CN104080456A - Antibiotic formulations - Google Patents

Antibiotic formulations Download PDF

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Publication number
CN104080456A
CN104080456A CN201280063872.1A CN201280063872A CN104080456A CN 104080456 A CN104080456 A CN 104080456A CN 201280063872 A CN201280063872 A CN 201280063872A CN 104080456 A CN104080456 A CN 104080456A
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preparation
suspension
oil
suspension preparation
solvent
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F·阿尔阿拉维
K·南加
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Bayer New Zealand Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—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
    • A61K31/54—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
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0068—Rumen, e.g. rumen bolus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Chemistry (AREA)
  • Oncology (AREA)
  • Engineering & Computer Science (AREA)
  • Communicable Diseases (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Dispersion Chemistry (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cephalosporin Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

A suspension formulation for administration to an animal, the suspension formulation including: at least one cephalosporin antibiotic or a pharmaceutically similar salt thereof; an oil; and a glycerol acetate solvent.

Description

Antibiotic formulations
Technical field
The present invention relates to antibiotic formulations.Specifically, the present invention relates to cephalosporin antibiotics suspension preparation, its preparation and application.
Background of invention
Cephalosporin antibiotics is a subset of antibiotic beta-lactam family and is used for the treatment of antibacterial infection, typically for veterinary industry.
The core texture of cephalosporin antibiotics shows below:
Cephalosporin antibiotics is as Martindale:The Complete Drug Reference, in the 35th edition summarize and be divided into several " generations ", the content of described document is incorporated to by reference.Generally believe that cephalosporin is to work by blocking the generation of the Peptidoglycan layer of bacteria cell wall.Although first generation cephalosporin is mainly the activity having for gram-positive bacterium (Gram-positive bacteria), constant generations has been strengthened for the activity of gram negative bacteria (Gram-negative bacteria) (even often had for the activity of gram-positive organism, to reduce be also like this).
Identified novel cephalosporin antibiotic, it has been designated as a specific generation.
The feature of cephalosporin antibiotics is to be difficult to provide with dosage form due to its low solubility and weak stability.
Although for example the cephalosporin antibiotics of ceftiofur (Ceftiofur) (third generation antibiotic) can per os or local application, has found its absorption difference when dosage forms for oral administration, and after intramuscular is used, absorb faster.Yet, ceftiofur fast degradation and must for example storing, to carry out when needed rehydration, commodity Excenel with sterilized powder form in aqueous solution tM.After in ceftiofur is dissolved in to sterilized water, bin stability is at room temperature limited to 12 hours, or in refrigerator 7 days at the most.
Therefore, instant (RTU) ceftiofur and other cephalosporin antibiotics are preferentially used for parenteral injection with oiliness (vegetable oil typically) form of suspension.
Yet the oily suspensions that contains cephalosporin antibiotics is because preparation is physically and/or chemically unstable and may have problems.Owing to suspension, the state with more than one exists for this, for example liquid and solid, and the indissoluble character of active substance itself.
May there are four subject matters relevant with described suspension:
A) particle is scattered in mediator;
B) divided particles sedimentation;
C) the described particle agglomeration in deposit to such an extent as to hinder to disperse when needed (typically be about to use before); With
D) cephalosporin antibiotics degraded.
To how avoiding these problems to carry out a lot of research in suspension, target is to realize in check gathering (being called flocculation).Use many dissimilar mediators to help flocculation, comprise sodium chloride solution or the acceptable vegetable oil of parenteral of preservation.
This flocculation should make particle precipitation, but separated when needed subsequently.As hereinbefore set forth, identified the additive of several special help cephalosporin antibiotics flocculating suspensions.
A kind of especially effectively antibiotic is ceftiofur.
