EP1528926A1 - Novel pharmaceutical composition of ceftiofur - Google Patents
Novel pharmaceutical composition of ceftiofurInfo
- Publication number
- EP1528926A1 EP1528926A1 EP02762626A EP02762626A EP1528926A1 EP 1528926 A1 EP1528926 A1 EP 1528926A1 EP 02762626 A EP02762626 A EP 02762626A EP 02762626 A EP02762626 A EP 02762626A EP 1528926 A1 EP1528926 A1 EP 1528926A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- oil
- ceftiofur
- oily suspension
- suspension
- resuspendibility
- Prior art date
- 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.)
- Withdrawn
Links
- 229960005229 ceftiofur Drugs 0.000 title claims description 24
- ZBHXIWJRIFEVQY-IHMPYVIRSA-N ceftiofur Chemical group S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC(=O)C1=CC=CO1 ZBHXIWJRIFEVQY-IHMPYVIRSA-N 0.000 title claims description 24
- 239000008194 pharmaceutical composition Substances 0.000 title description 5
- 239000000725 suspension Substances 0.000 claims abstract description 46
- 239000003623 enhancer Substances 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 239000000080 wetting agent Substances 0.000 claims abstract description 10
- 239000002270 dispersing agent Substances 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims description 22
- 235000012343 cottonseed oil Nutrition 0.000 claims description 13
- 239000002385 cottonseed oil Substances 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 11
- 239000003921 oil Substances 0.000 claims description 10
- 235000019198 oils Nutrition 0.000 claims description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 9
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 8
- 239000000787 lecithin Substances 0.000 claims description 8
- 235000010445 lecithin Nutrition 0.000 claims description 8
- 229940067606 lecithin Drugs 0.000 claims description 8
- 229920002675 Polyoxyl Polymers 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 235000005687 corn oil Nutrition 0.000 claims description 4
- 239000002285 corn oil Substances 0.000 claims description 4
- -1 diglyceride Chemical compound 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 3
- 235000019482 Palm oil Nutrition 0.000 claims description 3
- 235000019486 Sunflower oil Nutrition 0.000 claims description 3
- 239000003240 coconut oil Substances 0.000 claims description 3
- 235000019864 coconut oil Nutrition 0.000 claims description 3
- 239000004006 olive oil Substances 0.000 claims description 3
- 235000008390 olive oil Nutrition 0.000 claims description 3
- 239000002540 palm oil Substances 0.000 claims description 3
- 239000008159 sesame oil Substances 0.000 claims description 3
- 235000011803 sesame oil Nutrition 0.000 claims description 3
- 235000012424 soybean oil Nutrition 0.000 claims description 3
- 239000003549 soybean oil Substances 0.000 claims description 3
- 239000002600 sunflower oil Substances 0.000 claims description 3
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 3
- 239000008158 vegetable oil Substances 0.000 claims description 3
- 238000009736 wetting Methods 0.000 claims description 3
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 claims description 2
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group 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 claims description 2
- 235000019485 Safflower oil Nutrition 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000000194 fatty acid Substances 0.000 claims description 2
- 229930195729 fatty acid Natural products 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000008172 hydrogenated vegetable oil Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 238000009516 primary packaging Methods 0.000 claims description 2
- 235000005713 safflower oil Nutrition 0.000 claims description 2
- 239000003813 safflower oil Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 239000001384 succinic acid Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 abstract description 13
- 229930186147 Cephalosporin Natural products 0.000 abstract description 3
- 230000003115 biocidal effect Effects 0.000 abstract description 3
- 229940124587 cephalosporin Drugs 0.000 abstract description 3
- 150000001780 cephalosporins Chemical class 0.000 abstract description 3
- 239000002245 particle Substances 0.000 description 11
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- KEQFDTJEEQKVLM-JUODUXDSSA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-(furan-2-carbonylsulfanylmethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;hydron;chloride Chemical compound Cl.S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC(=O)C1=CC=CO1 KEQFDTJEEQKVLM-JUODUXDSSA-N 0.000 description 7
