CN104523687A - Veterinary compound-amoxicillin probenecid-salt soluble powder and preparation technology thereof - Google Patents
Veterinary compound-amoxicillin probenecid-salt soluble powder and preparation technology thereof Download PDFInfo
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- CN104523687A CN104523687A CN201410687658.4A CN201410687658A CN104523687A CN 104523687 A CN104523687 A CN 104523687A CN 201410687658 A CN201410687658 A CN 201410687658A CN 104523687 A CN104523687 A CN 104523687A
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- amoxicillin
- probenecid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- 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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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Bioinformatics & Cheminformatics (AREA)
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Abstract
The invention relates to a veterinary compound-amoxicillin probenecid-salt soluble powder and a preparation technology thereof. The soluble powder comprises the following raw materials in parts by weight: 3-20 parts of amoxicillin, 1-10 parts of a probenecid salt, 1-5 parts of a cosolvent, and 65-94 parts of an auxiliary material. The sterilization capability of amoxicillin is improved. Probenecid sodium/potassium is capable of competitively inhibiting secretion of amoxicillin in renal tubules, thereby prolonging the stay time of amoxicillin in the body and improving the demanded concentration of amoxicillin in blood. By proportioning of the two compositions according to certain amounts, the sterilization capability of amoxicillin can be effectively improved.
Description
Technical field
The present invention relates to a kind of soluble powder for animals, be specifically related to a kind of amoxicillin, probenecid salt soluble powder and preparation technology thereof.
Background technology
Amoxicillin be a kind of wide spectrum beta-lactam in antibiotic, sterilizing ability is strong, can kill most gram positive bacteria and part gram negative bacteria, is one of medicine conventional on veterinary clinic.At present about the preparation of solubility mainly contains amoxicillin soluble powder and compound amoxicillin soluble powder, the main component of compound amoxicillin soluble powder is amoxicillin and clavulanate potassium.About the preparation of compound recipe sodium benemid/potassium, amoxicillin soluble powder is not reported.Therefore this compound preparation has very large market prospect.But water insoluble, injection site zest, in animal body release rate are fast, blood drug level the is held time defect such as short that amoxicillin exists.So be the key ensureing amoxicillin sterilizing ability by increasing cosolvent, change administering mode and the elimination time extended in animal body.
Probenecid has another name called benemid, water-soluble hardly, be a kind of medicine for the treatment of chronic gout, simultaneously in the secretion of renal tubules, therefore the blood drug level increasing beta-lactam antibiotic and the effect extending action time can be had by antibiotic in competitive inhibition beta-lactam.Probenecid poorly water-soluble, but we to find that water-soluble probenecid sodium/potassium and probenecid have identical by lot of experiments be effect, and water solublity is better, therefore can come alternative probenecid and XiLin, amoxicillin soluble powder proportioning with sodium benemid/potassium.
Summary of the invention
The object of the invention is to overcome deficiency of the prior art and provide and a kind of animal compound amoxicillin, probenecid salt soluble powder and preparation technology thereof are provided, the present invention by improve amoxicillin water solublity, change administering mode and extend effective drug duration and improve the sterilizing ability of amoxicillin.
The object of the present invention is achieved like this:
A kind of animal compound amoxicillin, probenecid salt soluble powder, comprise the raw material of following weight mark: amoxicillin 3-20 part, probenecid salt 1-10 part, cosolvent 1-5 part, adjuvant 65-94 part.
Based on the above, described probenecid salt is sodium benemid or Potassium probenicid.
Based on the above, described cosolvent is sodium bicarbonate or sodium carbonate.
Based on the above, described adjuvant is glucose or sucrose or lactose or starch.
A preparation technology for animal compound amoxicillin, probenecid salt soluble powder, mixes according to above-mentioned parts by weight, thus makes compound preparation.
Based on the above, described compound preparation is soluble powder.
The present invention has the following advantages compared with existing preparation:
1. improve the water solublity of amoxicillin soluble powder.Amoxicillin is water insoluble, can improve the dissolubility of amoxicillin in water, for the preparation of soluble powder provides the most basic condition by interpolation cosolvent sodium bicarbonate or sodium carbonate.
2. avoid untoward reaction.Amoxicillin has the untoward reaction of local irritation, and as changed oral administration into, and amoxicillin oral result is good, can avoid the untoward reaction of local irritation and improve drug effect.Soluble powder is exactly a kind of preparation way of oral administration.
