CN105434453B - A kind of clindamycin phosphate for injection pharmaceutical composition and preparation method thereof - Google Patents
A kind of clindamycin phosphate for injection pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN105434453B CN105434453B CN201510025208.3A CN201510025208A CN105434453B CN 105434453 B CN105434453 B CN 105434453B CN 201510025208 A CN201510025208 A CN 201510025208A CN 105434453 B CN105434453 B CN 105434453B
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- tartrate
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- UFUVLHLTWXBHGZ-MGZQPHGTSA-N [(2r,3r,4s,5r,6r)-6-[(1s,2s)-2-chloro-1-[[(2s,4r)-1-methyl-4-propylpyrrolidine-2-carbonyl]amino]propyl]-4,5-dihydroxy-2-methylsulfanyloxan-3-yl] dihydrogen phosphate Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](OP(O)(O)=O)[C@@H](SC)O1 UFUVLHLTWXBHGZ-MGZQPHGTSA-N 0.000 title claims abstract description 88
- 229960002291 clindamycin phosphate Drugs 0.000 title claims abstract description 88
- 239000007924 injection Substances 0.000 title claims abstract description 70
- 238000002347 injection Methods 0.000 title claims abstract description 70
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 57
- 238000002360 preparation method Methods 0.000 title description 10
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- 239000008215 water for injection Substances 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 17
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 17
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract description 16
- 229940095064 tartrate Drugs 0.000 claims abstract description 16
- 239000000243 solution Substances 0.000 claims description 27
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- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 claims description 8
- AVTYONGGKAJVTE-OLXYHTOASA-L potassium L-tartrate Chemical compound [K+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O AVTYONGGKAJVTE-OLXYHTOASA-L 0.000 claims description 7
- 229940111695 potassium tartrate Drugs 0.000 claims description 7
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- 238000006116 polymerization reaction Methods 0.000 claims description 4
- 235000011006 sodium potassium tartrate Nutrition 0.000 claims description 4
- 238000010255 intramuscular injection Methods 0.000 claims description 3
- 239000007927 intramuscular injection Substances 0.000 claims description 3
- VZOPRCCTKLAGPN-ZFJVMAEJSA-L potassium;sodium;(2r,3r)-2,3-dihydroxybutanedioate;tetrahydrate Chemical compound O.O.O.O.[Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O VZOPRCCTKLAGPN-ZFJVMAEJSA-L 0.000 claims description 3
- 239000001476 sodium potassium tartrate Substances 0.000 claims description 3
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- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
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- OJMMVQQUTAEWLP-UHFFFAOYSA-N Lincomycin Natural products CN1CC(CCC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 OJMMVQQUTAEWLP-UHFFFAOYSA-N 0.000 description 2
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- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 description 2
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- AVTYONGGKAJVTE-UHFFFAOYSA-L potassium tartrate Chemical class [K+].[K+].[O-]C(=O)C(O)C(O)C([O-])=O AVTYONGGKAJVTE-UHFFFAOYSA-L 0.000 description 2
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- QCVGEOXPDFCNHA-UHFFFAOYSA-N 5,5-dimethyl-2,4-dioxo-1,3-oxazolidine-3-carboxamide Chemical compound CC1(C)OC(=O)N(C(N)=O)C1=O QCVGEOXPDFCNHA-UHFFFAOYSA-N 0.000 description 1
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention provides a kind of clindamycin phosphate for injection pharmaceutical compositions, and it includes clindamycin phosphate, polyethylene glycol, tartrate and water for injection, the clindamycin phosphate for injection pharmaceutical composition is safe and stable.The present invention also provides the methods for preparing the clindamycin phosphate for injection pharmaceutical composition.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, and in particular to a kind of clindamycin phosphate for injection pharmaceutical composition and its
Preparation method.
