US4606918A — Polyoxypropylene-polyoxyethylene block polymer ba…

Claim 1

Independent Claim 327 words

A method for enhancing the immunogenicity of an antigen which method comprises forming a multi-phase system by mixing an antigen with an adjuvant composition comprising: an immunopotentiating amount of an immunostimulating glycopeptide, wherein said glycopeptide is a compound of the formula ##STR4## wherein R and R 1 are the same or different and are hydrogen or an acyl radical containing from 1 to 22 carbon atoms; R 2 is an unsubstituted or substituted alkyl radical containing from 1 to 22 carbon atoms, or an unsubstituted or substituted aryl radical containing from 6 to 10 carbon atoms; R 3 is hydrogen, alkyl, or aryl of 7 to 10 carbon atoms; R 4 is hydrogen or alkyl of 1 to 6 carbon atoms; X is an aminoacyl moiety selected from the group consisting of alanyl, valyl, leucyl, isoleucyl, α-aminobutyryl, threonyl, methionyl, cysteinyl, glutamyl, glutaminyl, aspartyl, phenylalanyl, tyrosyl, tryptophanyl, lysyl, ornithinyl, arginyl, histidyl, asparginyl, prolyl, hydroxylprolyl, seryl, or glycyl; R 5 denotes a carboxyl group or a carboxyl group esterified with a lower alkanol, or the carbamoyl group, which, on the nitrogen atom, is unsubstituted or mono-substituted or di-substituted by alkyl, aryl, aralkyl, alkylidene, or carbamoylmethyl; and R 6 denotes a carboxyl group or a carboxyl group esterified with a lower alkanol, or the carbamoyl group, which, on the nitrogen atom, is unsubstituted or mono-substituted or di-substituted by alkyl, aryl, aralkyl, alkylidene, or carbamoylmethyl; and a multi-phase-forming amount of a non-toxic polyoxypropylenepolyoxyethylene block polymer which is liquid over a temperature range between about 15°-40° C., and which has a polyoxypropylene base with molecular weight between about 2250 and 4300, and which has polyoxyethylene in an amount between about 1 and 30%, in an amount of 0.2 to 49% by volume (v/v); a multi-phase-stabilizing amount of a glycol ether-based surfactant in an amount between 0.05 to 2.5% by volume (v/v); and buffered isoosmotic saline in a quantity sufficient to make volume; and administering said multi-phase system to a bird or mammal.

Claim 2

Independent Claim 327 words

A method for enhancing the immunogenicity of an antigen which method comprises forming a multi-phase system by mixing an antigen with an adjuvant composition comprising: an immunopotentiating amount of an immunostimulating glycopeptide, wherein said glycopeptide is a compound of the formula ##STR4## wherein R and R 1 are the same or different and are hydrogen or an acyl radical containing from 1 to 22 carbon atoms; R 2 is an unsubstituted or substituted alkyl radical containing from 1 to 22 carbon atoms, or an unsubstituted or substituted aryl radical containing from 6 to 10 carbon atoms; R 3 is hydrogen, alkyl, or aryl of 7 to 10 carbon atoms; R 4 is hydrogen or alkyl of 1 to 6 carbon atoms; X is an aminoacyl moiety selected from the group consisting of alanyl, valyl, leucyl, isoleucyl, α-aminobutyryl, threonyl, methionyl, cysteinyl, glutamyl, glutaminyl, aspartyl, phenylalanyl, tyrosyl, tryptophanyl, lysyl, ornithinyl, arginyl, histidyl, asparginyl, prolyl, hydroxylprolyl, seryl, or glycyl; R 5 denotes a carboxyl group or a carboxyl group esterified with a lower alkanol, or the carbamoyl group, which, on the nitrogen atom, is unsubstituted or mono-substituted or di-substituted by alkyl, aryl, aralkyl, alkylidene, or carbamoylmethyl; and R 6 denotes a carboxyl group or a carboxyl group esterified with a lower alkanol, or the carbamoyl group, which, on the nitrogen atom, is unsubstituted or mono-substituted or di-substituted by alkyl, aryl, aralkyl, alkylidene, or carbamoylmethyl; and a multi-phase-forming amount of a non-toxic polyoxypropylenepolyoxyethylene block polymer which is liquid over a temperature range between about 15°-40° C., and which has a polyoxypropylene base with molecular weight between about 2250 and 4300, and which has polyoxyethylene in an amount between about 1 and 30%, in an amount of 0.2 to 49% by volume (v/v); a multi-phase-stabilizing amount of a glycol ether-based surfactant in an amount between 0.05 to 2.5% by volume (v/v); and buffered isoosmotic saline in a quantity sufficient to make volume; and administering said multi-phase system to a bird or mammal.

