CN101919812B - Novel formulation of piperazine ferulate and preparation method thereof - Google Patents
Novel formulation of piperazine ferulate and preparation method thereof Download PDFInfo
- Publication number
- CN101919812B CN101919812B CN2010101630823A CN201010163082A CN101919812B CN 101919812 B CN101919812 B CN 101919812B CN 2010101630823 A CN2010101630823 A CN 2010101630823A CN 201010163082 A CN201010163082 A CN 201010163082A CN 101919812 B CN101919812 B CN 101919812B
- Authority
- CN
- China
- Prior art keywords
- piperazine ferulate
- injection
- piperazine
- ferulate
- group
- 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.)
- Expired - Fee Related
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a injection of piperazine ferulate and a preparation method thereof. The novel formulation of the piperazine ferulate is prepared by the steps of dissolving piperazine ferulate as a medicine component into a solvent and regulating the pH value to be 5.0-8.0 with a pH regulating agent so that the piperazine ferulate is fully dissolved to prepare an injection. The content of the piperazine ferulate in the novel formulation is 27-200mg/ml, and the agent is the water of injection. The invention broadens the clinical application range of the piperazine ferulate, has the characteristics of high medicine dissolubility, high bioavailability, rapid medicine administration, more quick effect-taking, stronger treatment effect, and the like, is especially suitable for preventing and treating patients suffering from heavy cerebral infarction, nephroma, coronary heart disease, vascular complication in diabetes mellitus and dysphagia, overcomes the problem of low dissolubility of the piperazine ferulate in the prior art, and realizes the solubilization of the piperazine ferulate by regulating the pH value with the pH regulating agent, wherein at least 500mg of piperazine ferulate can be dissolved in 10mlof water solution with pH value of 5.5.
Description
Technical field
The invention belongs to technical field of pharmaceuticals; A kind of endothelin-receptor antagonists injection and method for preparing; Be used for prevention and treatment of diseases such as coronary heart disease due to the Endothelin, cerebral infarction, kidney disease, diabetic vascular complications; Specifically, the injection and preparation method thereof that relates to a kind of piperazine ferulate.
Background technology
Piperazine ferulate, chemical name are 3-methoxyl group-4 hydroxyl cinnamic acid piperazine, come through ferulic acid and piperazine chemosynthesis.Ferulic acid is ubiquitous a kind of phenolic acid; In plant cell wall; Part with polysaccharide and the crosslinked formation cell wall of lignin; Be one of Effective Components of Chinese Herb such as Resina Ferulae, Radix Angelicae Sinensis, Rhizoma Chuanxiong, Rhizoma Cimicifugae, because of it has stronger antioxidant activity and antisepsis is widely used in medicine, pesticide, health product, cosmetic material and food additive aspect.In recent years, studying extensively and profoundly aspect its physiologically active, finding that ferulic acid and derivant thereof had biological activitys such as anti-blood is fastened, blood fat reducing, antiinflammatory, anti-cancer.
PLA Air Force General Hospital Wang Feng in 1999 etc. study report; Ferulate is a kind of new non-peptide-like endothelin receptor antagonist; Confirmed that the Resina Ferulae acid can combine with endothelin receptor is competitive; Has the identical antagonism Endothelin effect of bosentan (endothelin receptor antagonists thing, calendar year 2001 U.S.'s listing).Endothelin is the vasoactive polypeptide of a kind of tool, forms by 21 aminoacid, and be the product of residual gene in human evolution's history.Modern medicine study confirms that it is powerful virulence factor, and is closely related with disease development such as blood vessel heart and brain kidney, can intensive vasoconstrictive, and its intensity is 10 times of Angiotensin II, is 100 times of norepinephrine; Can promote the strong propagation of VSMC, endotheliocyte, mesangial cell, promote the formation of atherosclerosis, glomerular sclerosis; Also short hypercoagulability forms, and causes the generation of heart and brain acute events.Resina Ferulae acids drug main will comprise sodium ferulate, ferulic acid ligustrazine, piperazine ferulate.Wherein optimum with the clinical efficacy and the safety of piperazine ferulate, and be widely used in treatment of diseases such as coronary heart disease, cerebral infarction, diabetic vascular complications, kidney disease as basic medication, and included by China's pharmacopeia two ones of versions in 2005.
