitation, does not occur layering, turbid phenomenon.This illustrates that its physical stability is good, still can keep good stability after the side light naturally standing long period.
The mensuration of test example 1, diameter of aspirin particle
The size and distribution of the Flurbiprofen axetil fat emulsion injection obtained by the embodiment of the present invention is measured, concrete grammar is as follows: get Flurbiprofen axetil fat emulsion injection appropriate, measure its particle diameter and particle size distribution with laser granulometry, the results are shown in following table 1.
Table 1, particle size determination result
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | |
| Mean diameter (nm) | 152 | 153 | 152 | 153 | 153 | 152 |
| Polydispersity coefficient | 0.131 | 0.132 | 0.129 | 0.130 | 0.129 | 0.131 |
The study on the stability test of test example 2, Flurbiprofen axetil fat emulsion injection
1, take particle diameter as inspection target
The Flurbiprofen axetil fat emulsion injection prepared by embodiment 1-6 carries out accelerated test under being placed in 40 DEG C of 75%RH conditions, and in the 1st, 2,3, sampling in June, carry out droplet measurement with laser granulometry, the results are shown in Table 2.
Table 2, Flurbiprofen axetil fat emulsion injection change of size result
| Sample | 0 day | After 1 month | After 2 months | After 3 months | After 6 months |
| Embodiment 1 | 152 | 153 | 155 | 156 | 159 |
| Embodiment 2 | 153 | 154 | 155 | 157 | 159 |
| Embodiment 3 | 152 | 154 | 154 | 155 | 158 |
| Embodiment 4 | 153 | 153 | 155 | 156 | 158 |
| Embodiment 5 | 153 | 154 | 154 | 157 | 159 |
| Embodiment 6 | 152 | 154 | 155 | 157 | 158 |
As can be seen from Table 2, the Flurbiprofen axetil fat emulsion injection that prepared by the present invention has good stability.
2, with principal agent degradation product flurbiprofen for inspection target
Flurbiprofen axetil fat emulsion injection obtained by embodiment 1-3 is preserved 18 months at normal temperatures, with the content of principal agent degradation product flurbiprofen for inspection target, carries out long-time stability and investigate test.
The results are shown in Table 3.
Table 3, Flurbiprofen axetil fat emulsion injection be long-term stable experiment (unit: mg/ml) under 25 ± 2 DEG C of conditions
As can be seen from Table 3, the good stability of Flurbiprofen axetil fat emulsion injection of the present invention, the content of flurbiprofen is low, and it is almost unchanged in long term test under 25 ± 2 DEG C of conditions, show that the stability of Flurbiprofen axetil fat emulsion injection of the present invention is better, principal agent Flurbiprofen axetil is not easily degraded.
Also carried out the investigation of above-mentioned principal agent degradation product flurbiprofen to the Flurbiprofen axetil fat emulsion injection obtained by other embodiment of the present invention, it is similar that it obtains result.
The compatibility dilution stability of test example 3, Flurbiprofen axetil fat emulsion injection
Flurbiprofen axetil fat emulsion injection is intravenous formulations, and before administration, use after often needing to carry out compatibility dilution according to clinical application, therefore, the stability after compatibility dilution is extremely important.Desirable infatmul requires to use ultra-pure water, normal saline, glucose or blank plasma infinite dilution within the specific limits, without layering, breakdown of emulsion, does not also occur the phenomenons such as particle diameter becomes large, medicine precipitation.This test example has investigated the compatibility dilution stability of the Flurbiprofen axetil fat emulsion injection of the present invention and prior art.
Test specimen: the Flurbiprofen axetil fat emulsion injection that the embodiment of the present invention 2 is obtained;
Control sample: according to the Flurbiprofen axetil fat emulsion injection that the method for CN102988291A embodiment 1 is obtained.
Test method: adopt 0.9%NaCl solution, dilute with 1:5,1:10,1:20,1:50 ratio to above-mentioned sample, room temperature is placed, and observes cosmetic variation in 0h, 1h, 3h, 6h, 12h, 24h, 36h, 72h, measures particle diameter.Measurement result is in table 4 and table 5.
