Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2001-01-12
2001-10-30
Henley, III, Raymond (Department: 1641)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
Reexamination Certificate
active
06310094
ABSTRACT:
SUMMARY OF THE INVENTION
The present invention relates to a ready-to-use injectable, aqueous pharmaceutical composition for the treatment of cardiac conditions comprising methyl-3-[4-(2-hydroxy-3-isopropylamino propoxy] phenylpropionate hydrochloride (esmolol hydrochloride), a buffering agent and an osmotic-adjusting agent, and further relates to a method for its manufacture in a container.
BACKGROUND OF THE INVENTION
Esmolol hydrochloride is a short-acting beta-blocker used for treatment or prophylaxis of cardiac disorders in mammals. Most of the currently available beta-blockers are stable drugs which can be administered to cardiac patients over relatively long periods of time. However, it is often desirable in the critical care setting to quickly reduce heart work or improve rhythmicity during a cardiac crisis, e.g., during or shortly after a myocardial infarction. Conventional beta-blocking agents can be employed for such treatment, but their long durations of action can cause undesirable side effects.
Esmolol hydrochloride contains an ester functional group and possesses the typical beta-adrenergic blocking activity. However, it differs from conventional beta-blocking compound in that esmolol hydrochloride has a short duration in vivo due to the presence of the ester group. Thus, esmolol hydrochloride is advantageous compared to the conventional beta-blockers because of its unique short-acting activity. However, the ester group in esmolol hydrochloride is found to be unstable in an aqueous environment because of it extreme susceptibility to hydrolytic degradation.
The stability of esmolol in water is mediated by the rate of acid/base hydrolysis of the labile aliphatic methyl ester group. In the past, the rate of degradation of esmolol hydrochloride has been reduced by the use of acetate as a buffer, maintaining the pH as close to 5.0 as possible, minimizing the concentration of esmolol in the solution, and minimizing the concentration of buffer used. Prior art formulations maintain a reasonably long shelf-life, however, they are packaged in glass vials or ampules, and suffer from severe degradation upon autoclaving. As a result, prior art formulations are prepared aseptically. C.f. U.S. Pat. No. 4,857,552. However, terminal sterilization is typically preferred by regulatory authorities as a way of reducing microbiological burden and to ensure the safety of the finished product.
In addition, the formulation disclosed in U.S. Pat. No. 4,857,552 is a small volume injectable formulation. For the purposes of intravenous infusion, the disclosed formulation must be further diluted in pharmaceutically acceptable diluents prior to use. This creates a potential opportunity for calculation or dilution error in a hospital setting. Additionally, microbiological contamination of the product during dilution/aseptic handling is of primary concern. Therefore, there remains a need for a ready-to-use large volume parenteral esmolol hydrochloride that is microbiologically safe and stable in vitro during storage.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a stable, ready-to-use parenteral solution containing esmolol hydrochloride and a pharmaceutically acceptable buffering agent and an osmotic adjusting agent to adjust the tonicity of the solution. The solution can be packaged in a sealed container and subjected to terminal sterilization via autoclaving to reduce the microbiological burden of the formulation. Esmolol hydrochloride formulations of the prior art cannot survive autoclaving. The present invention is stable against hydrolytic degradation and other adverse chemical reactions, and possesses a pharmaceutically-acceptable shelf-life. The product is a ready-to-use infusion which can be used directly without requiring any additional procedures for dilution. This avoids the inconvenience of diluting a concentrated esmolol small volume parenteral formulation into infusion diluents prior to infusion along, eliminates the risk of microbiological contamination during aseptic handling and any potential calculation or dilution error. As a result, the present invention enhances patient safety and physician
urse compliance with use of esmolol injection.
The pH of the composition greatly effects its stability. The pH should be between 3.5 and 6.5, preferably between 4.5 and 5.5, more preferably about 5.0. The pH can be adjusted as known in the art by addition of sodium hydroxide or hydrochloric acid. Esmolol hydrochloride is present in the instant composition in an amount ranging from 0.1-100 mg/ml, preferably 1-10 mg/ml.
Suitable buffering agents are known in the art, and are present in the composition in an amount ranging from 0.1-5.0 mg/ml, preferably 0.4-3.0 mg/ml. Buffering agents include acetate, glutamate, citrate, tartrate, benzoate, lactate, gluconate, phosphate and glycine. The preferred buffering agent is acetate.
Suitable osmotic-adjusting agents are known in the art, and are present in the composition in an amount ranging from 1-10 mg/ml. Osmotic-adjusting agents include sodium chloride, dextrose, sodium bicarbonate, calcium chloride, potassium chloride, sodium lactate, Ringer's solution and lactated Ringer's solution. Preferred are sodium chloride, in an amount ranging from 4-60 mg/ml, more preferably 4-10 mg/ml, and dextrose, in an amount ranging from 25-60 mg/ml. Dextrose is preferably present in the composition of the present invention at a level no greater than 5% (weight by weight) in combination with sodium chloride.
Compositions according to the present invention are packaged in suitable sealed containers, which may be either glass or polymer-based. Polymeric containers are preferably flexible, and can be contain or be free of polyvinylchloride (PVC). Preferred containers are free of PVC, such as those disclosed in U.S. Pat. Nos. 5,849,843 and 5,998,019.
The polymeric containers can further be provided with a moisture barrier as a secondary packaging system to prevent the loss of water during storage and to further ensure the stability of the formulation. A preferred moisture barrier is an aluminum overpouch.
Procedures for filling compositions of the present invention in containers, and their subsequent processing are known in the art. Typical autoclave cycles in the pharmaceutical industry to achieve terminal sterilization of the final product are 121° C. for 15 minutes. The esmolol hydrochloride composition of the present invention can be autoclaved at a temperature ranging from 115 to 130° C. for a period of time ranging from 5 to 40 minutes with acceptable stability. Autoclaving is preferably carried out in the temperature range of 119° C. to 122° C. for a period of time ranging from 20 to 36 minutes.
REFERENCES:
patent: 4857552 (1989-08-01), Rosenberg et al.
Liu Jie
Owoo George
Pejaver Satish K.
Baxter International Inc.
Henley III Raymond
Jaconetty Kenneth E
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