In cattle, Ceftiofur Hydrochloride is a kind of broad-spectrum cephalosporin antibiotic, it has the activity for actinomyces pseudonecrophorus (Fusobacterium necrophorum) and B. melaninogenicus (Bacteroides melaninogenicus), and this is two kinds of main pathogens relevant to cattle footrot.It is active that Ceftiofur Hydrochloride also has the splendid in vitro and in vivo for pasteurella haemolytica (Pasteurella hemolytica) and pasteurella multocida (P.multocida.), this is two kinds of main pathogen antibacterials relevant with cattle respiratory disease (bovine respiratory disease, BRD).It is active and for the external activity of corynebacterium pyogenes (Corynebacterium pyogenes) that it also has the splendid in vitro and in vivo for Haemophilus somnus (Haemophilus somnus), and this is two kind other bacterial pathogens relevant to cattle respiratory disease.In addition, ceftiofur has the splendid external activity for other gram-negative pathogens, described other gram-negative pathogens for example has escherichia coli (E.coli), Salmonella choleraesuis (Salmonella choleraesuis), Salmonella typhimurtum (Salmonella typhimurium) and pleuropneumonia haemophilus (Haemophilus pleuropneumonia) and streptococcus agalactiae (Streptococcus agalactiae), streptococcus dysgalactiae (Streptococcus dysgalactiae), streptococcus uberis (Streptococcus uberis), bargen's streptococcus (Streptococcus bovis) and Streptococcus suis (Streptococcus suis).
In pig, ceftiofur has splendid active for for example Actinobacillus pleuropneumoniae (pleuropneumonia haemophilus) (Actinobacillus (Haemophilus) pleuropneumoniae), Salmonella choleraesuis, the gram-negative pathogens of pasteurella multocida and the in vitro and in vivo of Gram-positive pathogen Streptococcus suis, and all these pathogen may be individually or be relevant to pig bacterial respiratory tract disease (pig bacterial pneumonia) in combination.Ceftiofur also has splendid other gram-negative pathogens for for example escherichia coli and Salmonella typhimurtum and for the external activity of the Gram-positive pathogen of for example staphylococcus aureus (Staphylococcus aureus), streptococcus agalactiae, streptococcus dysgalactiae, streptococcus uberis and bargen's streptococcus.While testing in the multiple mouse disease model that is relating to escherichia coli, staphylococcus aureus, streptococcus agalactiae, pasteurella multocida or Salmonella typhimurtum, ceftiofur is effective.Yet these find clinical meaning in pig or unclear.
US 5,736, and 151 disclose a kind of oily suspensions, and it comprises ceftiofur and water, this water as flocculating agent in order to the better suspension again of this suspension to be provided.
US 4,902, and 683 disclose many excipient, and it is proposed and is suitable for helping the ceftiofur suspension for the preparation of systemic administration.
WO 2004/014390 discloses the purposes of suspension reinforcing agent in ceftiofur oiliness suspension again, wherein this again suspension reinforcing agent be to be selected from poly-hydrocarbon oxygen hydrogenated vegetable oil, poly-hydrocarbon oxygen vegetable oil, glycerol, propylene glycol or Polyethylene Glycol.
WO 2010-059747 disclose benzyl alcohol when for ceftiofur and ketoprofen (ketoprofen) as the purposes of suspension reinforcing agent again.
Although have discussion in these documents, but still need to identify the applicable additive of realizing the improved physical stability of the oily suspensions (especially those are designed to the suspension of parenteral injection) that contains cephalosporin antibiotics.
Equally, for improvement of the additive of the physical stability of the oily suspensions that contains cephalosporin antibiotics, can often cause the chemically unstable of antibiotic self, obviously caused the undesirable short shelf-life of preparation and/or use after effectiveness reduce.
For instance, US5,736,151 only make water as flocculating agent.It has been observed by the present inventors that described preparation can have limited shelf-life and general undesirable pharmacokinetic property.For having found similar result such as the supporting agent of glycols etc., as disclosed in WO 2004/014390.
Equally, use the additive such as glycols etc. can increase the cost relevant to producing described preparation, cause position reaction while transmitting, irritated etc.
Commercially available instant ceftiofur preparation is the Excenel RTU being sold by Pfizer tM.Excenel RTU is the suspension based on oily, and it uses a small amount of water as flocculating agent.According to the incidental description of Excenel RTU product, the suspension again of active substance need to be rocked 20-30 second.
Many suspension preparations are stored in vial.Found that this contributes to antagonism as the subject matter of being summarized about suspension above.Yet, about glass, there is contingency question, comprise production/storage cost of larger damaged probability and Geng Gao.Preferably the suspension with improved flocculation and/or stability being stored in to polyethylene terephthalate (PET, polyethylene teraphthate) maybe will overcome about being stored in other plastic jar of these problems in glass.Yet known PET bottle can cause caking, this means that available preparation stored is not good especially in PET bottle at present.As is known to the person skilled in the art, water and oxygen can diffuse through PET packing and absorb in content.This can accelerate active substance degraded, and disturbs physical stability, for example, by due to enhanced deposition and caking.
