Use of botulinum toxin for treatment of platysmal banding

Abstract

Provided herein are methods for improving the appearance of platysmal prominence associated with platysmal activity in a human patient by administering a composition comprising botulinum toxin type A to the platysma muscle of the human patient. Preferably, the method involves injecting the composition into the upper section of the platysma muscle below the mandibular line of the human patient and injecting the composition along one or more continuous neck bands on the neck of the human patient.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 607,987, filed December 8, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This article provides a method for improving the appearance of platysma protrusion associated with platysma muscle activity in a human patient by administering a composition containing botulinum toxin type A to the platysma muscle of that human patient. Background Technology

[0004] Botulinum toxin has been widely used for both therapeutic and cosmetic treatments. The U.S. Food and Drug Administration (FDA) has approved several botulinum toxin type A products for a variety of therapeutic and cosmetic indications, including onabotulinumtoxin A (BOTOX), approved in 1989. ® Allergan, an AbbVie company, North Chicago, Illinois, USA; abobotulinumtoxin A (DYSPORT) approved in 2009. ® Ipsen Ltd., Slough, UK; incobotulinumtoxin A (XEOMIN) approved in 2010. ® Merz Pharmaceuticals; Frankfurt, Germany); prabotulinumtoxin A (JEUVEAU) approved in 2019. ® Evolus, Inc., Newport Beach, CA, USA; and daxibotulinumtoxin A (DAXXIFY), approved in 2022. ® , Revance Therapeutics, Inc., Nashville, TN, USA).

[0005] Botulinum toxin has been used in investigational studies to improve the appearance of the lower face and treat platysma, but there have been several reports of adverse events associated with such treatment, including dysphagia and neck muscle weakness (see, for example, Obagi and Golubets, 2017, J Drugs Dermatol 16(9):929-930; Dominguez et al., 2016, Emergency Medicine 48(12):551-556; and Witmanowski and Błochowiak, 2020, Postepy Dermatol Alergol 37(6):853-861).

[0006] To date, there is still a need for a method that can effectively and safely treat the undesirable aesthetic effects of platysma muscle contraction using botulinum toxin.

[0007] References cited in this document should not be construed as an admission that the references are prior art of this disclosure. Summary of the Invention

[0008] This disclosure provides a method for improving (e.g., temporarily improving) the appearance of platysma prominence associated with platysma muscle activity in a human patient by administering a botulinum toxin type A composition to the neck of the patient. Specifically, if one side of the patient's neck has only one or two consecutive vertical neck bands, the method applies the botulinum toxin type A composition to that side of the patient's neck. Preferably, the method involves injecting a mandibular dose of the botulinum toxin composition below the patient's mandibular line on that side of the patient's neck and a neck band dose of the botulinum toxin composition along one or two consecutive vertical neck bands. In the method described herein, the consecutive vertical neck bands are vertical neck bands that extend continuously from the mandibular line of the human patient to the lower neck region.

[0009] In one aspect, this disclosure provides a method for improving (e.g., temporarily improving) the appearance of platysma protrusion associated with platysma activity in a particular human patient population, and the method includes quantifying the number of consecutive vertical neck bands on a first side of the neck of a human patient at maximum contraction, wherein the consecutive vertical neck bands are vertical neck bands that extend continuously from the mandibular line of the human patient to the lower neck region; and then applying a composition comprising botulinum toxin type A to the first side of the neck of a human patient identified as having only one or only two consecutive vertical neck bands at maximum contraction.

[0010] In one specific embodiment, this disclosure provides a method for improving (e.g., temporarily improving) the appearance of the platysma band associated with platysma muscle activity in a human patient, the method comprising quantifying the number of continuous vertical neck bands on a first side of the human patient’s neck at maximum contraction, wherein the continuous vertical neck bands are visible vertical neck bands that extend continuously from the mandibular line of the human patient to the lower neck region and cause mandibular line blunting (i.e., affecting mandibular line clarity); and then applying a composition comprising botulinum toxin type A to the first side of the neck of a human patient identified as having only one or only two continuous vertical neck bands at maximum contraction.