Background technology
Clindamycin phosphate is the clindamycin derivative of molecular design, it is in vitro without antibacterial activity, into machine
Body is hydrolyzed to clindamycin rapidly and shows its pharmacological activity, therefore antimicrobial spectrum, antibacterial activity and therapeutic effect and clindamycin phase
Together, but its fat-soluble and permeability is better than clindamycin, it is orally available also can intramuscular injection and intravenous drip administration.It can be mould with woods
Element is 4~8 times strong compared to its antibacterial action, and good absorbing, bone concentration is high, mainly has to gram-positive cocci and anaerobic bacteria very strong
Antibacterial activity.
Existing clindamycin phosphate injection is most of in preparation process to be gone out using the method for high-temperature sterilization
Bacterium, clindamycin phosphate are thermal instability drugs, are heated and easily generate the hydrolysis impurities such as lincomycin, clindamycin,
Easily generate oxidation impurities etc..Research shows that 60 DEG C of clindamycin phosphate this product can generate degradation, has within 30 minutes at 80 DEG C
Substance (impurity) reachable 5%~6% is closed, 30 minutes related substances (impurity) are up to 8%~10% at 100 DEG C.Using this side
Method carries out degerming, reduces Drug safety and validity.In order to solve the above-mentioned technical problem, patent CN1969875A,
CN102144966B, CN102133178B etc. report the sterile technology of preparing of clindamycin phosphate injection, can protect
The impurity of product will not be dramatically increased while demonstrate,proving sterile again, solves traditional clindamycin phosphate injection to a certain extent
The defects of liquid production technology.
But the stability of clindamycin phosphate injection is poor, is not easy to store, related substance increases with storage time
Add, easily cause the clinical symptoms such as allergic reaction.Existing research is it has been proved that the dissolubility and stability of clindamycin phosphate
Closely related with the pH value of solution, solution ph is high, and for clindamycin phosphate solubility with regard to big, solution is more not easy crystallization, but
The easier degradation of drug, vice versa.Patent CN102133178B etc. optimizes parenteral solution by screening the dosage of sodium hydroxide
PH value, help somewhat to the raising of medicine stability, but do not solve fundamentally dissolubility and stability it
Between there are the problem of.Therefore, there is an urgent need for a kind of safe and stable clindamycin phosphate injections to meet the need of clinical application
It asks.
The content of the invention
Present invention aims to solve the deficiencies of the prior art, and provides a kind of a kind of clindamycin phosphate for injection pharmaceutical compositions
Object and preparation method thereof.
On the one hand, it is mould it includes crin the present invention provides a kind of clindamycin phosphate for injection pharmaceutical composition
Plain phosphate, polyethylene glycol, tartrate and water for injection, wherein it is mould to include crin described in 0.1~100g per 100ml compositions
Plain phosphate, polyethylene glycol described in 0.01~50g, tartrate described in 0.01~50g, water for injection are surplus.
In a specific embodiment, it is preferable that include clindamycin phosphoric acid described in 1~80g per 100ml compositions
Ester, polyethylene glycol described in 0.1~10g, tartrate described in 0.02~30g, water for injection are surplus；It is highly preferred that per 100ml
Composition is comprising clindamycin phosphate described in 3~50g, polyethylene glycol described in 0.2~4g, tartrate described in 0.05~10g,
Water for injection is surplus；It is highly preferred that clindamycin phosphate described in 5~30g is included per 100ml compositions, described in 0.3~3g
Polyethylene glycol, tartrate described in 0.1~3g, water for injection are surplus；It is highly preferred that include 8~20g per 100ml compositions
The clindamycin phosphate, polyethylene glycol described in 0.5~2g, tartrate described in 0.2~1g, water for injection are surplus；Most
Preferably, per 100ml compositions comprising clindamycin phosphate described in 9~18g, polyethylene glycol described in 0.6~1.8g, 0.4~
Tartrate described in 0.8g, water for injection are surplus.
In a specific embodiment, the degree of polymerization of the polyethylene glycol is 100~800, is preferably 250-700,
More preferably 300-600, more preferably 300,400 or 600 are most preferably 400.