For instance, present inventor finds when by preparation stored in PET bottle time, commercially available ceftiofur formulation C efaguard tMthe active matter of (being sold by Stockguard) is less than 10% of labeling requirement.Test has disclosed Cefaguard tMpreparation has the Excenel of being similar to tMthe water content of RTU (instant).As discussed previously, aqueous suspension (for example, as US 5,736, described in 151) weak bin stability can be there is.
Therefore, a target of the present invention provides a kind of preparation that contains cephalosporin antibiotics, said preparation bin stability under more extensive condition and/or in long duration better and in suspension the reduction of surfactant concentration minimum or can not reduce, and/or can effectively be stored in PET bottle and have nothing to do in the being seen caking of current available preparation or other problem.
Can recognize, if compositions can keep active material concentration higher than labeling requirement in compared with long duration, have obvious commercial advantage.This has been avoided consumer or retailer to have to replenish the supply continually, becomes concerning supply or buying more attractive product.
Another target of the present invention is solve about the problems referred to above containing cephalosporin antibiotics suspension or at least to the public, provide the selection of use.
All reference materials of quoting in this description (comprising any patent or patent application) are all incorporated herein by reference.Do not admit that any reference material has formed prior art.The content that its author advocates has been stated in the discussion of relevant reference material, and applicant retains the right that the accuracy of institute's citing document and specific aim are queried.To be well understood to, in New Zealand or what its country in office, although announce with reference to a large amount of prior aries herein, this reference is not equivalent to admit a part for the common general knowledge in any these documents formation this areas.
Run through this description, word " comprises (comprise) " or its version such as " comprising (comprises) " or " comprising (comprising) " etc. is interpreted as inferring and comprises described key element, integer or step, or one group of key element, integer or step, but do not get rid of any other key element, integer or step, or one group of key element, integer or step.
According to the subsequent descriptions only providing with way of example, other side of the present invention and advantage will become apparent.
Brief summary of the invention
According to an aspect of the present invention, provide a kind of for being applied to the suspension preparation of animal,
This suspension preparation comprises
A) at least one cephalosporin antibiotics or its similar salt pharmaceutically;
B) oil; With
C) acetin solvent.
Use in the present invention acetin solvent that improved cephalosporin antibiotics active agent suspension is provided.Present inventor surprisingly finds, acetin solvent provides the mixing of improved oil and cephalosporin antibiotics and suspends and good anti-caking nature again.This is (shorten required time and reduce resource requirement) of crucial importance during preparatory phase not only, and be also extremely important for the suspension again before transmitting preparation by user.
In addition, find to compare with commercially available ceftiofur suspension, in suspension preparation, use acetin solvent to improve the shelf-life of suspension.This further discusses in the best mode part of presents.
Surprisingly, present inventor's discovery, according to the present invention, the suspension of preparation is stable especially, and has good agglomeration resistance feature, particularly like this in the time of in being stored in plastics PET bottle.As discussed previously, these results can contribute to overcome to cephalosporin antibiotics suspension because the bad storage feature in the container of other type is stored in many problems that current industrial practice in vial is relevant.
Run through this description, term " PET bottle " is interpreted as meaning any container or vessel, comprises polyethylene terephthalate (also referred to as poly-(PETP)).PET is comprised of the polymerized unit of PETP, and it has the C of repetition 10h 8o 4unit.
In addition, preliminary zooscopy shows to use the generation of acetin solvent to be longer than the suspension containing cephalosporin antibiotics of other known suspension containing cephalosporin antibiotics action time.
Also find position reaction when using acetin solvent to produce ratio expects low transmission.When comparing with the compositions based on aqueous solution, will expect that the present composition (based on non-aqueous solution) can cause significantly larger position reaction when injection.
Below will discuss other side of the present invention and advantage.
Run through this description, term " cephalosporin antibiotics " is interpreted as meaning the beta-Lactam antibiotic that a class derives from Acremonium (Acremonium).
Cephalosporin antibiotics comprises many different members, and it is divided into several " generations " conventionally.Exist at present as below summarized five large generations:
1st generation member comprises cefacetrile (Cefacetrile) (CEC (cephacetrile)), cefadroxil (Cefadroxil/cefadroxyl; Duricef), cefalexin (Cephalexin/cephalexin; Keflex), cefaloglycin (Cefaloglycin/cephaloglycin), cefalonium (Cefalonium/cephalonium), cefaloridine (cefaloridine/cephaloradine), cefalotin (Cefalotin/cephalothin; Keflin), cefapirin (Cefapirin/cephapirin; Cefadryl), cefatrizine (Cefatrizine), cefazaflur (Cefazaflur), cefazedone (Cefazedone), cefazolin (Cefazolin/cephazolin; Ancef, Kefzol), cefradine (Cefradine/cephradine; Velosef), cefroxadine (Cefroxadine), ceftezole (ceftezole).
