CN101416974A - Preparation method of doxycycline long-acting injection - Google Patents
Preparation method of doxycycline long-acting injection Download PDFInfo
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- CN101416974A CN101416974A CNA200710189806XA CN200710189806A CN101416974A CN 101416974 A CN101416974 A CN 101416974A CN A200710189806X A CNA200710189806X A CN A200710189806XA CN 200710189806 A CN200710189806 A CN 200710189806A CN 101416974 A CN101416974 A CN 101416974A
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- doxycycline
- injection
- solution
- long
- propylene glycol
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Abstract
The invention discloses a doxycycline long-acting injection which has the formula as follows: 5g to 20g of doxycycline, 10g to 60g of propylene glycol, 2g to 4g of MgCl2, 0.2g to 0.5g of Na2S2O5, and water used for injection. The preparation method comprises the following steps: 1. the doxycycline is added into the propylene glycol to obtain a solution (1); 2. the doxycycline hydrochloride, the MgCl2 and the Na2S2O5 are taken and dissolved in the water used for injection to obtain a solution (2); 3. the solution (2) is slowly added into the solution (1) and stirred while being added, and ethylene diamine is used for regulating the pH value to be 7.5 to 8.5; and 4. the water used for injection is added till the total volume reaches 100ml, and filtering, encapsulation and flowing steam sterilization at the temperature of 100 DEG C for 30min are carried out to obtain the finished product. The doxycycline long-acting injection has the advantages of less dosage, long half-life period, less adverse reaction, and the like.
Description
Technical field:
The present invention relates to a kind of preparation method of veterinary drug, particularly relate to a kind of preparation method of doxycycline long-acting injection.
Background technology:
Doxycycline is a broad spectrum antibiotic, and most of Gram-positives, gram negative bacteria are all had stronger antibacterial action, and is also very sensitive to mycoplasma (as mycoplasma hyopneumoniae), chlamydia, rickettsia, spirillum, protozoon etc.Doxycycline is the deoxidation thing of oxytetracycline, is a potent tetracycline antibiotics, and its antibacterial mechanisms is by synthetic each link of blocking-up bacterioprotein, suppresses duplicating of antibacterial, reaches antibacterial effect.The doxycycline hydrochloride preparation is used for the treatment of mycoplasma pneumoniae of swine and is of long duration, and clinical reflection is respond well.And existing bibliographical information, acute and chronic antibacterial, the mycoplasma infection determined curative effect of doxycycline hydrochloride for injection treatment respiratory system and urinary system, untoward reaction is few, safety is better, sensitive bacterial is infected determined curative effect, part index number (gram positive bacteria infects cure rate, mycoplasma clearing rate) is better than azithromycin, illustrates that doxycycline injection has application promise in clinical practice in treatment respiratory tract, urinary tract antibacterial and mycoplasma infection.Compare with tetracycline, it has, and antibacterial action is strong, persister is few, long half time and the few advantage of untoward reaction.But the duration of efficacy of common doxycycline injection is short, and administration is frequent, uses to the user to make troubles.And because doxycycline character instability, common doxycycline injection is degraded easily, and phenomenons such as variable color take place.The present invention releases a kind of long-acting doxycycline injection adopting, and its half-life will reach 48 hours, thereby solves the problem of frequent drug administration in actual applications.And, make the injection stable in properties of making by distinctive preparation technique, be difficult for taking place degraded and wait variation.
Summary of the invention:
In order to overcome above-mentioned defective, the invention provides a kind of preparation method of doxycycline long-acting injection, its half-life will reach 48 hours.Mainly solve the short technical problem of half-life of existing common doxycycline injection.And the injection of making is difficult for taking place degraded and waits variation than existing doxycycline injection stable in properties.
For achieving the above object, the present invention adopts following technical scheme:
The preparation method of described doxycycline injection, its doxycycline injection prescription is as follows:
Doxycycline 5-20g
Propylene glycol 10-60g
MgCL
2 2-4g
Na
2S
2O
5 0.2-0.5g
Water for injection adds to 100ml
The preparation method of described doxycycline injection, its preparation method is:
1, earlier doxycycline is added in the propylene glycol, gets solution (1);
2, get doxycycline hydrochloride, MgCL in addition
2, Na
2S
2O
5Be dissolved in water for injection and get solution (2);
3, solution (2) is slowly joined in the solution (1),, transfer pH value 7.5-8.5 with ethylenediamine with adding with stirring;
4, add water for injection at last to 100ml, filter, embedding, in 100 ℃ of flowing steam sterilizations 30 minutes promptly.
