CN1219449C - Addition of tetracyclines to animal foodstuffs - Google Patents
Addition of tetracyclines to animal foodstuffs Download PDFInfo
- Publication number
- CN1219449C CN1219449C CNB008163235A CN00816323A CN1219449C CN 1219449 C CN1219449 C CN 1219449C CN B008163235 A CNB008163235 A CN B008163235A CN 00816323 A CN00816323 A CN 00816323A CN 1219449 C CN1219449 C CN 1219449C
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- CN
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- Prior art keywords
- ctc
- gel
- pill
- food
- ion
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/195—Antibiotics
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K40/00—Shaping or working-up of animal feeding-stuffs
- A23K40/30—Shaping or working-up of animal feeding-stuffs by encapsulating; by coating
-
- 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
- A61K31/65—Tetracyclines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Polymers & Plastics (AREA)
- Epidemiology (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Zoology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Food Science & Technology (AREA)
- Veterinary Medicine (AREA)
- Animal Husbandry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Seasonings (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Fodder In General (AREA)
- Medicinal Preparation (AREA)
- Fertilizers (AREA)
Abstract
A method of medicating an animal foodstuff which comprises coating particles of the foodstuff (e.g. feed pellets) with a gel containing tetracycline (e.g. chlortetracycline) and a stabilising agent. The stabilising agent is a compound containing divalent metal ions, for example a basic salt of an alkaline earth metal.
Description
The present invention relates to TCs, especially (though not being exclusively) aureomycin is added in the animal food.
In giving the situation of animal medicinal preparation for oral administration, usually this medicament is added to or is mixed in the food of animal, thereby realize to animals administer.This method is specially adapted to give a large amount of medicaments to a rout, and for example a group pig or a large amount of poultry are because can be added to medicament like this in the food (as the feed pill) that provides to the cluster animal.
The useful especially medicine that one class often gives by this way in a large number is the broad-spectrum antibiotic of telracycline family, especially aureomycin (CTC), uses it always and treats and prevent a large amount of bacterial diseases.But when adding CTC in animal food, CTC is highly susceptible to rapid degraded, even and the amount that adds is excessive, still will emit titer of antibodies to be lower than the very big risk of acceptable level, especially if long-time and/or high temperature is preserved this food, this risk is bigger.
Katz and Fassbender studied and described the degraded of CTC in aqueous medium (Journal of theA.O.A.C., 50, (1967), 821-827), they have determined that the CTC epimerism turns to the main path of epimerization-CTC.Known this epimer is toxic to many animals, and this fact makes people more wish to find to make CTC stable method in food.Past has proposed this problem, for example in United States Patent (USP) 3019109.This patent awareness is to the CTC problem of loss of tiring, and the drying that proposes calcium hydroxide and CTC are added to collection smashs to pieces in the solid, then carries out the pelleting step.Thereby active component just is added to before pelleting in the food pill composition.
In our previous PCT application WO96/22028, described with pelleting before add the relevant problem of medicament.Particularly, unless use special-purpose factory to produce the specific product that has added medicine (this usually is unpractical economically), the adding medicine food of each batch tends to use and is commonly used to produce not that the machine of the food of adding medicine prepares.Therefore, if avoid cross pollution, need carry out conscientious cleaning after each batch process is finished, Hua Fei extra time and effort thus reduced efficient and increased running cost.
In WO96/22028, we disclose a kind of with medicament with bonding gel carrier coating, after finishing the pelleting step, this medicament is coated on the food pill, thereby has avoided the method for the problems referred to above.We have now found that this method is particularly useful to the way that CTC is coated to the animal food pill, because it has greatly overcome the instability problem of aforementioned CTC, and the problem before the pelleting of having avoided simultaneously relating in the method for United States Patent (USP) 3019109.The research of beginning concentrates on the use of the non-aqueous gel self that contains CTC, wishes that only getting rid of water just is enough to prevent epimerization.But, though that the CTC content of this non-aqueous gel kept in 18 months time is stable, in case just degraded fast of CTC when being coated onto gel on the pill; This shows residual water in the pill.Therefore, attempt to make CTC to keep stable in gel, discovery can reach this purpose by adding bivalent metal ion.Useful especially is the salt basic salt especially of II family element such as calcium and magnesium, as hydroxide, oxide and carbonate.Discovery contains the non-aqueous gel of viscosity of CTC and bivalent metal ion by use, can obtain the dressing food pill that CTC is evenly distributed in this food pill batch of material and the speed of epimerization is significantly delayed.
Therefore, one aspect of the present invention provides a kind of medicament is added to method in the animal food, and this method comprises uses the gel of compound that contains tetracycline medication (or its pharmaceutical salts or derivative) and contain bivalent metal ion with the step of the pill dressing of above-mentioned food.Preferably, this gel is non-aqueous, and this tetracycline medication is an aureomycin.
