Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Patent
1990-01-16
1992-01-07
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
424426, A61K 31545
Patent
active
050790072
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to the controlled release of antibiotics.
BACKGROUND OF THE INVENTION
It is known in the pharmaceutical art to prepare compositions which provide for slow release of pharmacologically-active substances contained in said compositions after oral administration to humans and animals. Such slow-release compositions are used to delay absorption of a medicament until it has reached certain portions of the alimentary tract. Such controlled release of a medicament in the alimentary tract further maintains a desired concentration of said medicament in the blood stream for a longer duration than would occur if conventional rapid release dosage forms are administered.
A controlled-release formulation comprising a matrix having dispersed therein both the pharmacologically-active salt form of a medicament and the free base form of the same medicament is described in U.S. Pat. No. 4,443,428. In each of the formulations described therein, the amount of excipients is in excess of 20% by weight. A similar formulation, but one that is based upon varying the water solubility of the active medicament, is described in WO-A-8102975.
Controlled-release formulations containing mixed esters of a medicament are described in FR-A-2571371.
Derwent abstracts a European patent application where a mixture of crystalline diasteromeric salts of a medicament causes production of isomers to produce a sustained release effect.
Ceftiofur (Formula I) is a known cephalosporin antibiotic, and is disclosed in U.S. Pat. No. 4,464,367.
SUMMARY OF THE INVENTION
The present invention particularly provides a formulation providing for the controlled release implant of a cephalosporin antibiotic, consisting of (a) a crystalline salt of the cephalosporin; (b) an amorphous salt of the cephalosporin; and (c) excipients; wherein the excipients comprise from 0% to 10% of the formulation, e.g. a tablet, by weight.
DESCRIPTION OF THE INVENTION
Intramuscular implantation is the preferred route of administration of the formulation.
The amount of crystalline salt can vary from 20% to 90%, preferably 80% to 90%, by weight. Crystalline salts that can be used include the hydrohalide salts, e.g. ceftiofur hydrochloride (preferred), ceftiofur hydrobromide and ceftiofur hydroiodide. In addition to the sodium salt, other alkali metal salts that can be used are the potassium and lithium salts, i.e., ceftiofur sodium salt, ceftiofur potassium salt and ceftiofur lithium salt.
The crystalline and amorphous salts can be blended and compressed with or without additional excipients to yield an implant with controlled-release characteristics.
A particularly effective formulation can be prepared utilizing ceftiofur monohydrochloride as the crystalline salt and the corresponding sodium salt, hydrate (ceftiofur sodium salt) as the amorphous salt.
Pellets of the formulations of this invention can be made by mixing the crystalline and amorphous salts and compressing them under standard press conditions.
Particularly effective formulations contain no excipients. Alternatively, excipients such as high molecular weight polyethylene glycols or polyvinyl pyrrolidone, up to 4% of total weight, as excipients, can be added to the formulation. Also, a lubricant and stabilizer such as stearic acid may be added. However, the weight of excipients should not exceed 10% and preferably 7% of the total tablet weight.
DESCRIPTION OF THE PREFERRED EMBODIMENT
The present invention is seen more fully by the example given below.
EXAMPLE
A powder mixture suitable for compression can readily be made by blending the proper weight to weight ratio (for example, 50/50) of crystalline ceftiofur hydrochloride and amorphous ceftiofur sodium salt in a glass mortar using appropriate mixing techniques. Portions of the mixture can be weighed and compressed using a standard laboratory Carver press and tablet tooling capable of containing the entire sample, e.g. 20.6 mm (13/16 inch) tablet tooling. Compression of up to 8.9 kN (2000 pounds) should be
REFERENCES:
patent: 4443428 (1984-04-01), Oshlack et al.
patent: 4877782 (1989-10-01), Cazers et al.
patent: 4902683 (1990-02-01), Amin et al.
Hulina Amy
Page Thurman K.
The Upjohn Company
Williams, Jr. Sidney B.
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