- 229960001356 ceftiofur hydrochloride Drugs 0.000 description 7
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 6
- 239000001593 sorbitan monooleate Substances 0.000 description 6
- 235000011069 sorbitan monooleate Nutrition 0.000 description 6
- 229940035049 sorbitan monooleate Drugs 0.000 description 6
- 230000016615 flocculation Effects 0.000 description 5
- 238000005189 flocculation Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- 230000002776 aggregation Effects 0.000 description 4
- 238000013019 agitation Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000007971 pharmaceutical suspension Substances 0.000 description 4
- 238000004062 sedimentation Methods 0.000 description 4
- 241000283690 Bos taurus Species 0.000 description 3
- 241000282898 Sus scrofa Species 0.000 description 3
- 239000004359 castor oil Substances 0.000 description 3
- 235000019438 castor oil Nutrition 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 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 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 229920002690 Polyoxyl 40 HydrogenatedCastorOil Polymers 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000005054 agglomeration Methods 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000015271 coagulation Effects 0.000 description 2
- 238000005345 coagulation Methods 0.000 description 2
- 230000001351 cycling effect Effects 0.000 description 2
- 239000008394 flocculating agent Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000000828 canola oil Substances 0.000 description 1
- 235000019519 canola oil Nutrition 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000011200 topical administration Methods 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
-
- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
Definitions
- This invention relates to a n ⁇ vel pharmaceutical composition comprising cephalosporin antibiotic or its pharmaceutically acceptable salts.
- the invention relates to oily suspension of Ceftiofur or its pharmaceutically acceptable salts. More particularly the present invention provides oily suspension of Ceftiofur hydrochloride, which has improved properties, such as resuspendibility and chemical stability.
- Ceftiofur is a third generation Cephalosporin antibiotic, which is administered to cattle and swine for control of bacterial infections of the respiratory tract. It is used in veterinary medicine as both, the sodium salt and the hydrochloride salt. It is administered
- Ceftiofur is poorly absorbed a1 ter oral administration while rapidly absorbed after intramuscular adm ⁇ istratio .
- the Ceftiofur hydrochloride intramuscular injection is an oily suspension.
- a suspension is a particular class or type of dispersion system in which the internal or suspended phase is dispensed uniformly with mechanical agitation through out the external phase, called the suspending medium or vehicle.
- the internal phase consisting of a homogenous or heterogeneous distribution of solid particles having a specific range of sizes, these particles are maintained uniformly in time throughout the suspending vehicle with
- the three general classes of pharmaceutical suspensions are orally administered suspensions, externally applied suspensions (topical) and injectable (parenterals) suspensions (Ref: A Martin & P Bustamante, Coarse Dispersion in physical pharmacy 45 th edn Lea and Febiger, Philadelphia, 1993, PP 117 - 124).
- the Parenteral suspensions are desi ied foil-' intramuscular, intradermal, intralesional, intraarticular or subcutaneous administration.
- Common vehicles for parenteral suspensions include preserved sodium chloride solution or a parenterally acceptable vegetable oil.(Ref: J P Partnoff, E M Cohen i & M M Henlay, Development of Parenteral and Sterile ophthalmic suspensions, Bull.
- Flocculation refers to the formation of a loose aggregation of discrete particles held togetner in s network-like structure either by physical absorption of macromolecules, bridging during chemical interaction, or ⁇ when the longer range Nander Waals forces of attraction exceeds the shorter range force of repulsion.
- Coagulation or flocculation refers to the massing of particles in a liquid state alone and sometimes in the form of a fluid gel structure.
- the aggregates tend to break up easily under the application of a small amount of sheaif stress such as gentle agitation of a bottle or vials or by the flow through a small orifice (hypodermic needle and for syringe)
- the table flocculation can be, produced if required by employing aseptic techniques using vehicle' components that are safe for intramuscular injection.