2nd generation member comprises cefaclor (Cefaclor; Ceclor, Distaclor, Keflor, Raniclor), cefonicid (Cefonicid; Monocid), cefprozil (Cefprozil/cefproxil; Cefzil), cefuroxime (Cefuroxime; Zefu, Zinnat, Zinacef, Ceftin, Biofuroksym, Xorimax), cefuzonam (Cefuzonam).The second generation cephalosporin with anti-anaerobic activity: cefmetazole (Cefmetazole), cefotetan (Cefotetan), cefoxitin (Cefoxitin).Following cephem is sometimes also classified in second generation cephalosporin: carbacephem (Carbacephem): Loracarbef (loracarbef; Lorabid); Cephamycin (Cephamycin): cefbuperazone (cefbuperazone), cefmetazole (cefmetazole; Zefazone), cefminox (cefminox), cefotetan (cefotetan; Cefotan), cefoxitin (cefoxitin; Mefoxin).
The 3rd generation member comprises cefcapene (Cefcapene), cefdaloxime (Cefdaloxime), cefdinir (Cefdinir; Zinir, Omnicef, Kefnir), cefditoren (Cefditoren), cefetamet (Cefetamet), cefixime (Cefixime; Zifi, Suprax), cefmenoxime (Cefmenoxime), cefodizime (Cefodizime), cefotaxime (Cefotaxime; Claforan), cephalo dimension star (Cefovecin; Convenia), cefpimizole (Cefpimizole), cefpodoxime (Cefpodoxime; Vantin, PECEF), cefteram (Cefteram), ceftibuten (Ceftibuten; Cedax), ceftiofur (Ceftiofur), ceftiolene (Ceftiolene), ceftizoxime (Ceftizoxime; Cefizox), ceftriaxone (Ceftriaxone; Rocephin).The third generation cephalosporin with anti-pseudomonas active: cefoperazone (Cefoperazone; Cefobid), ceftazidime (Ceftazidime; Fortum, Fortaz).Following cephem is sometimes also classified in third generation cephalosporin: oxacephem (Oxacephem): latamoxef (latamoxef/moxalactam).
The 4th generation member comprises cephalo power fixed (Cefclidine), cefepime (Cefepime; Maxipime), cefluprenam (Cefluprenam), Cefoselis (Cefoselis), cefozopran (Cefozopran), cefpirome (Cefpirome; Cefrom), cefquinome (Cefquinome).Following cephem sometimes also classified in the 4th generation cephalosporin: oxacephem: flomoxef (flomoxef).
The 5th generation member comprises Ceftobiprole (Ceftobiprole), CPT (Ceftaroline).
Identify other cephalosporin antibiotics, but be not yet designated as a specific generation.These cephalosporin antibiotics comprise cefaloram (Cefaloram), cefaparole (Cefaparole), cefcanel (Cefcanel), cefedrolor (Cefedrolor), cefempidone (Cefempidone), cefetrizole (Cefetrizole), cefivitril (Cefivitril), RP-42980 (Cefmatilen), cephalo pyrrole fixed (Cefmepidium), cefoxazole (Cefoxazole), cefrotil (Cefrotil), cefsumide (Cefsumide), CPT (Ceftaroline), ceftioxide (Ceftioxide), cefuracetime (Cefuracetime).
Cephalosporin antibiotics has internal construction features, similar stability and solubility characteristics and similar binding mode.Therefore, those skilled in the art will reasonably expect, in suspension preparation according to the present invention, use as at present known or as the cephalosporin antibiotics of the non-ceftiofur of research and development in the future/differentiate in any or combination and acetin solvent and oily combination will provide and identical favourable outcome described herein.
Preferably, cephalosporin antibiotics is the third generation cephalosporin antibiotic being selected from as listed above.
Most preferably, cephalosporin antibiotics is ceftiofur.
Preferably, suspension preparation comprises the approximately cephalosporin antibiotics between 1-30%w/v.
