Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector
Reexamination Certificate
1998-02-06
2004-09-14
Huff, Sheela (Department: 1642)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
C424S189100
Reexamination Certificate
active
06790445
ABSTRACT:
STATEMENT REGARDING FEDERALLY-SPONSORED R&D
Not applicable.
REFERENCE TO MICROFICHE APPENDIX
Not applicable.
FIELD OF THE INVENTION
The disclosure relates to thimerosal-free preservatives for vaccines.
BACKGROUND OF THE INVENTION
For multidose vaccine formulations, preservatives are required to prevent contamination of and to stabilize the composition of subsequent doses after the first dose is used. The preservative must enable the vaccine formulation to pass efficacy tests or antimicrobial challenge tests according to the United States Pharmacopeia (USP) in the U.S., British Pharmacopeia (BP), and European Pharmacopeia (EP) in Europe.
Thimerosal is a commonly-used preservative in vaccines. Thimerosal is a mercurial compound that is potentially toxic, and causes allergic reaction in about sixteen percent of the population. Thimerosal is also toxic to the environment.
It would be advantageous to find new and safer preservatives for vaccines to replace thimerosal. In this application, we report on new combinations of preservatives for vaccines: methyl and propyl parabens, benzyl alcohol, and 2-phenoxy-ethanol. These combination preservatives are non-toxic, yet effective.
One dose of vaccine (0.5 mL) has about 1 mg paraben. Toxicity of the parabens is relatively low, due to the ease and rapidity with which the body rids itself of these drugs. The LD
50
of methyl paraben in mice intraperitoneally is 1 g/kg.
One dose of vaccine has about 7.5 mg benzyl alcohol. This amount is below harmful levels. Benzyl alcohol is metabolized to benzoic acid, which is conjugated with glycine in the liver, and excreted as hippuric acid. The probable lethal dose of benzyl alcohol is 0.5-5.0 g/kg.
One dose of vaccine has 2 mcL of 2-phenoxyethanol. Toxicity of 2-phenoxyethanol is low. It has been in commercial use for several decades. The presence of 2-phenoxyethanol is known in volatile naturally occurring substances, such as green tea. The acute oral LD
50
in rats is 1.26-2.33 mL/kg. The acute dermal LD
50
in rabbits is 2.0 mL/kg.
Due to stringent antimicrobial requirements of the various pharmacopeias, finding the right preservative for vaccine formulations is a challenge. The pH of the vaccine should be maintained at approximately pH 7. pH also has an effect on the antimicrobial effectiveness of the preservatives. Solubility of some preservatives, such as the parabens, at pH 7 and at 4° C. is a limiting factor. Thus, the use of combination preservatives such as methyl and propyl parabens helps to solubilize more parabens. Each paraben has its own solubility for pH 7 and 4 degrees centigrade. Using both methyl and propyl parabens together rather than separately, helps to put more paraben in solution. Methyl paraben and propyl paraben work synergistically, since they exhibit differential antimicrobial activities.
The search for an effective buffer which maintains pH at pH 7 and which is safe for injectibles, is another challenge. Phosphate is the most commonly used buffer of choice for pH 7. However, phosphate buffer is incompatible with many forms of aluminum hydroxide adjuvant used in vaccine formulations. Other buffers effective at this pH range may not be safe for injectibles. In this application, we report the use of L-histidine, because it is an effective buffer at pH 7, and at 20-35 mM final concentration is safe to use in vaccines.
We have developed sample preparation and high performance liquid chromatography methods for analyzing these preservatives and their degradation products in vaccines. Methods for simultaneously analyzing some of these preservatives and their degradation products are not yet present in the literature.
SUMMARY OF THE INVENTION
New combinations of preservatives that pass antimicrobial testing requirements for United States Pharmacopeia (USP), British Pharmacopeia (BP), and European Pharmacopeia (EP). They are: (1) 1.5% benzyl alcohol; (2) 0.225% methyl paraben sodium, 0.025% propyl paraben sodium; and 0.9% benzyl alcohol, and (3) 0.225% methyl paraben sodium, 0.025% propyl paraben sodium, and 0.375% 2-phenoxyethanol. L-histidine is used as a buffer to keep pH of vaccines neutral. A new technique for analysis of combination preservatives and their degradation products in vaccines is also provided.
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Tracy, et al., “Preservatives for Poliomyelitis (Salk) Vaccine II”, Journal of Pharmaceutical Sciences vol. 53, No. 6, Jun. 1964, pp. 659-663.
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Hennessey John P.
Mancinelli Ralph J.
Ng Assunta S.
Huff Sheela
Merck & Co. , Inc.
Tribble Jack L.
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