CN105769762A - Ampicillin suspension injection and preparation method thereof - Google Patents
Ampicillin suspension injection and preparation method thereof Download PDFInfo
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- CN105769762A CN105769762A CN201610303791.4A CN201610303791A CN105769762A CN 105769762 A CN105769762 A CN 105769762A CN 201610303791 A CN201610303791 A CN 201610303791A CN 105769762 A CN105769762 A CN 105769762A
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- ampicillin
- injection
- oil
- suspension
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- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 title claims abstract description 72
- 229960000723 ampicillin Drugs 0.000 title claims abstract description 71
- 238000002347 injection Methods 0.000 title claims abstract description 62
- 239000007924 injection Substances 0.000 title claims abstract description 62
- 239000000725 suspension Substances 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 9
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 9
- 239000000375 suspending agent Substances 0.000 claims abstract description 9
- 239000000080 wetting agent Substances 0.000 claims abstract description 9
- 239000003921 oil Substances 0.000 claims description 21
- 235000019198 oils Nutrition 0.000 claims description 21
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- 239000007788 liquid Substances 0.000 claims description 14
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 239000000463 material Substances 0.000 claims description 11
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 claims description 8
- 235000006708 antioxidants Nutrition 0.000 claims description 8
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 8
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 8
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 8
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical group CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 6
- 229930003427 Vitamin E Natural products 0.000 claims description 6
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 claims description 6
- 239000004359 castor oil Substances 0.000 claims description 6
- 235000019438 castor oil Nutrition 0.000 claims description 6
- 239000000084 colloidal system Substances 0.000 claims description 6
- 238000011049 filling Methods 0.000 claims description 6
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 6
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 6
- 238000000227 grinding Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 238000007789 sealing Methods 0.000 claims description 6
- 235000010413 sodium alginate Nutrition 0.000 claims description 6
- 239000000661 sodium alginate Substances 0.000 claims description 6
- 229940005550 sodium alginate Drugs 0.000 claims description 6
- 239000001509 sodium citrate Substances 0.000 claims description 6
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 6
- 235000019165 vitamin E Nutrition 0.000 claims description 6
- 229940046009 vitamin E Drugs 0.000 claims description 6
- 239000011709 vitamin E Substances 0.000 claims description 6
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- 229920003081 Povidone K 30 Polymers 0.000 claims description 4
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical group CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 claims description 4
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical group CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 4
- 229940093471 ethyl oleate Drugs 0.000 claims description 4
- -1 flocculant Substances 0.000 claims description 3
- LOEIRDBRYBHAJB-UHFFFAOYSA-N 4,5,6,7-tetrabromo-1h-benzimidazole Chemical compound BrC1=C(Br)C(Br)=C2NC=NC2=C1Br LOEIRDBRYBHAJB-UHFFFAOYSA-N 0.000 claims description 2
- 239000008173 hydrogenated soybean oil Substances 0.000 claims description 2
- 150000002989 phenols Chemical class 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000008394 flocculating agent Substances 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 40
- 239000000047 product Substances 0.000 description 14
- 238000000034 method Methods 0.000 description 11
- 238000005516 engineering process Methods 0.000 description 10
- 239000000843 powder Substances 0.000 description 9
- KLOHDWPABZXLGI-YWUHCJSESA-M ampicillin sodium Chemical compound [Na+].C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C([O-])=O)(C)C)=CC=CC=C1 KLOHDWPABZXLGI-YWUHCJSESA-M 0.000 description 8
- 229960001931 ampicillin sodium Drugs 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 230000001133 acceleration Effects 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 238000004062 sedimentation Methods 0.000 description 5
- 235000010469 Glycine max Nutrition 0.000 description 4
- 244000068988 Glycine max Species 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000010255 intramuscular injection Methods 0.000 description 4
- 239000007927 intramuscular injection Substances 0.000 description 4
- 238000012552 review Methods 0.000 description 4
- 239000000273 veterinary drug Substances 0.000 description 4
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010022678 Intestinal infections Diseases 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000282849 Ruminantia Species 0.000 description 1
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 description 1
- 241001312524 Streptococcus viridans Species 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- IZNMWVDUFGUSMX-UHFFFAOYSA-N acetic acid;acetonitrile;methanol Chemical compound OC.CC#N.CC(O)=O IZNMWVDUFGUSMX-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 235000019636 bitter flavor Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960003026 cloxacillin sodium Drugs 0.000 description 1
- SCLZRKVZRBKZCR-SLINCCQESA-M cloxacillin sodium Chemical compound [Na+].N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C([O-])=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl SCLZRKVZRBKZCR-SLINCCQESA-M 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 206010014665 endocarditis Diseases 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000003736 gastrointestinal content Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
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
- A61K9/10—Dispersions; Emulsions
-
- 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
-
- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dispersion Chemistry (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an ampicillin suspension injection and a preparation method thereof. The 100ml of injection is prepared from the following components: 0.5 to 10.0g of ampicillin, 0.1 to 5.0g of suspending agent, 0.05 to 0.5g of antioxidant, 1.0 to 3.0g of wetting agent, 0.2 to 2.0g of flocculating agent and the balance of oil for injection. A special veterinary preparation for veterinarians is provided by using the ampicillin suspension injection prepared by the preparation method disclosed by the invention; the preparation method of the ampicillin suspension injection has the advantages of simplicity, high stability, better effect and high bioavailability; the effective shelf life reaches two years or over two years. By using a modern production process and equipment, scale and industrial production is facilitated.