Table 4, the compatibility stability of Flurbiprofen axetil fat emulsion injection of the present invention in 0.9%NaCl solution
Note: (-) represents stable
The compatibility stability of Flurbiprofen axetil fat emulsion injection in 0.9%NaCl solution of table 5, CN102988291A
Note: (-) represents stable; (+) represents that oil droplet, lamination appear in liquid level
As can be seen from above-mentioned result of the test, the Flurbiprofen axetil fat emulsion injection adopting the method for prior art obtained is after with 0.9%NaCl solution dilution, injection change of size after placement certain hour of each extension rate is larger, and after placement 36h, all there is oil droplet, lamination in liquid level; And Flurbiprofen axetil fat emulsion injection of the present invention is after with 0.9%NaCl solution dilution, injection size after placement certain hour of each extension rate does not have significant change substantially, and oil droplet and lamination do not appear in liquid level yet.
Also carried out above-mentioned test to the Flurbiprofen axetil fat emulsion injection obtained by other embodiment of the present invention, its result obtained is similar.
Claims (11)
1. a pharmaceutical composition for Flurbiprofen axetil, is characterized in that, described pharmaceutical composition is fat emulsion injection, and it is composed as follows:
2. pharmaceutical composition according to claim 1, is characterized in that, described fat emulsion injection composed as follows:
3. pharmaceutical composition according to claim 2, is characterized in that, described fat emulsion injection composed as follows:
4. pharmaceutical composition according to claim 3, is characterized in that, described fat emulsion injection composed as follows:
5. the pharmaceutical composition according to Claims 1 to 4 any one, it is characterized in that, described pH adjusting agent is sodium hydrogen phosphate and citrate buffer, and its consumption is for making described injection pH=4.5 ~ 6.5, and wherein the mol ratio of sodium hydrogen phosphate and citric acid is 4:1.
6. a preparation method for the pharmaceutical composition described in claim 1-5 any one, is characterized in that, described preparation method comprises the steps:
1) under nitrogen protection, soybean oil and lecithin are heated to 70-75 DEG C, add Flurbiprofen axetil and vitamin E while stirring, dissolve, obtain oil phase;
2) under nitrogen protection, in partial syringe water, add glycerol, dissolve, obtain aqueous phase;
3) under nitrogen protection, by step 1) oil phase add step 2) aqueous phase in, high speed shear disperse, regulate pH=4.5 ~ 6.5 by pH adjusting agent, add water for injection standardize solution, stir, obtain colostrum;
4) under nitrogen protection, colostrum is added in high pressure homogenizer, high pressure homogenize, obtain Emulsion;
5) Emulsion is crossed filtering with microporous membrane, inflated with nitrogen, embedding, sterilizing, obtain described fat emulsion injection.
7. preparation method according to claim 6, is characterized in that, step 3) described in high speed shear jitter time be 20 ~ 30 minutes, shear rate is 6000 ~ 8000rpm.
8. preparation method according to claim 6, is characterized in that, step 4) described in high pressure homogenize pressure be 600 ~ 1000bar, homogenization cycles is 3 ~ 5 times.
9. preparation method according to claim 8, is characterized in that, described homogenization cycles is 3 times.
10. preparation method according to claim 8, is characterized in that, step 4) described in high pressure homogenize process in, regulate condensate flow, control emulsion temperature be no more than 30 DEG C.