[0011] In one specific embodiment, this disclosure provides a method for improving (e.g., temporarily improving) the appearance of platysma protrusion as seen in a human patient at maximal contraction, the method comprising quantifying the number of continuous vertical neck bands on a first side of the human patient's neck at maximal contraction, wherein the continuous vertical neck bands are visible vertical neck bands that extend continuously from the mandibular line of the human patient to the lower neck region and cause mandibular line blunting (i.e., affecting mandibular line clarity); and then applying a composition comprising botulinum toxin type A to the first side of the neck of a human patient identified as having only one or only two continuous vertical neck bands at maximal contraction.

[0012] In one specific embodiment, this disclosure provides a method for improving (e.g., temporarily improving) the appearance of platysma band protrusion seen in a human patient at maximal contraction, the method comprising quantifying the number of continuous vertical neck bands on a first side of the human patient's neck at maximal contraction, wherein the continuous vertical neck bands are visible vertical neck bands that extend continuously from the mandibular line of the human patient to the lower neck region and cause mandibular line blunting (i.e., affecting mandibular line clarity); and then applying a composition comprising botulinum toxin type A to the first side of the neck of a human patient identified as having only one or only two continuous vertical neck bands at maximal contraction.

[0013] In one specific embodiment, this disclosure provides a method for improving (e.g., temporarily improving) the appearance of a vertical band connecting the jaw and neck as seen in a human patient at maximum contraction, the method comprising quantifying the number of continuous vertical neck bands on a first side of the human patient's neck at maximum contraction, wherein the continuous vertical neck bands are visible vertical neck bands that extend continuously from the human patient's jawline to the lower neck region and cause jawline blunting (i.e., affecting jawline clarity); and then applying a composition comprising botulinum toxin type A to the first side of the neck of a human patient identified as having only one or only two continuous vertical neck bands at maximum contraction.

[0014] Specific injection examples are also provided in this disclosure. For example, in one aspect, this disclosure provides a method for improving (e.g., temporarily improving) the appearance of platysma protrusion associated with platysma muscle activity in a human patient who has only one continuous vertical neck band at maximum contraction on a first side of the neck, the method comprising administering a composition comprising botulinum toxin type A to the first side of the neck of the human patient by injecting the following doses: (i) a mandibular line dose distributed among four injection sites below and parallel to the lower border of the mandible on the first side, and the four injection sites may include an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior to the angle of the mandible; and (ii) a neck band dose distributed among five injection sites along a single continuous vertical neck band.

[0015] In one specific embodiment, this disclosure provides a method for improving (e.g., temporarily improving) the appearance of the platysma band associated with platysma muscle activity in a human patient who has only one continuous vertical neck band at maximum contraction on a first side of the neck. The method includes administering a composition comprising botulinum toxin type A to the first side of the human patient's neck by injecting the following doses: (i) a mandibular line dose distributed among four injection sites below and parallel to the lower border of the mandible on the first side, and the four injection sites may include an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior to the angle of the mandible; and (ii) a neck band dose distributed among five injection sites along a single continuous vertical neck band; wherein the continuous vertical neck band is a visible vertical neck band that extends continuously from the mandibular line of the human patient to the lower neck region and causes mandibular line blunting (i.e., affecting mandibular line clarity).

[0016] In one specific embodiment, this disclosure provides a method for improving (e.g., temporarily improving) the appearance of platysma protrusion seen at maximum contraction in a human patient with only one continuous vertical neck band at maximum contraction on a first side of the neck, the method comprising administering a composition comprising botulinum toxin type A to the first side of the human patient's neck by injecting the following doses: (i) a mandibular line dose distributed among four injection sites below and parallel to the lower border of the mandible on the first side, and the four injection sites may include an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior to the angle of the mandible; and (ii) a neck band dose distributed among five injection sites along a single continuous vertical neck band; wherein the continuous vertical neck band is a visible vertical neck band that extends continuously from the mandibular line of the human patient to the lower neck region and causes mandibular line blunting (i.e., affecting mandibular line clarity).