In a specific embodiment, the tartrate is preferably sodium tartrate, potassium tartrate and potassium tartrate
One or more in sodium, more preferably sodium tartrate, potassium tartrate, sodium potassium tartrate tetrahydrate or potassium tartrate and sodium tartrate
Mixture is most preferably sodium tartrate.
In a specific embodiment, the clindamycin phosphate for injection pharmaceutical composition is noted available for vein
It penetrates or intramuscular injection.
On the other hand, the present invention provides the sides for being used to prepare the clindamycin phosphate for injection pharmaceutical composition
Method the described method comprises the following steps：
(1) polyethylene glycol, tartrate are added in water for injection, stirring and dissolving；
(2) clindamycin phosphate is added in, the pH value of solution is adjusted to 5.6-6.1 by stirring and dissolving；
(3) medicinal carbon, stirring and adsorbing are added in；
(4) coarse filtration is carried out using miillpore filter and takes off charcoal；
(5) add surplus water for injection and carry out refined filtration degerming to full dose, then with miillpore filter.
In a specific embodiment, in step 1, the amount of the water for injection is the 60%-80% with liquid measure.
In a specific embodiment, in step 2, it is unrestricted to adjust the reagent of pH, if can reach by
The pH value of solution adjusts the purpose to 5.6-6.1, is preferably hydrochloric acid, sodium hydroxide.
In a specific embodiment, in step 3, the dosage of the medicinal carbon is unrestricted, as long as energy
Achieve the purpose that adsorb completely, be preferably to be more preferably per 100ml compositions using 0.01~0.5g medicinal carbons
0.03~0.4g, more preferably 0.05~0.3g are most preferably 0.1~0.2g.With the medicinal carbon stirring and adsorbing when
Between it is unrestricted, as long as can achieve the purpose that adsorb completely, be preferably 15~20 minutes.
In a specific embodiment, in step 4, for carry out coarse filtration take off charcoal miillpore filter diameter from
Limitation is preferably 0.6-0.8 μm as long as can achieve the purpose that completely de- charcoal, more preferably 0.65 μm or 0.8 μm, most
Preferably 0.65 μm.
In a specific embodiment, in steps of 5, for carry out the diameter of the miillpore filter of refined filtration degerming from
Limitation is preferably 0.22 μm as long as can achieve the purpose that degerming.
In a specific embodiment, the preparation temperature and pressure of step 1-5 is unrestricted, as long as can reach system
Standby purpose is preferably normal temperature and pressure.
The present invention, as auxiliary material, not only increases clindamycin phosphate in acid pH using polyethylene glycol and tartrate
The dissolubility being worth in solution, while reduces the degradability of drug, and tartrate is as stabilizer and metal-chelator, greatly
Stability in the big preparation for improving clindamycin phosphate for injection pharmaceutical composition and storage, plays and expects not
The effect arrived.Provide that a kind of impurity content is low for clinic, the clindamycin phosphate medicine of the good injection of quality stability
Compositions.
Specific embodiment
If following embodiment and test example are not specifically noted, carried out under room temperature, normal pressure.
Embodiment 1
The water for injection of 800ml is taken, adds in 10g polyethylene glycol 400s, 5g sodium tartrates, stirring and dissolving；Add in 125g crins
The pH value of acquired solution is adjusted to 5.8 by mycin phosphate, stirring and dissolving using hydrochloric acid and sodium hydroxide solution；Add in 100g medicines
With activated carbon, stirring and adsorbing 15 minutes carries out coarse filtration using a diameter of 0.65 μm of miillpore filter and takes off charcoal；Benefit injects water to
Gained filtrate is carried out refined filtration degerming by 1000ml with a diameter of 0.22 μm of miillpore filter again, filling.
Embodiment 2
The water for injection of 800ml is taken, adds in 6g Macrogol 600s, 8g potassium tartrates, stirring and dissolving；It is mould to add in 90g crins
The pH value of acquired solution is adjusted to 5.9 by plain phosphate, stirring and dissolving using hydrochloric acid and sodium hydroxide solution；It is medicinal to add in 150g
Activated carbon, stirring and adsorbing 20 minutes carry out coarse filtration using a diameter of 0.65 μm of miillpore filter and take off charcoal；Benefit injects water to
Gained filtrate is carried out refined filtration degerming by 1000ml with a diameter of 0.22 μm of miillpore filter again, filling.
