Treatment of wrinkles on the upper face

JP2026097980APending Publication Date: 2026-06-16IPSEN BIOPHARM LTD
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Patent Information

Authority / Receiving Office
JP · JP
Patent Type
Applications
Current Assignee / Owner
IPSEN BIOPHARM LTD
Filing Date
2026-03-09
Publication Date
2026-06-16

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Abstract

A modified BoNT / A is provided for use in treating facial wrinkles. [Solution] Modified BoNT / A is administered by intramuscular injection to multiple sites on the target face, where the modified BoNT / A is administered in unit doses of 1 to 41 units per site, and 1 unit is the calculated median lethal dose (LD) in mice. 50 The amount of modified BoNT / A corresponding to ) where multiple sites are selected from: up to 2 sites of the corrugator supercilii muscle and 1 site of the procerus muscle to treat frown lines; up to 5 sites of the frontalis muscle to treat forehead wrinkles; and up to 3 sites of the lateral part of the orbicularis oculi muscle to treat wrinkles at the outer corner of the eye, where the total dose of modified BoNT / A administered during treatment is up to 574 units, and the modified BoNT / A contains modifications to one or more amino acid residues.
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Claims

1. A modified BoNT / A for use in treating facial wrinkles. Here, the modified BoNT / A is administered by intramuscular injection to multiple sites on the subject's face. The modified BoNT / A is administered in doses ranging from 1 to 41 units per site, and 1 unit is the calculated median lethal dose (LD50) in mice. 50 This is the amount of the modified BoNT / A corresponding to the said modification. The multiple body parts in question are selected from the following: To treat frown lines, a maximum of two areas of the corrugator supercilii muscle and one area of ​​the procerus muscle may be treated. To treat forehead wrinkles, the frontalis muscle can be treated in up to 5 areas; and To treat wrinkles around the outer corner of the eye, up to three areas of the lateral part of the orbicularis oculi muscle can be treated. The total dose of modified BoNT / A administered during the procedure is limited to a maximum of 574 units, and The modified BoNT / A includes modifications to one or more amino acid residues selected from the following: ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243, SER 1274, and THR 1277, The modification can be selected from the following: i. Substitution of acidic surface-exposed amino acid residues with basic amino acid residues; ii. Substitution of acidic surface-exposed amino acid residues with uncharged amino acid residues; iii. Substitution of uncharged surface-exposed amino acid residues by basic amino acid residues; iv. Insertion of basic amino acid residues; and v. Deletion of acidic surface-exposed amino acid residues

2. A modified BoNT / A for use in treating facial wrinkles. Here, the modified BoNT / A is administered by intramuscular injection to multiple sites on the subject's face. The modified BoNT / A is administered at a unit dose of 8.4 pg to 344.4 pg of modified BoNT / A per site. The multiple body parts in question are selected from the following: To treat frown lines, a maximum of two areas of the corrugator supercilii muscle and one area of ​​the procerus muscle may be treated. To treat forehead wrinkles, the frontalis muscle can be treated in up to 5 areas; and To treat wrinkles around the outer corner of the eye, up to three areas of the lateral part of the orbicularis oculi muscle can be treated. The total dose of modified BoNT / A administered during the procedure is limited to a maximum of 4821.6 pg, and, The modified BoNT / A includes modifications to one or more amino acid residues selected from the following: ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243, SER 1274, and THR 1277, The modification can be selected from the following: i. Substitution of acidic surface-exposed amino acid residues with basic amino acid residues; ii. Substitution of acidic surface-exposed amino acid residues with uncharged amino acid residues; iii. Substitution of uncharged surface-exposed amino acid residues by basic amino acid residues; iv. Insertion of basic amino acid residues; and v. Deletion of acidic surface-exposed amino acid residues

3. 5-10 pg (preferably 8.4 pg) of modified BoNT / A is the calculated median lethal dose (LD) in mice. 50 A modified BoNT / A for use according to claim 1, corresponding to ).

4. Modified BoNT / A for use according to any one of claims 1 to 3, wherein the unit dose of modified BoNT / A is selected from the following: 2 to 35 units, 6 to 35 units, 12 to 35 units, 12 to 24 units, most preferably 12 to 18 units.

5. Modified BoNT / A for use as described in claim 4. Here, the total dose of modified BoNT / A administered during the procedure is selected from the following: 574 units, 560 units, 384 units, most preferably 288 units; Preferably, the total dose is based on the administration of 16 units across 16 injection sites.

6. Modified BoNT / A for use according to any one of claims 1 to 5, wherein the unit dose of modified BoNT / A is selected from the following: 18 pg to 350 pg, 20 pg to 300 pg, most preferably 100 pg to 150 pg.

7. Modified BoNT / A for use according to any one of claims 1 to 6, wherein the total dose of modified BoNT / A administered during the treatment is selected from: up to 4850 pg, up to 4800 pg, most preferably up to 2400 pg.

8. A modified BoNT / A for use in treating facial wrinkles. Here, the modified BoNT / A is administered by intramuscular injection to multiple sites on the subject's face. The modified BoNT / A is administered at a unit dose of 0.5 to 73 units per site, and 1 unit is the calculated median lethal dose (LD) in mice. 50 This is the amount of the modified BoNT / A corresponding to the said modification. The multiple body parts in question are selected from the following: To treat frown lines, a maximum of two areas of the corrugator supercilii muscle and one area of ​​the procerus muscle may be treated. To treat forehead wrinkles, the frontalis muscle can be treated in up to 5 areas; and To treat wrinkles around the outer corner of the eye, up to three areas of the lateral part of the orbicularis oculi muscle can be treated. The total dose of modified BoNT / A administered during the procedure is limited to a maximum of 1019 units, and The modified BoNT / A includes the light chain and translocation domain of BoNT / A, as well as the BoNT / B receptor binding domain (H C (including domain)

9. A modified BoNT / A for use in treating facial wrinkles. Here, the modified BoNT / A is administered by intramuscular injection to multiple sites on the subject's face. The modified BoNT / A is administered at a unit dose of 12 pg to 1754 pg per site. The multiple body parts in question are selected from the following: To treat frown lines, a maximum of two areas of the corrugator supercilii muscle and one area of ​​the procerus muscle may be treated. To treat forehead wrinkles, the frontalis muscle can be treated in up to 5 areas; and To treat wrinkles around the outer corner of the eye, up to three areas of the lateral part of the orbicularis oculi muscle can be treated. The total dose of modified BoNT / A administered during the procedure is limited to a maximum of 24,500 pg, and The modified BoNT / A includes the light chain and translocation domain of BoNT / A, as well as the BoNT / B receptor binding domain (H C (including domain)

10. Modified BoNT / A for use as described in claim 8. Here, modified BoNT / A is the light chain and transposition domain of BoNT / A, as well as BoNT / BH C The modified BoNT / A contains the domain, and 20-30 pg (preferably 24.04 pg) of the modified BoNT / A is the calculated median lethal dose (LD) in mice. 50 ) corresponds to

11. Modified BoNT / A for use according to any one of claims 8 to 10, wherein the unit dose of modified BoNT / A is selected from the following: 0.5 to 62 units, 3 to 62 units, 10 to 62 units, 10 to 42 units, most preferably 10 to 21 units.

12. Modified BoNT / A for use as described in claim 11. The total dose of modified BoNT / A administered during the procedure is selected from the following: 1019 units, 998 units, 666 units, most preferably 333 units. Preferably, the total dose is based on the administration of 16 units per 16 injection sites.

13. Modified BoNT / A for use according to any one of claims 8 to 12, wherein the unit dose of modified BoNT / A is selected from the following: 12 pg to 1750 pg, 20 pg to 1500 pg, most preferably 250 pg to 500 pg.

14. Modified BoNT / A for use according to any one of claims 8 to 13, wherein the total dose of modified BoNT / A administered during the treatment is selected from: up to 24,500 pg, up to 24,000 pg, most preferably up to 8,000 pg.

15. A modified BoNT / A for use according to any one of claims 1 to 14. Here, the modified BoNT / A has a much greater safety ratio than 7, and the safety ratio is calculated as follows: the dose of toxin required for a -10% body weight change measured as pg / mouse, divided by the DAS ED 50 measured as pg / mouse, where ED 50 is the dose required to produce a DAS score of 2

16. A modified BoNT / A for use according to any one of claims 1 to 15. Here, the modified BoNT / A is intended for use in treating frown lines, and preferably the modified BoNT / A is administered to two sites on the corrugator supercilii muscle and one site on the procerus muscle, and more preferably the modified BoNT / A is administered to a total of five sites.

17. Modified BoNT / A for use according to claims 1 to 15, wherein the modified BoNT / A is for use in treating forehead wrinkles, and preferably the modified BoNT / A is administered to five sites of the frontalis muscle.

18. Modified BoNT / A for use according to claims 1 to 15. Here, the modified BoNT / A is intended for use in treating wrinkles around the outer corner of the eye. Preferably, the modified BoNT / A described above is administered to three sites on the lateral part of the orbicularis oculi muscle to treat wrinkles at the outer corner of the eye. More preferably, the modified BoNT / A is administered at a total of 6 sites.

19. Modified BoNT / A for use according to claims 16-18, wherein the modified BoNT / A is administered to site 8, 10, 12, 14, or 16.

20. Modified BoNT / A for use according to claims 16-18, wherein the modified BoNT / A is administered to sites 7, 9, 11, 13, or 15.

21. Modified BoNT / A for use according to claims 1-7 or 15-20. Here, the above modification comprises (preferably consisting of) one or more amino acid residues selected from the following: ASN 886, ASN 930, ASN 954, SER 955, GLN 991, ASN 1025, ASN 1026, ASN 1052, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243, SER 1274, or THR 1277, and Modified BoNT / A is encoded by a nucleic acid sequence having at least 70% sequence identity with a nucleic acid sequence selected from SEQ ID NOs: 3, 5, 7, and 9, and / or includes a polypeptide sequence having at least 70% sequence identity with a polypeptide sequence selected from SEQ ID NOs: 4, 6, 8, and 10.

22. Modified BoNT / A for use according to claims 1-7 or 15-21. Here, the above modification comprises (preferably consisting of) one or more amino acid residues selected from the following: ASN 886, ASN 930, SER 955, GLN 991, ASN 1026, ASN 1052, and GLN 1229, and modified BoNT / A are encoded by a nucleic acid sequence having at least 70% sequence identity with SEQ ID NO: 3, and / or a polypeptide sequence having at least 70% sequence identity with an amino acid sequence selected from SEQ ID NO:

4.

23. Modified BoNT / A for use according to claims 1-7 or 15-22, wherein the modification is a substitution, preferably with lysine or arginine.

24. Modified BoNT / A for use according to any one of claims 8 to 20, wherein the modified BoNT / A comprises a polypeptide sequence having at least 70% sequence identity with SEQ ID NO:

14.

25. The unit dosage form of modified botulinum neurotoxin A (BoNT / A). This unit dosage form includes: a. Modified BoNT / A from 1 to 41 units, where 1 unit is the calculated median lethal dose (LD) in mice. 50 ) is the amount of the modified BoNT / A corresponding to that; or b. Modified BoNT / A from 8.4pg to 350pg; and c. Optionally, pharmaceutically acceptable carriers, excipients, adjuvants, and / or salts. d. Herein, the modified BoNT / A includes modifications to one or more amino acid residues selected from the following: ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243, SER 1274, and THR 1277, The modification can be selected from the following: i. Substitution of acidic surface-exposed amino acid residues with basic amino acid residues; ii. Substitution of acidic surface-exposed amino acid residues with uncharged amino acid residues; iii. Substitution of uncharged surface-exposed amino acid residues by basic amino acid residues; iv. Insertion of basic amino acid residues; and v. Deletion of acidic surface-exposed amino acid residues

26. The unit dosage form according to claim 25, including the following: a. Modified BoNT / A from 1 to 35 units; or b. Modified BoNT / A, ranging from 10pg to 300pg.

27. The unit dosage form of modified botulinum neurotoxin A (BoNT / A). This unit dosage form includes: a. Modified BoNT / A from 0.5 units to 73 units, where 1 unit is the calculated median lethal dose (LD) in mice. 50 ) is the amount of the modified BoNT / A corresponding to that; or b. Modified BoNT / A from 12pg to 1754pg; and c. Optionally, pharmaceutically acceptable carriers, excipients, adjuvants, and / or salts. d. Here, the modified BoNT / A is the light chain and translocation domain of BoNT / A, as well as the BoNT / B receptor binding domain (H C (including domain)

28. The unit dosage form according to claim 27, including the following: a. Modified BoNT / A from 0.8 units to 62 units; or b. Modified BoNT / A, ranging from 20pg to 1500pg.

29. The kit includes the following: a. The unit dosage form according to any one of claims 25 to 28; and b. Instructions for the use of the same dosage form in the treatment of facial wrinkles; and c. Diluent as desired.