[0017] In one specific embodiment, this disclosure provides a method for improving (e.g., temporarily improving) the appearance of a prominent platysma band seen at maximum contraction in a human patient with only one continuous vertical neck band at maximum contraction on a first side of the neck, the method comprising administering a composition comprising botulinum toxin type A to the first side of the human patient's neck by injecting the following doses: (i) a mandibular line dose distributed among four injection sites below and parallel to the lower border of the mandible on the first side, and the four injection sites may include an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior to the angle of the mandible; and (ii) a neck band dose distributed among five injection sites along a single continuous vertical neck band; wherein the continuous vertical neck band is a visible vertical neck band that extends continuously from the mandibular line of the human patient to the lower neck region and causes mandibular line blunting (i.e., affecting mandibular line clarity).

[0018] In one specific embodiment, this disclosure provides a method for improving (e.g., temporarily improving) the appearance of a vertical band connecting the jaw and neck as seen at maximum contraction in a human patient with only one continuous vertical neck band at maximum contraction on a first side of the neck, the method comprising administering a composition comprising botulinum toxin type A to the first side of the human patient's neck by injecting the following doses: (i) a mandibular line dose distributed among four injection sites below and parallel to the lower border of the mandible on the first side, and the four injection sites may include an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior to the angle of the mandible; and (ii) a neck band dose distributed among five injection sites along a single continuous vertical neck band; wherein the continuous vertical neck band is a visible vertical neck band that extends continuously from the mandibular line of the human patient to the lower neck region and causes mandibular line blunting (i.e., affecting mandibular line clarity).

[0019] In another aspect, this disclosure provides a method for improving (e.g., temporarily improving) the appearance of platysma protrusion associated with platysma muscle activity in a human patient having only two consecutive vertical neck bands at maximum contraction on a first side of the neck, the method comprising administering a composition comprising botulinum toxin type A to the first side of the human patient's neck by injecting the following doses: (i) a mandibular line dose distributed among four injection sites below and parallel to the lower border of the mandible on the first side, and the four injection sites optionally including an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior to the angle of the mandible; (ii) a first neck band dose distributed among five injection sites along a first consecutive vertical neck band; and (iii) a second neck band dose distributed among five injection sites along a second consecutive vertical neck band; and wherein the administration step delivers a total unilateral dose of botulinum toxin type A ranging from about 15 units to about 20 units to the first side of the human patient's neck.

[0020] In one specific embodiment, this disclosure provides a method for improving (e.g., temporarily improving) the appearance of the platysma band associated with platysma muscle activity in a human patient having only two consecutive vertical neck bands at maximum contraction on a first side of the neck, the method comprising administering a composition comprising botulinum toxin type A to the first side of the human patient's neck by injecting the following doses: (i) a mandibular line dose distributed among four injection sites below and parallel to the mandibular border in the upper segment of the platysma muscle on the first side, and the four injection sites optionally including an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior to the angle of the mandible; (ii) a first neck band dose distributed among five injection sites along a first consecutive vertical neck band; and (iii) a second neck band dose distributed among five injection sites along a second consecutive vertical neck band; wherein the consecutive vertical neck band is a visible vertical neck band that extends continuously from the mandibular line of the human patient to the lower neck region and causes blunting of the mandibular line, and wherein the administration step delivers a total unilateral dose ranging from about 15 units to about 20 units of botulinum toxin type A to the first side of the human patient's neck.

[0021] In one specific embodiment, this disclosure provides a method for improving (e.g., temporarily improving) the appearance of the platysma band associated with platysma muscle activity in a human patient having only two consecutive vertical neck bands at maximum contraction on a first side of the neck, the method comprising administering a composition comprising botulinum toxin type A to the first side of the human patient's neck by injecting the following doses: (i) a mandibular line dose distributed among four injection sites below and parallel to the lower border of the mandible on the first side, and the four injection sites optionally including an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior to the angle of the mandible; (ii) a first neck band dose distributed among five injection sites along a first consecutive vertical neck band; and (iii) a second neck band dose distributed among five injection sites along a second consecutive vertical neck band; wherein the administration step delivers a total unilateral dose of botulinum toxin type A ranging from about 15 units to about 20 units to the first side of the human patient's neck.