3. improve the sterilizing ability of amoxicillin.Sodium benemid/potassium can emulative suppression amoxicillin in the secretion of renal tubules, thus extend its time of staying in vivo, and improve amoxicillin in blood need concentration.Both carry out according to certain amount the sterilizing ability that proportioning effectively can improve amoxicillin.
Accompanying drawing explanation
Fig. 1 is the peak area of amoxicillin is vertical coordinate (Y), with the concentration of amoxicillin in blood plasma for abscissa (X) drawing standard curve.
Fig. 2 is that the blood concentration-time curve after sodium selenite single dose gastric infusion carries out matched curve.
Detailed description of the invention
Below in conjunction with specific embodiment, the invention will be further described.
Embodiment 1: get amoxicillin 5g, sodium benemid 1.5 g, glucose 93.5g conventionally mix, namely form compound preparation, this compound preparation is solvable granular structure.
Embodiment 2: get amoxicillin 10g, Potassium probenicid 3 g, glucose 87g conventionally mix, namely form compound preparation, this compound preparation is solvable granular structure.
Embodiment 3: get amoxicillin 20g, sodium benemid 6g, sodium bicarbonate 2 g, glucose 74g conventionally mix, and namely form compound preparation, and this compound preparation is solvable granular structure.
Embodiment 4: get Amoxicillin Sodium 10g, sodium benemid 3g, lactose 87g conventionally mixes, and namely forms compound preparation, this compound preparation is solvable granular structure.
Embodiment 5: get amoxicillin 10g, sodium benemid 3 g, starch 87g conventionally mixes, and namely forms compound preparation, and this compound preparation is solvable granular structure.
Embodiment 6: get amoxicillin 20g, sodium benemid 6 g, sodium carbonate 2g, sucrose 72g conventionally mix, namely form compound preparation, this compound preparation is solvable granular structure.
Optimum formula is: get amoxicillin 10g, sodium benemid 3 g, glucose 87g conventionally mix, namely form compound preparation, this compound preparation is solvable granular structure.
Medicine all has certain toxicity, so when forming compound preparation, under the condition ensureing its effect of drugs, should reduce its folk prescription kind as far as possible.Consider the cost of medicine, we consider, while guarantee amoxicillin and probenecid drug effect and soluble powder formulation requirements, to reduce the kind of other adjuvants simultaneously.According to " People's Republic of China's veterinary drug allusion quotation " inner amoxicillin soluble (10%) and amoxicillin powder (10%) specification requirement, specification is decided to be 100g by us: amoxicillin 10g+ probenecid 3g.
The consideration of comprehensive above reason, we determine that optimum formula is: get amoxicillin 10g, sodium benemid 3 g, glucose 87g conventionally mix, namely form compound preparation, this compound preparation is solvable granular structure.
dissolubility test
One, test material
Nessler colorimetric tube, distilled water, sodium bicarbonate
Two, for reagent thing
For sample 1: sodium benemid 1.5g, amoxicillin powder 5g, glucose 93.5g.
For sample 2: sodium benemid 3.0g, amoxicillin powder 10g, glucose 87.0g.
For sample 3: sodium benemid 4.5g, amoxicillin powder 15g, glucose 81.5g.
For sample 4: sodium benemid 6.0g, amoxicillin powder 20g, glucose 74.0g.
Three, test method
Get each 1g of above-mentioned test sample, put in beaker, the solution of the 100mL that adds water, stir, observe dissolving situation.If any insoluble situation, add sodium bicarbonate, add 0.5g at every turn, if insoluble, progressively increase, extremely to dissolving completely.
Four, result of the test
Dissolubility test result is as table 1:
| Sample | Dissolubility | Add sodium bicarbonate amount (g) | Add cosolvent dissolubility |
| For sample 1 | Dissolve | - | - |
| For sample 2 | Dissolve | - | - |
| For sample 3 | Insoluble | 1.0 | Dissolve |
| For sample 4 | Insoluble | 2.0 | Dissolve |
Five, discussion and analysis
By dissolubility test result, we can find out: affecting the deliquescent main component of this compound medicine is amoxicillin, and when amoxicillin is below 10%, its water solublity is fine, can reach dissolved state.If content just needs more than 10% to add cosolvent sodium bicarbonate, and the interpolation amount of cosolvent becomes positive correlation with the amount of amoxicillin.So this preparation, with 100 meterings, if the amount of amoxicillin is below 10%, does not need to add cosolvent.If need to add cosolvent more than 10%.
animality is tested:
One, test material
1.1 test apparatus
Waters high performance liquid chromatograph: C18 post, waters2695,248 UV-detector; Hermle company of High speed refrigerated centrifuge: Z323K Germany; Numerical control ultrasonic cleaner: KQ3200DE, Kunshan ultrasonic instrument company limited; Electronic analytical balance: FA2004, upper current chart level instruments and meters company limited.Single track micropipettor: 720GN series, Genex Beta company.