The divalent ion that has shown this alkaline earth (II family) metal is effectively in the methods of the invention, especially calcium and magnesium.The source of ion is unimportant, though and usually use this ion easily with the form of the salt of ion far and away, also can use the form of complex.Therefore, term " compound " is understood to include complex in this article.
The present invention also provides the final food pill by the said method dressing.After having applied this gel dressing, suspension media can be absorbed into and reach big or lesser extent in the pill, pill is produced the useful effect of dry a little and sclerosis.Depend on the transmission characteristic accurately of pill composition, the residual component of gel (being CTC, bivalent metal ion and gelling agent) tends to be retained in or near the surface of this pill.Therefore, this final pill and those just add CTC before carrying out the pelleting step pill (as United States Patent (USP) 3019109) is differentiable physically, thereby the present invention provides a kind of animal food of pill shape on the other hand, and the single pill of described food has the top layer that contains tetracycline medication (or its pharmaceutical salts or derivative), contains the compound and the gelling agent of bivalent metal ion.
Another aspect of the invention is provided for the composition with pill shape animal food dressing, and said composition contains suspension media, gelling agent, tetracycline medication (or its pharmaceutical salts or derivative) and contains the compound of bivalent metal ion.
Gel packaging technique by among the WO96/22028 that uses our earlier application can obtain all advantages described in this application.The most important thing is that this technology provides the reliable method in the food pill that a kind of CTC that accurately and equably will determine dosage is added to known quantity.In addition, because the character of gel, the container that mixes usefulness does not usually stay CTC basically and pollutes after use.
In this specification, term " gel " refers to any sticking viscous suspension, and term " gelling agent " refers to any thickener that can produce this suspension.Gel is preferably mobile low and have the high viscosity solution or the suspension of good adhesiveness.Particularly preferably be thixotropic gel.The example of operable suitable gelling agent is modified cellulosic polymer, synthetic polymer, natural polysaccharide, clay, protein and colloidal silica, but also can use other gelling agent.Can produce this suspension media by any suitable non-aqueous liquid, crude vegetal is preferable as soybean oil.
Consistent with expection, stablizing effect increases along with the increase of divalent ion concentration.But in the experiment of using calcium hydroxide, when the concentration of calcium hydroxide during greater than 15%w/w, we have run into the problem of control gel viscosity aspect, consequently are difficult to handle and the suction gel.The effective range of calcium hydroxide concentration is 1-15%w/w, 5-10%w/w the best.
Use the experiment of calcium hydroxide as can be seen from us, pellet sizes may produce significantly influence to the degree of CTC stabilisation, and the pill that separates tricklelyer is better significantly.
We have also found can improve the static stabilization of CTC in the gel by adding a spot of antioxidant.Use Yoshinox BHT (BHT) to experimentize.To reach at 0.02% o'clock be significant to the concentration at antioxidant of obviously delaying of the formation of epimerization-CTC, and the remarkable increase that stability has when higher concentration is just much smaller.Owing to usually 0.02% BHT is recommended as the Cmax of BHT, is optimum amount so get this amount.Also can use other oil-soluble inhibitor (as ascorbyl palmitate), preferable maximum recommended concentration with them is used.
Though we mention aureomycin in entire description, the similar substance between various tetracycline medications on structure and chemical property means that the inventive method can be used for all these compounds.Therefore, should not think that to quoting as proof of CTC be the restriction of the present invention being used the scope of other special compound.
The present invention only adopts the mode of embodiment to be described in more detail below in conjunction with following each experimental test.
In preparation process, we seek to determine CTC at non-aqueous gel, comprise bulk gels itself and apply the stability of the CTC in the gel of animal food pill.Therefore, our preparation contains the gel of 10%CTC, 5% silica, 0.01%BHT and soybean oil (complementing to 100%).The reversed-phase HPLC method of use standard is measured the CTC content in 18 months inner gels, found that this content obviously descends.But, when will this identical gel being coated on the animal food pill, epimerization have fast taken place.Use the pill that obtains from BOCM Pauls to test in environment temperature (about 20 ℃), will be in the data rows table 1 below that isomers forms at one month time interpolation:
Table 1
The formation of epimer in the pill of unsettled gel dressing
Which day after on-test
Epimerization-CTC percentage
1 4.9
12 31.4
17 33.2
31 43.3
When off-test, the amount of epimerization-CTC is near equilibrium concentration.