[0022] In one specific embodiment, this disclosure provides a method for improving (e.g., temporarily improving) the appearance of platysma protrusion seen in a human patient with only two consecutive vertical neck bands at maximum contraction on a first side of the neck, the method comprising administering a composition comprising botulinum toxin type A to the first side of the human patient's neck by injecting the following doses: (i) a mandibular line dose distributed among four injection sites below and parallel to the mandibular border in the upper segment of the platysma muscle on the first side, and the four injection sites optionally including an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior to the angle of the mandible; (ii) a first neck band dose distributed among five injection sites along a first consecutive vertical neck band; and (iii) a second neck band dose distributed among five injection sites along a second consecutive vertical neck band; wherein the consecutive vertical neck bands are visible vertical neck bands that extend continuously from the mandibular line of the human patient to the lower neck region and cause blunting of the mandibular line, and wherein the administration step delivers a total unilateral dose ranging from about 15 units to about 20 units of botulinum toxin type A to the first side of the human patient's neck.

[0023] In one specific embodiment, this disclosure provides a method for improving (e.g., temporarily improving) the appearance of platysma band protrusion seen in a human patient with only two consecutive vertical neck bands at maximum contraction on a first side of the neck, the method comprising administering a composition comprising botulinum toxin type A to the first side of the human patient's neck by injecting the following doses: (i) a mandibular line dose distributed among four injection sites below and parallel to the lower border of the mandible on the first side, and the four injection sites optionally including an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior to the angle of the mandible; (ii) a first neck band dose distributed among five injection sites along a first consecutive vertical neck band; and (iii) a second neck band dose distributed among five injection sites along a second consecutive vertical neck band; wherein the consecutive vertical neck bands are visible vertical neck bands that extend continuously from the mandibular line of the human patient to the lower neck region and cause blunting of the mandibular line, and wherein the administration step delivers a total unilateral dose ranging from about 15 units to about 20 units of botulinum toxin type A to the first side of the human patient's neck.

[0024] In one specific embodiment, this disclosure provides a method for improving (e.g., temporarily improving) the appearance of a vertical band connecting the jaw and neck as seen in a human patient with only two consecutive vertical neck bands at maximum contraction on a first side of the neck, the method comprising administering a composition comprising botulinum toxin type A to the first side of the human patient's neck by injecting the following doses: (i) a mandibular line dose distributed among four injection sites below and parallel to the lower border of the mandible in the upper segment of the platysma muscle on the first side, and the four injection sites optionally including an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior to the angle of the mandible; (ii) a first neck band dose distributed among five injection sites along a first consecutive vertical neck band; and (iii) a second neck band dose distributed among five injection sites along a second consecutive vertical neck band; wherein the consecutive vertical neck band is a visible vertical neck band that extends continuously from the mandibular line of the human patient to the lower neck region and causes blunting of the mandibular line, and wherein the administration step delivers a total unilateral dose ranging from about 15 units to about 20 units of botulinum toxin type A to the first side of the human patient's neck.

[0025] On the other hand, this disclosure provides a method for improving (e.g., temporarily improving) the appearance of platysma prominence associated with platysma muscle activity in a human patient having only one continuous vertical neck band at maximum contraction on a first side of the neck and only two continuous vertical neck bands at maximum contraction on a second side of the neck. The method comprises administering a composition containing botulinum toxin type A to the neck of the human patient by injecting the following dosage: (i) a first mandibular line dose distributed among four injection sites in the upper segment of the platysma muscle below and parallel to the mandibular border, and the four injection sites optionally including an anterior injection site aligned with the corner of the mouth. (ii) a posterior injection site anterior to the angle of the mandible; (iii) a first neck band dose distributed among five injection sites along a single continuous vertical neck band on the first side; (iv) a second mandibular line dose distributed among four injection sites in the upper segment of the platysma muscle below and parallel to the lower border of the mandible, and the four injection sites may optionally include an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior to the angle of the mandible; (v) a first neck band dose distributed among five injection sites along a first continuous vertical neck band on the second side; and (v) a second neck band dose distributed among five injection sites along a second continuous vertical neck band on the second side.