Embodiment 3
The water for injection of 600ml is taken, adds in 18g polyethylene glycol 400s, 3g sodium tartrates, 1g potassium tartrates, stirring and dissolving；
122g clindamycin phosphates are added in, the pH value of acquired solution is adjusted to by stirring and dissolving using hydrochloric acid and sodium hydroxide solution
5.7；200g medicinal carbons are added in, stirring and adsorbing 15 minutes carries out coarse filtration using a diameter of 0.65 μm of miillpore filter and takes off charcoal；
Benefit injects water to 1000ml, and gained filtrate is carried out refined filtration degerming with a diameter of 0.22 μm of miillpore filter again, filling.
Embodiment 4
The water for injection of 800ml is taken, adds in 15g Liquid Macrogols, 6g sodium potassium tartrate tetrahydrates, stirring and dissolving；Add in 180g grams
The pH value of acquired solution is adjusted to 5.9 by woods mycin phosphate, stirring and dissolving using hydrochloric acid and sodium hydroxide solution；Add in 200g
Medicinal carbon, stirring and adsorbing 20 minutes carry out coarse filtration using a diameter of 0.8 μm of miillpore filter and take off charcoal；Add water for injection
To 1000ml, gained filtrate is subjected to refined filtration degerming with a diameter of 0.22 μm of miillpore filter again, it is filling.
Comparative example 1：Commercially available clindamycin phosphate for injection pharmaceutical composition (is purchased from the limited public affairs of Chongqing Lay U.S. medicine company share
Department)；
Comparative example 2：The clindamycin phosphate for injection pharmaceutical composition prepared according to patent CN102144966B embodiments 1
Object；
Comparative example 3：The clindamycin phosphate for injection pharmaceutical composition prepared according to patent CN102133178B embodiments 1
Object.
Tests below example is the clindamycin phosphate for injection pharmaceutical composition prepared to above-described embodiment and comparative example
The stability test of progress.
Test example 1：The quality determination of 1-4 clindamycin phosphate for injection pharmaceutical compositions of the embodiment of the present invention
Assay method is with reference to Chinese Pharmacopoeia 2010 editions the second enlarged editions " clindamycin phosphate for injection pharmaceutical composition medicine
Product standard ", specific assay method and standard are as follows：
PH value：With reference to two annex VI H of Chinese Pharmacopoeia.
Color：5 bottles of this product is taken, is compared respectively with No. 2 standard color solutions of yellow (two the first methods of annex IX A of Chinese Pharmacopoeia)
Compared with, must not more depth to meet regulation.
Related substance：Lincomycin, clindamycin, maximum single miscellaneous and total impurities are with reference to 2010 editions second supplements of Chinese Pharmacopoeia
This " clindamycin phosphate for injection pharmaceutical composition drug standards " measure.
Visible foreign matters：It is measured with reference to Chinese Pharmacopoeia two the first methods of annex IX H of version in 2010.
Insoluble granule：It is measured with reference to two annex IX C of Chinese Pharmacopoeia version in 2010.
Undue toxicity：With reference to two Ⅺ C of annex annex of Chinese Pharmacopoeia.
Bacterial endotoxin：With reference to two Ⅺ E of annex of Chinese Pharmacopoeia.
Depressor：With reference to two Ⅺ G of annex of Chinese Pharmacopoeia.
It is sterile：With reference to two Ⅺ H of annex of Chinese Pharmacopoeia.