More preferably, suspension preparation comprises 5-6%w/v cephalosporin antibiotics.Present inventor has determined needs the Ceftiofur Hydrochloride that concentration is 5.35%w/v that 5% ceftiofur base is provided.The upper limit of concentration of cephalosporin depends on produced preparation viscosity conventionally, because final preparation will become too sticky and cannot effectively inject.
Run through this description, it is liquid at ambient temperature that term " oil " is interpreted as, have hydrophobicity and dissolve in any material in organic solvent.
Preferably, oil derives from plant, animal or synthetic source.
More preferably, oil is to be selected from Oleum Brassicae campestris, Semen Maydis oil, Oleum Gossypii semen, olive oil, Oleum Arachidis hypogaeae semen, Oleum sesami, soybean oil, safflower oil, Oleum Cocois, Oleum helianthi, Petiolus Trachycarpi oil, monoglyceride, Diglyceride and triglyceride medium chain succinic acid triglyceride.
Most preferably, oil is Oleum Gossypii semen.
Suspension preparation can comprise the approximately oil between 70-99%w/v.Yet, should be appreciated that oil can be enough to make suspension to be increased to the amount use of volume required (in right amount) (for example 1000ml).
Run through this description, term " acetin solvent " (also referred to as glyceryl acetate) is interpreted as meaning the ester producing with acid esterification glycerol.
Multi-products can be produced by this reaction, comprises single acetyl glycerol, diacetyl glycerol and triacetyl glycerol (being more generally called glyceryl triacetate).
Preferably, acetin solvent is to be selected from vinegar essence, diacetin and glyceryl triacetate.
Most preferably, acetin solvent is glyceryl triacetate.
Expection glyceryl triacetate is compared the particularly preferred effect of performance with vinegar essence or diacetin, yet, can preferably use from any in these solvents of this group.
Glyceryl triacetate is also referred to as triglyceride 1,2,3-triacetoxyl group propane and glyceryl triacetate.Glyceryl triacetate is three esters of glycerol and acetic acid.
Glyceryl triacetate compound (with relevant vinegar essence and diacetin compound) has been described as having percutaneous and solvent property and has had universal architecture:
A plurality of patents openly described glyceryl triacetate as solvent the purposes in the veterinary formulation that contains different activities agent and different transfer modes (referring to for example NZ 234802, NZ 520707 and NZ 306249).
Although known use glyceryl triacetate is as solvent, the reaction that in this area, fully the agent of understanding different activities produces for solvent may be completely different, usually affects the physical stability of preparation and the chemical stability of active substance itself.For this reason, can not also will be the solvent that is suitable for cephalosporin antibiotics from using a kind of type of solvent to dope exactly same solvent type anthelmintic formulation.
Equally, the preparation of particular type (such as impregnating agent, dashing agent, parenteral Injectable solution, suspension, bolus etc.) has significant impact to the type of solvent for use and the suitability.
In addition, the present invention becomes complicated because of the soluble character of cephalosporin antibiotic activity material, thereby the preparation that is oily suspensions form need to be provided.The difficulty of preparation cephalosporin antibiotics (for example ceftiofur) is clearly illustrated in US 5,736,151, the US 4,902,683 and WO 2004/014390 that above discussed.
Although carried out a lot of research in this field, do not determine yet that so far acetin solvent (for example glyceryl triacetate) can improve storage feature, shelf-life and the persistency of the oily suspensions that contains cephalosporin antibiotics active substance.
In addition, present inventor has determined that the position response class of preparation as herein described when injection is similar to or is better than current available reference substance.In the situation that be not limited to possible binding mode, present inventor thinks that this is useful but beyond thought effect may be owing to using acetin solvent.Carry out further research and confirmed these results.
Preferably, suspension preparation comprises the approximately acetin solvent between 0.05 to 5%w/v.
More preferably, suspension preparation comprises about 0.5%w/v acetin solvent.
Other ceftiofur preparation (for example, described in WO 2004/014390) discloses use 0.5%w/v glycol.It has been observed by the present inventors that the acetin solvent (for example glyceryl triacetate) that uses same amount shockingly makes the mixing of suspension as the substitute (as disclosed in WO 2004/014390) of glycol and suspension feature, shelf-life and acting duration are improved substantially again.
Preferably, suspension preparation comprises surfactant.Almost any surfactant all can be used for the present invention and should be appreciated that those skilled in the art can differentiate the surfactant that is suitable for said preparation.
