Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-02-17
2001-05-01
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S574000
Reexamination Certificate
active
06225304
ABSTRACT:
FIELD OF THE INVENTION
The instant invention relates to a readily water-soluble ingestible form of amoxicillin formed by the reaction with a hydrocylatedpolycarboxylic acid of the formula
where x and y are 0 or 1 and z is 0 to 3. This water-soluble form possesses palatability and unique storage stability. The water-soluble form of the invention allows feeding orally to animals, as well as humans, without loss of antibiotic benefits. This water-soluble form is derived from an anhydrous solid, particulate mixture of the amoxicillin and the hydroxylatedpolycarboxylic acid.
BACKGROUND OF THE INVENTION
Penicillin constitutes one of the most important and widely-used groups of antiobiotics. Although numerous other antimicrobial groups of antiobiotics have been produced since the first penicillin became available, penicillins and new derivatives of the basic penicillin nucleus are still being widely researched and, when proved to be successful, produced in large quantities. Many of the new derivative compounds have unique advantages making them the preferred drug of choice for the treatment of infectious diseases. One such compound is amoxicillin which is a member of the class of aminopenicillins. One unique advantage of amoxicillins is their efficacy toward a much broader spectrum of infections when compared to penicillins.
More specifically, amoxicillion is a widely employed antibiotic having the following formula:
It is effective against a wide range of gram-negative and gram-positive bacteria. It is used in the treatment of infections of the urinary and respiratory tracts and of skin and soft tissues due to sensitive pathogens. In treating humans, it is typically administered orally, e.g., in a tablet form or an oral suspension.
The treatment of animals with an amoxicillin is fraught with many difficulties. For example, injecting amoxicillin is time consuming and costly, especially with large numbers of animals are involved. It is also potentially hazardous to the animal because a needle can break off in the animal and/or create an infective injection site. Feeding even a farmyard animal, let alone a wildlife species, with an amoxicillin tablet is minimally a taxing chore.
Amoxicillin slowly dissolves in the acidic environment of the normal stomach, e.g., pH of less than 3.0. It is available in the form of suspensions and tablets.
Amoxicillin hydrochoride and amoxicillin monohydrate are readily dissolved in forms which are 50% neutrally charged. The neutrally charged form has limited solubility compared to the ionized drug forms.
Amoxicillins are somewhat less active than penicillin G against gram-positive cocci sensitive to the latter agent. The meningococci and
L. monocytogenes
are sensitive to the drug. Many pneumococcal isolates have varying levels of resistance to ampicillin. Penicillin-resistant strains should be considered ampicillin/amoxicillin resistant.
H. influenzae
and the virdians group of streptococci usually are inhibited by very low concentrations of ampicillin. However, strains of type b
H. influenzae
that are highly resistant to ampicillin have been recovered from children with meningitis. It is estimated that 25% to 30% of cases of
H. influenzae
meningitis are now caused by ampicillin-resistant strains. Enterococci are about twice as sensitive to ampicillin, on a weight basis, as they are to penicillin G (MIC for ampicillin averages 1.5 mg/ml). Although most strains of
N. gonorrhoeae, E. coli, P. mirabilis,
Salmonella, and Shigella highly susceptible when ampicillin was first used in the early 1960s, an increasing percentage of these species is now resistant. From 30% to 50% of
E. coli,
a significant number of
P. mirabilis,
and practically all speices of Enterobacter are presently insensitive. Resistant strains of Salmonella (plasmid mediated) have been recovered with increasing frequency in various parts of the world. Most strains of Shigella are now resistant. Most strains of Pseudomonas, Klebsila, Serratia, Acinetobacter, and indole-positive Proteus also are resistant to this group of penicillins; these antibiotics are less active agains
B. fragilis
than is pencillin G. However, concurrent admistration of &bgr;-lactamase inhibitor such as clavulante of sulbacam markedly expands the spectrum of activity of these drugs.
Amoxicillin, a penicillinase-susceptible semi-synthetic pencillin, is a close chemical and pharmacological relative of ampicillin. The drug is stable in acid and is designed or oral use. It is more rapidly and completely absorbed from the gastrointestinal tract than is ampicillin, which is the major difference between the two. The antimicrobial spectrum of amoxicillin is essentially identical to that of ampicillin, with the important exception that amoxicillin appears to be less effective than ampicillin for shigellosis (Neu, 1979).
Peak concentrations of amoxicillin (AMOXIL, others) in plasma are two to two and one-half times greater for amoxicillin than for ampicillin after oral administration of the same doses; they are reached at 2 hours and average about 4 &mgr;g/ml when 250 mg is adminstered. Food does not interfere with absorption. Perhaps because of more complete absorption of this congener, the incidence of diarrhea with amoxicillin is less than that following administration of ampicillin. The incidence of other adverse effects appears to be similiar. While the half-life of amoxicillin is similar to that for ampicillin, effective concentrations of orally administered amoxicilin are detectabale in the plasma for twice as long as with ampicillin, again because of the more complete absorption. About 20% of amoxicillin is proteinbound in plasma, a value similar to that for ampicillin. Most of a dose of the antibiotic is excreted in an active form in the urine. Probenecid delays excretion of the drug. (See Gordon et al., 1972)
U.S. Pat. No. 5,725,879 (Daoudal) describes a veterinary tablet for promoting ingestion of medicinal substances by domestic animals, especially by cats. U.S. Pat. No. 5,725,879 fails to disclose that the composition can be orally administered either directly or through drinking water.
U.S. Pat. No. 5,643,902 (Cracknell) describes a formulation comprising amoxycillin or a veterinary acceptable derivative thereof, clavulanic acid or a veterinary acceptable derivative thereof, and a veterinarily acceptable carrier is used in the treatment of farrowing fever and/or bacterial pneumonia in pigs. U.S. Pat. No. 5,643,902 fails to disclose or teach a water-soluble form of the amoxicillin compound useful in treating animals, as well as humans, without loss of antibiotic benefits. Moreover, the preferred veterinarily acceptable carriers include acceptable oils such as mineral oils or fractionated cocunut oil. And finally, the formulation is administered to the animal by intramuscular injection.
U.S. Pat. No. 4,145,429 (Clarke) describes a fluid pharmaceutical formulation for oral administration to animals comprising a medicament, an edible oil, and an oleophilic clay (thickening agent). For the same reasons given above, U.S. Pat. No. 4,145,429 fails to disclose or teach a water-soluble form of the amoxicillin compound useful in treating animals, as well as humans, without loss of antibiotic benefits. Again, an oil-based formulation teaches away from applicants' present invention.
U.S. Pat. No. 3,940,483 (Dursch) describes dry solid antibiotic compositions of a solid acidic, basic or amphoteric antibiotic, inclusive of amoxicillin, such as cephalexin, and a suitable solid basic or acidic additive, for reconstitution as injectables upon addition of water. According to this patent, antibiotics of limited water solubility are formulated for parenteral application either as aqueous suspensions, or by preparing water soluble derivatives (e.g., salts, esters of complexes) of the parent compound, which upon parenteral administration are either in equilibrium with the parent compound, or which are transformed back into the parent compound in the patient's system. The patentee states that a solids in suspensio
Soderland Pat
Strobel Michael
Pharmaceutical Solutions, Inc.
Ryan John W.
Weddington Kevin E.
Wilmer Cutter & Pickering
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