- Ceftiofur HGJl a biocompatible oil (selected from canola oil, corn oil, cottonseed oil, olive oil, p'eanut oil, sesame oil, soybean oil, safflower oil, coconut oil, sunflower oil and palm oil) and water present in an amount between 0.25% and 20.20% of the composition as a flocculating agent in order to have better resuspendibility than the formulation having no water.
- a biocompatible oil selected from canola oil, corn oil, cottonseed oil, olive oil, p'eanut oil, sesame oil, soybean oil, safflower oil, coconut oil, sunflower oil and palm oil
- water present in an amount between 0.25% and 20.20% of the composition as a flocculating agent in order to have better resuspendibility than the formulation having no water.
- the main objective of the present invention is to develop a suspension of Ceftiofur or its' pharmaceutically acceptable salts which has high physico-chemical stability and easy to administer.
- Another objective of the present invention is to provide a physically stable suspension using resuspendibility enhancers and a chemically stable suspension by reducing the moisture content.
- the present invention relates to an oily suspension comprising ceftiofur or its pharmaceutically acceptable salts, at least a biocompatible oil, a wetting agent, a dispersing agent, a resuspendibility enhancer.
- the said composition comprises of 0.025% to 1.0% by weight of wetting ageni;, 0.05% > ,to 2.5% by weight of dispersing agent and 0.05%> to 10% by weight of a resuspendibility enhancer.
- the said composition comprises of 0.025% to 0.1% by weight of a
- step (i) heating a biocompatible oil to a temperature in the range of 40°C to 160°C, based on the dosage form, ii) adding a wetting agent, to step (i) liquid and allowing to cool with stirring, iii) adding a dispersing agent and a resuspendibility enhancer to step (ii) mixture with stirring, if required, iv) stirring the mixture at about 160°C up to 2 hrs, v) adding Ceftiofur or its pharmaceutically acceptable salt to step (iv) mixture
- step (v) mixture using a suitable homogenizer and vii) I filling in the primary packaging components.
- Figure 1 represents a graphical representation of sedimentation rate of various formulae using different flocculating agents.
- an oily suspension comprising ceftiofur or its pharmaceutically acceptable salts, at least a biocompatible oil, a wetting agent, a dispersing agent, a resuspendibility enhancer and optionally acceptable excipients.
- an injectable suspension which has improved physical stability using resuspendibility enhancers.
- an injectable s sp ⁇ nsion which has greater chemical stability by reducing the moisture content.
- the pharmaceutically acceptable salts of Ceft ⁇ fur are 'selected from sodium, hydrochloride or hydrobromide, preferably Ceftiofur hydr ⁇ chloridej.
- Ceftiofur or its pharmaceutically acceptable salt may be present in amount of 1% to 20% by weight of the suspension, preferably in amount of 1%> to 10%. Further, the Ceftiofur hydrochloride may be present in an amount of 10 mg to about 200mg/ml, preferably in an amount of 10 mg to about lOOmg/ml.
- the biocompatible oil used may be selected from the group consisting of monoglyceride, diglyceride, triglyceride medium
- the wetting and dispersing agents used in the suspension are selected from lecithin, fatty acid ester of sorbitan or glyceirol.
- the resuspendibility enhancer is selected from polyoxyl hydrogenated vegetable oil, polyoxyl vegetable oil, glycerol, propylene glycol, polyethylene glycols.
- Ceftiofur hydrochloride is used for oral, topical or parenteral administration.
- the oily suspension can be
- the oily suspension of the present invention has improved resuspendibility.
- the addition of the resuspendibility enhancers improves the particle interaction, which result in a "loDse" particle aggregation so when the suspension is shaken the particles can separate to some extent and a uniform dose can be obtained.
