Injectable aqueous dispersions of propofol
AssigneeJagotec AG
InventorsAWADHESH K. MISHRA, GARY W. PACE, MICHAEL G. VACHON
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Abstract
It was found that certain propofol compositions, prepared as an injectable aqueous dispersion of a water-insoluble matrix consisting of propofol and propofol-soluble agents, were capable of substantially limiting or inhibiting the growth of certain microorganisms and did not display the incidence of irritation at the injection site as evidenced by the in-vivo experiments.
Claims14
A stable, sterile, and injectable aqueous dispersion of a water-insoluble microdroplet matrix of mean diameter from about 50 nm to about 1000 nm consisting essentially of
- (a) between about 1% to about 15% of propofol;
- (b) between about 1% to about 8% of a propofol soluble diluent;
- (c) between about 0.5% to about 5% of a surface stabilizing amphiphilic agent;
- (d) of a pharmaceutically acceptable water-soluble polyhydroxy additive that acts as a tonicity modifier;
- and
- (e) provided the ratio of propofol to diluent is about 1:4 to about 1:0.1 and the ratio of propofol to amphiphlic agent is about 1:0.8 to about 1:2.5, and the composition has a viscosity of from about 0.8 to about 15 centipoise, wherein the formulation
- prevents microbial growth, defined as no more than 0.5 log increase from the initial inoculum, of each of Staphylococcus aureus (ATCC 6538), Escherichia coli (ATCC 8739 and ATCC 8454), Pseudomonas aeruginosa (ATCC 9027), Candida albicans (ATCC 10231), and Aspergillus niger (ATCC 16403) for at least 7 days as measured by a test wherein a washed suspension of each said organism is added to a separate aliquot of a formulation at approximately 1000 colony forming units (cfu) per mL, at a temperature in the range 20-25° C., whereafter said aliquots are incubated at 20-25° C. and are tested for viability of the microorganisms in the inoculated formulation as determined by counting the colonies of said organism after 24, 48 hours and 7 days or other suitable length of time;
- results in little or no irritation at the site of injection as evidenced by a test wherein said composition is administered as a single daily bolus injection of 12.5 mg/kg, given on the basis of body weight, for 2 or 3 successive days over a period of approximately 30 seconds, in the caudal vein of a rat such that no visual increase in the diameter of the rat tail is noted after 48 hrs post injection.
The method of reducing or substantially completely eliminating irritation upon injection of formulations containing propofol by administering a stable, sterile, and antimicrobial, aqueous dispersion of water-insoluble microdroplet matrix of mean diameter from about 50 nm to about 1000 nm consisting essentially of about 1% to about 15% of propofol as the active ingredient, up to about 7% of a propofol soluble diluent, and about 0.8% to about 4% of a surface stabilizing amphiphilic agent, and the aqueous phase of the composition consisting of a pharmaceutically acceptable water-soluble polyhydroxy tonicity modifier, the composition being devoid of additional bactericidal or bacteriostatic preservative agents, provided the ratio of propofol to diluent is about 1:4 to about 1:0.1 and the ratio of propofol to amphiphlic agent is about 1:0.8 to about 1:2.5, and the composition has a viscosity of from about 0.8 to about 15 centipoise.
The method of inducing anesthesia comprising administering to a subject in need of same an anesthetic inducing amount of a stable, sterile, and antimicrobial injectable aqueous dispersion of a water-insoluble microdroplet matrix of mean diameter from about 50 nm to about 1000 nm consisting essentially of about 1% to about 15% of propofol as the active ingredient, up to about 7% of a propofol soluble diluent, and about 0.8% to about 4% of a surface stabilizing amphiphilic agent, and the aqueous phase of the composition consisting of a pharmaceutically acceptable water-soluble polyhydroxy tonicity modifier, the composition being devoid of additional bactericidal or bacteriostatic preservative agents, provided the ratio of propofol to diluent is about 1:4 to about 1:0.1 and the ratio of propofol to amphiphlic agent is about 1:0.8 to about 1:2.5, and the composition has a viscosity of from about 0.8 to about 15 centipoise.
Dependencies are inferred from the claim text.