Description
Technical field
The invention belongs to veterinary drug pharmaceutical technology field, be specifically related to a kind of ampicillin suspension injection and preparation method thereof.
Background technology
Ampicillin (English name: AmpiciLLin), another name: ampicillin, Ampicillin.This product is white crystalline powder；Mildly bitter flavor.This product is slightly soluble in water, insoluble in chloroform, ethanol, ether or expressed oi；Dilute acid soln or dilute alkaline soln dissolve.For semisynthetic penbritin, its free acid is containing 3 molecular crystalline water.
To gram-negative bacteria, as Bacillus typhi, escherichia coli etc. effectively but are easily generated drug resistance.Gram positive bacteria effect is similar to benzylpenicillin, viridans streptococci and enterococcal effect is more excellent, the effect of other bacterium is poor.The S. aureus L-forms of penicillin resistant G is invalid.Urinary system caused by sensitive organism, respiratory system, biliary tract, intestinal infection and meningitis, endocarditis etc..
At present, on China veterinary drug market, the veterinary drug preparation that raw material is made based on ampicillin has: the products such as ampicillin soluble powder, ampicillin soluble powder of sodium, Ampicillin Sodium For Injection, Ampicillin Sodium For Injection cloxacillin sodium, and corresponding veterinary medical quality standard, on people's medicine, preparation also has: ampicillin sheet, ampicillin granule, Ampicillin Capsule, ampicillin dry suspension, has corresponding medicine national quality quality.And for the research of ampicillin suspension injection, it does not have corresponding report and production.
When ampicillin is taken orally, nonruminant can absorb 30%-55%, and gastrointestinal content can reduce bioavailability, and ruminant absorbs worse, and the bioavailability that sheep is taken orally is only 2.1%.Intramuscular injection good absorbing, bioavailability is more than 80%.Can be widely distributed to various tissues after absorption, reach therapeutic effect.
Due to ampicillin slightly soluble in water, running into acid, alkali or oxidant etc. and namely lost efficacy rapidly, aqueous solution is placed in room temperature and was easily lost efficacy, and its aqueous solution is unstable, when not easily preparing into aqueous injection.Therefore, do not see corresponding patent and product for ampicillin suspension injection, not yet issue quality standard.
Summary of the invention
During for overcoming ampicillin as oral formulations, absorbance is relatively low, during as aqueous injection, aqueous stability is poor, the technical problem to be solved in the present invention is to provide the formula of a kind of ampicillin suspension injection for animals, the preparation method that a kind of veterinary drug ampicillin suspension injection is provided simultaneously, its preparation method is simple, stability is strong, effect is better, bioavailability is high, is suitable for poultry and uses.
For achieving the above object, the present invention can take following technical proposals:
A kind of ampicillin suspension injection of the present invention and preparation method, it is characterized by containing principal agent ampicillin, suspending agent, wetting agent, flocculant, antioxidant one-tenth be grouped into.
Described a kind of ampicillin suspension injection, this 100mL injection includes following component ampicillin 0.5～10.0g, suspending agent 0.1～5.0g, antioxidant 0.05～0.5g, wetting agent 1.0～3.0g, flocculant 0.2～2.0g, and surplus is oil for injection.
Described antioxidant is vitamin E or 2,6-di-tert-butyl-4-methy phenols (BHT).
Described wetting agent is Arlacel-60 or Arlacel-80.