Assay：It is measured according to high performance liquid chromatography (two annex V D of Chinese Pharmacopoeia).Chromatographic condition is fitted with system
It is filler (4.6mm × 250mm, 5 μm) with property experiment with octyl silane group silica gel；Phosphoric acid (is taken with phosphate buffer
Potassium dihydrogen 13.61g adds water 1000ml to make dissolving, and pH value is adjusted to 2.5)-acetonitrile (80 with 85% phosphoric acid solution:20) it is flowing
Phase；Detection wavelength is 210nm.Clindamycin phosphate reference substance is weighed respectively and clindamycin reference substance is each appropriate, adds flowing
Phased soln simultaneously dilutes the mixed solution being made in every 1ml respectively containing about 0.3mg, measures 20 μ l injection liquid chromatographs, records chromatography
Figure.The retention time at clindamycin phosphate peak is about 16 minutes, point between clindamycin phosphate peak and clindamycin peak
It should be not less than 6.0 from degree；Another (1) the 20 μ l of reference substance solution taken under Related substances separation item inject liquid chromatograph, record color
Spectrogram, the separating degree of impurity A peak (relative retention time is about 0.97) between clindamycin phosphate peak should be not less than 1.0.
Measuring method is appropriate for the accurate this product that measures, and is quantitatively diluted and is made in every 1ml containing about clindamycin 0.3mg with mobile phase
Solution, precision measure 20 μ l injection liquid chromatograph, record chromatogram.Separately take clindamycin phosphate reference substance appropriate, together
Method measures.By external standard method with C in calculated by peak area test sample18H33ClN2O5The content of S.The wherein content of clindamycin phosphate
It is to be measured by base value (i.e. 100%) of labelled amount.
Measurement result is as shown in table 1.
The quality determination result of the clindamycin phosphate for injection pharmaceutical composition of 1. embodiment 1-4 of table
Test example 2：The clindamycin phosphate for injection pharmaceutical composition of 1-4 of the embodiment of the present invention and comparative example 1-3
Stability
Assay method is with reference to Chinese Pharmacopoeia 2010 editions the second enlarged editions " clindamycin phosphate for injection pharmaceutical composition medicine
Product standard ".
Experiment 1：Influence factor is tested
Under the conditions of 40 ± 2 DEG C, the clindamycin phosphate for injection medicine group of embodiment 1-4 and comparative example 1-3 is measured
The stability of object is closed, the results are shown in Table 2.
The clindamycin phosphate for injection pharmaceutical composition of table 2. embodiment 1-4 and comparative example 1-3 is in 40 ± 2 DEG C of conditions
Under quality determination result
Experiment 2：Accelerated stability test
Under the conditions of 30 ± 2 DEG C, the clindamycin phosphate for injection medicine group of embodiment 1-4 and comparative example 1-3 is measured
The stability of object is closed, the results are shown in Table 3.
The clindamycin phosphate for injection pharmaceutical composition of table 3. embodiment 1-4 and comparative example 1-3 is in 30 ± 2 DEG C of conditions
Under quality determination result
In summary, at 40 ± 2 DEG C and 30 ± 2 DEG C of experimental condition, the injection crin of 1-4 of embodiment of the present invention preparations
The related content of material of mycin phosphate pharmaceutical composition and the clindamycin phosphate for injection pharmaceutical composition of comparative example 1-3
Rise, clindamycin phosphate content reduce, but the clindamycin phosphate for injection pharmaceutical composition of the embodiment of the present invention
The related content of material increase rate and clindamycin phosphate content of object reduce rate and are significantly lower than comparative example product.Adding
After speed experiment 6 months, each key index of product of the embodiment of the present invention is in clindamycin phosphate for injection pharmaceutical composition
Within the drug standards (2010 editions the second enlarged editions of Chinese Pharmacopoeia) prescribed limit, and the related substance of comparative example product exceeds or
Be near the mark limit, shows clindamycin phosphate for injection pharmaceutical composition of the present invention compared with prior art products, stablizes
Property significantly improves.