The preparation method of described doxycycline long-acting injection, the propylene glycol that uses in its long-acting injection can also with the ethanol of equivalent, glycerol, glycerin methylal, PEG-400, a-ketopyrrolidine etc. or wherein both mix substitute.
The preparation method of described doxycycline long-acting injection, the doxycycline that uses in its long-acting injection can substitute with the doxycycline hydrochloride of equivalent; Perhaps both use simultaneously.
The present invention adopts suitable single solvent or mixed solvent to make solvent.Solvent can adopt propylene glycol, ethanol, glycerol, PEG-400, glycerin methylal, a-ketopyrrolidine etc.Propylene glycol can be made the intramuscular injection solvent, and toxicity is little, and nonirritant can be dissolved many organic drugs, and the mixed solvent of a certain proportion of propylene glycol and water can delay the hydrolysis of medicine, increases stability.And when the propylene glycol consumption is suitable, make its medicine that the effect of prolongation of effect be arranged.PEG-400 can make injection solvent, can dissolve many water miscible inorganic salts and water-insoluble organic drug, this product has certain Stabilization to some medicines with hydrolysis, can with water, ethanol, glycerol, propylene glycol equal solvent with any than mixing, and Tetracyclines is had the prolongation of effect effect.Also need add anti-hydrolysis medicine (magnesium chloride, magnesium oxide etc.) antioxidant (water antioxidant sulfites, ascorbic acid, Na
2S
2O
5, formaldehyde and sodium bisulphite etc.).Used the principle of latent solvent to increase the dissolubility of medicine.Solvent or mixed solvent in this invention can make the unsettled shortcoming of doxycycline injection character be overcome simultaneously, and the stability experiment examination can be preserved more than 24 months at normal temperatures.
To long-acting doxycycline injection adopting pharmacokinetics experimentation
1. experimental animal:. 6 of healthy piglets, male and female half and half, in 2 weeks of clinical observation, performance is healthy, body weight 18-25kg.6 pigs are divided into two groups of duration of test at random to be raised routinely, freely drinks water and searches for food (not containing antibacterials in the feedstuff).
2. test material: common doxycycline injection long-acting doxycycline injection adopting
3. administration and blood specimen collection: dosage is 10mg/kg, takes a blood sample from vena cava anterior.Before administration, adopt blank blood 10mL.2 kinds of injection musculi collis injection back respectively at 12,24,48, the 72h 5mL that takes a blood sample, place the heparinization centrifuge tube, separated plasma behind 4 ℃, the centrifugal 10min of 4000r/min ,-20 ℃ of preservations are to be measured.
4. doxycycline concentration determination: C in the blood plasma
18Solid phase extraction column, earlier with the drip washing of 2mL methanol, reuse 2mL water wash is with the activation pillar.Blood sampling 1mL is added on the pillar, earlier with 5% methanol solution 3mL drip washing, use acetonitrile one aqueous solution (50:50 at last, containing 0.15% trifluoroacetic acid) 3mL elutes doxycycline, and eluent flow rate is 20/min, collects eluent, after with freeze drier eluent being volatilized, be settled to 1mL with mobile phase, the centrifugal 10min of 12000r/min gets supernatant 20uL and injects the high performance liquid chromatograph analysis.Chromatographic condition: chromatographic column is Kromasil C
18(250mm * 4.6mm, 5um), 30 ℃ of column temperatures, mobile phase is 0.01mol/L oxalic acid solution one acetonitrile, one methanol (55:25:20), and flow velocity is 0.8mL/min, and the detection wavelength is 350nm, sample size 20uL.
5. date processing and analysis: calculate blood drug level according to the external standard standard curve method
6 results and analysis.
6.1 doxycycline concentration in the blood plasma: after measured, doxycycline blood plasma standard curve is in 0.1～5.0ug/mL concentration range internal linear relation good (r=0.9996), blood drug level is respectively 0.1,1, during 5ug/mL, relative recovery is followed successively by 104.0%, 93.9%, 100.8%
6.2 chromatographic behavior: endogenous material reaches the baseline separation effect in doxycycline and the blood plasma, and peak shape is sharp-pointed, retention time 6.5-6.6min
6.4 the detection method of doxycycline in the blood plasma
Chromatography detects the concentration of doxycycline in the blood plasma, and method is easy, sensitive, accurate, and every index all meets biological sample and measures requirement, can be used for doxycycline pharmacokinetic in animal body.