- Ceftiofur (as Ceftiofur HC1): 50g
- Lecithin 0.5 g Sorbitan monooleate: 0.5g Propylene glycol: 5 g Cottonseed oil q.s. to 1000ml 800ml of Cottonseed oil is heated to above 100 °C and lecithin is added and stirred well until dissolvjed. The oil containing the wetting agent is then cooled with continuous stirring. Sorbitan monooleate is added next with agitation. Next the required amount of propylene g col is addbd and mixed well with stirring. Sterile Ceftiofur Hydrochloride is addeld and rrjixed for 15jto 45 minutes. Volume is made up to 1000 ml by adding sufficient amount of cottonseed oil. The suspension is then homogenized using a suitable hompgenizer! It is then filled in vials, closed with a stopper, sealed and sterilized.
- Ceftiofur (as Ceftiofur HC1): 50g
- Lecithin 0.5 g Sorbitan monooleate: 0.5g Polyethylene Glycol- 400: 5 g Cottonseed oil q.s. to 1000ml
- Hydrochloride is added and mixed for 15 to 45 minutes. Volume is made up to 1000 ml addiijg sufficient amount of cottonseed oil. The suspension is then homogenized using a suitable homogenizer. It is then filled in vials, closed with a stopper, sealed and sterilized.
- Ceftiofur (as Ceftiofur HC1): 50g
- Lecithin 0.5 g
- Sorbitan monooleate 0.5g
- Ceftiofur (as Ceftiofur HC1): 50g Lecithin: 0.5 g Sorbitan monooleate: 0.5g Polyoxyl 40 hydrogenated castor oil: lg Cottonseed oil q.s. to 1000ml
- the stability of suspensions, and ultimately their shelf life is based on both chemical and physical stability.
- the chemical stability is assessed to insure that the product does not become subpotent during shelf life.
- the chemical stability of the current formilation has been studied extensively at different temperatures and different time periods. The results for example 3 are shown below:
- I Resuspendibility is a very important parameter that determines the dosage accuracy in the dispensed volume of the suspension during the entire shelf life of the product. If the resuspension is not adequate the initial doses shall be subpotent as some small amount of drug remains at the bottom of the container. The invention describes of such formulation where the resuspendibility is achieved effortlessly to get uniform dispersion. Freeze-Thaw Study
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Health & Medical Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
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Abstract
The present invention relates to a pharmaceutical oily suspension comprising cephalosporin antibiotic or its pharmaceutically acceptable salt, at least a biocompatible oil, a wetting agent, a dispersing agent and a resuspendibility enhancer, said suspension has improved properties, such as resuspendibility and chemical stability and process thereof.
Description
NOVEL PHARMACEUTICAL COMPOSITION OF CEFTIOFUR
TECHNICAL FIELD
1 This invention [relates to a n^vel pharmaceutical composition comprising cephalosporin antibiotic or its pharmaceutically acceptable salts. Particularly the invention relates to oily suspension of Ceftiofur or its pharmaceutically acceptable salts. More particularly the present invention provides oily suspension of Ceftiofur hydrochloride, which has improved properties, such as resuspendibility and chemical stability.
BACKGROUND ART
Ceftiofur is a third generation Cephalosporin antibiotic, which is administered to cattle and swine for control of bacterial infections of the respiratory tract. It is used in veterinary medicine as both, the sodium salt and the hydrochloride salt. It is administered
I, intramuscularly to cattle! and swine. It is also intended to be used as crystalline free acid for intramuscular and subcutaneous administration in cattle and swine. Ceftiofur is poorly absorbed a1 ter oral administration while rapidly absorbed after intramuscular admφιistratio . The Ceftiofur hydrochloride intramuscular injection is an oily suspension.
A suspension is a particular class or type of dispersion system in which the internal or suspended phase is dispensed uniformly with mechanical agitation through out the external phase, called the suspending medium or vehicle. The internal phase, consisting of a homogenous or heterogeneous distribution of solid particles having a specific range of sizes, these particles are maintained uniformly in time throughout the suspending vehicle with|the aid of a single, or a particular combination of suspending agents.
The three general classes of pharmaceutical suspensions are orally administered suspensions, externally applied suspensions (topical) and injectable (parenterals) suspensions (Ref: A Martin & P Bustamante, Coarse Dispersion in physical pharmacy 45th edn Lea and Febiger, Philadelphia, 1993, PP 117 - 124). The Parenteral suspensions are desi ied foil-' intramuscular, intradermal, intralesional, intraarticular or subcutaneous administration. Common vehicles for parenteral suspensions include preserved sodium chloride solution or a parenterally acceptable vegetable oil.(Ref: J P Partnoff, E M Cohen i & M M Henlay, Development of Parenteral and Sterile ophthalmic suspensions, Bull.
Parenter. Drug Assoc 31 : 136-143 (1977)).
The stability of suspensions is complicated by the fact that the physical stability of pharmaceutical suspensions and the factors affecting such stability are equally important to
chemical stability. This i's based on the fact that since a suspension exists in more than one state [(liquid and solid), there are different ways in which the system can undergo either chemical or physical change (Ref: T Higuchi, some physical chemical aspects of suspension formulation, J. Am. Pharm. Assoc. Sci Ed; 47: 657-660 (1958)).
I Haines & Martin, Hiestand and Econow & Coworkers (Ref : J. Pharm. Sci., 61; 268 - 272, (1972 and J. Pharm. Sci., 52; 757 - 762, 1031-1038, (1963)) and are generally credited with j establishing the structured particle concept or flocculated pharmaceutical suspension.
The following definitions will prove useful in differentiating the three closely related terms flocculation, agglomeration and coagulation.
Flocculation refers to the formation of a loose aggregation of discrete particles held togetner in s network-like structure either by physical absorption of macromolecules, bridging during chemical interaction, or^ when the longer range Nander Waals forces of attraction exceeds the shorter range force of repulsion.
In agglomeration, a large number of particles are closely bound together as aggregates either in a dry or liquid state.
Coagulation or flocculation refers to the massing of particles in a liquid state alone and sometimes in the form of a fluid gel structure.
! '
The main advantages of the stable flocculated systems are as follows:
1. The aggregates tend to break up easily under the application of a small amount of sheaif stress such as gentle agitation of a bottle or vials or by the flow through a small orifice (hypodermic needle and for syringe)
2. j In contrast to deflocculated systems, the stable flocculation will settle rapidly and may [be easily; resuspended even after standing for prolonged time period of storage.
3. The table flocculation can be, produced if required by employing aseptic techniques using vehicle' components that are safe for intramuscular injection.
There ' are several methods of producing flocculated pharmaceutical suspensions. The choice of method depends on the properties of the drug and the class of suspension desired.
The relevant prior art methods, which teach adaptation of diverse methods of preparation, are as follows.
US Patent No. 5,736,151 claims a pharmaceutical composition comprising
Ceftiofur HC1 & water. This patent claims a pharmaceutical composition comprising a
1 i
Ceftiofur HGJl, a biocompatible oil (selected from canola oil, corn oil, cottonseed oil, olive
oil, p'eanut oil, sesame oil, soybean oil, safflower oil, coconut oil, sunflower oil and palm oil) and water present in an amount between 0.25% and 20.20% of the composition as a flocculating agent in order to have better resuspendibility than the formulation having no water.
US Patent No. 4,902,683, discloses crystalline hydrochloride and hydrobromide
OBJECTIVE OF THE INVENTION
The main objective of the present invention is to develop a suspension of Ceftiofur or its' pharmaceutically acceptable salts which has high physico-chemical stability and easy to administer.'
Another objective of the present invention is to provide a physically stable suspension using resuspendibility enhancers and a chemically stable suspension by reducing the moisture content.
Still another objective of the present invention is to provide a suspension with adequate dis ersion of the particles in the vehicle.
Yet another objective of the present invention is to provide a suspension which does I not foηή caking of the dispersed particles in the sediment which is difficult to redisperse.
SUMMARY OF THE INVENTION
Accordingly, the present invention relates to an oily suspension comprising ceftiofur or its pharmaceutically acceptable salts, at least a biocompatible oil, a wetting agent, a dispersing agent, a resuspendibility enhancer.
Preferably the said composition comprises of 0.025% to 1.0% by weight of wetting ageni;, 0.05%> ,to 2.5% by weight of dispersing agent and 0.05%> to 10% by weight of a resuspendibility enhancer.
More preferably, the said composition comprises of 0.025% to 0.1% by weight of a
i) heating a biocompatible oil to a temperature in the range of 40°C to 160°C, based on the dosage form, ii) adding a wetting agent, to step (i) liquid and allowing to cool with stirring, iii) adding a dispersing agent and a resuspendibility enhancer to step (ii) mixture with stirring, if required, iv) stirring the mixture at about 160°C up to 2 hrs, v) adding Ceftiofur or its pharmaceutically acceptable salt to step (iv) mixture
' and mixing well with stirring, vi) homogenizing step (v) mixture using a suitable homogenizer and vii) I filling in the primary packaging components.
BRIEF DESCRIPTION OF ACCOMPANYING DRAWING
Figure 1 represents a graphical representation of sedimentation rate of various formulae using different flocculating agents.
DETAILED DESCRIPTION OF THE INVENTION
In accordance, 'applicants have| initiated formulation trials to stabilize the suspension physically and chemically using agents such as polyoxyl hydrogenated castor oil, Dolyoxyl castor oil, glycerol, propylene glycol, polyethylene glycol, alcohols and the like. Different formulations were kept in stoppered cylinders and the rate of sedimentation
was όalculated. The comparative sedimentation ratio (Ratio of sedimentation volume to total volume of the suspension) of different batches of Ceftiofur hydrochloride is shown in Figure 1.
In an embodiment of the present invention provides an oily suspension comprising ceftiofur or its pharmaceutically acceptable salts, at least a biocompatible oil, a wetting agent, a dispersing agent, a resuspendibility enhancer and optionally acceptable excipients.
In another embodiment of the present invention, there is provided an injectable suspension, which has improved physical stability using resuspendibility enhancers. i In still another embodiment of the present invention there is provided an injectable s spώnsion, which has greater chemical stability by reducing the moisture content.
In an Embodiment of the present invention, the pharmaceutically acceptable salts of Ceftφfur are 'selected from sodium, hydrochloride or hydrobromide, preferably Ceftiofur hydrψchloridej.
In an embodiment of the present invention Ceftiofur or its pharmaceutically acceptable salt may be present in amount of 1% to 20% by weight of the suspension, preferably in amount of 1%> to 10%. Further, the Ceftiofur hydrochloride may be present in an amount of 10 mg to about 200mg/ml, preferably in an amount of 10 mg to about lOOmg/ml.
In an embodiment of the present invention, the biocompatible oil used may be selected from the group consisting of monoglyceride, diglyceride, triglyceride medium
,l chain succinic acid triglyceride, corn oil, cottonseed oil, olive oil, sesame oil, soybean oil, safflφwer oil, i coconut oil, sunflower oil or palm oil, preferably cottonseed oil, peanut oil, corn oil is used.
In yetl another embodiment of the present invention, the wetting and dispersing agents used in the suspension are selected from lecithin, fatty acid ester of sorbitan or glyceirol.
In yet another embodiment of the present invention, the resuspendibility enhancer is selected from polyoxyl hydrogenated vegetable oil, polyoxyl vegetable oil, glycerol, propylene glycol, polyethylene glycols. In yet another embodiment of the present invention, the oily suspension of
Ceftiofur hydrochloride is used for oral, topical or parenteral administration. i In yet another embodiment of the present invention, the oily suspension can be
I I steriljzed by sterilization techniques known in the art.
The oily suspension of the present invention has improved resuspendibility. The addition of the resuspendibility enhancers improves the particle interaction, which result in a "loDse" particle aggregation so when the suspension is shaken the particles can separate to some extent and a uniform dose can be obtained.
The present invention is detailed by the examples below, which are provided by way |of illustiiation only and should not be considered to limit the scope of the invention.
Exaάiple 1
1 !
Composition: Ceftiofur (as Ceftiofur HC1): 50g
Lecithin: 0.5 g Sorbitan monooleate: 0.5g Propylene glycol: 5 g Cottonseed oil q.s. to 1000ml 800ml of Cottonseed oil is heated to above 100 °C and lecithin is added and stirred well until dissolvjed. The oil containing the wetting agent is then cooled with continuous stirring. Sorbitan monooleate is added next with agitation. Next the required amount of propylene g col is addbd and mixed well with stirring. Sterile Ceftiofur Hydrochloride is addeld and rrjixed for 15jto 45 minutes. Volume is made up to 1000 ml by adding sufficient amount of cottonseed oil. The suspension is then homogenized using a suitable hompgenizer! It is then filled in vials, closed with a stopper, sealed and sterilized.
Example 2
Composition: Ceftiofur (as Ceftiofur HC1): 50g
Lecithin: 0.5 g Sorbitan monooleate: 0.5g Polyethylene Glycol- 400: 5 g Cottonseed oil q.s. to 1000ml
Hydrochloride is added and mixed for 15 to 45 minutes. Volume is made up to 1000 ml
addiijg sufficient amount of cottonseed oil. The suspension is then homogenized using a suitable homogenizer. It is then filled in vials, closed with a stopper, sealed and sterilized.
Example 3
Composition:
Ceftiofur (as Ceftiofur HC1): 50g
Lecithin: 0.5 g
Sorbitan monooleate: 0.5g
Polyoxyl 40 hydrogenated castor oil: lg
sufficient amount of cottonseed oil. It is then filled in vials, closed with a stopper, sealed and sterilized. Example 4 Composition:
Ceftiofur (as Ceftiofur HC1): 50g Lecithin: 0.5 g Sorbitan monooleate: 0.5g Polyoxyl 40 hydrogenated castor oil: lg Cottonseed oil q.s. to 1000ml
800 ml of Cottonseed oil is heated to above 100°C and lecithin is added and stirred well until dissolved. Sorbitan monooleate is added next with agitation. Next the required amount of Pclyoxyl 40 hydrogenated castor oil is added and mixed well with stirring. The oily mixturei is heated to 160°C, for 2 hours and is then cooled. Sterile Ceftiofur Hydrochloride is added and mixed for 15 to 45 minutes. The suspension is then homogenized using suitable homogenizer. Nolume is made up to 1000 ml by adding sufficient amount of cottonseed oil. It is then filled in vials, closed with a stopper and sealed.
Chemical Stability and Shelf-life
The stability of suspensions, and ultimately their shelf life, is based on both chemical and physical stability. The chemical stability is assessed to insure that the product does not become subpotent during shelf life. The chemical stability of the current formilation has been studied extensively at different temperatures and different time periods. The results for example 3 are shown below:
Resuspendibility or Physical Stability
I Resuspendibility is a very important parameter that determines the dosage accuracy in the dispensed volume of the suspension during the entire shelf life of the product. If the resuspension is not adequate the initial doses shall be subpotent as some small amount of drug remains at the bottom of the container. The invention describes of such formulation where the resuspendibility is achieved effortlessly to get uniform dispersion. Freeze-Thaw Study
Samples were subjected to four cycles of 0°C & 40°C each of 48 hours and then observed for any physical changes in the suspension characteristics and also analyzed for chemical stability. The results are shown below:
Test Example No. 1 Example No. 3
Physical Appearance No significant change No significant change
Appearance after Freeze-thaw No significant change No significant change cycling
Initial Assay (% Label Claim) 99.79 99.16
Assay after Freeze-thaw cycling 97.81 95.66
(% p abel Claim)
Claims
Claims:
pharmaceutically acceptable salt is present in an amount of 1%> to 20%> by weight of the suspension.