Described suspending agent is one or both materials composition of sodium alginate, polyvinylpyrrolidone K17, PVP K30, aluminium stearate.
Described flocculant is citric acid or sodium citrate.
Described oil for injection is one or both materials composition of ethyl oleate, 10# white oil, oil with hydrogenated soybean and castor oil hydrogenated.
Present invention simultaneously provides the preparation technology of a kind of above-mentioned ampicillin suspension injection, its step is as follows:
The first step: take oil for injection and heat to 115～125 DEG C, be incubated 1～2 hour, add suspending agent, stirring and dissolving, cool to less than 50 DEG C, standby；
Second step: by the material of the first step as, in colloid mills, adding ampicillin, with the speed of 4000r/min, high speed shear 30min, make suspension, standby；
3rd step: by second step liquid, is sequentially added into antioxidant, flocculant, wetting agent, stirring while adding, until completely uniform, then continuously grinding 10min, standby；
4th step: the liquid after the 3rd step being ground, as in high pressure homogenizer, with pressure 50-55 MPa, carries out high pressure homogenize, then, and filling and sealing,.
A kind of ampicillin provided by the invention suspension injection and preparation method thereof, it has the advantages of: employ existing new equipment, new technology, improves existing traditional processing technology, makes production process more efficiently, fast；Production efficiency improves, and energy consumption reduces；Improve the dosage form of ampicillin, add the novel form of the ampicillin suspension injection of animal specific；Safety is high, good effect, and during intramuscular injection, zest is little；Stability is relatively strong, and in storage period, drug effect is not easily lost.
Detailed description of the invention
For making the present invention easier to understand, below in conjunction with specific embodiment, the present invention is expanded on further.Should be understood that these embodiments are merely to illustrate the present invention rather than restriction the scope of the present invention, NM specific experiment method in the following example, generally conventionally experimental technique carries out.
Embodiment 11% (g/mL) ampicillin suspension injection and preparation method thereof
Ampicillin 1g, vitamin E 0.05g, polyvinylpyrrolidone K170.25g, sodium alginate 0.25g, sodium citrate 0.5g, Arlacel-80 1g, oil with hydrogenated soybean 40g, 10# white oil are added to 100mL.
Preparation technology:
The first step: take oil with hydrogenated soybean and 10# white oil, after mixing, heating, to 115～125 DEG C, is incubated 1～2 hour, adds polyvinylpyrrolidone K17, sodium alginate, stirring and dissolving, cools to less than 50 DEG C, standby；
Second step: by the material of the first step as, in colloid mills, adding ampicillin, with the speed of 4000r/min, high speed shear 30min, make suspension, standby；
3rd step: by second step liquid, is sequentially added into vitamin E, sodium citrate, Arlacel-80, stirring while adding, until completely uniform, then continuously grinding 10min, standby；
4th step: the liquid after the 3rd step is ground, as, in high pressure homogenizer, with pressure 50 MPas, carrying out high pressure homogenize, then, filling and sealing,.
Embodiment 22% (g/mL) ampicillin suspension injection and preparation method thereof
Ampicillin 2g, BHT0.1g, PVP K30 0.4g, aluminium stearate 0.4g, citric acid 0.8g, Arlacel-80 1.5g, 10# white oil 40g, castor oil hydrogenated are added to 100mL.
Preparation technology:
The first step: take 10# white oil and castor oil hydrogenated, after mixing, heating, to 115～125 DEG C, is incubated 1～2 hour, adds PVP K30, aluminium stearate, stirring and dissolving, cools to less than 50 DEG C, standby；
Second step: by the material of the first step as, in colloid mills, adding ampicillin, with the speed of 4000r/min, high speed shear 30min, make suspension, standby；
3rd step: by second step liquid, is sequentially added into BHT, citric acid, Arlacel-80, stirring while adding, until completely uniform, then continuously grinding 10min, standby；
4th step: the liquid after the 3rd step is ground, as, in high pressure homogenizer, with pressure 50 MPas, carrying out high pressure homogenize, then, filling and sealing,.
Embodiment 35% (g/mL) ampicillin suspension injection and preparation method thereof
Ampicillin 5g, vitamin E 0.2g, polyvinylpyrrolidone K171g, sodium alginate 0.5g, sodium citrate 1g, Arlacel-80 1g, oil with hydrogenated soybean 50g, 10# white oil are added to 100mL.