[0026] In one specific embodiment, this disclosure provides a method for improving (e.g., temporarily improving) the appearance of the platysma band associated with platysma muscle activity in a human patient who has only one continuous vertical neck band at maximum contraction on a first side of the neck and only two continuous vertical neck bands at maximum contraction on a second side of the neck. The method comprises administering a composition containing botulinum toxin type A to the neck of the human patient by injecting the following doses: (i) a first mandibular line dose distributed among four injection sites in the upper segment of the platysma muscle below and parallel to the mandibular border on the first side, wherein the four injection sites optionally include an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior to the angle of the mandible; (ii) along… (iii) A first neck band dose distributed among five injection sites by a single continuous vertical neck band on the first side; (iv) a second mandibular line dose distributed among four injection sites below and parallel to the lower border of the mandible in the upper segment of the platysma muscle on the second side, and the four injection sites optionally include an anterior injection site consistent with the corner of the mouth and a posterior injection site anterior to the angle of the mandible; (v) a first neck band dose distributed among five injection sites along the first continuous vertical neck band on the second side; and (v) a second neck band dose distributed among five injection sites along the second continuous vertical neck band on the second side; wherein the continuous vertical neck band is a visible vertical neck band that extends continuously from the mandibular line of the human patient to the lower neck region and causes blunting of the mandibular line.

[0027] In one specific embodiment, this disclosure provides a method for improving (e.g., temporarily improving) the appearance of platysma protrusion seen at maximum contraction in a human patient who has only one continuous vertical neck band at maximum contraction on a first side of the neck and only two continuous vertical neck bands at maximum contraction on a second side of the neck, the method comprising administering a composition comprising botulinum toxin type A to the neck of the human patient by injecting the following doses: (i) a first mandibular line dose distributed among four injection sites below and parallel to the lower border of the mandible on the first side, and the four injection sites optionally including an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior to the angle of the mandible; (ii) along the first (iii) A first neck band dose distributed among five injection sites by a single continuous vertical neck band on one side; (iv) a second mandibular line dose distributed among four injection sites below and parallel to the lower border of the mandible in the upper segment of the platysma muscle on the second side, and the four injection sites may optionally include an anterior injection site consistent with the corner of the mouth and a posterior injection site anterior to the angle of the mandible; (v) a first neck band dose distributed among five injection sites along the first continuous vertical neck band on the second side; and (v) a second neck band dose distributed among five injection sites along the second continuous vertical neck band on the second side; wherein the continuous vertical neck band is a visible vertical neck band that extends continuously from the mandibular line of the human patient to the lower neck region and causes blunting of the mandibular line.

[0028] In one specific embodiment, this disclosure provides a method for improving (e.g., temporarily improving) the appearance of platysma band protrusion seen at maximum contraction in a human patient who has only one continuous vertical neck band at maximum contraction on a first side of the neck and only two continuous vertical neck bands at maximum contraction on a second side of the neck, the method comprising administering a composition comprising botulinum toxin type A to the neck of the human patient by injecting the following doses: (i) a first mandibular line dose distributed among four injection sites below and parallel to the lower border of the mandible on the first side, and the four injection sites optionally including an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior to the angle of the mandible; (ii) along (iii) A first neck band dose distributed among five injection sites by a single continuous vertical neck band on the first side; (iv) a second mandibular line dose distributed among four injection sites below and parallel to the lower border of the mandible in the upper segment of the platysma muscle on the second side, and the four injection sites optionally include an anterior injection site consistent with the corner of the mouth and a posterior injection site anterior to the angle of the mandible; (v) a first neck band dose distributed among five injection sites along the first continuous vertical neck band on the second side; and (v) a second neck band dose distributed among five injection sites along the second continuous vertical neck band on the second side; wherein the continuous vertical neck band is a visible vertical neck band that extends continuously from the mandibular line of the human patient to the lower neck region and causes blunting of the mandibular line.

[0029] In one specific embodiment, this disclosure provides a method for improving (e.g., temporarily improving) the appearance of a vertical band connecting the jaw and neck as seen at maximum contraction in a human patient who has only one continuous vertical neck band at maximum contraction on a first side of the neck and only two continuous vertical neck bands at maximum contraction on a second side of the neck, the method comprising administering a composition comprising botulinum toxin type A to the neck of a human patient by injecting the following doses: (i) a first mandibular line dose distributed among four injection sites below and parallel to the lower border of the mandible on the first side, in the upper segment of the platysma muscle, and the four injection sites optionally including an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior to the angle of the mandible; (ii) (iii) A first neck band dose distributed among five injection sites along a single continuous vertical neck band on the first side; (iv) a second mandibular line dose distributed among four injection sites below and parallel to the lower border of the mandible in the upper segment of the platysma muscle on the second side, and the four injection sites optionally include an anterior injection site consistent with the corner of the mouth and a posterior injection site anterior to the angle of the mandible; (v) a first neck band dose distributed among five injection sites along the first continuous vertical neck band on the second side; and (v) a second neck band dose distributed among five injection sites along the second continuous vertical neck band on the second side; wherein the continuous vertical neck band is a visible vertical neck band that extends continuously from the mandibular line of the human patient to the lower neck region and causes blunting of the mandibular line.

[0030] In another aspect, this disclosure provides a method for treating the appearance of the platysma band associated with platysma muscle activity in a human patient using a composition comprising botulinum toxin type A, wherein the treatment comprises administering intramuscularly to a first side of the neck of the human patient: a) a first mandibular line dose distributed among four injection sites in the upper segment of the platysma muscle on the first side of the neck of the human patient, wherein the first mandibular line dose is about eight units of botulinum toxin type A; and b) a first neck band dose distributed among five injection sites along the first platysma band on the first side of the neck of the human patient, wherein the first neck band dose is about five units of botulinum toxin type A; and wherein the appearance of the platysma band in the human patient is safely and effectively treated.

[0031] In a specific implementation, the method further includes administering to the second side of the patient's neck intramuscularly: a) a second mandibular line dose distributed among four injection sites in the upper segment of the platysma muscle on the second side of the human patient's neck, wherein the second mandibular line dose is approximately eight units of botulinum toxin type A; and b) a second neck band dose distributed among five injection sites along the first platysma band on the second side of the human patient's neck, wherein the second neck band dose is approximately five units of botulinum toxin type A.

[0032] In a specific implementation, the method further includes intramuscular administration of a third neck band dose, distributed along the third platysma band among five injection sites, to at least one side of the first or second side of the neck of a human patient, wherein the third neck band dose is approximately five units of botulinum toxin type A.

[0033] In a specific implementation, the method further includes administering a fourth neck band dose distributed among five injection sites along the fourth platysma band, wherein the fourth neck band dose is approximately five units of botulinum toxin type A, and wherein the human patient has two platysma bands located on each of the first and second sides of the human patient's neck.

[0034] In one embodiment, the application step delivers a total bilateral dose of 26 units of botulinum toxin type A. In another embodiment, the application step delivers a total bilateral dose of 31 units of botulinum toxin type A. In yet another embodiment, the application step delivers a total bilateral dose of 36 units of botulinum toxin type A.

[0035] In a specific implementation, the first platysma band on the first side of the neck of the human patient, the first platysma band on the second side, the third platysma band on at least one of the first or second sides, and / or the fourth platysma band are visible continuous vertical neck bands at maximum contraction, which extend continuously from the mandibular line of the human patient to the lower neck region and cause mandibular line blunting.

[0036] In the specific implementation plan, the four mandibular line injection sites are applied below and parallel to the lower edge of the patient's mandible.