The piperazine ferulate preparation kind of having gone on the market at present has piperazine ferulate sheet, piperazine ferulate dispersible tablet, piperazine ferulate capsule, is oral formulations.But piperazine ferulate is a kind of slightly solubility material, and dissolubility is very low in water, and the atomic ethanol that is dissolved in, and is insoluble to chloroform.Therefore; The piperazine ferulate oral formulations exists significantly not enough; As the medicine disintegrate is difficult, drug dissolution is low, bioavailability is poor, onset is slow; Thereby all inapplicable, or limited its clinical effectiveness to a certain extent for serious symptom cerebral infarction, nephropathy, coronary heart disease, diabetic vascular complications patient, dysphagia patients.
Summary of the invention
Technical problem to be solved by this invention provides and a kind ofly can overcome that piperazine ferulate oral preparation medicament dissolution is poor in the prior art, bioavailability is low, onset waits novel formulation of piperazine ferulate of shortcoming and preparation method thereof slowly; It is the piperazine ferulate injection; Can significantly improve the piperazine ferulate bioavailability; Onset is more rapid, for disease patients such as serious symptom coronary heart disease, cerebral infarction, nephropathy, diabetic vascular complications provide a kind of even more ideal medicine.
The present invention addresses the above problem the technical scheme that is adopted: the injection of piperazine ferulate; With the piperazine ferulate is that medicinal component is dissolved in the solvent; Through pH regulator agent regulator solution pH value is that 5.0-8.0 dissolves piperazine ferulate fully; Process injection, the content of said piperazine ferulate is 27-200mg/ml, and said solvent is a water for injection.
Another object of the present invention is exactly to overcome the low problem of piperazine ferulate dissolubility in the present technology.Piperazine ferulate belongs to the slightly solubility material, and dissolubility is very low in water.This has also limited the change of piperazine ferulate administering mode.The present invention discovers that piperazine ferulate can strengthen its dissolubility through regulating the solvent pH value.
Piperazine ferulate injection of the present invention is meant the feasible injection type of acceptable clinically pharmaceutics, comprises injection with small volume, high-capacity injection, powder ampoule agent for injection.The solvent of piperazine ferulate injection of the present invention is a water for injection, comprises and is not limited to the transfusion of purified water, sodium chloride, glucose infusion liquid.
Piperazine ferulate injection of the present invention, the solubilization method that is adopted is regulated the solvent pH value through the pH regulator agent and is realized that making its solution pH value scope is 5.0-8.0, and preferred pH scope is: 5.5-7.5.The 10mlpH value is that 5.5 aqueous solution can dissolve the 500mg piperazine ferulate at least.
The above-mentioned pH regulator agent that the present invention relates to can be alkaline matter, strong base-weak acid salt.Alkaline matter, comprise and be not limited to sodium hydroxide, potassium hydroxide, calcium hydroxide one or more.Strong base-weak acid salt, comprise and be not limited to sodium carbonate, sodium bicarbonate, sodium lactate, potassium carbonate, sodium citrate, potassium citrate, sodium hydrogen phosphate, dipotassium hydrogen phosphate one or more.
The invention further relates to the piperazine ferulate injection can also add acceptable accessories according to the preparation needs, like cosolvent, isoosmotic adjusting agent, antioxidant, to strengthen dissolubility, stability, the effectiveness of medicine.Further, this piperazine ferulate injection also can adopt pharmaceutically acceptable mode to process lyophilized formulations, comprises adding lyophilizing support, freeze drying protectant.