Claim 3

Dependent Claim 24 words

The method of claim 1 wherein said adjuvant further comprises a metabolizable, non-toxic oil in an amount between 1 to 30% by volume (v/v).

Claim 4

Dependent Claim 19 words

The method of claim 1 wherein said glycopeptide is present in an amount between 0.01 to 2% by weight/volume.

Claim 5

Dependent Claim 153 words

The method of claim 3 wherein the glycopeptide of Formula I is substituted as follows: R and R 1 are the same or different and are selected from the group consisting of hydrogen or an acyl radical containing from 1 to 22 carbon atoms; R 2 is methyl; R 3 is hydrogen; X is an aminoacyl moiety selected from the group consisting of L-seryl, L-alanyl, L-valyl, L-leucyl, L-isoleucyl, L-α-aminobutyryl, L-seryl, L-threonyl, L-methionyl, L-cysteinyl, L-phenylalanyl, L-tyrosyl, L-tryptophenyl, L-lysyl, L-ornithyl, L-arginyl, L-histidyl, L-glutamyl, L-glutamanyl, L-aspartyl, L-asparaginyl, L-prolyl, or L-hydroxyprolyl, being present in an amount between 0.01 to 1% (w/v); said block polymer has a polyoxypropylene base of molecular weight between 2,750 and 3,550 and wherein the percentage of polyoxyethylene in the total molecule is 5-20%, said polymer being present in an amount between 0.2 to 20% (v/v); and said glycol ether surfactant is a polysorbate surfactant present in an amount of 0.2 to 1% (v/v).

Claim 6

Dependent Claim 56 words

The method of claim 4 wherein said glycopeptide is a compound of Formula I wherein R, R 1 and R 3 are hydrogen, R 2 is methyl, R 4 is methyl or hydrogen, X is L-valyl, L-alanyl, L-seryl, L-threonyl or L-α-aminobutyryl, R 5 is carboxyl, carbamoyl or n-butyl carboxylate and R 6 is carboxyl or carbamoyl.

Claim 7

Dependent Claim 64 words

The method of claim 5 wherein said glycopeptide is N-acetylmuramyl-L-threonyl-D-isoglutamine, N-acetyl-L-α-aminobutyryl-D-isoglutamine, 6-O-stearoyl-N-acetylmuramyl-L-α-aminobutyryl-D-isoglutamine, or N-acetyldesmethylmuramyl-L-alanyl-D-isoglutamine present in an amount between 0.01 to 1% (w/v); said block polymer is comprised of a polyoxypropylene base of molecular weight 3550 and has a percentage polyoxyethylene in the total molecule of 10% and is present in an amount between 0.2 to 5% (v/v); and said polysorbate is TWEEN 80.

Claim 8

Dependent Claim 39 words

The method of claim 5 wherein said glycopeptide is n-butyl-N-acetylmuramyl-L-alanyl-D-glutaminate, N-acetylmuramyl-L-alanyl-D-isoglutamine, or N-acetylmuramyl-L-seryl-D-isoglutamine; and said block polymer is comprised of a polyoxypropylene base of molecular weight 3,550 and which contains 10% polyoxyethylene as a percentage of the total molecule.

Claim 9

Dependent Claim 28 words

The method of claim 5 wherein said glycopeptide is N-acetylmuramyl-L-threonyl-D-isoglutamine present in an amount of 0.5% (w/v), and said block polymer is present in an amount of 2.5%.

Claim 10

Dependent Claim 19 words

The method of claim 2 wherein said glycopeptide is present in an amount between 0.01 to 2% by weight/volume.