1.2 experimental animal
Sodium selenite 16, male and female half and half, body weight 16-30kg, conventional raising one week before test, normal assays stops drinking-water in first 6 hours.
1.3 for reagent thing
Amoxicillin standard substance (Chinese veterinary drug detects institute); Probenecid standard substance (National Institute for Food and Drugs Control); Amoxicillin soluble powder (Henan An Jin biological medicine company limited provides, content 10%); Amoxicillin, probenecid soluble powder (Henan An Jin biological medicine company limited provides, content 10%).
Test method
2.1 chromatographic condition
Chromatographic column: C18,250mm × 4.6mm(i.d), particle diameter 5um, or quite.
Mobile phase: phosphate buffer (PH7.2)-methanol (85:15).
Flow velocity: 1.0mL/min.
Determined wavelength: 229nm
Sample size: 20uL
2.2 test grouping and administering modes
Test is divided into 2 groups, and often organize 5, first group is amoxicillin group, gavages amoxicillin test solution (100mg/ only); Second group is amoxicillin group, gavages amoxicillin, Probenecid Solution (100mg/ only).
The collection of 2.3 blood and pretreatment
Before perfusion, (0h) vena cava anterior blood sampling 5mL is as blank.After perfusion 5,15,30,45min and 1,1.5,2,3,4,6,8,12,24h respectively takes a blood sample once, take a blood sample 5mL at every turn.EDTA anticoagulant, the centrifugal 5min of 3000r/min, separated plasma, to be measured in-20 DEG C of Refrigerator stores.
Get blood plasma 200uL and be placed in 1mL plastic centrifuge tube, then add acetonitrile 200uL, the centrifugal 10min of DL 40s, 1500r/min, gets supernatant sample introduction.
The drafting of 2.4 standard curves
In 7 2mL centrifuge tube containing 0.2mL blank plasma, add appropriate amoxicillin standard solution, make its ultimate density be respectively 0.10,0.50,1.00,2.00,5.00,10.00,20.00ug/mL, by 2.3 processing samples, get 20mL sample introduction.With the chromatographic peak area of amoxicillin, linear regression is done to concentration, draw out standard curve.
2.5 precision measure
Get blank plasma 0.2mL4 part, add appropriate amoxicillin standard solution, make its final concentration be respectively 0.50,1.00,5.00 and 10.00ug/mL.By above-mentioned 2.3 processing samples, get 20uL sample introduction and measure its peak area.In one day, replication 4 times, namely obtains withinday precision.The next day of by 4 increment product in 7d, replication 4 times, namely obtains day to day precision.
2.6 determination of recovery rates
Get 3 and be diluted to blank plasma and mobile phase the sample that amoxicillin concentration is 1.00,5.0 and 10.00ug/mL respectively, measure its peak area according to machine upper after above-mentioned 2.3 process.The response rate is asked respectively with the percent value of the peak area with blank plasma samples of the peak area of mobile phase dilute sample and corresponding concentration.
2.7 pharmacokinetic parameters calculate
By the data 3P87 computed in software pharmacokinetic parameters measured.
interpretation of result
3.1 chromatographic isolation
Under above-mentioned chromatographic separation condition, the retention time of amoxicillin is 7.5min, and chromatographic peak peak shape is sharp-pointed, good with the separating substances in blood plasma, there is not interference.
3.2 standard curve
With the peak area of amoxicillin for vertical coordinate (Y), with the concentration of amoxicillin in blood plasma for abscissa (X) drawing standard curve, obtain standard curve Y=14509X+392.27, coefficient R 2=0.999.
Standard curve is as Fig. 1.
3.3 precision measurement results
Plasma is 0.5,1.0,5.0, the withinday precision of 10.0ug/mL amoxicillin and day to day precision be all less than 4%, meet the requirements.
3.4 determination of recovery rates results
Plasma is 1.0,5.0, the response rate of 10.0ug/mL amoxicillin is all greater than 96%, meet the requirements.
3.5 pharmacokinetic parameters results
Blood concentration-time curve after sodium selenite single dose gastric infusion carries out matching, the results are shown in Figure 2.And blood concentration-time data are carried out 3P87 software analysis, its pharmacokinetic parameters sees the following form 2.
Table 2 pharmacokinetic parameters table
| Parameter | Amoxicillin, probenecid soluble powder | Amoxicillin soluble powder |
| T 1/2（ka）/min | 42.35±8.26 | 31.36±7.96 |
| T 1/2a(kel)/min | 231.25±15.28 | 96±18.24 |
| T max/min | 45.31±11.32 | 30.12±9.64 |
| C max/(mg/mL) | 19.95±11.28 | 19.31±8.92 |
| AUC(mg/mL.min) | 38.06±1.68 | 21.29±1.26 |
4. discuss
Blood concentration-time and the pharmacokinetic parameters result result of this test show, amoxicillin when 1.5h about, concentration in blood reduces half, and recurs amoxicillin just will arrive half when 4h.Meanwhile, amoxicillin is when about 8h, and the amoxicillin in blood is lower than the detectability of instrument, and compound recipe still has at 24h the amoxicillin that very content is very low.Wherein the T1/2 (kel) of amoxicillin and AUC is about 2 times of folk prescription amoxicillin.As can be seen here, probenecid obviously can extend the amoxicillin time of staying in vivo, and can the higher bacteriocidal concentration of the maintenance of long period in vivo.
Claims (6)
1. animal compound amoxicillin, a probenecid salt soluble powder, is characterized in that: the raw material comprising following weight mark: amoxicillin 3-20 part, probenecid salt 1-10 part, cosolvent 0-5 part, adjuvant 65-94 part.
2. a kind of animal compound amoxicillin according to claim 1, probenecid salt soluble powder, is characterized in that: described probenecid salt is sodium benemid or Potassium probenicid.
3. a kind of animal compound amoxicillin according to claim 1, probenecid salt soluble powder, is characterized in that: described cosolvent is sodium bicarbonate or sodium carbonate.
4. a kind of animal compound amoxicillin according to claim 1, probenecid salt soluble powder, is characterized in that: described adjuvant is glucose or sucrose or lactose or starch.
5. a preparation technology for animal compound amoxicillin as claimed in claim 1, probenecid salt soluble powder, is characterized in that: mix according to above-mentioned parts by weight, thus make compound preparation.
6. the preparation technology of a kind of animal compound amoxicillin according to claim 5, probenecid salt soluble powder, is characterized in that: described compound preparation is soluble powder.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105997885A (en) * | 2016-05-19 | 2016-10-12 | 合肥中龙神力动物药业有限公司 | Veterinary-use soluble powder and preparation method and application method thereof |
| CN106074543A (en) * | 2016-07-13 | 2016-11-09 | 福建傲农生物科技集团股份有限公司 | A kind of water solublity synergistic composition containing amoxicillin and application thereof |
| CN106344522A (en) * | 2016-11-11 | 2017-01-25 | 河北利华药业有限公司 | Amoxicillin granule for livestock and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101199520A (en) * | 2007-12-25 | 2008-06-18 | 河北科星药业有限公司 | Beta-Lacetam anti-biotic compound dose for animal containing benemid |
-
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- 2014-11-26 CN CN201410687658.4A patent/CN104523687A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101199520A (en) * | 2007-12-25 | 2008-06-18 | 河北科星药业有限公司 | Beta-Lacetam anti-biotic compound dose for animal containing benemid |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105997885A (en) * | 2016-05-19 | 2016-10-12 | 合肥中龙神力动物药业有限公司 | Veterinary-use soluble powder and preparation method and application method thereof |
| CN106074543A (en) * | 2016-07-13 | 2016-11-09 | 福建傲农生物科技集团股份有限公司 | A kind of water solublity synergistic composition containing amoxicillin and application thereof |
| CN106074543B (en) * | 2016-07-13 | 2019-06-21 | 福建傲农生物科技集团股份有限公司 | A kind of water-soluble synergistic composition and its application containing Amoxicillin |
| CN106344522A (en) * | 2016-11-11 | 2017-01-25 | 河北利华药业有限公司 | Amoxicillin granule for livestock and preparation method thereof |
| CN106344522B (en) * | 2016-11-11 | 2019-04-09 | 河北利华药业有限公司 | A kind of amoxicillin granules for animals and preparation method thereof |
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Application publication date: 20150422 |