A kind of method for preparing of above-mentioned piperazine ferulate injection comprises the steps:
A. take by weighing the 80-300g piperazine ferulate;
B. piperazine ferulate is added 1500-3000ml water for injection, stir, slowly adding pH regulator agent adjusting pH value is 5.5-8.0, and piperazine ferulate is dissolved fully;
C. in above-mentioned piperazine ferulate solution, add active carbon, decarbonization filtering after stirring at room 10-60 minute;
D. above-mentioned filtrating reuse filtering with microporous membrane, benefit adds to the full amount of water for injection; Be sub-packed in the brown ampoule, sealing by fusing through pressure sterilizing, promptly obtains the piperazine ferulate injection with small volume.
E. if be sub-packed in the 100ml glass bottle, jump a queue, roll lid,, promptly get the piperazine ferulate high-capacity injection through pressure sterilizing.
F. if be sub-packed in the 10ml cillin bottle, lyophilizing promptly gets the piperazine ferulate powder ampoule agent for injection.
G. in the above-mentioned B step, piperazine ferulate solution is antioxidant 5-50g, cosolvent 10-150g, isoosmotic adjusting agent 10-100g, freeze drying protectant 10-100g as required also.
In sum, the invention has the beneficial effects as follows:
1, the present invention has expanded the clinical scope of application of piperazine ferulate; Have that medicine dissolution property is high, bioavailability is high, administration is fast, onset is rapider; Characteristics such as therapeutical effect is stronger are particularly useful for the control of serious symptom cerebral infarction, nephropathy, coronary heart disease, diabetic vascular complications patient, dysphagia patients.
2, the present invention can overcome the low problem of piperazine ferulate dissolubility in the present technology, regulates the solubilising that the solvent pH value can be realized piperazine ferulate through the pH regulator agent, and the 10ml pH value is that 5.5 aqueous solution can dissolve the 500mg piperazine ferulate at least.
The specific embodiment
Below in conjunction with embodiment the present invention is done further detailed description, but embodiment of the present invention is not limited thereto.
Embodiment 1:
The preparation of piperazine ferulate injection with small volume
A. take by weighing 80 piperazine ferulates;
B. piperazine ferulate is added 1800ml water for injection, stir, slowly add 20% sodium carbonate liquor and regulate pH value, make the solution pH value reach 6.2, this moment, piperazine ferulate dissolved fully;
C. in above-mentioned piperazine ferulate solution, add an amount of active carbon, stirring at room is decarbonization filtering after 30 minutes;
D. above-mentioned filtrating reuse filtering with microporous membrane, benefit adds to the full amount of water for injection; Be sub-packed in the brown ampoule of 10ml, sealing by fusing through pressure sterilizing, promptly obtains the piperazine ferulate injection with small volume.
Embodiment 2:
The preparation of piperazine ferulate powder ampoule agent for injection
A. take by weighing the 300g piperazine ferulate;
B. piperazine ferulate is added 3000ml water for injection, stir, slowly add the 2mol/L sodium hydroxide solution and regulate pH value, making pH value is 7.5, and piperazine ferulate is dissolved fully; Add 200g mannitol again, stir, make dissolving fully;
C. in above-mentioned piperazine ferulate solution, add active carbon, stirring at room is decarbonization filtering after 60 minutes;
D. above-mentioned filtrating reuse filtering with microporous membrane, benefit adds to the full amount of water for injection; Be sub-packed in the 10ml cillin bottle, lyophilizing promptly gets injection piperazine ferulate injectable powder.
Embodiment 3:
The preparation of piperazine ferulate high-capacity injection
A. take by weighing the 100g piperazine ferulate;
B. piperazine ferulate is added 2000ml water for injection, stir, slowly add sodium lactate solution and regulate pH value, make pH reach 5.8, stir, piperazine ferulate dissolves fully.
C. in above-mentioned piperazine ferulate solution, add active carbon, stirring at room is decarbonization filtering after 30 minutes;
D. above-mentioned filtrating reuse filtering with microporous membrane, benefit adds to the full amount of water for injection; Be sub-packed in the 100ml glass bottle, jump a queue, roll lid,, promptly get the piperazine ferulate high-capacity injection through pressure sterilizing.