Preparation technology:
The first step: take oil with hydrogenated soybean and 10# white oil, after mixing, heating, to 115～125 DEG C, is incubated 1～2 hour, adds polyvinylpyrrolidone K17, sodium alginate, stirring and dissolving, cools to less than 50 DEG C, standby；
Second step: by the material of the first step as, in colloid mills, adding ampicillin, with the speed of 4000r/min, high speed shear 30min, make suspension, standby；
3rd step: by second step liquid, is sequentially added into vitamin E, sodium citrate, Arlacel-80, stirring while adding, until completely uniform, then continuously grinding 10min, standby；
4th step: the liquid after the 3rd step is ground, as, in high pressure homogenizer, with pressure 50 MPas, carrying out high pressure homogenize, then, filling and sealing,.
Embodiment 410% (g/mL) ampicillin suspension injection and preparation method thereof
Ampicillin 10g, BHT1g, polyvinylpyrrolidone K172g, aluminium stearate 1g, citric acid 1g, Arlacel-60 2g, ethyl oleate 40g, castor oil hydrogenated are added to 100mL.
Preparation technology:
The first step: take ethyl oleate and castor oil hydrogenated, after mixing, heating, to 115～125 DEG C, is incubated 1～2 hour, adds polyvinylpyrrolidone K17, aluminium stearate, stirring and dissolving, cools to less than 50 DEG C, standby；
Second step: by the material of the first step as, in colloid mills, adding ampicillin, with the speed of 4000r/min, high speed shear 30min, make suspension, standby；
3rd step: by second step liquid, is sequentially added into BHT, citric acid, Arlacel-60, stirring while adding, until completely uniform, then continuously grinding 10min, standby；
4th step: the liquid after the 3rd step is ground, as, in high pressure homogenizer, with pressure 50 MPas, carrying out high pressure homogenize, then, filling and sealing,.
Each embodiment is all further illustrating the present invention above, in practice process, it is not limited solely to above opereating specification, based on each composition shown in the content of weight of the present invention, a kind of ampicillin suspension injection of preparation and preparation method thereof, all should calculate as the scope of the invention.
Experiment and research
One. adopt the present invention to prepare the stability test of ampicillin suspension injection
1. instrument and reagent
1.1 instruments
YJQ-2 water circulation constant temperature formula heater (Shanghai analytical tool factory), BCD-182W refrigerator (Hua Ling refrigerator factory), P3000 type high performance liquid chromatograph (Beijing innovation Tong Heng precision instrument company limited), RC-1 type dissolution tester (Shanghai Lu Si precision instrument company limited), water isolation type electro-heating standing-temperature cultivator (Tianjin precision instrument factory).
1.2 reagents
Ampicillin suspension injection (according to embodiment 1, embodiment 2, embodiment 3 method prepare)
2. test method and result
2.1 detection methods (described " annex " means one annex of " Chinese veterinary pharmacopoeia " version in 2010)
2.1.1 character this product is the suspension of subparticle, and after standing, subparticle sinks, uniformly milky suspension after jolting.
2.1.2 dispersibility takes this product 1 bottle, and firmly jolting 30 seconds, is transferred in glass container by test sample, must not observe caking or precipitate
2.1.3 sedimentation takes this product 1 bottle, and firmly jolting 30 seconds, takes test sample 10mL and put (internal diameter 1.0-1.5cm) in scale test tube, must not precipitate in 10 minutes.
2.1.4 granularity takes this product, shakes up, and measures according to granularity and particle size distribution method (annex 98 pages, the first method), must not less than 90% containing 15 μm of particles below, and 20 μm of particles below less than 95%, must not must not have the granule of more than 50 μm.
2.1.5 assay
Ampicillin measures according to high performance liquid chromatography (annex 36 pages).
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler；Water-acetonitrile-1moL/L potassium dihydrogen phosphate-1moL/L acetum (909: 80: 10: 1) is mobile phase；Flow velocity is 1mL per minute；Column temperature 30 DEG C；Detection wavelength 254nm.Number of theoretical plate calculates by peak, ampicillin and is not less than 1000.
It is appropriate that algoscopy precision measures this product after shaking up, (1moL/L potassium dihydrogen phosphate 10mL and 1moL/L acetum 1mL is taken with diluent, it is diluted with water to 1000mL, shake up) dissolve and make in every 1mL the solution containing about ampicillin 1mg, precision measures 20 μ L, inject chromatograph of liquid, record chromatogram；Separately take ampicillin reference substance appropriate, be measured in the same method.And get final product with calculated by peak area by external standard method.
