WO1998024413A1 - Composition antibacterienne orale de fluoroquinolone a usage veterinaire, pour des traitements de longue duree, et procede de traitement associe - Google Patents

Composition antibacterienne orale de fluoroquinolone a usage veterinaire, pour des traitements de longue duree, et procede de traitement associe Download PDF

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Publication number
WO1998024413A1
WO1998024413A1 PCT/US1996/019221 US9619221W WO9824413A1 WO 1998024413 A1 WO1998024413 A1 WO 1998024413A1 US 9619221 W US9619221 W US 9619221W WO 9824413 A1 WO9824413 A1 WO 9824413A1
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WO
WIPO (PCT)
Prior art keywords
veterinary composition
ruminating
ruminant
difloxacin
fluoroquinolone
Prior art date
Application number
PCT/US1996/019221
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English (en)
Inventor
Douglas W. Danielson
Eric Nichols
Brent Husband
Original Assignee
American Cyanamid Company
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by American Cyanamid Company filed Critical American Cyanamid Company
Priority to BR9612813-5A priority Critical patent/BR9612813A/pt
Priority to NZ336164A priority patent/NZ336164A/en
Priority to PCT/US1996/019221 priority patent/WO1998024413A1/fr
Priority to IL13027096A priority patent/IL130270A0/xx
Priority to AU12774/97A priority patent/AU1277497A/en
Publication of WO1998024413A1 publication Critical patent/WO1998024413A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0068—Rumen, e.g. rumen bolus

