CN105147707B - A kind of Rhodiola pamiro-alaica glucose injection and preparation method thereof - Google Patents
A kind of Rhodiola pamiro-alaica glucose injection and preparation method thereof Download PDFInfo
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- CN105147707B CN105147707B CN201510515597.8A CN201510515597A CN105147707B CN 105147707 B CN105147707 B CN 105147707B CN 201510515597 A CN201510515597 A CN 201510515597A CN 105147707 B CN105147707 B CN 105147707B
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Abstract
The invention discloses a kind of Rhodiola pamiro-alaica glucose injection and preparation method thereof, which contains Rhodiola pamiro-alaica, 2 aminoisobutyric acids and glucose.After adding in 2 aminoisobutyric acids in the Rhodiola pamiro-alaica injection formula of the present invention, there is more good palliative treatment effect to late tumor Bone tumour, while reduce the dosage of Rhodiola pamiro-alaica, alleviate the toxic side effect of drug, reduce production cost.
Description
Technical field
The invention belongs to western medicine injection preparation fields, are related to a kind of Rhodiola pamiro-alaica parenteral solution, more particularly to a kind of
Rhodiola pamiro-alaica glucose injection and preparation method thereof.
Background technology
There is 30%-70% patient that Bone tumour occurs in malignant tumour late period, intractable pain occur, and Bone tumour occurs
Account for about 70% (Dong Zhiwei, Clinical Oncologies [M] Beijing of paddy milling at the heavy burdens such as vertebra, pelvis, hip joint position:The people defend
Raw publishing house, 2002:371) quality of life of patients, is seriously affected.It is generally acknowledged that metastatic carcinoma of bone causes the mechanism of pain to be:Tumour
Bone tissue is transferred to, osteoclast activity increase is caused to lead to osteolysis i.e. osteoclasia;Tumour cell can be secreted simultaneously
Induced pain medium such as prostaglandin, lactic acid etc., so as to aggravate the pain.
Rhodiola pamiro-alaica is bisphosphonates, is the potent inhibitor of osteoclast activity, optionally inhales
Bone tissue is invested, osteoclast precursor is inhibited to be converted to mature osteoclast, mitigates destruction of bone caused by tumour, improves ostalgia
Symptom, it is easy to use, but curative effect declines after routine dose is invalid to some cases or curative effect is held time short, more course of therapy
(Liao Sihai observes [J] the effect of various dose Coursed by Malignant Tumor osseous metastatic bone pain, Qiqihar Medical College's journal,
The 10th phase of volume 27 in 2006).If using large dosage administration, although curative effect is more notable, fever can be increased simultaneously, disliked
The heart, pectoralgia, uncomfortable in chest, the dizzy toxic side effects such as weak.
Invention content
In view of various deficiencies existing for various dose Rhodiola pamiro-alaica, it is an object of the invention to by Pamidronic Acid
The prescription of two sodium injections is studied, and provides that a kind of toxic side effect is low, the injection of curative effect significantly more Rhodiola pamiro-alaica
Liquid and preparation method thereof.
In order to achieve the object of the present invention, inventor screening pharmaceutic adjuvant experiment in it was unexpectedly observed that in parenteral solution
The 2- aminoisobutyric acids (2-Aminoisobutyric acid) of low dosage are added in prescription, can not only improve the steady of parenteral solution
It is qualitative, and the metastasis of cancer pain relief curative effect of drug can be significantly increased.Specifically, the purpose of the present invention is be achieved
's:
A kind of Rhodiola pamiro-alaica glucose injection, the parenteral solution contain Rhodiola pamiro-alaica, 2- aminoisobutyric acids and
Glucose.
Preferably, Rhodiola pamiro-alaica and 2- ammonia in Rhodiola pamiro-alaica glucose injection parenteral solution as described above
The isobutyric mass ratio of base is 1:0.02-0.30.
It is further preferred that Rhodiola pamiro-alaica glucose injection as described above, wherein Rhodiola pamiro-alaica and 2-
The mass ratio of aminoisobutyric acid is 1:0.04-0.16.
Still further preferably, Rhodiola pamiro-alaica glucose injection as described above, wherein Rhodiola pamiro-alaica with
The mass ratio of 2- aminoisobutyric acids is 1:0.08.