Find that the speed of degraded depends critically upon the content of moisture in the pill.The dissimilar food pill that uses two kinds of water contents to differ greatly carries out parallel laboratory test, has determined above-mentioned discovery, and wherein, employed pill is that water content is that 8.03% Rowetts pill and water content are 13.63% BOCM pill.Gel contains 10%CTC, 4% silica, 0.01%BHT and soybean oil (complementing to 100%), and test is carried out under environment temperature (about 20 ℃).The results are shown in the following table 2:
Table 2
The moisture dependence that epimerization-CTC forms
Which day epimerization after beginning to test-CTC percentage water content %
Rowetts：
1 3.6 8.03
9 5.3 8.03
13 5.0 8.03
BOCM：
3 2.9 13.63
9 15.3 13.63
12 17.4 13.63
The formation speed of also finding epimerization-CTC is temperature dependent; as from following table 3 as can be seen, in the table data be to use contain 10%CTC, 5% silica and 0.01%BHT in soybean oil gel and obtain from the pill that BOCM Pauls obtains:
Table 3
The temperature dependency that epimerization-CTC forms
CTC after 24 hours
The beginning time difference is to isomery
Difference after 24 hours to
Temperature (℃)
The beginning concentration of CTC (ppm w/w)
Concentration (ppm w/w)
Change-CTC%
Isomerization-CTC%
5 354.98 328.60 1.47 3.4
25 354.98 265.48 1.47 19.3
40 354.98 194.09 1.47 40.0
Tested the static stabilization of calcium hydroxide at various variable concentrations.Prepare 3 parts of gels in soybean oil that contain 10%CTC and 6% silica, difference is their Ca (OH)
2Concentration difference (be respectively 1%, 2% and 3%w/w), Ca (OH)
2Provide by BDH.In addition, prepare the 4th part of gel in soybean oil that contains 10%CTC, 5% silica and 0.01%BHT.To the pill that obtains from BOCM Pauls, 25 ℃ store 8 days then with each part gel dressing.The amount of the epimer that exists in the sample when experiment finishes is listed in the following table 4:
Table 4
Ca (OH)
2The influence that concentration forms epimerization-CTC
Calcium hydroxide content (%w/w)
The amount of epimerization-CTC (%w/w)
0 28.6
1 16.9
2 11.8
5 8.6
The gel that use contains the calcium hydroxide that obtains from BDH of 10%w/w carries out other comparative test.In this test, the concentration that epimer after 5 days is tested in discovery is to be 19.5% after 10.7%, 11 day.
Use is carried out the test of relevant calcium hydroxide from different suppliers' acquisitions and the remarkable different sample of pellet sizes.Ellis﹠amp; The average grain diameter of Everard product is greatly greater than the particle diameter of BDH product.Prepare two parts of same gels in soybean oil that contain 10%CTC, 5% silica and 0.01%BHT, difference only is that a copy of it adds the Ellis﹠amp of 5%w/w; The Ca of Everard (OH)
2, another part then adds the Ca (OH) of the BDH of 5%w/w
2Then this gel is coated to from the pill of BOCM Pauls acquisition, measures the speed of epimerization after 3 days and 7 days, in the epimer percentage that exists.The results are shown in the following table 5:
Table 5
Ca (OH)
2Pellet sizes is to the influence of CTC stability
Ca (OH)
2The source
Epimerization-CTC% after 3 days Epimerization-CTC% after 7 days
Ellis&Everard 5.0 17.9
BDH 4.9 11.4
Use 4 parts of identical Croxton﹠amp that contain 10%w/w; The additional stabilizing influence that the antioxidant that the gel research in soybean oil of the calcium hydroxide that Garry provides, 10%CTC and 6% silica adds produces, difference only are the oxidation preventive content (be respectively 0,0.02%, 0.04% and 0.06% BHT) of 4 parts of gels.To test in environment temperature (about 20 ℃) from the pill dressing of BOCM Pauls acquisition with gel.After 6 days and 15 days, measure the speed of epimerization, in the amount of epimerization-CTC of existing in the sample.The results are shown in the following table 6:
Table 6
The additional static stabilization of antioxidant
Antioxidant (BHT, %w/w)
Epimerization-CTC% after 6 days
Epimerization-CTC% after 15 days
0 19.3 31.4
0.02 8.7 20.4
0.04 8.2 21.9
0.06 8.1 14.2
Be the example of preparation gel of the present invention below, with gel with food pill (BOCM Pauls) dressing, and in the formation of test epimerization-CTC down of long-time internal environment temperature (about 20 ℃):
Embodiment 1: calcium hydroxide
Be prepared as follows gel:
wt％
Aureomycin 10%
Calcium hydroxide 10%
Silica (Aerosil 200) 5.0%
BHT 0.01％
Soybean oil complements to 100%
Following table 7 has been listed the amount of the epimerization-CTC that records in process of the test:
Table 7
The test result of embodiment 1
Epimerization-the CTC% which day after beginning to test exists
14 2.8
22 11.00
30 17.08
78 22.29
Embodiment 2: magnesium hydroxide
Under two different storage temperatures (25 ℃ and 40 ℃), use the Mg (OH) that contains 5%w/w
2Gel with BOCM Pau; The pill dressing that s provides carries out parallel test, measures the content of CTC when beginning to test and when the 4th day and the 5th day.The results are shown in the following table 8:
Table 8
The test result of embodiment 2
Fate after beginning to test
CTC content (μ gg
-1
)
Epimerization-CTC%
During beginning 545.199 3.6
25 ℃ of preservations
4 498.628 8.8
5 481.890 16.9
40 ℃ of preservations
4 259.691 30.7
5 208.345 29.8
Claims (10)
1. one kind is added to method in the animal food with medicament, and it comprises with the gel of compound that contains aureomycin and contain bivalent metal ion calcium ion or magnesium ion the pill dressing of described food.