7. conclusion: according to the pharmacokinetic parameters of above-mentioned 2 kinds of injection, can use common doxycycline injection, need administration 2 times every day, and when using long-acting doxycycline injection adopting, only need administration 1 time every day, dosage is 10mg/kg, successive administration 3-5d.Long-acting doxycycline injection adopting is owing to can make the effective blood drug concentration prolongation of holding time, can reduce administration number of times again, save manpower and time, alleviate the stress that frequent injection brings to ill domestic animal, therefore will have more wide application prospect at veterinary clinic.
The pharmacokinetic parameter (n=6) of the different doxycycline injections of table 1. pig intramuscular injection
The present invention has following beneficial effect:
It is few that the present invention has dosage, long half time and untoward reaction are few, can make the prolongation of holding time of active drug concentration, can reduce administration number of times again, save manpower and time, alleviate the advantages such as stress that frequent injection brings to ill domestic animal, therefore will have more wide application prospect at veterinary clinic.And, make the injection stable in properties of making by distinctive preparation technique, be difficult for taking place degraded and wait variation.
The specific embodiment:
The preparation method of doxycycline long-acting injection of the present invention, its injection prescription is as follows:
Doxycycline 5-20g
Propylene glycol 10g--60g
MgCL
2 2-4g
Na
2S
2O
5 0.2-0.5g
Water for injection adds to 100ml
Embodiment 1,
Get doxycycline 10g, propylene glycol 20g, PEG-400 30g, MgCL
22g, Na
2S
2O
50.2g, water for injection adds to 100ml, its preparation method is:
1. earlier propylene glycol and PEG-400 are mixed, get doxycycline again and be added in the mixed solvent, get solution (1);
2. get MgCL in addition
2, Na
2S
2O
5Be dissolved in water for injection and get solution (2);
3. solution (2) is slowly joined in the solution (1),, transfer pH value 7.5 with adding with stirring;
4. add water for injection at last to 100ml, filter, embedding, in 100 ℃ of flowing steam sterilizations 30 minutes promptly.
Embodiment 2,
Get doxycycline 10g, doxycycline hydrochloride 10.8g, propylene glycol 40g, MgCL
22g, Na
2S
2O
50.2g, water for injection adds to 100ml, its preparation method is:
1. earlier doxycycline is added in the propylene glycol, gets solution (1);
2. get doxycycline hydrochloride, MgCL in addition
2, Na
2S
2O
5Be dissolved in water for injection and get solution (2);
3. solution (2) is slowly joined in the solution (1),, transfer pH value 8.0 with adding with stirring;
4. add water for injection at last to 100ml, filter, embedding, in 100 ℃ of flowing steam sterilizations 30 minutes promptly.
Embodiment 3,
Get doxycycline 5g, doxycycline hydrochloride 5.4g, ethanol 30g, PEG-400 30gMgCL
22g, Na
2S
2O
50.2g, water for injection adds to 100ml, its preparation method is:
1. earlier ethanol and PEG-400 are mixed, get doxycycline again and be added in the mixed solvent, get solution (1);
2. get doxycycline hydrochloride, MgCL in addition
2, Na
2S
2O
5Be dissolved in water for injection and get solution (2);
3. solution (2) is slowly joined in the solution (1),, transfer pH value 8.0 with adding with stirring;
4. add water for injection at last to 100ml, filter, embedding, in 100 ℃ of flowing steam sterilizations 30 minutes promptly.
Embodiment 4,
Get doxycycline hydrochloride 10.8g, propylene glycol 30g, PEG-400 30g MgCL
22g, Na
2S
2O
50.2g, water for injection adds to 100ml, its preparation method is:
1. earlier propylene glycol and PEG-400 are mixed, get doxycycline hydrochloride again and be added in the mixed solvent, get solution (1);
2. get MgCL in addition
2, Na
2S
2O
5Be dissolved in water for injection and get solution (2);
3. solution (2) is slowly joined in the solution (1),, transfer pH value 7.5 with adding with stirring;
4. add water for injection at last to 100ml, filter, embedding, in 100 ℃ of flowing steam sterilizations 30 minutes promptly.
Embodiment 5,
Get doxycycline 20g, propylene glycol 40g, PEG-400 20g, MgCL
22g, Na
2S
2O
50.2g, water for injection adds to 100ml, its preparation method is:
1. earlier propylene glycol and PEG-400 are mixed, get doxycycline again and be added in the mixed solvent, get solution (1);
2. get MgCL in addition
2, Na
2S
2O
5Be dissolved in water for injection and get solution (2);
3. solution (2) is slowly joined in the solution (1),, transfer pH value 7.5 with adding with stirring;
4. add water for injection at last to 100ml, filter, embedding, in 100 ℃ of flowing steam sterilizations 30 minutes promptly.
Embodiment 6,
Get doxycycline 10g, doxycycline hydrochloride 10.8g, propylene glycol 40g, PEG-400 20gMgCL
22g, Na
2S
2O
50.2g, water for injection adds to 100ml, its preparation method is:
1. earlier propylene glycol and PEG-400 are mixed, get doxycycline again and be added in the mixed solvent, get solution (1);
2. get doxycycline hydrochloride, MgCL in addition
2, Na
2S
2O
5Be dissolved in water for injection and get solution (2);
3. solution (2) is slowly joined in the solution (1),, transfer pH value 8.0 with adding with stirring;
4. add water for injection at last to 100ml, filter, embedding, in 100 ℃ of flowing steam sterilizations 30 minutes promptly.
Embodiment 7,
Get doxycycline 5g, propylene glycol 10g, MgCL
22g, Na
2S
2O
50.2g, water for injection adds to 100ml, its preparation method is:
1. earlier doxycycline is added in the propylene glycol, gets solution (1);
2. get MgCL in addition
2, Na
2S
2O
5Be dissolved in water for injection and get solution (2);
3. solution (2) is slowly joined in the solution (1),, transfer pH value 7.5 with adding with stirring;
4. add water for injection at last to 100ml, filter, embedding, in 100 ℃ of flowing steam sterilizations 30 minutes promptly.
Embodiment 8,
Get doxycycline 15g, propylene glycol 30g, MgCL
23g, Na
2S
2O
50.4g, water for injection adds to 100ml, its preparation method; Except that 3. embodiment 7 steps are transferred pH value be 8.0 other method with embodiment 7.
Embodiment 9,
Get doxycycline 20g, propylene glycol 60g, MgCL
24g, Na
2S
2O
50.5g, water for injection adds to 100ml, its preparation method: except that 3. embodiment 7 steps are transferred pH value be 8.5 other method with embodiment 7.
The foregoing description 1,2,3,4,5,6,7,8,9, in, the propylene glycol that preparation is used in the doxycycline long-acting injection can also substitute with ethanol, glycerol, glycerin methylal, PEG-400, the a-ketopyrrolidine of equivalent, perhaps wherein both mix substitute; Can substitute with the doxycycline hydrochloride of equivalent at the employed doxycycline of the preparation west plain long-acting injection of ring; Perhaps both use simultaneously.
Claims (4)
1, a kind of doxycycline long-acting injection, its prescription is as follows:
Doxycycline 5-20g
Propylene glycol 10-60g
MgCL
2 2-4g
Na
2S
2O
5 0.2-0.5g
Water for injection adds to 100ml.
2, a kind of preparation method of doxycycline long-acting injection the steps include:
1 〉, earlier doxycycline is added in the propylene glycol, solution (1);
2 〉, get doxycycline hydrochloride, MgCL in addition
2, Na
2S
2O
5Be dissolved in water for injection and get solution (2);
3 〉, solution (2) is slowly joined in the solution (1), with adding, with ethylenediamine accent pH value 7.5-8.5 with stirring;
4〉add water for injection to 100ml, at last, filter, embedding, in 100 ℃ of flowing steam sterilizations 30 minutes promptly.
3, a kind of doxycycline long-acting injection according to claim 1, it is characterized in that: the propylene glycol that uses in the described doxycycline long-acting injection prescription can also substitute with ethanol, glycerol, glycerin methylal, PEG-400, the a-ketopyrrolidine of equivalent, perhaps wherein both mix substitute.
4, a kind of doxycycline long-acting injection according to claim 1 is characterized in that: the doxycycline that uses in the described doxycycline long-acting injection prescription can substitute with the doxycycline hydrochloride of equivalent; Perhaps both use simultaneously.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200710189806XA CN101416974A (en) | 2007-10-22 | 2007-10-22 | Preparation method of doxycycline long-acting injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200710189806XA CN101416974A (en) | 2007-10-22 | 2007-10-22 | Preparation method of doxycycline long-acting injection |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101416974A true CN101416974A (en) | 2009-04-29 |
Family
ID=40628100
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA200710189806XA Pending CN101416974A (en) | 2007-10-22 | 2007-10-22 | Preparation method of doxycycline long-acting injection |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107708665A (en) * | 2015-03-23 | 2018-02-16 | 贝尔生物制药有限公司 | Medicinal Fourth Ring promotor composition for dermatological use |
-
2007
- 2007-10-22 CN CNA200710189806XA patent/CN101416974A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107708665A (en) * | 2015-03-23 | 2018-02-16 | 贝尔生物制药有限公司 | Medicinal Fourth Ring promotor composition for dermatological use |
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Open date: 20090429 |