Rhodiola pamiro-alaica glucose injection of the present invention, contains Rhodiola pamiro-alaica after preparation
0.06-0.24mg/mL, 2- aminoisobutyric acid 4-10 μ g/mL and glucose 0.02-0.2g/mL.
It is further preferred that Rhodiola pamiro-alaica glucose injection as described above, contains pa rice after preparation
Disodium hydrogen phosphate 0.12mg/mL, 2- aminoisobutyric acid 4.8-9.6 μ g/mL and glucose 0.05g/mL.
In embodiment preferred for this invention, Rhodiola pamiro-alaica glucose injection as described above, by as follows
The component composition of dosage:Rhodiola pamiro-alaica 0.12mg/mL, 2- aminoisobutyric acid 4.8-9.6 μ g/mL, glucose 0.05g/mL,
Appropriate pH adjusting agent, surplus are water for injection.
It is further preferred that Rhodiola pamiro-alaica glucose injection as described above, the pH adjusting agent is phosphoric acid.
In addition, the preparation method of Rhodiola pamiro-alaica parenteral solution of the present invention, includes the following steps:By glucose and
2- aminoisobutyric acids are added in water for injection, and stirring adds in needle-use activated carbon, be sufficiently stirred, filtering decarbonization to dissolving, gained filter
Liquid is adjusted with phosphoric acid to pH5.5-6.5, then adds in Rhodiola pamiro-alaica, is stirred to Rhodiola pamiro-alaica and is completely dissolved, and is added in
Surplus water for injection constant volume, miillpore filter aseptic filtration is filling, and moist heat sterilization obtains parenteral solution.
Compared with prior art, Rhodiola pamiro-alaica glucose injection of the present invention is reducing the same of dosage
When increase metastasis of cancer pain relief curative effect, can be seen that compared with blank group especially by the result of the test of table 1, rat in
The 8th day mechanical paw withdrawal threshold value after prepared by osteocarcinoma pain model is substantially reduced, and difference is statistically significant (P < 0.05).With model
Group is compared, and each treatment group rat mechanical paw withdrawal threshold value in the 13rd day after the preparation of osteocarcinoma pain model improves, wherein 2-Amin+
The machinery paw withdrawal threshold value raising of Pam groups is apparent, and difference is statistically significant (P < 0.05);2-Amin groups, Pam groups only show machine
Tool paw withdrawal threshold value increases trend, but no significant difference (P > 0.05).In the 18th day after the preparation of osteocarcinoma pain model,
Rhodiola pamiro-alaica and drug combination treatment group machinery paw withdrawal threshold value are improved compared with model group, statistically significant (the P < of difference
0.05th, P < 0.01).From the point of view of comparison by each group machinery paw withdrawal threshold value, 2- aminoisobutyric acids can cooperate with Rhodiola pamiro-alaica
Mechanical paw withdrawal threshold value, the two combination synergistic effect quick with machinery pain is reduced are improved to Cancer pain rat.This imply that this
After adding in the 2- aminoisobutyric acids of low dosage in the Rhodiola pamiro-alaica injection formula of invention, have more to late tumor Bone tumour
It is acted on for good palliative treatment, while reduces the dosage of Rhodiola pamiro-alaica, alleviated the toxic side effect of drug, reduce
Production cost.
Specific embodiment
It is the specific preparation example of the present invention below, technical scheme of the present invention is done and is further described, but it is of the invention
Protection domain be not limited to these embodiments.It is every to be included in this hair without departing substantially from the change of present inventive concept or equivalent substitute
Within bright protection domain.
Embodiment 1-4:The preparation of Rhodiola pamiro-alaica glucose injection
The prescription content of 1 embodiment 1-4 Rhodiola pamiro-alaica glucose injections of table
Constituent content | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 |
Rhodiola pamiro-alaica (mg/mL) | 0.06 | 0.12 | 0.12 | 0.24 |
2- aminoisobutyric acids (μ g/mL) | 4.8 | 4.8 | 9.6 | 9.6 |
Glucose (g/mL) | 0.05 | 0.05 | 0.05 | 0.05 |
pH | 6.5 | 6.0 | 5.5 | 6.0 |
Preparation process:Glucose and 2- aminoisobutyric acids are added in 80% water for injection, stirring is added in dissolving
The needle-use activated carbon of 0.1% (W/V), is sufficiently stirred, filtering decarbonization, and gained filtrate is adjusted with phosphoric acid to pH5.5-6.5, Ran Houjia
Enter Rhodiola pamiro-alaica, stir to Rhodiola pamiro-alaica and be completely dissolved, add in surplus water for injection constant volume, 0.22 μm of miillpore filter
Aseptic filtration, filling, moist heat sterilization obtains clear solution.
Embodiment 5:Influence experimental study of the drug to rat breast cancer metastatic carcinoma of bone pain model
Breast cancer Walker256 cell cryopreservation tubes are taken out, are put into quick-thawing in 37 DEG C of water baths rapidly.Dry cryopreservation tube
On it is water stain, with 75% alcohol disinfecting nozzle of volume fraction, nozzle is unscrewed on superclean bench, cell suspension is sucked out with suction pipe,
It moves into centrifuge tube, then adds the RPMI-1640 culture mediums of 10% fetal calf serum containing mass fraction in right amount, piping and druming hangs cell
Floating, 1000r/min centrifugation 5min abandon supernatant, repeat to be rinsed 1 time with culture medium, culture bottle is inoculated in after adding in appropriate culture medium
In, it is placed in incubator and cultivates, next day replaces 1 subculture and continues to cultivate, and observes growing state, and it is thin to choose exponential phase
Born of the same parents are inoculated in Wistar rat abdominal cavities, and inoculum concentration is 256 cell 0.5mL (cell concentrations 2 × 10 of Walker7mL-1), raising
1 week, there are a large amount of ascites in rat abdominal cavity, take yellowish knurl ascites 3mL, add 0.9% physiological saline 7mL mixings of mass fraction,
1500r/min centrifuges 5min, takes precipitation, and after being rinsed with 0.9% physiological saline 10mL of mass fraction, 1200r/min is centrifuged again
5min, abandons supernatant, and cell precipitation is suspended with 0.9% physiological saline of 3mL mass fractions, is diluted to cell suspension after cell count
2×107mL-1It is spare.
Female Wistar rats 40, weight 180-200g.It is randomly divided into blank group, model group, 2-Amin groups, Pam
Group and 2-Amin+Pam groups, every group of 8 animals.Rat breast cancer metastatic carcinoma of bone pain model is established as follows:With quality point
After several 4% chloraldurate 400mg/kg intraperitoneal injection of anesthesia, refer to so that rat toe is reactionless to pincers clamp for anesthesia satisfaction
Mark, sterilizes and cuts 1/3 skin under left tibias, detaches muscle, exposure tibial bone face.Take No. 5 draw point heads perpendicular to bone face into
Needle extracts syringe needle after having apophysis to break sense, and the 5 μ L of breast cancer Walker256 cell suspensions for taking preparation with syringe inject marrow
Intracavitary with bacteria-free bone wax sealing of hole, successively with 0.9% normal saline flushing of mass fraction and sutures.After the operation of inoculated tumour cell
Animal is positioned in cage and continues to raise.Sham-operation rat (i.e. blank group) injects 0.9% physiological saline of mass fraction of equivalent.
Administration of beginning in the 8th day after the operation of inoculated tumour cell.2-Amin groups:After osteocarcinoma pain model is successfully prepared, it is subcutaneously injected
2- aminoisobutyric acids 0.8mg/kg;Pam groups:After osteocarcinoma pain model is successfully prepared, Rhodiola pamiro-alaica 20mg/ is slowly subcutaneously injected
kg;2-Amin+Pam groups:After osteocarcinoma pain model is successfully prepared, 2- aminoisobutyric acids 0.8mg/kg+ is subcutaneously injected and slowly subcutaneously notes
Penetrate Rhodiola pamiro-alaica 10mg/kg;Model group:After osteocarcinoma pain model is successfully prepared, 0.9% physiology salt of mass fraction is subcutaneously injected
Water;Blank group:0.9% physiological saline of mass fraction is subcutaneously injected.The dosage rate of each group is 2 times/week, is administered 4 weeks altogether.It connects
Postoperative 8th, 13,18,23,28 day of kind tumour cell stimulates In The Rat Sole softness position with electronics von Frey pain threshold detectors,
2~3s of time of contact, reading when paw withdrawal occur or licking foot reaction is mechanical paw withdrawal threshold value, counts each group experiment measurement result.
Can be seen that compared with blank group according to the result of the test of table 1, rat in osteocarcinoma pain model preparation after the 8th day
Mechanical paw withdrawal threshold value is substantially reduced, and difference is statistically significant (P < 0.05).Compared with model group, each treatment group rat is in bone
Mechanical paw withdrawal threshold value improves from the 13rd day after the preparation of pain caused by cancer model, and the wherein mechanical paw withdrawal threshold value raising of 2-Amin+Pam groups is bright
Aobvious, difference is statistically significant (P < 0.05);2-Amin groups, Pam groups only show mechanical paw withdrawal threshold value raising trend, but poor
Different not statistically significant (P > 0.05).In the 18th day after the preparation of osteocarcinoma pain model, Rhodiola pamiro-alaica and drug combination were controlled
Treatment group machinery paw withdrawal threshold value is improved compared with model group, and difference is statistically significant (P < 0.05, P < 0.01).It is contracted by each group machinery
From the point of view of the comparison of sufficient threshold value, 2- aminoisobutyric acids can cooperate with Rhodiola pamiro-alaica to improve mechanical paw withdrawal threshold to Cancer pain rat
Value, the two combination synergistic effect quick with machinery pain is reduced.
Table 1:The comparison (g) of postoperative different time points rat machinery paw withdrawal threshold value
Continued 1:The comparison (g) of postoperative different time points rat machinery paw withdrawal threshold value
Model group compared with blank,★P < 0.05,★★P < 0.01;
Treatment group compared with model group,▲P < 0.05,▲▲P < 0.01.
Claims (7)
1. a kind of Rhodiola pamiro-alaica glucose injection, it is characterised in that:The active constituent of the parenteral solution is by Pamidronic Acid two
The mass ratio of sodium and 2- aminoisobutyric acids composition, wherein Rhodiola pamiro-alaica and 2- aminoisobutyric acids is 1:0.02-0.30.
2. Rhodiola pamiro-alaica glucose injection according to claim 1, it is characterised in that:Pa rice phosphorus in the parenteral solution
The mass ratio of acid disodium and 2- aminoisobutyric acids is 1:0.04-0.16.
3. Rhodiola pamiro-alaica glucose injection according to claim 2, it is characterised in that:Pa rice phosphorus in the parenteral solution
The mass ratio of acid disodium and 2- aminoisobutyric acids is 1:0.08.
4. Rhodiola pamiro-alaica glucose injection according to claim 1, it is characterised in that:The parenteral solution contains pa rice
Disodium hydrogen phosphate 0.12mg/mL, 2- aminoisobutyric acid 4.8-9.6 μ g/mL and glucose 0.05g/mL.
5. Rhodiola pamiro-alaica glucose injection according to claim 4, it is characterised in that:The parenteral solution by using as follows
The component composition of amount:Rhodiola pamiro-alaica 0.12mg/mL, 2- aminoisobutyric acid 4.8-9.6 μ g/mL, glucose 0.05g/mL, pH
Appropriate conditioning agent, surplus are water for injection.
6. Rhodiola pamiro-alaica glucose injection according to claim 5, it is characterised in that:The pH adjusting agent is
Phosphoric acid.
7. a kind of preparation method of the glucose injection of Rhodiola pamiro-alaica according to claim 5, it is characterised in that including
Following steps:Glucose and 2- aminoisobutyric acids are added in water for injection, stirring adds in needle-use activated carbon, fully to dissolving
Stirring, filtering decarbonization, gained filtrate are adjusted to pH5.5-6.5 with phosphoric acid, then add in Rhodiola pamiro-alaica, stir to pa rice phosphorus
Acid disodium is completely dissolved, and adds in surplus water for injection constant volume, miillpore filter aseptic filtration is filling, and moist heat sterilization obtains parenteral solution.
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