Embodiment 4:
Acute toxicity testing
(1) the lumbar injection piperazine ferulate records LD
50Be 3135mg ± 759mg/ kg body weight/mice, be equivalent to clinical 313 times of drafting adult's dosage.(2) the intravenous injection piperazine ferulate is measured its LD
50Be 2484mg ± 638mg/ kg body weight/mice, be equivalent to clinical 248 times of drafting adult's dosage.Prove absolutely that the safety of piperazine ferulate injection is very high, it is fully feasible changing injection into by tablet.。
Embodiment 5:
Rat teratogenesis mutagenicity test
Carried out rat teratogenic test, Salmonella reversion test, mouse bone marrow cells micronucleus test and chromosomal aberration test with piperazine ferulate, proved that piperazine ferulate does not still have teratogenesis and mutagenesis under heavy dose.
Embodiment 6:
Subacute toxicity test
With piperazine ferulate give every each quiet notes 400mg of Canis familiaris L. next day of (being equivalent to clinical 3 times of drafting adult's dosage) once, totally 30 times, administration time is 2 months, and continues to observe 4 months, has carried out the observation of half a year altogether.Stop solid liquor-saturated, the triglyceride of weight, erythrocyte, leukocyte, platelet, hemoglobin, differential blood count, serum transaminase, alkali phosphatase, blood peroxidase, gallbladder, the total fat of blood, non-protein nitrogen, protein electrophoresis, total protein, albumin, etc. with the matched group comparison; Difference that there are no significant, pathological tissue are observed also no abnormality seen pathological changes.
Embodiment 7:
Piperazine ferulate is to the influence of MCAO rat RCBF
1 materials and methods
1.1 animal divides into groups
Choose 120 of healthy male Wistar rats; In 12 ages in week, body weight (300 ± 20) g is divided into 5 groups at random; Be sham operated rats, model control group (abbreviation model group), piperazine ferulate injection A group, piperazine ferulate injection B group, piperazine ferulate tablet group, every group each 24.By putting to death time point, every group is divided into again: 1 week of postoperative, 2 weeks, 3 weeks are organized each 8.
1.2 the modeling of animal
Model group and piperazine ferulate injection A group, piperazine ferulate injection B group, the capable right side of piperazine ferulate tablet treated animal near-end middle cerebral artery electric coagulation; Make middle cerebral artery occlusion MCAO model; The sham operated rats rats underwent is opened the cranium art equally; But do not close MCA with fixed attention, all the other operate same model group.
1.3 medication
Piperazine ferulate injection A group, piperazine ferulate injection B treated animal be lumbar injection piperazine ferulate 15mg/kg/ day, 10mg/kg/ day respectively; Piperazine ferulate tablet group is irritated stomach and is given piperazine ferulate sheet 10mg/kg/ day.Sham operated rats, model group be lumbar injection isodose normal saline respectively, totally 2 weeks.In modeling success administration in back 7 days, solid feed and water freely absorb.
1.4 sample preparations
Each experimental group animal is finished medicine feed in the corresponding time respectively, and after last was measured infarction side frontal lobe RCBF, broken end was got brain, is divided into several layers along coronalplane is on average every at a distance from 2mm, and 4% paraformaldehyde is fixed, gradient alcohol dehydration, FFPE.The up thickness of microtome is the sections of 4 μ m continuous coronal, and section is divided into groups subsequent use.
1.5 the detection of index
This experiment is chosen infarction kitchen range and surrounding tissue thereof as observing main region.Adopt laser Doppler flowmetry (LDF) to measure infarction side frontal lobe RCBF.
1.6 statistical analysis
With all data input microcomputers, use the SAS8.1 software kit and carry out statistical analysis.Continuous data representes that with x ± s measurement data relatively adopts one factor analysis of variance, the Newman-Keuls check.Dependency between index adopts the rectilinear correlation analysis.
2 results
The influence of experimental rat right side frontal lobe RCBF (rCBF) and piperazine ferulate, the result sees table 1.
