Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-05-03
2002-08-20
Bansal, Geetha P. (Department: 1642)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C514S021800, C530S324000
Reexamination Certificate
active
06436901
ABSTRACT:
The present invention relates to compositions containing hirudin and in particular to stable powder formulations.
Hirudin, an anticoagulant naturally occurring in leeches (
Hirudo medicinalis
), is not a single polypeptide species but a class of equally acting polypeptides consisting of at least four representatives designated hirudin variant 1 (HV1), hirudin variant 2 (HV2) (cf. European Patent Application No. 158 564) hirudin variant 3 (PA) [cf. PCT-Application No. 86/03493] and “des-(Val)
2
-hirudin” (cf. European Patent Application No. 158 986). The variants differ in structure from each other by a number of amino acids (especially, the N-terminal sequence of HV1 is Val-Val-Tyr, that of HV2 and of HV3 is Ile-Thr-Tyr and that of “des-(Val)
2
-hirudin” is Thr-Tyr) but have an accumulation of hydrophobic amino acids at the N-terminus and of polar amino acids at the C-terminus, a tyrosine residue (Tyr
63
) present as sulphate monoester, three disulphide bridges and the anticoagulant activity in common.
In the past few years cDNAs and synthetic genes coding for hirudin variants have been cloned and expressed in microbial hosts. Although the expression products lack the sulphate monoester group at Tyr
63
- and were therefore designated “desulphatohirudins”—they turned out to exhibit approximately the same biological activity as the natural, sulphated hirudins. Desulphatohirudin variant HV1 has been expressed in
Escherichia coli
(European Patent Applications No. 158 564 and 168 342) and in
Saccharomyces cerevisiae
(European Patent Applications No. 168 342, 200 655, 225 633, 252 854 and 341 215). Similarly, desulphatohirudin HV2 has been expressed in
Escherichia coli
(European Patent Applications No. 158 564) and in
Saccharomyces cerevisiae
(European Patent Application No. 200 655, PCT-Application No. 86/01224] and des-(Val)
2
-desulphatohirudin has been expressed in
Escherichia coli
(European Patent Application No. 158 986).
According to the present invention, the term “hirudin” is intended to embrace hirudin, desulphathohirudin, a hirudin variant or a desulphatohirudin variant or a mutant thereof, respectively, described in the literature and in particular a desulphatohirudin compound or a mutant thereof obtainable from a transformed microorganism strain containing DNA which codes for a desulphatohirudin or a mutant thereof. Such desulphatohirudins are, for example, desulphatohirudin variant HV1, HV1 modified (a, b), HV2, HV2 modified (a, b, c), HV3, variants of HV3 and des (Val
2
)-desulphatohirudin.
Preferred desulphatohirudins are those having the formula (SEQ ID NO: 1)
Val Val Tyr Thr Asp Cys Thr Glu Ser Gly Gln Asn Leu Cys Leu Cys
(I)
1 5 10 15
Glu Gly Ser Asn Val Cys Gly Gln Gly Asn Xaa Cys Ile Leu Gly Ser
20 25 30
Asp Gly Glu Xaa Asn Gln Cys Val Thr Gly Glu Gly Thr Pro Xaa Pro
35 40 45
Gln Ser Xaa Asn Asp Gly Asp Phe Glu Glu Ile Pro Glu Xaa
50 55 60
in which
a) Xaa at 27, 36 end 47 are each Lys, Xaa at 51 is His and Xaa at 62 is the peptide residue Glu-Tyr-Leu-Gln (HV1 ), or
b) Xaa at 27 is Ile or Glu and Xaa at 36,47,51 and 62 are as defined in a) (HV1 modified a), or
c) Xaa at 36 is Ile or Glu and Xaa at 27, 47, 51 and 62 are as defined in a) (HV1 modified a), or
d) Xaa at 47 is Ile or Glu and Xaa at 27, 36, 51 and 62 are as defined in a) (HV1 modified a), or
e) Xaa at 51 is Leu or Asp and Xaa at 27, 36, 47 and 62 are as defined in a) (HV1 modified a), or
f) Xaa at 62 is selected from the group consisting of Glu-Tyr, Glu-Tyr-Leu, Glu-Asp-Leu-Gln, Glu-Glu-Leu-Gln, Glu-Tyr-Lys-Arg, Glu-Asp-Lys-Arg, Glu-Lys-Leu-Gln, Ser-Phe-Arg-Tyr, Trp-Glu-Leu-Arg, Glu-Tyr-Leu-Gln-Pro and Glu-Tyr-Leu-Gln-Arg and Xaa at 27, 36, 47 and 51 are as defined in a) (HV1 modified b),
or having the formula (SEQ ID NO: 2)
Leu Thr Tyr Thr Asp Cys Thr Glu Ser Gly Gln Asn Leu Cys Leu Cys
(II)
1 5 10 15
Glu Gly Ser Asn Val Cys Gly Gln Gly Asn Lys Cys Ile Leu Gly Ser
20 25 30
Asp Gly Glu Lys Asn Gln Cys Val Thr Gly Glu Gly Thr Pro Lys Pro
35 40 45
Gln Ser His Asn Asp Gly Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu
50 55 60
Gln
65
or having the formula (SEQ ID NO: 3)
Ile Thr Tyr Thr Asp Cys Thr Glu Ser Gly Gln Asn Leu Cys Leu Cys
(III)
1 5 15
Glu Gly Ser Asn Val Cys Gly Lys Gly Asn Lys Cys Ile Leu Gly Ser
20 25 30
Asn Gly Lys Gly Asn Gln Cys Val Thr Gly Glu Gly Thr Pro Xaa Pro
35 40 45
Glu Ser His Asn Asn Gly Asp Phe Glu Glu Ile Pro Glu Glu Xaa Leu
50 55 60
Gln
65
in which
a) Xaa at 47 is Asn and Xaa at 63 is Tyr (HV2), or
b) Xaa at 47 is Lys, Arg or His and Xaa at 63 is Tyr (HV2 modified a), or
c) Xaa at 63 is Glu or Asp and Xaa at 47 is Asn (HV2 modified b), or having the formula SEQ ID NO: 4)
Val Val Tyr Thr Asp Cys Thr Glu Ser Gly Gln Asn Leu Cys Leu Cys
(IV)
1 &emsp
Bansal Geetha P.
Pfeiffer Hesna J.
UCP Gen-Pharma AG
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