3. The oily suspension as claimed in claim 1, wherein Ceftiofur or its pharmaceutically acceptable salt is present preferably in amount of 1% to 10%.
4. The oily suspension as claimed in claim 1, wherein said composition comprises of 0.025%) to 1.0% by weight of wetting agent, 0.05% to
2.5% by weight of dispersing agent and 0.05% to 10% by weight of resuspendibility enhancer.
5. The oily suspension as claimed in claim 4, wherein said composition preferably comprises of 0.025% to 0.1% w/v of wetting agent, 0.05% to 0.5% w/v of dispeising agent and 0.05% to 10% w/v of resuspendibility enhancers.
6. The oily suspension as claimed in claim 1, wherein the pharmaceutically acceptable salt oij Ceftiofur is selected from sodium, hydrochloride or hydrobromide.
7. The oily suspension as claimed in claim 1, wherein the biocompatible oil used is selected from the group consisting of monoglyceride, diglyceride, triglyceride medium chain succinic acid triglyceride, corn oil, cottonseed oil, olive oil, sesame oil, soybean oil, safflower oil, coconut oil, sunflower oil or palm oil.
8. The oily suspension as claimed in claim 1, wherein the wetting and dispersing agent used is selected from lecithin, fatty acid ester of sorbitan or glycerol. 9. The oily suspension as claimed in claim 1, wherein the resuspendibility enhancer used is selected from polyoxyl hydrogenated vegetable oil, polyoxyl vegetable oil,
orally, topically or parenterally.
3. A process for the preparation of novel oily suspension, which comprises: i) heating a biocompatible oil to a temperature in the range of 40°C to 160°C, based on the dosage form, ii) adding a wetting agent to step (i) liquid and allowing to cool, with stirring, iii) adding a dispersing agent and a resuspendibility enhancer to step (ii) mixture with stirring, if required iv) stirring the mixture of step (iii) at about 160°C up to 2 hrs v) adding Ceftiofur or its pharaiaceutically acceptable salt to step (iv) mixture and mixing well with stirring, vi) homogenizing step (v) mixture using a suitable homogenizer, and vii) filling in the primary packaging components.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/IB2002/003165 WO2004014390A1 (en) | 2002-08-05 | 2002-08-07 | Novel pharmaceutical composition of ceftiofur |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1528926A1 true EP1528926A1 (en) | 2005-05-11 |
Family
ID=34179245
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP02762626A Withdrawn EP1528926A1 (en) | 2002-08-07 | 2002-08-07 | Novel pharmaceutical composition of ceftiofur |
Country Status (2)
Country | Link |
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EP (1) | EP1528926A1 (en) |
AU (2) | AU2002328168B2 (en) |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB831096A (en) * | 1956-12-20 | 1960-03-23 | Ici Ltd | Cyanacethydrazide derivatives and compositions containing them |
US5736151A (en) * | 1996-12-09 | 1998-04-07 | Pharmacia & Upjohn Company | Antibiotic oil suspensions |
US6268356B1 (en) * | 1998-04-20 | 2001-07-31 | Pharmaceutical Resources, Inc. | Flocculated suspension of megestrol acetate |
-
2002
- 2002-08-07 EP EP02762626A patent/EP1528926A1/en not_active Withdrawn
- 2002-08-07 AU AU2002328168A patent/AU2002328168B2/en not_active Expired
-
2008
- 2008-10-17 AU AU2008229988A patent/AU2008229988A1/en not_active Abandoned
Non-Patent Citations (2)
Title |
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None * |
See also references of WO2004014390A1 * |
Also Published As
Publication number | Publication date |
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AU2002328168B2 (en) | 2008-08-21 |
AU2002328168A1 (en) | 2004-02-25 |
AU2008229988A1 (en) | 2008-11-06 |
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