Table 1 is respectively organized rat right side cortex of frontal lobe rCBF and is measured (AU .x ± s)
| Group | 1 week of postoperative | 2 weeks of postoperative | 3 weeks of postoperative |
| Sham operated rats | 112.48±11.99 | 116.46±12.05 | 116.89±12.57 |
| Model group | 84.62±7.83※※ | 87.51±7.47※※ | 86.25±6.52※※ |
| Piperazine ferulate injection A group | 99.22±6.51▲ | 108.97±7.02▲▲ | 113.68±7.25▲▲ |
| Piperazine ferulate injection B group | 94.38±6.28▲ | 105.69±6.15▲▲ | 109.44±7.36▲▲ |
| Piperazine ferulate tablet group | 87.21±5.33 | 99.61±5.75▲ | 101.73±8.72▲ |
Annotate: with the sham operated rats comparison same period, ※ ※ P＜0.01; With the model group comparison same period, ▲ P＜0.05.
The result shows, compares with sham operated rats, and 1 week of model group animal postoperative, 2 weeks, 3 all infarction side cortex of frontal lobe rCBF values significantly descend, and shows this experiment modeling success.And rise in various degree appears through the rCBF of piperazine ferulate treatment infarction side cortex of frontal lobe, and no matter the prompting piperazine ferulate is oral or drug administration by injection, can both expansion of cerebral vascular, and the cerebral blood flow increasing amount is improved the ischemic area blood supply insufficiency.But it is aspect prevention effect, more remarkable with drug administration by injection.Compare with model group, 1 all ferulic acid piperazine injection A groups, the rise of ferulic acid piperazine injection A treated animal infarction side cortex of frontal lobe rCBF value after surgery be (P＜0.05) significantly; And piperazine ferulate sheet treated animal infarction side cortex of frontal lobe rCBF value rise not obvious (P＞0.05).2 weeks of postoperative, 3 weeks, ferulic acid piperazine injection A group, ferulic acid piperazine injection A treated animal infarction side cortex of frontal lobe rCBF value continue to increase, and relatively have utmost point significant difference (P＜0.01) with model group; And piperazine ferulate sheet treated animal infarction side cortex of frontal lobe rCBF value compares P＞0.05 with model group.The result shows no matter piperazine ferulate is oral or drug administration by injection, can both expansion of cerebral vascular, and the cerebral blood flow increasing amount is improved the ischemic area blood supply insufficiency.But under same dose, the drug administration by injection therapeutic effect is more remarkable.
Embodiment 8:
The piperazine ferulate injection is to the influence of rat suppository formation and blood viscosity
1 materials and methods
1.1 material
50 of healthy male Wistar rats, body weight 252 ± 18g.Extracorporeal thrombosis forming device (SDZ2A1 type), jiangsu wuxi county Electronic Instruments Plant product; L GPABER platelet aggregation thrombin appearance, L G2R220 type blood viscosity analyzer all are diligent generation Supreme Being's scientific instrument Company products in Beijing.
1.2 experiment medicine
Aspirin Enteric-coated Tablets (Aspirin, ASP), the 25mg/ sheet, Beijing the 8th pharmaceutical factory produces; Lyophilized thrombin test kit, thromboplastin reagent box, partial thromboplastin test kit are reagent place of skill association of Huashan hospital of Shanghai Medical Univ product; Pentobarbital sodium, Shanghai import packing.
1.3 experimental procedure
Rat is divided into 5 groups (10 every group) at random: (1) matched group: distilled water 10ml/kg; (2) the heavy dose of group of piperazine ferulate injection, dosage 15mg/kg/ day; (3) piperazine ferulate injection small dose group, dosage 10mg/kg/ day; (4) piperazine ferulate sheet group, dosage 10mg/kg/ day; (5) aspirin group, dosage 50mg/kg) matched group is with the distilled water lumbar injection of 10ml/kg the weight of animals, and piperazine ferulate sheet group, aspirin group are with the medicine liquid irrigation stomach of equal volume; All the other groups are all used corresponding equal-volume medicinal liquid lumbar injection, and continuous 7 days, once a day; 1h after the last administration; With pentobarbital sodium (30.0mg/kg the weight of animals) anesthesia, cut open the belly, with the silication syringe from abdominal aortic blood with the determination experiment index.
1.4 experimental index and assay method
2ml blood is used for external thrombus and forms mensuration, promptly according to the Chandler in vitro method, at once blood is injected in the rotating ring, and the blood volume of injection is full of rotating ring (1.8ml) below 1/2; Sealing is put on the extracorporeal thrombosis forming device rapidly, rotation 10min (experimental temperature is 37 ℃); Inclining thrombosis, and length is measured in the normal saline washing; The weighing weight in wet base is put 80 ℃ of baking oven 3h with the thrombosis bar, claims its dry weight after the constant weight; 1.8ml blood (3.8% sodium citrate anticoagulant) is measured plasma prothrombin time (PT), kaolin partial prothrombin time (KPTT), thrombin time (TT), its operational approach is undertaken by the test kit description.
1.5 statistical procedures
(x ± s) expression by the SPSS10.0 software processes, adopts the between group variable analysis to draw the P value to experimental data with mean ± standard deviation.
2 results
2.1 ordinary circumstance
Each treated animal food ration of experimental session does not have significant difference, and each organizes body weight similar (P＞0.05).
2.2 piperazine ferulate is to the thrombotic influence of rats in vitro, the result sees table 2.Compare with matched group; Piperazine ferulate tablet group has the trend (P＞0.05) that shortens thrombosis length and alleviate wet weight of thrombus and dry weight; And the big small dose group of piperazine ferulate injection can shorten thrombosis length and alleviate wet weight of thrombus and dry weight; Effect is (P＜0.05) obviously, and wherein the heavy dose of group effect of piperazine ferulate significantly (P＜0.01) is suitable with the aspirin group.Show that piperazine ferulate can effectively shorten thrombosis length and alleviate wet weight of thrombus and dry weight, but drug administration by injection is stronger than oral administration pharmacological action.Prompting piperazine ferulate drug administration by injection can improve its bioavailability, and onset is rapider, more remarkable treatment effect.
Table 2 piperazine ferulate to the thrombotic influence of rats in vitro (x ± s, n=10)
| Group | Thrombosis length | Wet weight of thrombus | The thrombosis dry weight |
| Matched group | 23.18±2.14 | 139.47±12.35 | 25.62±3.41 |
| The aspirin group | 16.38±1.02** | 101.83±15.09** | 17.52±3.76** |
| The heavy dose of group of piperazine ferulate injection | 16.99±1.33** | 105.87±13.49** | 17.77±3.38** |
| Piperazine ferulate injection small dose group | 18.35±2.01* | 110.59±11.46* | 19.66±3.50* |
| Piperazine ferulate tablet group | 21.11±2.25 | 128.30±12.23 | 22.84±3.33 |
Annotate: compare * P＜0.05 with the matched group group; * P＜0.05
2.3 piperazine ferulate is to the influence of rat clotting time, the result sees table 3.Compare with matched group; The heavy dose of group of piperazine ferulate injection, the PT of piperazine ferulate injection small dose group, KPTT, TT all obviously prolong; Wherein the heavy dose of group of piperazine ferulate injection PT, KPTT, TT prolong more remarkable (P＜0.01), and be suitable with the aspirin group.And PT, KPTT, the TT of piperazine ferulate tablet group have only prolongation trend (P＞0.05).The prompting piperazine ferulate has prolong rats clotting time effect.Its action intensity and administering mode, dosage are relevant.Drug administration by injection is superior to oral administration; Dosage is big more, and pharmacodynamics effect is strong more.
Table 3 piperazine ferulate is to the influence of rat clotting time
| Group | PT | KPTT | TT |
| Matched group | 10.95±2.01 | 36.44±3.20 | 13.52±3.87 |
| The aspirin group | 18.45±1.93** | 51.27±4.26** | 19.67±3.58* |
| The heavy dose of group of piperazine ferulate injection | 18.02±1.89** | 50.53±3.88** | 19.51±3.44* |
| Piperazine ferulate injection small dose group | 16.38±2.15* | 45.62±3.77* | 17.66±3.81* |
| Piperazine ferulate tablet group | 12.64±2.22 | 40.15±3.27 | 15.25±3.68 |
Annotate: compare * P＜0.05 with the matched group group; * P＜0.05
Cardiovascular and cerebrovascular disease is particularly common in the gerontal patient, is to cause dead commonly encountered diseases.Data shows that blood viscosity increases with age growth, and causes thrombosis easily, strengthens blood coagulation activity, promotes that the state of an illness takes place, development.Blood viscosity increases, and artery blood flow speed is slowed down and Peripheral resistance increases, and causes cerebral ischemia, brings out or increases the weight of cardiovascular and cerebrovascular disease.Thrombosis then is the immediate cause that myocardial infarction, cerebral infarction take place in the blood vessel.Therefore, often adopt medicine to prevent and treat cardiovascular and cerebrovascular disease clinically to improve blood viscosity, anticoagulant, antithrombotic.Piperazine ferulate can shorten thrombosis length and alleviate wet weight of thrombus and dry weight, and PT, KPTT, TT are all obviously prolonged; Wherein piperazine ferulate injection action effect obviously is better than the piperazine ferulate tablet.And its pharmacological action intensity and dosage are closely related.Dosage is big more, and pharmacological action is strong more.This experimental result shows that we are through strengthening the dissolubility of piperazine ferulate, and preparation becomes injection, can improve the bioavailability of piperazine ferulate, strengthens its pharmacological action intensity, thereby improves therapeutic effect
As stated, just can realize the present invention preferably.
Claims (10)
1. the injection of piperazine ferulate; It is characterized in that; With the piperazine ferulate is that medicinal component is dissolved in the solvent, is that 5.0-8.0 dissolves piperazine ferulate fully through pH regulator agent regulator solution pH value, processes injection; The content of said piperazine ferulate is 27-200mg/ml, and said solvent is a water for injection.
2. the injection of piperazine ferulate according to claim 1 is characterized in that, said solvent pH value is 5.5-7.5.
3. the injection of piperazine ferulate according to claim 1 and 2 is characterized in that, said pH regulator agent is alkaline matter and/or strong base-weak acid salt.
4. the injection of piperazine ferulate according to claim 3 is characterized in that, said alkaline matter is a kind of or above-mentioned multiple mixture that constitutes with arbitrary proportion in sodium hydroxide, potassium hydroxide, the calcium hydroxide.
5. the injection of piperazine ferulate according to claim 3; It is characterized in that said strong base-weak acid salt is a kind of or above-mentioned multiple mixture that constitutes with arbitrary proportion in sodium carbonate, sodium bicarbonate, sodium lactate, potassium carbonate, sodium citrate, potassium citrate, sodium hydrogen phosphate, the dipotassium hydrogen phosphate.
6. the method for preparing of the injection of any said piperazine ferulate of claim 1-5 is characterized in that, comprises the steps:
A. take by weighing the 80-300g piperazine ferulate;
B. piperazine ferulate is added 1500-3000ml water for injection, stir, slowly adding pH regulator agent adjusting pH value is 5.5-8.0, and piperazine ferulate is dissolved fully;
C. in above-mentioned piperazine ferulate solution, add active carbon, decarbonization filtering after stirring at room 10-60 minute;
D. with the filtrating reuse filtering with microporous membrane of step C, mending adds to the full amount of water for injection promptly gets the piperazine ferulate injection.
7. the method for preparing of the injection of piperazine ferulate according to claim 6 is characterized in that, in the said B step, piperazine ferulate solution also adds antioxidant 5-50g.
8. the method for preparing of the injection of piperazine ferulate according to claim 6 is characterized in that, in the said B step, piperazine ferulate solution also adds has cosolvent 10-150g.
9. the method for preparing of the injection of piperazine ferulate according to claim 6 is characterized in that, in the said B step, piperazine ferulate solution also adds has isoosmotic adjusting agent 10-100g
10. the method for preparing of the injection of piperazine ferulate according to claim 6 is characterized in that, in the said B step, piperazine ferulate solution also adds has freeze drying protectant 10-100g.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101630823A CN101919812B (en) | 2010-05-05 | 2010-05-05 | Novel formulation of piperazine ferulate and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101630823A CN101919812B (en) | 2010-05-05 | 2010-05-05 | Novel formulation of piperazine ferulate and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101919812A CN101919812A (en) | 2010-12-22 |
| CN101919812B true CN101919812B (en) | 2012-01-25 |
Family
ID=43335203
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010101630823A Expired - Fee Related CN101919812B (en) | 2010-05-05 | 2010-05-05 | Novel formulation of piperazine ferulate and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101919812B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116251065B (en) * | 2023-02-20 | 2024-04-26 | 山东齐发药业有限公司 | APTM soluble powder intermediate, soluble powder and preparation method |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1442141A (en) * | 2003-04-14 | 2003-09-17 | 成都世纪联合生物医药有限公司 | Ferulic acid salt injection agent |
-
2010
- 2010-05-05 CN CN2010101630823A patent/CN101919812B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN101919812A (en) | 2010-12-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111529524A (en) | Application of N6022 in prevention and treatment of aortic dissection and aortic aneurysm | |
| CN101919812B (en) | Novel formulation of piperazine ferulate and preparation method thereof | |
| CN102516079B (en) | Synthetic method of novel ferulic acid derivative | |
| RU2454237C1 (en) | High-molecular heparin composition with anticoagulant, anti-platelet, fibrinolytic and fibrin depolymerisation properties | |
| CN104146990A (en) | Application of phloretin in preparation of medicine for preventing and/or treating diabetes | |
| KR20170095926A (en) | Sulfonamide pharmaceutical composition | |
| Taiwo et al. | Cardiovascular effects of Vernonia amygdalina in rats and the implications for treatment of hypertension in diabetes | |
| CN105142650A (en) | Rapid infusion of autologous bone marrow derived stem cells | |
| CN107648598B (en) | A kind of pharmaceutical composition for treating acute ischemic cerebral apoplexy | |
| CN100446775C (en) | Chonsurid for venous injection administration and its preparing method | |
| CN100509000C (en) | Dispersion tablet of red sage root for coronary artery and preparation method thereof | |
| RU2487704C2 (en) | Method for prevention of reperfusion injuries of donor organs | |
| KR20030035482A (en) | Compositin of Korean Red Ginseng Including Oriental Herbs for Improving Sexual Function and Manufacturing Method the Same and Its Use | |
| CN107405371A (en) | For treating and preventing the coniferous tree resin of aseptic inflammation | |
| CN109381435B (en) | Dexlansoprazole freeze-dried powder injection, preparation method and application thereof | |
| CN106924273A (en) | Bletilla glycosides is preparing the application in heparin antagonist object space face | |
| KR20220163389A (en) | Medical Uses of Anhydroicaritin | |
| CN102091326B (en) | Transdermal medicament delivery preparation for treating hemorrhoid diseases caused by expansion or varix of anal subcutaneous veniplex and preparation method thereof | |
| CN102861045B (en) | Medicinal composition for treating neuropathic pain | |
| CN102920726B (en) | Medicinal composition for preventing and treating neuropathic pain | |
| CN100408045C (en) | Medicinal composition for treating cardio-cerebro-vascular diseases | |
| CN107802632B (en) | Traditional Chinese medicine effective component composition for treating rheumatic arthritis and rheumatoid arthritis and application thereof | |
| CN101628022A (en) | Safflower dripping pill and preparation method thereof | |
| CN100457130C (en) | Refined puncturevine fruit saponin capable of being administered by injection, its preparing process and injecta | |
| CN106822114B (en) | Application of MTCA in preparation of medicines for reducing blood sugar or blood fat |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20120125 Termination date: 20170505 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |