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Last Updated: October 19, 2019

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Claims for Patent: 6,313,092

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Summary for Patent: 6,313,092
Title: Method for increasing the electrotransport flux of polypeptides
Abstract:Methods for modifying polypeptide agents to enhance their transdermal electrotransport flux are provided. The polypeptide is modified by reducing the potential of the polypeptide for forming .alpha.-helical or .beta.-sheet segments. In particular, amino acid residues known to stabilize .alpha.-helical and .beta.-sheet segments can be replaced with destabilizing residues and known helix breakers. Modified molecules and compositions including the molecules are also provided.
Inventor(s): Holladay; Leslie A. (Mountain View, CA), Oldenburg; Kevin R. (Fremont, CA)
Assignee: ALZA Corporation (Mountain View, CA)
Application Number:09/007,466
Patent Claims:1. A method of making an analog of a parent polypeptide having enhanced electrotransportability, wherein said parent polypeptide has an amino acid sequence of 10 to 50 amino acid residues and at least one .alpha.-helical segment, said method comprising the steps of:

a. determining the amino acid sequence for said parent polypeptide;

b. establishing a modified sequence of amino acids by replacing one or more amino acids in the .alpha.-helical segment of the parent polypeptide sequence with a substituted amino acid wherein the P.alpha. value of the substituted amino acid is less than the P.alpha. value for the amino acid that was replaced in the parent polypeptide sequence; and

c. producing the analog comprising the modified sequence established in step b.

2. The method of claim 1, wherein the substituted amino acid is selected from the group consisting of Pro, Gly and Asn, and the parent polypeptide has 10-40 amino acid residues.

3. The method of claim 1, wherein said parent polypeptide is a parathyroid hormone molecule as depicted in SEQ ID NO:6.

4. The method of claim 3, wherein the analog is a parathyroid hormone analog as depicted in SEQ ID NO:7.

5. The method of claim 3, wherein the analog is a parathyroid hormone analog as depicted in SEQ ID NO:8.

6. The method of claim 1, wherein said parent polypeptide is hirulog as depicted in SEQ ID NO:9.

7. The method of claim 6, wherein the analog is hirulog-B2 as depicted in SEQ ID NO:10.

8. The method of claim 1, wherein said analog is produced by chemical synthesis.

9. The method of claim 1, wherein said analog is produced recombinantly.

10. A method of making an analog of a parent polypeptide having enhanced electrotransportability, wherein said parent polypeptide has an amino acid sequence 10 to 50 amino acid residues long and at least one sheet segment, said method comprising the steps of:

a. determining the amino acid sequence for said parent polypeptide;

b. establishing a modified amino acid sequence by substituting one or more amino acids in the parent polypeptide sequence with a substituted amino acid wherein the P.sub..beta. value of the substituted amino acid is less than the P.sub..beta. value for the amino acid that was replaced in the parent polypeptide sequence; and

c. producing the analog comprising the modified sequence established in step b.

11. The method of claim 10, wherein the substituted amino acid residue is a member selected from the group consisting of Pro, Gly and Asp and the parent polypeptide has 10-40 amino acid residues.

12. The method of claim 10, wherein said analog is produced by chemical synthesis.

13. The method of claim 10, wherein said analog is produced recombinantly.

14. An electrotransport reservoir composition comprising:

a gel matrix; and

an analog whose amino acid sequence is comprised of a sequence that differs from a parent polypeptide sequence, the parent polypeptide sequence having 10-50 amino residues and at least one .alpha.-helical seqment analog sequence being identical to the .alpha.-helical segment that is different from the parent polypeptide sequence with the exception of haveing at least one amino acid residue substituted in .alpha.-helical segment parent polypeptide that is differnt from the corresponding amino acid in said parent polypeptide such that said different amino acid has a lower P.alpha. value than the corresponding residue in the parent polypeptide, wherein the substituted amino acid is selected from the group consisting of the twenty naturally occuring amino acids and homoisoleucine, asaleucine, 2-(methylenecyclopropyl)glycine, S-methylcysteine, S-(propyl-1-enyl)cysteine, homoserine, ornithine, norleucine, norvaline, homoarginine, 3-(3-carboxyphenyl)alanine, cyclohexylalanine, mimosine, pipecolic acid, 4-methylglutamic acid, canavanine, and 2,3-diaminopropionic acid.

15. An electrotransport device comprising:

a circuit connected to a source of electrical energy;

first and second electrodes including first and second reservoirs, respectively, connected to the source of electrical energy; and

an electrotransport composition according to claim 14 in at least one of the reservoirs.

16. An electrotransport reservoir composition comprising:

a gel matrix; and

an analog whose amino acid sequence comprises a sequence derived from a parent polypeptide, said parent polypeptide having 10-50 amino acid residues and at least one .beta.-sheet segment, said derived sequence having at least one amino acid residue substituted in the .beta.-sheet segment sequence of the parent polypeptide such that said substituted amino acid has a lower P.beta. value than the corresponding residue in the parent polypeptide, wherein the substituted amino acid is one of the 20 naturally occurring amino acids and homoisoleucine, asaleucine, 2-(methylenecyclopropyl)glycine, S-methylcysteine, S-(propyl-1-enyl)cysteine, homoserine, ornithine, norleucine, norvaline, homoarginine, 3-(3-carboxyphenyl)alanine, cyclohexylalanine, mimosine, pipecolic acid, 4-methylglutamic acid, canavenine, and 2,3-diaminopropionic acid.

17. An electrotransport device comprising:

a circuit connected to a source of electrical energy;

first and second electrodes including first and second reservoirs, respectively, connected to the source of electrical energy; and

an electrotransport composition according to claim 16 in at least one of the reservoirs.

Details for Patent 6,313,092

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Nps Pharms Inc NATPARA parathyroid hormone INJECTABLE;INJECTION 125511 001 2015-01-23   Start Trial ALZA Corporation (Mountain View, CA) 2015-06-06 RX Orphan search
Nps Pharms Inc NATPARA parathyroid hormone INJECTABLE;INJECTION 125511 002 2015-01-23   Start Trial ALZA Corporation (Mountain View, CA) 2015-06-06 RX Orphan search
Nps Pharms Inc NATPARA parathyroid hormone INJECTABLE;INJECTION 125511 003 2015-01-23   Start Trial ALZA Corporation (Mountain View, CA) 2015-06-06 RX Orphan search
Nps Pharms Inc NATPARA parathyroid hormone INJECTABLE;INJECTION 125511 004 2015-01-23   Start Trial ALZA Corporation (Mountain View, CA) 2015-06-06 RX Orphan search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

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