Claim 11

Dependent Claim 153 words

The method of claim 9 wherein the glycopeptide of Formula I is substituted as follows: R and R 1 are the same or different and are selected from the group consisting of hydrogen or an acyl radical containing from 1 to 22 carbon atoms; R 2 is methyl; R 3 is hydrogen; X is an aminoacyl moiety selected from the group consisting of L-seryl, L-alanyl, L-valyl, L-leucyl, L-isoleucyl, L-α-aminobutyryl, L-seryl, L-threonyl, L-methionyl, L-cysteinyl, L-phenylalanyl, L-tyrosyl, L-tryptophenyl, L-lysyl, L-ornithyl, L-arginyl, L-histidyl, L-glutamyl, L-glutamanyl, L-aspartyl, L-asparaginyl, L-prolyl, or L-hydroxyprolyl, being present in an amount between 0.01 to 1% (w/v); said block polymer has a polyoxypropylene base of molecular weight between 2,750 and 3,550 and wherein the percentage of polyoxyethylene in the total molecule is 5-20%, said polymer being present in an amount between 0.2 to 20% (v/v); and said glycol ether surfactant is a polysorbate surfactant present in an amount of 0.2 to 1% (v/v).

Claim 12

Dependent Claim 56 words

The method of claim 10 wherein said glycopeptide is a compound of Formula 1 wherein R, R 1 and R 3 are hydrogen, R 2 is methyl, R 4 is methyl or hydrogen, X is L-valyl, L-alanyl, L-seryl, L-threonyl or L-α-aminobutyryl, R 5 is carboxyl, carbamoyl or n-butyl carboxylate and R 6 is carboxyl or carbamoyl.

Claim 13

Dependent Claim 64 words

The method of claim 11 wherein said glycopeptide is N-acetylmuramyl-L-threonyl-D-isoglutamine, N-acetyl-L-α-aminobutyryl-D-isoglutamine, 6-O-stearoyl-N-acetylmuramyl-L-α-aminobutyryl-D-isoglutamine, or N-acetyldesmethylmuramyl-L-alanyl-D-isoglutamine present in an amount between 0.01 to 1% (w/v); said block polymer is comprised of a polyoxypropylene base of molecular weight 3550 and has a percentage polyoxyethylene in the total molecule of 10% and is present in an amount between 0.2 to 5% (v/v); and said polysorbate is TWEEN 80.

Claim 14

Dependent Claim 38 words

The method of claim 11 wherein said glycopeptide is n-butyl-N-acetylmuramyl-L-alanyl-D-glutaminate, N-acetylmuramyl-L-alanyl-D-isoglutamine, or N-acetylmuramyl-L-seryl-D-isoglutamine; and said polymer is comprised of a polyoxypropylene base of molecular weight 3,550 and which contains 10% polyoxyethylene as a percentage of the total molecule.

Claim 15

Dependent Claim 27 words

The method of claim 11 wherein said glycopeptide is N-acetylmuramyl-L-threonyl-D-isoglutamine present in an amount of 0.5% (w/v), and said copolymer is present in an amount of 2.5%.

Claim 16

Dependent Claim 38 words

An adjuvant which comprises: (a) 0.01-3% (w/v) N-acetylmuramyl-L-threonyl-D-isoglutamine; (b) 2.5% (w/v) polyoxypropylene-polyoxyethylene block polymer having a polyoxypropylene base of molecular weight 3,250 wherein polyoxyethylene comprises 10% of the polymer; and (c) 0.2-1% (w/v) polyoxyethylene 20 sorbitan monooleate surfactant.

Claim 17

Dependent Claim 38 words

An adjuvant which comprises: (a) 0.01-3% (w/v) N-acetylmuramyl-L-threonyl-D-isoglutamine; (b) 2.5% (w/v) polyoxypropylene-polyoxyethylene block polymer having a polyoxypropylene base of molecular weight 3,250 wherein polyoxyethylene comprises 10% of the polymer; and (c) 0.2-1% (w/v) polyoxyethylene 20 sorbitan monooleate surfactant.

Annuity Stage	Window Opens	Payment Deadline	Surcharge Period Until	Estimated Fee	Status
3.5 Years (Year 4)	1989-08-18	1990-02-17	1990-08-19	$2000.00	Window Closed / Lapsed
7.5 Years (Year 8)	1993-08-18	1994-02-17	1994-08-19	$3760.00	Window Closed / Lapsed
11.5 Years (Year 12)	1997-08-18	1998-02-17	1998-08-19	$7700.00	Window Closed / Lapsed

Polyoxypropylene-polyoxyethylene block polymer based adjuvants

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