Definitions

  • the present invention concerns an oral veterinary composition, containing the fluoroquinolone antimicrobial agent difloxacin or a pharmaceutically acceptable salt thereof.
  • a ruminating animal e.g. , a cow or a feedlot calf
  • the present veterinary composition surprisingly provides (1) ready and extensive absorption of the fluoroquinolone from the rumen into the circulating blood and (2) an unexpectedly extended duration of therapeutic antimicrobial blood level.
  • orally administered antimicrobials are not readily absorbed from the gastrointestinal tract of ruminating animals. Typically, the drug will be poorly absorbed, and will show blood levels of questionable therapeutic efficacy. Typically, the blood levels of an orally-administered antimicrobial are substantially lower than that of a dose administered parenterally . It is believed that fluoroquinolones are biodegraded in the rumen of adult ruminating animals, resulting in less active ingredient available for absorption.
  • one object: of the present invention is to provide a novel veterinary composition providing a blood concentration of a fluoroquinolone antimicrobial nearly equal to the concentration provided by the same dose of the drug administered parenterally.
  • a further object of the present invention is to provide a novel veterinary composition which provides an effective concentration of antimicrobial agent in the blood stream of a ruminating or pre-ruminating (including a milk-fed non- ruminating) ruminant over an extended length of time.
  • a further object of the present invention is to provide a simple and effective method for treating bacterial infections in ruminants.
  • an oral veterinary composition comprising an effective amount of difloxacin or a pharmacologically acceptable salt thereof, in a pharmacologically acceptable, orally acceptable carrier, and a method of treating bacterial infection in a ruminant, comprising the step of orally administering the present veterinary composition to a ruminant in need thereof.
  • Fig. 1 is a graph showing mean plasma difloxacin concentrations in ruminating cattle after administration of difloxacin (5 mg/kg of body weight) per os (in a capsule) and by gavage (in a suspension);
  • Fig. 2 is a graph showing the concentration of difloxacin (in ⁇ g/mL) against time (in h) for two examples of the present oral veterinary bolus (5 and 10 mg/kg);
  • Fig. 3 is a graph showing average plasma difloxacin concentrations in ruminating cattle after administration of a difloxacin bolus (5 mg/kg or 10 mg/kg of body weight) as a function of time, with the IC counter 0 levels against Haemophilus somnus , Pasteurella multocida and Pasteurella hemolytica provided for reference; and
  • Fig. 4 is a graph plotting the average plasma difloxacin concentration (in ⁇ g/mL) in pre-ru inating ruminants as a function of time (in h) for two examples of the present oral veterinary composition (5 and 10 mg/kg) , with the MIC 90 levels against H . somnus , P . mul tocida and P. hemolytica provided for reference.
  • the present invention concerns an oral veterinary composition containing a fluoroquinolone (preferably difloxacin) or a pharmaceutically acceptable salt thereof.
  • a veterinary composition providing an extended duration of therapeutic antimicrobial blood levels is one formulated in a manner which provides an effective concentration of a fluoroquinolone, or pharmacologically acceptable salt thereof, for a length of time sufficiently long to effectively treat a microbial (e.g., bacterial) infection.
  • the present veterinary composition provides a concentration of the fluoroquinolone (or a pharmacologically acceptable salt thereof) in the ruminant which exceeds the MIC 90 level for a given bacterium or bacteria for a length of time of at least 24 hours, and more preferably at least 48 hours, thus enabling a daily or less frequent dosing regimen.
  • the present invention also concerns a method of treating a bacterial infection in a ruminant which may comprise, consist essentially of, or consist of, orally administering an effective amount of the present composition to a ruminant in need thereof .
  • a "non- ruminating" or “pre-ruminating” ruminant is considered to be an animal still nursing or otherwise ingesting little or no roughage (e.g., a "calf" feeding on milk).
  • the rumen is not designed to digest milk, and as a result, the non-ruminating or nursing animal is able to "tunnel" milk directly into its stomach, thus bypassing the rumen.
  • the rumen of a ruminant is : induced to function as a result of feeding grasses, roughages or concentrates (e.g., hay, alfalfa, corn, etc.) to the animal.
  • a functioning rumen also depends upon other factors, such as the physiological development of the particular animal. Typically, however, feeding roughages or concentrates to a nursing animal of from 3 to 8 months of age will result in the onset of normal physiological functions of the rumen (i.e., the ability to digest cellulosic materials) .
  • the phrase "consisting essentially of” refers to (a) one or more additional components in the composition which do not materially affect the properties of the composition, and/or (b) one or more additional steps in the merhod which do not materially affect the beneficial effects of the method.
  • Fluoroquinolone antimicrobial agents including difloxacin, pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the same and general methods of treating bacterial infections (including infections in non- ruminant animals) are disclosed in U.S. Patent Nos. 4,730,000 and 5,145,853, the entireties of which are incorporated herein by reference.