Most preferably, surfactant is single oleic acid sorbitan ester (for example Span80).
Preferably, preparation comprises dispersant.Almost any dispersant all can be used for the present invention and should be appreciated that those skilled in the art can differentiate the dispersant that is suitable for said preparation.
Most preferably, dispersant is HSPC (for example Phospolipon H90).
Therapeutic Method
According to a further aspect in the invention, provide a kind of to animal use substantially suspension preparation as described herein for treatment pre-bacteriological protection infects or due to the method for condition of illness.
Preferably, antibacterial infection or condition of illness to be treated or prevention are cattle bacterial respiratory tract disease or pig bacterial respiratory tract disease.
Alternatively, antibacterial infection or condition of illness to be treated or prevention are cattle footrots.
In another alternate embodiment, antibacterial to be treated or prevention infects or condition of illness is cattle metritis.
Yet, should be appreciated that the present invention can be used for treating known any infection or condition of illness present or that cephalosporin antibiotics is suitable in the future.
Preferably, Therapeutic Method comprises with the ratio of the cephalosporin antibiotics of every kilogram of the weight of animals to be treated every day between about 0.5-5mg and uses substantially preparation as described herein to the animal that has needs.
Preferably, Therapeutic Method is to be undertaken by injection.Yet present inventor also recognizes that preparation can be through being configured to per os or local application.For instance, present inventor predicts the present invention can have special advantage in dosage forms for oral administration, and wherein cephalosporin antibiotics typically demonstrates bad absorption.Use the acceptable solvent of glycerol aspect the Absorption Characteristics of active substance, thering is special effect.
Given dose used can be depending on animal to be treated and condition of illness/infection.
For instance, it has been observed by the present inventors that animal and the disease/condition of illness that following dosage is particularly suited for summarizing in following table:
A considerable advantage of the present invention is improved bin stability and suspension feature again in PET bottle.
Based on following preferred dose, clearly single 125ml PET bottle can be enough to be used in treating an animal of full dosage, or several animals even, and this depends on requirement.For preparation of the present invention, effectively use the ability of PET bottle that the considerable advantage that is better than typically must being stored in the previous preparation in more frangible and expensive vial is provided.
Preparation method
According to a further aspect in the invention, provide a kind of method of preparing substantially preparation as described above, wherein said method comprises the following steps:
(a) a certain amount of oil is added in the first container,
(b) a certain amount of oil added in second container and be heated between the temperature between room temperature and 100 ℃;
(c) a certain amount of dispersant is added in described second container;
(d) a certain amount of surfactant is added in the 3rd container;
(e) acetin solvent is added in described the 3rd container;
(f) by the contents mixed of first, second, and third container together;
(g) cephalosporin antibiotics is added in the content of described mixing; With
(h) optionally, with oil, described mixture is supplied volume required.
A kind of method of preparing ceftiofur preparation is disclosed in WO 2004/014390.Yet described technique is quite consuming time and need high temperature, for example, up to 160 ℃, continue 2 hours.
Preparation method of the present invention has more production friendly, because neither need to heat widely, does not also need for example long incubative time described in WO 2004/014390.Present inventor believe use glyceryl triacetate shockingly make with oily mix better, thereby make total preparation technology easier and still less consuming time.
Preferably, the heating steps in (b) comprises oil is heated between 15-90 ℃.
The time of the mixture incubation that preferably, will be produced by step (b) between 5 minutes and 60 minutes.
According to a further aspect in the invention, provide a kind of purposes for the preparation of comprising substantially the medicament of suspension preparation as described above, described medicament is used for the treatment of or prevents the antibacterial of the animal of needs to infect or condition of illness.
Preferably, described purposes is be used for the treatment of or prevent cattle and/or pig bacterial respiratory tract disease, cattle footrot or cattle metritis.
Accompanying drawing summary
Other side of the present invention will become apparent according to description subsequently, and described description only provides with way of example and with reference to the embodiment that encloses.