2. the method for claim 1 is characterized in that, described gel is non-aqueous.
3. the method for claim 1 is characterized in that, described compound is a calcium hydroxide.
4. method as claimed in claim 3 is characterized in that the concentration range of described calcium hydroxide is 1-15%w/w.
5. method as claimed in claim 4 is characterized in that the concentration range of described calcium hydroxide is 5-10%w/w.
6. as each described method among the claim 1-5 of front, it is characterized in that described gel also contains antioxidant.
7. method as claimed in claim 6 is characterized in that described antioxidant is a Yoshinox BHT.
8. method as claimed in claim 7 is characterized in that the concentration of described Yoshinox BHT mostly is 0.02%w/w most.
9. the animal food of a pill shape, its single pill has the top layer of containing aureomycin, containing the compound and the gelling agent of bivalent metal ion calcium ion or magnesium ion.
10. composition that is used for graininess animal food dressing, the compound that said composition contains suspension media, gelling agent, aureomycin and contains bivalent metal ion calcium ion or magnesium ion.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9928343.4A GB9928343D0 (en) | 1999-11-30 | 1999-11-30 | Addition of tetracyclines to animal foodstuffs |
| GB9928343.4 | 1999-11-30 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1402616A CN1402616A (en) | 2003-03-12 |
| CN1219449C true CN1219449C (en) | 2005-09-21 |
Family
ID=10865472
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB008163235A Expired - Fee Related CN1219449C (en) | 1999-11-30 | 2000-11-29 | Addition of tetracyclines to animal foodstuffs |
Country Status (6)
| Country | Link |
|---|---|
| CN (1) | CN1219449C (en) |
| AU (1) | AU784626B2 (en) |
| BR (1) | BR0015956A (en) |
| GB (1) | GB9928343D0 (en) |
| MX (1) | MXPA02005218A (en) |
| WO (1) | WO2001039608A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106011212A (en) * | 2016-06-03 | 2016-10-12 | 浦城正大生化有限公司 | Extraction process of chlortetracycline premixed agent |
| CN105997894B (en) * | 2016-07-04 | 2018-10-16 | 广州市义和化工有限公司 | Veterinary chlortetracycline premix and preparation method thereof |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3019109A (en) * | 1960-05-10 | 1962-01-30 | American Cyanamid Co | Stabilization of antibiotics in feeds and feed supplements |
| US3157512A (en) * | 1960-06-22 | 1964-11-17 | American Cyanamid Co | Stabilization of animal and poultry feeds containing antibiotics |
| SE8103843L (en) * | 1981-06-18 | 1982-12-19 | Astra Laekemedel Ab | PHARMACEUTICAL MIXTURE |
| GB9413873D0 (en) * | 1994-07-09 | 1994-08-31 | Norbrook Lab Ltd | Long-acting oxytetracycline composition |
| GB9500863D0 (en) * | 1995-01-17 | 1995-03-08 | Grampian Pharm Ltd | Medicated animal foodstuffs |
| US6210710B1 (en) * | 1997-04-28 | 2001-04-03 | Hercules Incorporated | Sustained release polymer blend for pharmaceutical applications |
-
1999
- 1999-11-30 GB GBGB9928343.4A patent/GB9928343D0/en not_active Ceased
-
2000
- 2000-11-29 CN CNB008163235A patent/CN1219449C/en not_active Expired - Fee Related
- 2000-11-29 MX MXPA02005218A patent/MXPA02005218A/en active IP Right Grant
- 2000-11-29 BR BR0015956-5A patent/BR0015956A/en not_active IP Right Cessation
- 2000-11-29 AU AU17167/01A patent/AU784626B2/en not_active Ceased
- 2000-11-29 WO PCT/GB2000/004543 patent/WO2001039608A1/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| AU1716701A (en) | 2001-06-12 |
| MXPA02005218A (en) | 2004-08-23 |
| GB9928343D0 (en) | 2000-01-26 |
| BR0015956A (en) | 2002-08-06 |
| WO2001039608A1 (en) | 2001-06-07 |
| AU784626B2 (en) | 2006-05-18 |
| CN1402616A (en) | 2003-03-12 |
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