  • antimicrobial agents and salts possess a wide spectrum of antimicrobial activity, including activity against gram-positive and gram-negative microorganisms, such as Staphylococcus , Lactobacillus , Streptococcus, Sarcina, Escherichia, Enter -ob acte , Klebsiella, Pseudomonas, Acinetobacter, Proteus, Citrobacter, Nisseria, Bacillus, Bacteroides, Peptococcus, Clostridium, Salmonella, Shigella, Serratia, Haemophilus, Pasteurella, Brucella , and others.
  • Pharmaceutically acceptable salts include, e.g., salts obtained by reacting a fluoroquinolone with a mineral acid such as hydrochloric acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, boric acid, nitric acid, etc.; an alkyl- or arylsulfonic acid such as ethanesulfonic acid, ethanesulfonic acid, laurylsulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.
  • a mineral acid such as hydrochloric acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, boric acid, nitric acid, etc.
  • an alkyl- or arylsulfonic acid such as ethanesulfonic acid, ethanesulfonic acid, laurylsulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.
  • a "free base equivalent weight" of a pharmaceutically acceptable salt of a fluoroquinolone refers to the corresponding weight of the salt which provides the equivalent weight of free base fluoroquinolone.
  • a composition containing 1.09 g of difloxacin hydrochloride provides a "free base equivalent weight" of 1.00 g of difloxacin.
  • the present veterinary composition also comprises a pharmaceutically acceptable, orally acceptable carrier.
  • a carrier is "orally acceptable" if it can be administered to a ruminant orally, and can be digested by the ruminant.
  • Orally acceptable carriers include conventional solid and liquid carriers, excipients and/or diluents which are digestible in ruminants which can be sterilized, if desired or necessary.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, granules, effervescing granules, gels, pastes, troches and pastilles.
  • the active compound is admixed with at least one conventional inert diluent such as cellulose, silica, sucrose, lactose, starch or modified starch.
  • Such dosage forms can also comprise, as in normal practice, additional substances other than inert diluents, e.g., conventional lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise conventional buffering agents. Tablets and pills can additionally be prepared with conventional enteric coatings.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing conventional inert diluents, such as water. Besides such inert diluents, the present composition may also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
  • the present veterinary composition is in the form of a bolus.
  • a "bolus” typically refers to a large pill (e.g. > 5 grams) .
  • a "bolus” refers to a solid ready-to-swallow pharmaceutical preparation, which may be administered orally and which may have extended duration of therapeutic antimicrobial blood levels properties.
  • the present bolus contains a sufficient amount of fluoroquinolone (more preferably, difloxacin) or a pharmaceutically acceptable salt thereof to provide an effective dosage of the antimicrobial in the ruminant to which the bolus is administered, even if only administered once daily or less frequently to the ruminant.
  • the present bolus preferably contains at least 100 mg (for example, for administration to a pre-ruminating or non- ruminating ruminant), more preferably at least 1,000 mg (for example, for administration to a ruminating ruminant) , and even more preferably at least 1,500 mg of the fluoroquinolone (preferably difloxacin) or a free base equivalent weight of a pharmaceutically acceptable salt thereof.
  • the present bolus may contain, for example, a maximum of 10,000 mg of difloxacin (preferably at most 5,000 mg) or a free base equivalent weight of a pharmaceutically acceptable salt thereof.
  • a preferred formulation may include the following ingredients, in the quantities indicated:
  • the proportions of the ingredients may be modified to give compositions with different dosage strengths, without affecting the properties of the composition.
  • the present invention is not limited to single- dosage administration of the composition, it is preferred that the present method consist of orally administering an effective amount of the composition in a single dosage to a ruminant in need thereof.
  • the present method may consist essentially of or consist of orally administering the present composition to a ruminant in need thereof as needed to maintain an effective blood level in the ruminant for a length of time sufficient to treat the microbial infection.
  • the ruminants to whom the present composition is administered include animals of the genera Bos (cows) , Ovis (sheep) , Capra (goats) , Lama (llamas) and Bison (buffalo) , preferably Bos .
  • Particularly preferred ruminants include members of the species Bos taurus , Bos gaurus , Bos javanicus, Bos mutus grunniens, Bos primigenius , Capra hircus, Ovis ammon, Ovis aries, Ovis musimon, Ovis orientalis , Lama guanico and Bison bison , most preferably Bos taurus .
  • the present method comprises administering the composition to a ruminant in need thereof with the aid of a "balling gun.”
  • a balling gun is a tulip-shaped device comprising a tube with one concave, bell- shaped end and a plunger at the opposite end. The composition is placed in the bell end of the balling gun, the bell end of the balling gun is placed into or down the throat of the ruminant, and the plunger is depressed, thus releasing the composition into the throat or esophagus of the ruminant.