Test example 3：Security test
Experiment 1：The cavy whole body mistake of clindamycin phosphate for injection pharmaceutical composition prepared by 1-4 of the embodiment of the present invention
Quick property experiment
Test method：24 cavys are randomly divided into four groups：Clindamycin phosphate for injection pharmaceutical composition low dosage
Group, clindamycin phosphate for injection pharmaceutical composition high dose group, positive controls and negative control group, 6/every group；Into
Enter the 1st, 3 and 5 day of experiment, cavy is injected intraperitoneally respectively and gives corresponding preparation：Clindamycin phosphate for injection drug
Composition low dose group --- priming dose 40mg/kg；Clindamycin phosphate for injection pharmaceutical composition high dose group ---
Priming dose 80mg/kg；Negative control --- 0.9% sodium chloride injection；Positive control --- 10% egg white.Every time after administration
Observe behavior and the state of animal.The 10th day after the administration of last sensitization, sensitization was given in ear vein injection to each test group respectively
The relative medicine of 5 multiple doses of dosage is excited.State and the behavior of animal are observed after administration immediately, according to hierarchical table
(table 4 and table 5), which gives the performance of animal, to be judged.Clindamycin phosphate for injection pharmaceutical composition prepared by embodiment 1-4
Cavy systemic anaphylaxis result of the test be shown in table 6-9.
4. symptoms of allergic of table
| 0 is normal | 7 are short of breath | 14 instability of gait |
| 1 is restless | 8 urinations | 15 jumps |
| 2 perpendicular hairs | 9 defecation | 16 pant |
| 3 tremble | 10 shed tears | 17 spasm |
| 4 scratch nose | 11 expiratory dyspnea | 18 rotations |
| 5 sneezes | 12 heavy breathing toot sounds | 19 cheyne-stokes respiration |
| 6 coughs | 13 purpuras | 20 is dead |
5. whole body sensitization evaluation criterion of table
| Score | ||
| 0 | - | Allergic reaction is negative |
| 1-4 | + | Allergic reaction weakly positive |
| 5-10 | ++ | Allergic reaction is positive |
| 11-19 | +++ | Allergic reaction strong positive |
| 20 | ++++ | The extremely strong positive of allergic reaction |
The cavy systemic anaphylaxis result of the test of the clindamycin phosphate for injection pharmaceutical composition of 6. embodiment 1 of table
The cavy systemic anaphylaxis result of the test of the clindamycin phosphate for injection pharmaceutical composition of 7. embodiment 2 of table
The cavy systemic anaphylaxis result of the test of the clindamycin phosphate for injection pharmaceutical composition of 8. embodiment 3 of table
The cavy systemic anaphylaxis result of the test of the clindamycin phosphate for injection pharmaceutical composition of 9. embodiment 4 of table
Result of the test：After excitation administration, positive controls animal shows strong allergic symptom, and lethal dies.It is negative right
Allergic reaction is had no according to group and tested group (high dose group and low dose group), it is therefore, of the invention under this experimental condition
Clindamycin phosphate for injection pharmaceutical composition prepared by embodiment 1-4 is without sensitization.
Experiment 2：The hemolytic experiment of clindamycin phosphate for injection pharmaceutical composition prepared by 1-4 of the embodiment of the present invention
1. experimental method
The preparation of (1) 2% red blood cell suspension：Whole blood is gathered from arteria carotis by healthy rabbit, is put into beaker, with disinfection
Cotton swab stirs blood, except defibrinating, removes fibrinous red blood cell, adds 0.9% sodium chloride injection of 10 times of volumes,
2500rpm centrifuges 10min after mixing, abandons supernatant, is so centrifuged repeatedly washing until the not aobvious red of supernatant, and gained is red
Blood cell is made into 2% red blood cell suspension with 0.9% sodium chloride injection.
(2) the clindamycin phosphate for injection pharmaceutical composition of Example 1 presses clinical medicine dose concentration 6mg/ml
Carry out hemolytic experiment.0.9% sodium chloride injection of negative control group, positive control distilled water.Each pipe final volume is 5ml,
Experimental implementation is carried out according to table 11：
10. hemolytic of table tests agents useful for same
(3) vortex 1min mixings, when incubation 3 is small in 37 DEG C of water baths.It is observed in 15~180min.