Implement best mode of the present invention
embodiment 1: preparation 1
* * 5.35% Ceftiofur Hydrochloride provides 5% (50mg/mL) ceftiofur base
embodiment 2: preferred preparation procedure
Step 1
Clean and dry, pack 65% aseptic Oleum Gossypii semen in preparing vessel
Step 2
At another, clean and dry pack 25% aseptic Oleum Gossypii semen into and be heated to 60-65 ℃ in preparing vessel
Add Phospolipon H90 (HSPC) and disperse when stirring
Step 3
At another clean and dry aseptic single oleic acid sorbitan ester (Span80) that packs aequum in preparing vessel into
Add aseptic glyceryl triacetate and mix
Step 4
Step 2 and step 3 are added in step 1 and fully mixing
Add aseptic Ceftiofur Hydrochloride and make its suspension and fully mix
With aseptic Semen Gossypii oil subsidy foot, to final volume, mix and fully stir evenly
embodiment 3: evaluation group compound and shelf-life/stability features
The research of reporting relates to three pilot-scales batch (3.5L-lot number T1707, T1708, T1709), and it is to use preparation technology mentioned above to produce.Then produced batch is packaged in the clean PET bottle of 125mL and recommends as ACVM, record at regular intervals Physical and chemical characteristics.
The result of storing under 25 ℃/60%RH, 30 ℃/65%RH and 40 ℃/75%RH after 9-12 month is provided in detail.Comparison with the reference ceftiofur compositions of testing in PET bottle under the same terms (40 ℃/75%RH) is provided.Stability protocol continues to carry out and in the time can obtaining more data, Jiang Xiang regulatory authorities provide upgrade and suitable suggestion with consideration for further study.
PRELIMINARY RESULTS shows that the preparation of embodiment 1 has useful storage and suspension feature and under various conditions stable storage again in PET bottle.
After three months (under 40 ℃/75%RH), the compositions display of embodiment 1 reduces 0.9%w/v ceftiofur (being hydrochloride form).According to the average loss % of the active substance seen in a batch T1707, T1708 and the T1709 under these conditions, calculate described value 0.9%w/v.
By this be presented at the reference group compound that reduces 2.3%w/v ceftiofur in same time section and compare.
In longer testing time section, even can be larger by this stability difference between the compositions of contemplated embodiments 1 and reference group compound.
This has emphasized commercial significance of the present invention, because the compositions of embodiment 1 can be stored longer time section, more than remaining on labeling requirement simultaneously.
The preparation of embodiment 1 is long-term store after, by rocking bottle, make active substance desired time that suspends again be less than 5 seconds.Even if this shows long time stored harmful caking phenomenon that also do not exist in PET bottle.
According to described in following test condition assessment batch:
test composition is analyzed
Lot number: T1707 storage requirement: 25 ℃/60%RH
Batch size: 3.5L packing: the clean PET bottle of 125mL
Lot number: T1707 storage requirement: 30 ℃/65%RH
Batch size: 3.5L packing: the clean PET bottle of 125mL
Lot number: T1707 storage requirement: 40 ℃/75%RH
Batch size: 3.5L packing: the clean PET bottle of 125mL
Lot number: T1708 storage requirement: 25 ℃/60%RH
Batch size: 3.5L packing: the clean PET bottle of 125mL
Lot number: T1708 storage requirement: 25 ℃/60%RH
Batch size: 3.5L packing: the clean PET bottle of 125mL
Lot number: T1708 storage requirement: 40 ℃/75%RH
Batch size: 3.5L packing: the clean PET bottle of 125mL
Lot number: T1709 storage requirement: 25 ℃/60%RH
Batch size: 3.5L packing: the clean PET bottle of 125mL
Lot number: T1709 storage requirement: 30 ℃/65%RH
Batch size: 3.5L packing: the clean PET bottle of 125mL
Lot number: T1709 storage requirement: 40 ℃/75%RH
Batch size: 3.5L packing: the clean PET bottle of 125mL
reference group compound
compositions (4 ℃) at the beginning at 40 ℃ 3 months
describe canescence homogenizing oily suspensions. canescence homogenizing oily suspensions.
ceftiofur (being HCl form) 5.13 5.01
? ? ?
embodiment 4: biological usability research
Carry out zooscopy to measure preparation 1 when the biological usability for pig and Niu Shi.Result proof preparation 1 and reference product Excenel tMthere is bioequivalence.
embodiment 5: position reaction during injection
Use preparation 1 and business reference product Excenel tMthe result of the zooscopy of making comparisons is presented in test formulation or reference substance in pig or Niu Zhongwu position reaction swelling phenomenon.
Embodiment 6: residual volume research
Zooscopy has shown that preparation has low-down residual volume in the institute of cattle and pig in a organized way.When for cattle, concerning milk, the retention period (withhold period, WHP) of expection is zero.
Only with way of example, described various aspects of the present invention and should be appreciated that and can modify and add and do not depart from it as defined scope in the claims of enclosing it.

