Formulations of hydrophobic proteins in an immunogenic composition having improved tolerability
AssigneeWyeth
InventorsSusan Kay Hoiseth, Thomas Newell Metcalf, III, Yury Vladimirovich Matsuka, Michael Hagen, Lakshmi Khandke
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Abstract
The present invention provides a method for producing a less-painful immunogenic composition of a hydrophobic protein in a pharmaceutically acceptable carrier suitable for administering to a mammal, comprising the steps of (a) solubilizing said hydrophobic protein with a zwitterionic detergent to make a first composition; (b) altering said first composition, such that the altered composition produces a reduction in pain as measured in the rat footpad model as compared to said first composition.
Claims38
A non-painful immunogenic composition of a hydrophobic protein suitable for injection in a human comprising:
- (a) a hydrophobic protein;
- (b) an amount of a zwitterionic detergent that is less than the amount required to solubilize the protein;
- and
- (c) an amount of a pharmaceutically acceptable nonionic detergent effective to maintain solubility of the protein in a pharmaceutically acceptable carrier and,
- wherein the zwitterionic detergent is selected from the group consisting of n-Octyl-N,N-dimethyl-3-ammonio-1-propanesulfonate;
- n-Decyl-N,N-dimethyl-3-ammonio-1-propanesulfonate;
- n-Dodecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate;
- n-Tetradecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate;
- 3-(N,N-n-Hexadecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate;
- 3-[(3-Cholamidopropyl) dimethylammonio]-1-propanesulfonate;
- 3-[(3-Cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonate;
- and n-Dodecyl-N,N-dimethylglycine.
A method for producing a less-painful immunogenic composition of a hydrophobic protein in a pharmaceutically acceptable carrier suitable for administering to a mammal, comprising the steps of
- (a) solubilizing said hydrophobic protein with a zwitterionic detergent to make a first composition;
- (b) altering said first composition, such that the altered composition is less painful as compared to said first composition,
- wherein the altering step (b) is selected from the group consisting of (i) diluting the zwitterionic detergent where the hydrophobic protein is in a precipitated form, (ii) exchanging the zwitterionic detergent with a non-pain causing nonionic detergent, and (iii) adding a non-pain causing nonionic detergent but keeping the concentration of the zwitterionic detergent constant.
A method of reducing the pain associated with administering an immunogenic composition comprising a hydrophobic protein and a zwitterionic detergent into a mammal, which method comprises
- (a) altering said composition, such that the altered composition is less painful as compared to the unaltered composition, and
- (b) administering said immunogenic composition,
- wherein the altering step (a) is selected from the group consisting of (i) diluting said zwitterionic detergent where the hydrophobic protein is in a precipitated form, (ii) exchanging said zwitterionic detergent with a non-pain causing nonionic detergent, and (iii) adding a non-pain causing nonionic detergent but keeping the concentration of the zwitterionic detergent constant.
A method of reducing the pain associated with administering an immunogenic composition comprising a hydrophobic protein and a zwitterionic detergent into a mammal, which method comprises
- (a) altering said composition, such that the altered composition produces a reduction in pain as measured in the rat footpad model as compared to the unaltered composition, and
- (b) administering said immunogenic composition
- wherein the altered composition produces at least about a 50% reduction in pain as measured in the rat footpad model as compared to the unaltered composition.
A method of maintaining solubility of a hydrophobic protein in an immunogenic composition, which method comprises:
- solubilizing a hydrophobic protein in a non-pain causing nonionic detergent, wherein non-pain causing nonionic detergent is alpha-[4-(1,1,3,3-tetramethylbutyl)phenyl]-omega-hydroxypoly(oxy-1,2-ethanediyl).
A method for immunizing humans with compositions containing hydrophobic membrane proteins without causing pain, which method comprises selecting alpha-[4-(1,1,3,3-tetramethylbutyl)phenyl]-omega-hydroxypoly(oxy-1,2-ethanediyl (Triton X-100) as a pharmaceutically acceptable detergent for maintaining solubility of hydrophobic proteins in the final formulation;
- wherein the concentration of Triton X-100 is above the CMC.
Dependencies are inferred from the claim text.