  • feed or second active agent e.g., a nutrient such as a vitamin, essential amino acid, etc. ; a second pharmaceutically active compound such as a second antibacterial compound, an antiviral agent or other antimicrobial agent; etc.
  • a "feed” refers to a commercially available product digestible in ruminants, sold for the purpose of feeding ruminants, and also includes those substances such as hay, grasses, concentrates, etc., grown and/or prepared at the location where the ruminants are kept (e.g. , farm) for the purpose of feeding the same to the ruminants.
  • the present method may further comprise, consist essentially of, or consist of co-administering a feed or second active agent to a ruminant in need thereof.
  • the difloxacin hydrochloride is absorbed when administered to an animal having a functioning rumen.
  • absorption of any drug from the rumen is surprising in view of the fact that the rumen typically contains a large amount of material (e.g., in cows, up to 50 gallons) .
  • the material in a functioning rumen is mostly cellulosic in nature, and is able to chemically or physically bind drugs. Rumen microflora are also able to inactivate, bind or chemically alter orally administered drugs. Therefore, it is even more unexpected that the absorption of the drug can be improved by formulating it into an oral composition (particularly a solid composition, and more particularly a bolus) .
  • Another surprising result provided by the present invention is the "extended duration of therapeutic antimicrobial blood levels" properties that the present composition exhibits in ruminating and non-ruminating ruminants.
  • the present composition is able to provide an effective dose of fluoroquinolone antimicrobial over quite an extended period of time (preferably at least 48 hours in a ruminating ruminant, and at least 72 hours in a non-ruminating or pre-ruminating ruminant) .
  • the length of time during which an effective concentration of a fluoroquinolone antimicrobial is maintained in the blood stream of both ruminating and non-ruminating ruminants by the present composition is unexpected.
  • EXPERIMENT 1 tested the plasma concentration of a fluoroquinolone antimicrobial (difloxacin) as a function of time, provided by a solid composition administered to ruminating steers in accordance with two different techniques.
  • the steers were placed in a single pen, and started on a diet of ad libitum grower ration. Water was offered free choice. The animals were acclimated 7 days prior to the start of the study. Physical examinations were performed on each steer before the start of the study to ensure that they had no clinical or subclinical disease. The steers were observed daily during the test period.
  • Difloxacin oral suspension was administered at 5 mg base activity/kg as a gavage using standard techniques.
  • the difloxacin capsule was administered at 5 mg base activity/kg using standard techniques.
  • Day 0 weights were determined and dosages were based on those weights.
  • Gelatin capsules were prepared at the time of dosing.
  • Blood samples were collected into EDTA glass evacuated tubes by venipuncture of the left or right jugular veins. Blood samples were harvested at post- injection hours 0, 0.083, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72.
  • A, and A- are the time zero plasma drug concentrations, K, is the apparent rate constant of absorption and K 2 is the apparent rate constant of elimination.
  • the plasma concentration-time data were also analyzed using statistical moments (Gibaldi et al, Pharmacokinetics , Marcel Dekker Inc., New York (1982)).
  • the AUC and AUMC were calculated using the method described by Dunne et al. Estimation of noncompartmenta] parameters: a technical note. Journal of Pharmacokinetics and Biophar aceuticals , 17, 131-137 (1989)).
  • Mean plasma difloxacin and concentrations at steady-state ( C SS , AV ) were estimated from the relationship:
  • Table 1 Mean plasma difloxacin concentrations in ruminating cattle after administration of a difloxacin capsule per os or suspension by gavage (5 mg difloxacin/kg body weight)
  • Table 2 Mean plasma pharmacokinetic parameters for difloxacin in ruminating cattle after administration (5 mg difloxacin/kg body weight) of a difloxacin capsule per os or suspension by gavage
  • the compartmental model is represented by the general equation:
  • K is the apparent rate constant of absorption
  • K 2 is the apparent rate constant of elimination
  • t( ) 1 is the apparent half-life of absorption
  • t( ) 2 is the apparent half-life of elimination.
  • the noncompartmental model is based on observations and computations from means of 4 independent sampling units at each of 14 postdosing time periods.
  • C max is the maximum plasma concentration observed;
  • C 24 is the plasma drug concentration at 24 hours after dosing;
  • C S3 av is the average drug concentration in plasma during a dosing interval at steady state on administering the stated dose every 24 hours;
  • t max is the observed time of peak plasma concentration;
  • MRT refers to the mean residence time;
  • AUC (0-t) is the area under the tissue drug concentration-time curve from zero to time t.
  • AUC ( 0- ⁇ ) is the area under the tissue drug concentration-time curve from zero to infinity.
  • AUMC refers to the area under the curve of a plot of the product of time and plasma drug concentration-time.
  • Experiment 2 determined the plasma pharmacokinetics and tissue residue depletion in ruminating steers following a single administration of a difloxacin bolus (at a dosage of either 5 or 10 mg free base equivalent/kg body weight) .
  • Tl and T2 Difloxacin -HCl bolus, 1134.0 mg base equivalent/bolus (5 mg/kg); T3 and T4 : Difloxacin -HCl bolus, 2268.0 mg base equivalent/bolus (10 mg/kg).
  • Steers were acclimated to the test environment 7 days prior to the start of the study. Physical examinations were performed on each steer before the start of the study to ensure that they had no clinical or subclinical disease. The steers were placed in individual pens and started on a diet of free choice hay. Water was offered free choice.
  • Blood samples were collected in the same manner and volume as in Experiment 1, but at time 0 and at 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 504 and 672 hours after test article administration. Following collection, blood samples were treated and stored in the same manner as in Experiment 1.
  • Table 3 Mean plasma difloxacin concentrations in calves receiving a single 5 mg/kg or 10 mg/kg oral dose
  • Table 4 Mean plasma pharmacokinetic parameters for difloxacin in calves receiving a single 5 mg/kg or 10 mg/kg oral dosage
  • Experiment 3 determined the plasma pharmacokinetics in ruminating steers in a feedlot environment following a single administration of a difloxacin bolus (at a dosage of either 5 or 10 mg free base equivalent/kg body weight) .
  • Tl Difloxacin -HCl bolus, 1277.0 mg base equivalent/bolus (5 mg/kg); T2 : Difloxacin -HCl bolus, 2518.0 mg base equivalent/bolus (10 mg/kg) .
  • the 12 steers were randomly allocated to treatment. On study day 0, difloxacin was administered orally via a bolus at 5.0 (Tl) or 10.0 (T2) mg base equivalent/kg of body weight. Boluses were shaved, as necessary, to more accurately dose the animal at the desired levels, based on the animal's body weight.
  • Blood samples were collected in the same manner and volume as in Experiment 1, but at time 0 and at 1, 2, 4, 6, 9, 11, 13, 15, 18, 20, 24, 36, 48, 72, 120 and 168 hours after test article administration. Following collection, blood samples were treated and stored in the same manner as in Experiment 1. Cattle plasma samples were analyzed for difloxacin using a protein precipitation and ultrafiltration process followed by high performance liquid chromatography (HPLC) with fluorescence detection. An internal standard (A-56681.1 hydrochloride, obtained from Abbott Laboratories) was added to the plasma followed by a large volume of base and then a small volume of acid. After centrifugation to precipitate proteins, the supernatant was placed above an ultrafiltration membrane and centrifuged again. The ultrafiltrate was injected into the liquid chromatograph.
  • HPLC high performance liquid chromatography
  • the compartmental model is represented by the equation given in Experiment 1 above, and the noncompartmental model is based on observations and computations from means of 6 independent sampling units at each of the 17 post-dosing time periods.
  • AUC was calculated using the trapezoidal method from time 0-168 hours, and the C. ax is the observed C max .
  • the "half life” was calculated using RSTRIP II exponential stripping and parameter estimation software (produced by MICROMATH' M Scientific Software, Salt Lake City, Utah) .
  • Table 6 Pharmacokinetic parameter summary for difloxacin in 5- to receiving a single 5 mg/kg or 10 mg/kg oral dosage
  • Experiment 4 determined the plasma pharmacokinetics in non-ruminating, non-neonate "veal" calves following a single administration of a difloxacin bolus (at a dosage of either 5 or 10 mg free base equivalent/kg body weight) .
  • Tl Difloxaci -HCl bolus, 226.8 mg base equivalent/bolus (5 mg/kg); T2 : Difloxacin- HCl bolus, 453.6 mg base equivalent/bolus (10 mg/kg) .
  • Calves were acclimated to the test environment 7 days prior to the start of the study. Physical examinations were performed on each calf before the start of the study to ensure that they had no clinical or subclinical disease. The calves were individually housed, with approximately 48 square feet per head. The calves were given water ad libitum and were fed a commercial milk replacer, according to label directions. The calves did not have functioning rumens . The calves were observed daily throughout the test period.
  • Blood samples were collected in the same manner and volume as in Experiment 1, but at time 0 and at 1, 4, 7, 10, 12, 15, 18, 21, 24 and 36 hours and at 2, 3, 4, 5, 6, 7 and 14 days after test article administration. Following collection, blood samples were treated and stored in the same manner as in Experiment 1.
  • Calf plasma samples were analyzed for difloxacin in the same manner as Experiment 3, and pharmacokinetic analysis was conducted in the same manner as Experiment 1.
  • the average difloxacin plasma levels after oral administration of either bolus are presented graphically in Fig. 3.
  • the MIC 90 levels of the bacteria H . somnus (0.25 ⁇ g/mL), P. multocida and P. hemolytica (both 0.12 ⁇ g/mL) are presented in the graph for reference.
  • the compartmental model is represented by the equation given in Experiment 1 above, and the noncompartmental model is based on observations and computations from means of 3 independent sampling units at each of 18 postdosing time periods.
  • Table 8 "AUC,” C railx and “half life” are determined as described in Experiment 3.
  • C., ax /MIC go and AUC/MIC 90 ratios and average values are presented in Table 7 for each of the animals tested, with reference to the above- described bacteria.
  • Table 7 Raw data summary and mean plasma difloxacin concentrations in veal calves receiving a single 5 mg/kg or 10 mg/kg oral dose
  • Table 8 Pharmacokinetic parameter summary for difloxacin in veal calves receiving a single 5 mg/kg or 10 mg/kg oral dosage