2. experimental result is evaluated
Haemolysis is whether there is in observation each test tube of different time points.Criterion is as follows：
(1) full haemolysis：The clear and bright red of solution, residual that test tube bottom is acellular.
(2) part haemolysis：A small amount of cell residue is arranged at solution clear and bright red or brown, test tube bottom.
(3) without haemolysis：Red blood cell all sinks, and upper strata is light colourless clear liquid.
(4) it is aggregated：Not haemolysis has the red flocculent precipitation of erythrocyte agglutination in solution, cannot disperse after shaking.
3. experimental result
(1)15min：No. 1-5 pipe, No. 6 negative control pipes have a small amount of red blood cell to sink, and liquid level is slightly layered, and No. 7 positives are right
It looks after as red half clear solution.
(2)60min：1-5 pipes have red blood cell sinking, and liquid level has layering, and upper strata liquid level is milky；No. 6 negative controls
Pipe has red blood cell sinking, and liquid level has layering；No. 7 positive control pipes are red clear solution.
(3)120min：No. 6 yellowish clear and bright liquid of negative control test tube solution upper end 1.0cm, below 1.0cm are muddy red
Color liquid.No. 7 positive control pipes are red clear liquid.1-5 pipes have red blood cell sinking, and liquid level has layering, and upper strata liquid level is
Milky.
(4)180min：It is observed after 2500rpm centrifugations 5min, the upper strata of 1-5 pipes is milky emulsion, and the bottom is red
Color erythroprecipitin；No. 6 yellowish clear liquids in negative control test tube solution upper strata, the bottom are red erythroprecipitin；No. 7
Positive control pipe is red clear liquid.
4. experiment conclusion
Do not find embodiment 1 prepare clindamycin phosphate for injection pharmaceutical composition have to red blood cell agglutination and
Haemolysis.The hemolytic result of the test of the clindamycin phosphate for injection pharmaceutical composition of embodiment 2-4 and embodiment 1
As a result it is similar and do not show.
Experiment 3：The blood vessel irritation of clindamycin phosphate for injection pharmaceutical composition prepared by 1-4 of the embodiment of the present invention
Experiment
Test method：Share 3 rabbit.Every rabbit right ear vein bolus infusion clindamycin phosphate pharmaceutical composition
Object, Drug level are clinical application concentration 6mg/ml；The left ear vein of every rabbit injects 0.9% sodium chloride injection as cloudy
Property control, medication volume is identical with the volume for the clindamycin phosphate for injection pharmaceutical composition that corresponding auris dextra is injected.Daily
Once, successive administration 3 days.The front and rear cosmetic variation with rabbit ear when small of last dose 72 of observation administration.Observe injection site position
Whether the irritations such as swelling, hemostasis, vessel retraction are had.After the last administration 72 it is small when, animal is put to death, from rabbit auricular vein portion
Rabbit auricular vein is cut to the ear portion, 4% neutral formalin is fixed, and is cut into slices after conventional dehydration, transparent, waxdip embedding, bush
Essence-eosin stains (hematoxylin-eosin staining, abbreviation HE are dyed), does histopathologic slide's inspection.
Result of the test：The 2-4 days range estimation observer's rabbit auricular veins after injection, auris dextra injection site blood vessel are in aubergine,
Blood vessel periphery pneumonedema rises；Morphological examination, which has no intravascular, hemostasis and inflammatory cell infiltration.The result shows that continuous three days inject
With people's clinic isoconcentration drug, test specimen is irritant to rabbit auricular vein.The clindamycin for injection of embodiment 2-4
The vascular stimulation tests result of phosphate pharmaceutical composition is similar to the result of embodiment 1 and does not show.
In conclusion clindamycin phosphate for injection pharmaceutical composition and existing skill prepared by 1-4 of the embodiment of the present invention
Art is significantly improved compared to stability, and with security.
Claims (17)
1. a kind of clindamycin phosphate for injection pharmaceutical composition, which is characterized in that include clindamycin phosphate, poly- second two
Alcohol, tartrate and water for injection, wherein including clindamycin phosphate described in 8~20g, 0.5~2g institutes per 100ml compositions
Polyethylene glycol, tartrate described in 0.2~1g are stated, water for injection is surplus, and the degree of polymerization of the polyethylene glycol is 300-600.