2.2 accelerated tests
2.2.1 temperature accelerated test
Homemade for difference lot number ampicillin suspension injection (ampoule is bottled) is placed on holding saturated nacl aqueous solution (temperature 40 ± 2 DEG C, relative humidity is 75 ± 5%) close drying device in, exsiccator is put in 40 DEG C of water isolation type electro-heating standing-temperature cultivators, places six months.Detect by injection stability high spot reviews project, result of the test following (see table 1, table 2, table 3).
Table 1 temperature accelerated test result (lot number: 20130301)
Table 2 temperature accelerated test result (lot number: 20130302)
Table 3 temperature accelerated test result (lot number: 20130303)
Showing from table 1, table 2, table 3 result: three batch samples, after the temperature accelerated test of 6 months, its character, dispersibility, sedimentation, granularity and content, all in acceptability limit, illustrate the stable in properties under temperature accelerated test of product.
2.3 humidity accelerated tests
Three batch samples are placed on and fill NaCL saturated solution (relative humidity 75 ± 1%, 25 DEG C) hermetic container in place 10 days, in the 5th day, 10 days separately sampled, by injection stability high spot reviews project, testing result following (see table 4, table 5, table 6):
Table 4 humidity accelerated test result (lot number: 20130301)
Table 5 humidity accelerated test result (lot number: 20130302)
Table 6 humidity accelerated test result (lot number: 20130303)
From table 4, table 5, table 6 result it can be seen that three batch samples, after the humidity accelerated test of 10 days, its character, dispersibility, sedimentation, granularity and content, all in acceptability limit, illustrate the stable in properties under humidity accelerated test of product.
2.4 acceleration by light tests
By three batch samples, being placed in the container that intensity of illumination is 4500 ± 500LX, in 5 days, sample was taken out in timing in 10 days, by injection stability high spot reviews project, testing result following (see table 7, table 8, table 9)
Table 7 acceleration by light result of the test (lot number: 20130301)
Table 8 acceleration by light result of the test (lot number: 20130302)
Table 9 acceleration by light result of the test (lot number: 20130303)
From table 7, table 8, table 9 result it can be seen that three batch samples, after the Illumination test of 10 days, the equal conformance with standard regulation of the dispersibility of its sample, sedimentation, granularity and content, but the character of injection deepens, the content of principal agent declines very fast, it sees that light is susceptible to oxidation, therefore this product needs shading to preserve.
Comprehensive above result of the test, ampicillin suspension injection is under temperature, humidity, acceleration by light test, and the stability of injection is relatively strong, and by the standard of Xi Nianzhu, the injection of this test is in shading, airtight preservation.
2.5 keep sample test for a long time
According to the ampicillin suspension injection (ampoule is bottled) that above-mentioned example produces, it is placed on room temperature and keeps sample in room, place 24 months.And in 3 months, 6 months, 9 months, 18 months, 24 months, be sampled respectively, detect by stability high spot reviews project, result of the test following (see table 10, table 11, table 12).
Table 10 keeps sample result of the test (lot number: 20130301) for a long time
Table 11 keeps sample result of the test (lot number: 20130302) for a long time
Table 12 keeps sample result of the test (lot number: 20130303) for a long time
From table 10, table 11, table 12 result it can be seen that three samples, after the test that keeps sample for a long time, the equal conformance with standard of the character of its sample, dispersibility, sedimentation, granularity and content specifies, and all in acceptability limit.
Comprehensive above result of the test, ampicillin suspension injection is in accelerated test and keeps sample under test for a long time, and stability is relatively strong, meets the requirements, and by the stability test standard of Xi Nianzhu, this test products shelf-life at normal temperatures is more than 2 years.
Two. ampicillin suspension injection prepared by the employing present invention pharmacokinetics research in pig body
1. materials and methods
1.1 medicines
Ampicillin suspension injection: adopt the present invention to prepare.
Ampicillin Sodium For Injection (powder pin): lot number is 20150526, Chuzhou City Chun Mudongbao Science and Technology Ltd. produces.
Ampicillin reference substance: content is 85.7%, and lot number is 130410-200706, Nat'l Pharmaceutical & Biological Products Control Institute provide.
Ampicillin (raw material): content is 98.6%, lot number is 31015055162, and Zhuhai United Laboratories Ltd produces.
1.2 test solution methods
HPLC method.Mobile phase: glacial acetic acid-acetonitrile-methanol solution.