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Pharmacology & Pharmacy (AREA)
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Abstract

La présente invention se rapporte à une formulation vétérinaire administrée per os, contenant comme agent antibactérien un fluoroquinolone ou un sel pharmaceutiquement acceptable de celui-ci ainsi qu'à un procédé pour traiter des infections microbiennes chez un ruminant. Administrée per os à un ruminant (vache ou veau élevé en batterie), la présente composition vétérinaire assure une absorption facile et complète du fluoroquinolone depuis le rumen dans le sang circulant et permet de conserver un niveau thérapeutique de l'agent antibactérien dans le sang pendant une durée étonnamment longue.
PCT/US1996/019221 1996-12-06 1996-12-06 Composition antibacterienne orale de fluoroquinolone a usage veterinaire, pour des traitements de longue duree, et procede de traitement associe WO1998024413A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
BR9612813-5A BR9612813A (pt) 1996-12-06 1996-12-06 Composição antibacteriana de fluoroquinolona veterinária oral para duração prolongada de terapia e método de tratamento
NZ336164A NZ336164A (en) 1996-12-06 1996-12-06 Oral veterinary fluoroquinolone antibacterial composition for extended duration of therapy and method of treating
PCT/US1996/019221 WO1998024413A1 (fr) 1996-12-06 1996-12-06 Composition antibacterienne orale de fluoroquinolone a usage veterinaire, pour des traitements de longue duree, et procede de traitement associe
IL13027096A IL130270A0 (en) 1996-12-06 1996-12-06 Oral veterinary fluoroquinolone antibacterial composition for extended duration of therapy and method of treating
AU12774/97A AU1277497A (en) 1996-12-06 1996-12-06 Oral veterinary fluoroquinolone antibacterial composition for extended durati on of therapy and method of treating

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1996/019221 WO1998024413A1 (fr) 1996-12-06 1996-12-06 Composition antibacterienne orale de fluoroquinolone a usage veterinaire, pour des traitements de longue duree, et procede de traitement associe

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6083422A (en) * 1997-12-04 2000-07-04 The B.F. Goodrich Company Thickened bleach compositions

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11529310B2 (en) 2020-12-08 2022-12-20 Ruminant Biotech Corp Limited Devices and methods for delivery of substances to animals

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4853225A (en) * 1985-12-05 1989-08-01 Merck Patent Gesellschaft Mit Beschrankter Haftung Process for implanting a medicament depot
US5223246A (en) * 1990-02-14 1993-06-29 Takeda Chemical Industries, Ltd. Effervescent composition, its production and use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4853225A (en) * 1985-12-05 1989-08-01 Merck Patent Gesellschaft Mit Beschrankter Haftung Process for implanting a medicament depot
US5223246A (en) * 1990-02-14 1993-06-29 Takeda Chemical Industries, Ltd. Effervescent composition, its production and use

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6083422A (en) * 1997-12-04 2000-07-04 The B.F. Goodrich Company Thickened bleach compositions

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IL130270A0 (en) 2000-06-01

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