11. preparation methoies according to claim 6-10 any one, is characterized in that, step 5) described in sterilizing be 121 DEG C of sterilizings 15 minutes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410633307.5A CN104434901B (en) | 2014-11-12 | 2014-11-12 | A kind of pharmaceutical composition of Flurbiprofen axetil |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410633307.5A CN104434901B (en) | 2014-11-12 | 2014-11-12 | A kind of pharmaceutical composition of Flurbiprofen axetil |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104434901A CN104434901A (en) | 2015-03-25 |
| CN104434901B true CN104434901B (en) | 2016-03-02 |
Family
ID=52882166
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410633307.5A Active CN104434901B (en) | 2014-11-12 | 2014-11-12 | A kind of pharmaceutical composition of Flurbiprofen axetil |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104434901B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11839590B2 (en) | 2018-10-10 | 2023-12-12 | Grand life science (wuhan) co., LTD | Flurbiprofen axetil emulsion for injection and preparation method thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106490656A (en) * | 2016-12-13 | 2017-03-15 | 厦门惠盈动物科技有限公司 | A kind of emulsification liquid additive premix production system and production technology |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102670502A (en) * | 2012-05-17 | 2012-09-19 | 北京阜康仁生物制药科技有限公司 | S(+)-flurbiprofen axetil injection emulsion |
| CN102988291A (en) * | 2012-12-13 | 2013-03-27 | 哈药集团技术中心 | Flurbiprofen axetil fat emulsion injection composition and preparation method thereof |
-
2014
- 2014-11-12 CN CN201410633307.5A patent/CN104434901B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102670502A (en) * | 2012-05-17 | 2012-09-19 | 北京阜康仁生物制药科技有限公司 | S(+)-flurbiprofen axetil injection emulsion |
| CN102988291A (en) * | 2012-12-13 | 2013-03-27 | 哈药集团技术中心 | Flurbiprofen axetil fat emulsion injection composition and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11839590B2 (en) | 2018-10-10 | 2023-12-12 | Grand life science (wuhan) co., LTD | Flurbiprofen axetil emulsion for injection and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104434901A (en) | 2015-03-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20230147697A1 (en) | Topical formulations having enhanced bioavailability | |
| Peng et al. | Characterization of cubosomes as a targeted and sustained transdermal delivery system for capsaicin | |
| Sinsuebpol et al. | Preparation and in vivo absorption evaluation of spray dried powders containing salmon calcitonin loaded chitosan nanoparticles for pulmonary delivery | |
| US8465757B2 (en) | Nanoemulsion of resveratrol-phospholipid complex and method for preparing the same and applications thereof | |
| CN103393631B (en) | Flurbiprofen axetil pharmaceutical composition | |
| RU2635473C2 (en) | Preservative-free topical composition, including hyaluronic acid | |
| Yadav et al. | Screening of ionically crosslinked chitosan-tripolyphosphate microspheres using Plackett–Burman factorial design for the treatment of intrapocket infections | |
| CN104434901B (en) | A kind of pharmaceutical composition of Flurbiprofen axetil | |
| CN104490779A (en) | Flurbiprofen axetil fat emulsion injection | |
| CN104352566A (en) | Oil-in-water compound chlortetracycline nanoemulsion | |
| TW202005652A (en) | Pharmaceutical formulation | |
| WO2017143877A1 (en) | Pharmaceutical composition of diclofenac sodium for injection, and preparation method therefor | |
| BRPI0821739B8 (en) | drug delivery system for administering a pharmaceutically active amphiphilic cationic substance comprising nanoparticles, pharmaceutical composition and drug delivery system preparation method | |
| CN108143715A (en) | A kind of florfenicol residues | |
| JP2007045788A (en) | Method for preparing aqueous solution of glycyrrhizinic acid having high concentration | |
| CN104784115A (en) | Flurbiprofen axetil microsphere injection and preparation method thereof | |
| CN103877013A (en) | Asarin injection and preparation method thereof | |
| JP2012012325A (en) | Nanoparticle of anti-inflammatory compound and method for producing the same | |
| CN108743569A (en) | Salbutamol sulfate aerosol inhalation solution and preparation method thereof | |
| CN106937944A (en) | A kind of injection metronidazole freeze-dried powder and preparation method thereof | |
| CN115645368A (en) | Bortezomib fat emulsion injection and preparation method thereof | |
| AU2018204106A1 (en) | Topical formulations having enhanced bioavailability | |
| CN104771362A (en) | Clarithromycin ion pair lipid microsphere injection and preparation method thereof | |
| CN104983678A (en) | Ornidazole infusion preparation and preparation technology thereof | |
| CN110870850A (en) | Flurbiprofen axetil injection and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |