CN106580891A - Aescin B injection and preparation method thereof - Google Patents
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A—HUMAN NECESSITIES
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- 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
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Abstract
The invention discloses an aescin B injection which contains aescin B and amino acids. The weight ratio of aescin B to amino acids is (10-50):(1-10). The invention further discloses a preparation method of the injection. Compared with the prior art, the higher anti-inflammatory and anti-effusion activity, and the lower vascular irritation and liver and kidney toxicity are achieved.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to a kind of aescine B injection, the invention further relates to the side of preparation
Method.
Background technology
Aescine is that the total saponins for obtaining, the water dissolution of aescine are extracted from Hippocastanaceae buckeye seed
Degree is poor, is to increase its dissolubility, is often made into sodium salt.Aescine mainly contains 4 kinds of compositions, and China's national standard presses liquid
Before and after phase chromatograph appearance, aescine A, aescine B, aescine C and aescine D are named as successively.
Aescine has the multiple efficacies such as antiinflammatory, edema, can be used for the treatment of the diseases such as cerebral edema, wound, mesh
Front many administering modes using intravenous injection.CN 102836133A disclose a kind of notoginsenoside sodium freezing-dried powder pin and its preparation
Method, it is made using aescine, the freeze drying protectant tert-butyl alcohol and water for injection, but due to aescine have compared with
Strong blood vessel irritation, also with stronger nephrotoxicity, easily causes acute renal failure, so as to limit its clinical practice.
CN 1491657A disclose a kind of pharmaceutical composition being made up of aescine and diclofenac salt, and double chlorine are fragrant
The addition zest for substantially alleviating aescin for injection of hydrochlorate and the pain for causing.CN 1931176A disclose one
The pharmaceutical composition of kind of aescine, it is made up of pharmaceutical carriers such as escin and lysines, and the two combination is with significant
Synergistic function, and reduce aescine to blood vessel and the zest of muscle, but nephrotoxicity can not be reduced.Try
Test and show, the anti-inflammatory activity of aescine is got over the purity positive correlation of aescine, i.e. aescine A, total purity of B, C, D
Height, relevant content of material is fewer, and activity is stronger, and the blood vessel irritation contrast of aescine, i.e. aescine A, B, C, D
Total purity it is higher, relevant content of material is fewer, and zest is bigger.
The content of the invention
The purpose of the present invention is for defect present in prior art, there is provided a kind of aescine B injection, is not only had
There is higher therapeutic activity, while vascular stimulation and nephrotoxicity can also be reduced, so as to better meet clinical treatment.
Aescine B injection provided by the present invention, containing aescine B and aminoacid, the aescine B and ammonia
The weight ratio of base acid is 10～50: 1～10.
Preferably, the aminoacid is in glycine, lysine, proline, aspartic acid, L-Tyrosine, cysteine
One or more of combination in any.
Preferably, the aescine B and the weight ratio of aminoacid are 30～40: 2～6.
Preferably, described aescine B injection is also containing acceptable auxiliary element on medicament.
Preferably, the injection is freeze-dried powder, and the auxiliary element is pH adjusting agent and Mannitol.
Preparation method provided by the present invention is comprised the following steps：
1) aescine B, aminoacid, Mannitol are dissolved in into water for injection and mixed solution is obtained, it is sweet in the mixed solution
The concentration of dew alcohol is 10～20g/100ml, and the concentration of aescine B is 0.5～2g/100ml；
2) pH value for adjusting mixed solution with pH adjusting agent is 4.5～6.5；
3) solution filter membrane or filter element filtering after pH value will be adjusted；
4) lyophilization after fill, obtains final product.
Preferably, the pH adjusting agent is lactic acid.Aescine B property is unstable, can improve stable with acid for adjusting pH
Property, the wherein stability of lactic acid is best, and lactic acid can also reduce zest.
Preferably, the lyophilization includes pre-freeze, once distillation and re-dry three phases, the operation step in each stage
It is rapid as follows：
Pre-freeze：First temperature of charge is rapidly decreased to into -25～-20 DEG C, is kept for 0.5～1 hour, then again delay temperature of charge
Slowly -40～-35 DEG C are down to, 2～5 hours are incubated；
Once distil：Temperature of charge is increased to -15～-5 DEG C and to be incubated 3～5 little by control vacuum below 20 handkerchiefs
When；
Re-dry：Temperature of charge is raised to into 30～40 DEG C, 10～15 hours are incubated.
The quality of the pharmaceutical preparations and stability can be improved using above lyophilized technique.
The invention has the beneficial effects as follows：
1) compared with prior art, the present invention has higher antiinflammatory, exudation activity.Animal experiment shows that mice is quiet
Arteries and veins injects 0.125mg/Kg, and more than 60%, up to more than 70% is can reach to inhibitory rate of intumesce；Mouse mainline
1mg/Kg, the suppression ratio to oozing out can reach more than 40%, up to 58%.
2) injection site has no that obvious stimulation is reacted, and pathology section examination has no that blood vessel and its peripheral cell have degeneration, bad
Dead and obvious pathological abnormalities, show vascular irritation of the present invention.
3) every biochemical indicator and liver, Kidney coefficients compare without significant difference with physiological saline group, its pathological section
Observation and physiological saline group basic simlarity, have no that liver and kidney cells have degeneration, necrosis and obvious pathological abnormalities, show the liver of the present invention
Nephrotoxicity is very low.
4) the freeze-dried powder outward appearance that the present invention is provided is full, without atrophy, subside, the phenomenon such as tomography, solubility and quality it is steady
Qualitative good, storage period was up to 1 year.
Specific embodiment
By the following examples the present invention is described in detail.Raw material aescine B used in following examples
The purity that obtained using chromatography separating method from aescine up to more than 98% sterling.
Embodiment 1
1) 30g aescine B, 2g glycine, 200g Mannitol are dissolved in into 2000ml waters for injection and mixed solution, institute is obtained
The concentration for stating Mannitol in mixed solution is 10g/100ml, and the concentration of aescine B is 1.5g/100ml, the concentration of glycine
For 0.1g/100ml；
2) pH value for adjusting mixed solution with lactic acid is 6.5；
3) membrane filtration of the solution after pH value with 0.22 μm will be adjusted；
4) lyophilization after fill.
Cryodesiccated program is as follows：
Pre-freeze：First temperature of charge is rapidly decreased to into -20 DEG C, is kept for 1 hour, then again temperature of charge is slowly dropped to into -40
DEG C, it is incubated 4 hours；
Once distil：Temperature of charge is increased to -10 DEG C and is incubated 4 hours by control vacuum below 20 handkerchiefs；
Re-dry：Temperature of charge is raised to into 35 DEG C, 12 hours are incubated.
Embodiment 2
1) 40g aescine B, 6g lysines, 800g Mannitol are dissolved in into 4000ml waters for injection and mixed solution, institute is obtained
The concentration for stating Mannitol in mixed solution is 20g/100ml, and the concentration of aescine B is 1g/100ml, and the concentration of lysine is
0.15g/100ml；
2) pH value for adjusting mixed solution with lactic acid is 4.5；
3) membrane filtration of the solution after pH value with 0.22 μm will be adjusted；
4) lyophilization after fill.
Cryodesiccated program is as follows：
Pre-freeze：First temperature of charge is rapidly decreased to into -25 DEG C, is kept for 0.5 hour, be then again slowly dropped to temperature of charge -
35 DEG C, it is incubated 5 hours；
Once distil：Temperature of charge is increased to -5 DEG C and is incubated 3 hours by control vacuum below 20 handkerchiefs；
Re-dry：Temperature of charge is raised to into 40 DEG C, 10 hours are incubated.
Embodiment 3
1) 25g aescine B, 5g aspartic acids, 150g Mannitol are dissolved in into 1250ml waters for injection and mixed solution are obtained,
The concentration of Mannitol is 12g/100ml in the mixed solution, and the concentration of aescine B is 2g/100ml, aspartic acid it is dense
Spend for 0.4g/100ml；
2) pH value for adjusting mixed solution with lactic acid is 5.5；
3) membrane filtration of the solution after pH value with 0.22 μm will be adjusted；
4) lyophilization after fill.
Cryodesiccated program is as follows：
Pre-freeze：First temperature of charge is rapidly decreased to into -22 DEG C, is kept for 0.5 hour, be then again slowly dropped to temperature of charge -
38 DEG C, it is incubated 3 hours；
Once distil：Temperature of charge is increased to -15 DEG C and is incubated 5 hours by control vacuum below 20 handkerchiefs；
Re-dry：Temperature of charge is raised to into 30 DEG C, 15 hours are incubated.
Test example
1. anti-inflammatory activity test
Trial drug：By aescine B respectively with glycine, lysine, proline, aspartic acid, L-Tyrosine, half Guang ammonia
Acid, tryptophan, glutamic acid are mixed by 15: 1 weight ratio, and make freeze-dried powder according to a conventional method, while with aescine B jelly
Dry powder pin is positive control.
The healthy male mouse of kunming 100 of 25～30g of body weight is taken, is divided into 10 big groups, per group of 10 mices, intravenous injection
0.125mg/Kg (in terms of aescine B), blank injecting normal saline after 30 minutes, per Mus auris dextra dimethylbenzene is smeared
0.06ml, after 2 hours mice was put to death, and with card punch ears disk is laid, and was weighed, and calculated the swelling of each Mus, in detail side
Method reference literature CN1931176A.Result of the test is shown in Table 1.
The anti-inflammatory activity of the aescine B injection of table 1
| Packet | Trial drug | Number of animals (n) | Swelling value (x ± s.mg) | Suppression ratio (%) |
| 1 | Aescine B+glycine | 10 | 6.06 | 67.3 |
| 2 | Aescine B+lysine | 10 | 7.54 | 59.4 |
| 3 | Aescine B+proline | 10 | 7.89 | 57.5 |
| 4 | Aescine B+aspartic acid | 10 | 6.46 | 65.2 |
| 5 | Aescine B+L-Tyrosine | 10 | 5.33 | 71.3 |
| 6 | Aescine B+cysteine | 10 | 8.63 | 53.5 |
| 7 | Aescine B+tryptophan | 10 | 10.17 | 45.2 |
| 8 | Aescine B+glutamic acid | 10 | 9.86 | 46.9 |
| 9 | Aescine B (positive control) | 10 | 11.12 | 40.1 |
| 10 | Normal saline (blank) | 10 | 18.56 | —— |
As can be seen from the above tests：Compared with blank, aescine B and its amino acid composition are respectively provided with substantially
Anti-inflammatory activity.Compared with aescine B positive control, the 1st～6 group is respectively provided with significant difference, especially the 5th group of swelling suppression
Rate processed has reached more than 70%, and the 7th, 8 groups do not have notable differences compared with positive control, illustrate glycine, lysine, dried meat ammonia
Acid, aspartic acid, L-Tyrosine, cysteine can further improve the anti-inflammatory activity of aescine B.
2. exudation activity test
Trial drug is with test example 1.
The method of reference literature CN 1931176A test examples 6, takes healthy kunming mice 100, is divided into 10 groups, per group 10
Only, intravenous injection 1mg/Kg (in terms of aescine B), blank injecting normal saline, after 1 hour, the Yi Wen of intravenous injection 1%
Think blue normal saline, while the acetum 0.2ml of peritoneal injection 1%, after 20 minutes mice is put to death, cut off abdominal cavity, use physiology salt
Water 6ml, by several times washing abdominal cavity, cleaning mixture is merged, plus normal saline 10ml, and 300rpm × 20 minute are centrifuged, and takes supernatant,
Mensuration absorbance value at 590nm, the results are shown in Table 2.
The exudation activity of the aescine B injection of table 2
| Packet | Trial drug | Number of animals (n) | Absorbance | Suppression ratio (%) |
| 1 | Aescine B+glycine | 10 | 0.1865 | 50.5 |
| 2 | Aescine B+lysine | 10 | 0.1888 | 49.9 |
| 3 | Aescine B+proline | 10 | 0.2080 | 44.8 |
| 4 | Aescine B+aspartic acid | 10 | 0.2197 | 41.7 |
| 5 | Aescine B+L-Tyrosine | 10 | 0.1575 | 58.2 |
| 6 | Aescine B+cysteine | 10 | 0.1937 | 48.6 |
| 7 | Aescine B+tryptophan | 10 | 0.2536 | 32.7 |
| 8 | Aescine B+glutamic acid | 10 | 0.2656 | 29.5 |
| 9 | Aescine B (positive control) | 10 | 0.2759 | 26.8 |
| 10 | Normal saline (blank) | 10 | 0.3768 | —— |
As can be seen from the above tests：Compared with blank, aescine B and its amino acid composition are respectively provided with substantially
Exudation activity.Compared with aescine B positive control, the 1st～6 group is respectively provided with significant difference, and especially the 5th group oozes out
Suppression ratio has reached more than 55%, and the 7th, 8 groups do not have notable differences compared with positive control, illustrate glycine, lysine, dried meat
Propylhomoserin, aspartic acid, L-Tyrosine, cysteine can further improve the exudation activity of aescine B.
3. vascular stimulation tests
Trial drug is same as Example 1.
The method of list of references CN 1931176A test examples 3, takes the rabbit 30 that body weight is 2Kg and is only divided into 10 groups, per group 3
Only, group technology is identical with test example 1.Each trial drug in terms of contained aescine B, per rabbit daily 1ml: 5mg, blank
Injecting normal saline, injects for three days on end from same auricular vein, puts to death animal within the 4th day, cuts administration ear edge, observes medicine pair
The stimulation of vein, and make check pathological section, it is as a result as follows：
1st～8 group is showed no obvious stimulation reaction, pathology section examination and physiological saline group basic simlarity, has no blood vessel
And its peripheral cell has degeneration, necrosis and obvious pathological abnormalities；The 9th group of serious congestion and edema of appearance, most of injection site shows
Puce, pathological section shows there is serious degenerative, necrosis and thrombosiss；The ear of the 10th group of animal has no that obvious stimulation is anti-
Should, pathological section no abnormality seen.
Result above shows：Aminoacid can significantly reduce the blood vessel irritation of aescine B.
4. Liver and kidney toxicity test
Healthy kunming mice 100 is taken, is divided into 10 groups, 10 per group, intravenous injection 5mg/Kg (in terms of aescine B),
Successive administration 7d, matched group intravenous injection normal saline. weigh before administration and record, fasting 12h, weighs before putting to death.15% is black
Smooth intraperitoneal injection of anesthesia, ventral aorta blood sampling is drawn to separate serum, determine each group rat blood serum histidine amino group transferring enzyme (ALT), day
Winter histidine amino group transferring enzyme (AST), blood urea nitrogen (BUN), four biochemical indicators of creatinine (Cr).Rat is put to death, liver, kidney is taken and is determined
Organ coefficient (dirty/body ratio)=Organ weight/weight × 100%, takes the tissue of liver and kidney, respectively with 4% first
Aldehyde solution is fixed, conventional dehydration, paraffin embedding, section, HE dyeing, the microstructure of light Microscopic observation liver and renal tissue.
Result of the test is shown in Table 3, table 4.
Impact of the aescine B injection of table 3 to mice biochemical marker level
The aescine B injection of table 4 is to mouse liver, the impact of Kidney coefficients
| Packet | Trial drug | Number of animals (n) | Liver coefficient | Kidney coefficients |
| 1 | Aescine B+glycine | 10 | 6.828±0.549 | 1.788±0.254 |
| 2 | Aescine B+lysine | 10 | 6.855±0.582 | 1.786±0.269 |
| 3 | Aescine B+proline | 10 | 6.811±0.643 | 1.793±0.258 |
| 4 | Aescine B+aspartic acid | 10 | 6.836±0.594 | 1.795±0.268 |
| 5 | Aescine B+L-Tyrosine | 10 | 6.894±0.567 | 1.769±0.289 |
| 6 | Aescine B+cysteine | 10 | 6.821±0.467 | 1.803±0.371 |
| 7 | Aescine B+tryptophan | 10 | 6.923±0.633 | 1.801±0.225 |
| 8 | Aescine B+glutamic acid | 10 | 6.845±0.612 | 1.826±0.345 |
| 9 | Aescine B (positive control) | 10 | 8.668±0.862 | 2.955±0.342 |
| 10 | Normal saline (blank) | 10 | 6.821±0.768 | 1.742±0.237 |
The 1st～8 group of every biochemical indicator and liver, Kidney coefficients are can be seen that from the result of the test of table 3 and table 4
Compare with physiological saline group without significant difference, its pathology section examination and physiological saline group basic simlarity have no that liver and kidney cells have
Degeneration, necrosis and obvious pathological abnormalities；The serious Liver and kidney enlargement of 9th group of appearance, every biochemical indicator is significantly increased, pathological section table
It is bright to have the pathological changes such as severe haemorrhage, degeneration, necrosis.Result above shows：Aminoacid can significantly reduce the liver of aescine B
Nephrotoxicity.
Claims (8)
1. a kind of aescine B injection, it is characterised in that：Containing aescine B and aminoacid, the aescine B and ammonia
The weight ratio of base acid is 10～50: 1～10.
2. aescine B injection as claimed in claim 1, it is characterised in that：The aminoacid be glycine, lysine,
The combination in any of one or more in proline, aspartic acid, L-Tyrosine, cysteine.
3. aescine B injection as claimed in claim 1, it is characterised in that：The weight of the aescine B and aminoacid
Than for 30～40: 2～6.
4. the aescine B injection as described in claims 1 to 3 any one, it is characterised in that：Also containing can connect on medicament
The auxiliary element received.
5. aescine B injection as claimed in claim 4, it is characterised in that：The injection is freeze-dried powder, described auxiliary
Furtherance is divided into pH adjusting agent and Mannitol.
6. a kind of method for preparing aescine B injection described in claim 5, it is characterised in that comprise the following steps：
1) aescine B, aminoacid, Mannitol are dissolved in into water for injection and mixed solution, Mannitol in the mixed solution is obtained
Concentration be 10～20g/100ml, the concentration of aescine B is 0.5～2g/100ml；
2) pH value for adjusting mixed solution with pH adjusting agent is 4.5～6.5；
3) solution filter membrane or filter element filtering after pH value will be adjusted；
4) lyophilization after fill, obtains final product.
7. the preparation method of aescine B injection as claimed in claim 6, it is characterised in that：The pH adjusting agent is lactic acid.
8. the preparation method of aescine B injection as claimed in claim 6, it is characterised in that：The lyophilization includes pre-
Freeze, once distil and re-dry three phases, the operating procedure in each stage is as follows：
Pre-freeze：First temperature of charge is rapidly decreased to into -25～-20 DEG C, is kept for 0.5～1 hour, then again slowly drop temperature of charge
To -40～-35 DEG C, 2～5 hours are incubated；
Once distil：Temperature of charge is increased to -15～-5 DEG C and is incubated 3～5 hours by control vacuum below 20 handkerchiefs；
Re-dry：Temperature of charge is raised to into 30～40 DEG C, 10～15 hours are incubated.
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| CN104873469A (en) * | 2015-06-04 | 2015-09-02 | 武汉爱民制药有限公司 | Preparation method for sodium aescinate freeze-dried emulsion for injection |
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