1.3 experimental animals
Health pig 12, body weight 25kg ± 4.0kg, purchased from pig farm, Zhenyang, Henan.
1.4 administration and blood specimen collections
12 pigs being randomly divided into 2 groups, uses ampicillin suspension injection for the 1st group, the 2nd group, with Ampicillin Sodium For Injection (powder pin), carries out intramuscular injection by 20mg/kg dosage respectively.
Primary blank blood sample is adopted before administration, after administration respectively at the 0.25th, 0.50,0.75,1.00,2.00,3.00,5.00,9.00,12.00,24.00,36.00,48.00,72.00,96.00,108.00,120.00h takes a blood sample 5mL from vena cava anterior, it is placed in the centrifuge tube containing heparin, mixing, 3000r/min is centrifuged 10min, separated plasma, carries out HPLC mensuration.
1.5 data process
Adopt " MCPKP " pharmacokinetics calculation procedure that data are processed.
Result of the test
Result shows: the 1st group of elimination half-life (t1/2 β) respectively 12.45h ± 5.18h and 1.96h ± 1.03h with the 2nd group；(tmax) respectively 2.15h ± 0.37h and 0.78h ± 0.35h during peak；Peak concentration (Cmax) respectively 19.40 μ g/mL ± 2.09 μ g/mL and 21.90 μ g/mL ± 2.32 μ g/mL；Area under curve (AUC) respectively 629.43 μ g/ (mL h) ± 31.82 μ g/ (mL h) and 210.32 μ g/ (mL h) ± 10.28 μ g/ (mL h)；Valid density is held time tcp (ther) respectively 21.90h ± 10.36h and 1.92h ± 1.06h, and in blood, minimum active drug concentration is 0.8 μ g/mL.
3 discuss
This result of the test shows: adopting ampicillin suspension injection prepared by the present invention with after 20mg/kg body weight intramuscular injection, the elimination half-life is 12.45h ± 5.18h, hence it is evident that be longer than Ampicillin Sodium For Injection (powder pin).
Pharmacokinetics is analyzed result and is shown: ampicillin suspension injection and the Ampicillin Sodium For Injection (powder pin) pharmacokinetics in pig body meet two-compartment model.When eliminating half-life, peak, peak concentration, valid density hold time and the parameter such as area under curve there were significant differences (P < 0.05).
Blood drug level testing result shows: the valid density of the ampicillin suspension injection of the present invention is held time for 12.45h ± 5.18h, and Ampicillin Sodium For Injection (powder pin) is only 1.96h ± 1.03h；The former is considerably longer than the latter.This illustrates that the ampicillin suspension injection of the present invention eliminates relatively slow than Ampicillin Sodium For Injection (powder pin), and the time maintaining blood drug level in vivo is long.
Claims (2)
1. an ampicillin suspension injection, it is characterised in that: by ampicillin, suspending agent, antioxidant, wetting agent, flocculant, oil for injection forms, and described antioxidant is vitamin E or 2,6-di-tert-butyl-4-methy phenols (BHT)；Described wetting agent is Arlacel-60 or Arlacel-80；Described suspending agent is one or both materials composition of sodium alginate, polyvinylpyrrolidone K17, PVP K30, aluminium stearate；Described flocculant is citric acid or sodium citrate；Described oil for injection is one or both materials composition of ethyl oleate, 10# white oil, oil with hydrogenated soybean and castor oil hydrogenated.
Above-mentioned each component every 100mL injection includes following component: ampicillin 0.5～10.0g, suspending agent 0.1～5.0g, antioxidant 0.05～0.5g, wetting agent 1.0～3.0g, flocculant 0.2～2.0g, and surplus is oil for injection.
2. the preparation method of a kind of ampicillin according to claim 1 suspension injection, it comprises the steps:
The first step: take oil for injection and heat to 115～125 DEG C, be incubated 1～2 hour, add suspending agent, stirring and dissolving, cool to less than 50 DEG C, standby；
Second step: by the material of the first step as, in colloid mills, adding ampicillin, with the speed of 4000r/min, high speed shear 30min, make suspension, standby；
3rd step: by second step liquid, is sequentially added into antioxidant, flocculant, wetting agent, stirring while adding, until completely uniform, then continuously grinding 10min, standby；
4th step: the liquid after the 3rd step being ground, as in high pressure homogenizer, with pressure 50-55 MPa, carries out high pressure homogenize, then, and filling and sealing,.
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