Claims (25)

1. for being applied to a suspension preparation for animal, described suspension preparation comprises:
A) at least one cephalosporin antibiotics or its similar salt pharmaceutically;
B) oil; With
C) acetin solvent.
2. suspension preparation as claimed in claim 1, wherein said cephalosporin antibiotics is to be selected from third generation cephalosporin antibiotic.
3. suspension preparation as claimed in claim 2, wherein said cephalosporin antibiotics is ceftiofur.
4. as suspension preparation in any one of the preceding claims wherein, the concentration of wherein said cephalosporin antibiotics is between 1-30%w/v.
5. as suspension preparation in any one of the preceding claims wherein, the concentration of wherein said cephalosporin antibiotics is between 5-6%w/v.
6. as suspension preparation in any one of the preceding claims wherein, wherein said oil be selected from following: Oleum Brassicae campestris, Semen Maydis oil, Oleum Gossypii semen, olive oil, Oleum Arachidis hypogaeae semen, Oleum sesami, soybean oil, safflower oil, Oleum Cocois, Oleum helianthi, Petiolus Trachycarpi oil, monoglyceride, Diglyceride and triglyceride medium chain succinic acid triglyceride.
7. suspension preparation as claimed in claim 6, wherein said oil is Oleum Gossypii semen.
8. as suspension preparation in any one of the preceding claims wherein, wherein said acetin solvent is to be selected from vinegar essence, diacetin and glyceryl triacetate.
9. suspension preparation as claimed in claim 8, wherein said acetin solvent is glyceryl triacetate.
10. as suspension preparation in any one of the preceding claims wherein, wherein said acetin solvent is included in described preparation with the amount within the scope of 0.05-5%w/v.
11. as suspension preparation in any one of the preceding claims wherein, and wherein said acetin solvent is included in described preparation with the amount within the scope of 0.5%w/v.
12. as suspension preparation in any one of the preceding claims wherein, and wherein said preparation comprises surfactant.
13. suspension preparations as claimed in claim 12, wherein said surfactant is single oleic acid sorbitan ester.
14. as suspension preparation in any one of the preceding claims wherein, and wherein said preparation comprises dispersant.
15. suspension preparations as claimed in claim 14, wherein said dispersant is HSPC.
16. 1 kinds of containers that comprise a certain amount of as suspension preparation in any one of the preceding claims wherein, is characterized in that described container made by PET (polyethylene terephthalate) substantially.
To animal, use the method as suspension preparation in any one of the preceding claims wherein for 17. 1 kinds, it is used for the treatment of or pre-bacteriological protection infects or due to condition of illness.
18. methods as claimed in claim 17, wherein said suspension preparation is to use between the ratio between every day every kilogram of animal 0.5 to 5mg.
19. purposes for the preparation of the medicament that comprises the suspension preparation as described in any one in claim 1 to 15, described medicament is used for the treatment of or prevents the antibacterial of animal to infect or condition of illness.
20. purposes as claimed in claim 19, wherein described antibacterial infection or condition of illness to be treated or prevention are cattle bacterial respiratory tract disease, pig bacterial respiratory tract disease, foot rot or metritis.
21. 1 kinds of methods of preparing the suspension preparation as described in any one in claim 1 to 15, wherein said method comprises the following steps:
A. a certain amount of oil is added in the first container;
B. a certain amount of oil is added in second container, and be heated between the temperature between room temperature and 100 ℃;
C. a certain amount of dispersant is added in described second container;
D. a certain amount of surfactant is added in the 3rd container;
E. described acetin solvent is added in described the 3rd container;
F. by the contents mixed of described first, second, and third container together;
G. described cephalosporin antibiotics is added in the content of described mixing; With
H. optionally with oil, described mixture is supplied volume required.
22. methods as claimed in claim 21, wherein the described heating steps in (b) comprises described oil is heated between 15-90 ℃.
23. methods as described in claim 21 or 22, wherein will be from step b) the mixture incubation of the gained time between 5 minutes and 60 minutes.
24. 1 kinds of suspension preparations, it is as described herein and with reference to the embodiment 1 in best mode part.
25. 1 kinds of methods, it is for the preparation of as described herein and with reference to the suspension preparation of the embodiment 2 in best mode part.
CN201280063872.1A 2011-12-23 2012-12-21 Antibiotic formulations Pending CN104080456A (en)

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