2. clindamycin phosphate for injection pharmaceutical composition according to claim 1, which is characterized in that per 100ml groups
Object is closed comprising clindamycin phosphate described in 9~18g, polyethylene glycol described in 0.6~1.8g, tartrate described in 0.4~0.8g,
Water for injection is surplus.
3. clindamycin phosphate for injection pharmaceutical composition according to claim 1 or 2, which is characterized in that described poly-
The degree of polymerization of ethylene glycol is 300,400 or 600.
4. clindamycin phosphate for injection pharmaceutical composition according to claim 3, which is characterized in that the poly- second two
The degree of polymerization of alcohol is 400.
5. clindamycin phosphate for injection pharmaceutical composition according to claim 1 or 2, which is characterized in that the wine
Stone hydrochlorate is the one or more in sodium tartrate, potassium tartrate and sodium potassium tartrate tetrahydrate.
6. clindamycin phosphate for injection pharmaceutical composition according to claim 5, which is characterized in that the tartaric acid
Salt is sodium tartrate, potassium tartrate, sodium potassium tartrate tetrahydrate or potassium tartrate and the mixture of sodium tartrate.
7. clindamycin phosphate for injection pharmaceutical composition according to claim 6, which is characterized in that the tartaric acid
Salt is sodium tartrate.
8. clindamycin phosphate for injection pharmaceutical composition according to claim 1 or 2, which is characterized in that the note
It penetrates and can be used for intravenous injection or intramuscular injection with clindamycin phosphate pharmaceutical composition.
9. a kind of method of the clindamycin phosphate for injection pharmaceutical composition prepared described in claim 1 or 2, the method
Comprise the following steps：
(1) polyethylene glycol, tartrate are added in water for injection, stirring and dissolving；
(2) clindamycin phosphate is added in, the pH value of solution is adjusted to 5.6-6.1 by stirring and dissolving；
(3) medicinal carbon, stirring and adsorbing are added in；
(4) coarse filtration is carried out using miillpore filter and takes off charcoal；
(5) add surplus water for injection and carry out refined filtration degerming to full dose, then with miillpore filter.
10. according to the method described in claim 9, it is characterized in that, in step 3, per 100ml compositions using 0.01~
Medicinal carbon described in 0.5g.
11. according to the method described in claim 10, it is characterized in that, in step 3, per 100ml compositions using 0.03~
Medicinal carbon described in 0.4g.
12. according to the method for claim 11, which is characterized in that in step 3, per 100ml compositions using 0.05~
Medicinal carbon described in 0.3g.
13. according to the method for claim 12, which is characterized in that in step 3, per 100ml compositions using 0.1~
Medicinal carbon described in 0.2g.
14. the method described in claim 9, which is characterized in that in steps of 5, for carrying out the miillpore filter of refined filtration degerming
A diameter of 0.22 μm；And in step 4, for carry out that coarse filtration takes off the miillpore filter of charcoal a diameter of 0.6~0.8 μm.
15. the method described in claim 14, which is characterized in that in step 4, for carrying out the miillpore filter that coarse filtration takes off charcoal
A diameter of 0.65 μm or 0.8 μm.
16. the method described in claim 15, which is characterized in that in step 4, for carrying out the miillpore filter that coarse filtration takes off charcoal
A diameter of 0.65 μm.
17. the method described in claim 9, which is characterized in that in step 2, use sodium hydroxide and hydrochloric acid conditioning solution
pH。
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| CN101780032A (en) * | 2009-01-16 | 2010-07-21 | 海南中化联合制药工业有限公司 | Clindamycin phosphate injection preparation and preparation method thereof |
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| CN101708314A (en) * | 2009-12-10 | 2010-05-19 | 中国人民解放军第二军医大学 | Chinese medicinal essential oil injection solution, injection and preparation method thereof |
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