[0037] In the specific implementation plan, the four mandibular line injection sites are applied approximately 1 to 2 cm below the lower edge of the patient's mandible and parallel to that lower edge.

[0038] In a specific implementation plan, the first mandibular line injection site is the anterior injection site aligned with the corner of the patient's mouth, the fourth mandibular line injection site is the posterior injection site in front of the mandibular angle, and the second and third mandibular line injection sites are equidistant from the first and fourth mandibular line injection sites.

[0039] In a specific implementation plan, the first injection site for the first neckband dose, the second neckband dose, the third neckband dose, or the fourth neckband dose is approximately 1 to 2 cm below the mandibular line injection site.

[0040] In the specific implementation plan, the neck band injection sites are spaced approximately 1 to 2 cm apart.

[0041] In a specific implementation, the treatment provides a temporary improvement in the appearance of the platysma band. Attached Figure Description

[0042] Figure 1 An illustration of platysma protrusion at maximal contraction, accompanied by the Allergan Platysma Protrusion Scale (APPS) for assessing the severity of platysma protrusion in human patients (i.e., subjects or participants). The APPS is used independently by clinicians or investigators (referred to as C-APPS) and subjects (referred to as P-APPS) to assess the severity of platysma protrusion.

[0043] Figures 2A to 2B. Schematic diagrams of injection sites for treating moderate platysma herniation (Figure 2B) and severe platysma herniation (Figure 2A).

[0044] Figures 3A to 3B Within a 120-day period following administration of high-dose (HD) or low-dose (LD) botulinum toxin type A (BOTOX), at maximum contraction, based on investigator assessment using C-APPS (… Figure 3A ) or the subject's self-assessment using P-APPS ( Figure 3B The response rate (%) of participants achieving at least a grade 1 improvement relative to baseline was defined as a 95% confidence interval (CI). HD: High dose. LD: Low dose. CI: Confidence interval.

[0045] Figure 4 Example 2 illustrates a phase 3 clinical trial, in which two phase 3 studies (study 1, also known as the M21-309 study or phase 3 clinical trial 1, and study 2, also known as the M21-310 study or phase 3 clinical trial 2) are conducted within the first 4 months, and for eligible subjects, an 8-month open-label extension treatment study begins on the exit date (day 120) of phase 3 clinical trial 1.

[0046] Figure 5In the ITT cohort of the Phase 1 / 3 clinical trial (i.e., Study 1 or the M21-309 study), the response rate (%) of participants who achieved a Grade 1 (mild) or Grade 2 (mild) improvement relative to baseline at the maximum contraction on Day 14, the primary time point, based on both investigator-assessed C-APPS and participant-assessed P-APPS. *p<0.0001, or in the mITT cohort of the Phase 1 / 3 clinical trial who achieved a Grade 2 improvement relative to baseline at the maximum contraction on Day 14, the primary time point, based on investigator-assessed C-APPS or participant-assessed P-APPS. Error bars are 95% confidence intervals. ITT refers to the intention-to-treat cohort, which includes all randomized participants, and mITT refers to the modified intention-to-treat cohort, which includes all randomized participants with a baseline summative score ≥19 on the Neck and Lower Face Appearance Questionnaire (ANLFQ): Impact. In the Phase 23 clinical trial (i.e., Study 2 or M21-310 study), the ITT and mITT populations achieved comparable response rates (%) (see Table 8, Figures 6A to 6C).

[0047] Figures 6A through 6C. Response rates (%) of participants achieving Grade 1 (mild) or Grade 2 (mild) improvement relative to baseline at the time of maximum contraction from day 14 to day 120 in the ITT population of studies M21-309 and M21-310, based on both investigator-assessed C-APPS and participant-assessed P-APPS (Figure 6A); and response rates (%) of participants achieving at least 2-grade improvement relative to baseline from day 14 to day 120 in the mITT population of studies M21-309 and M21-310, based on investigator-assessed C-APPS (Figure 6B) or participant-assessed P-APPS (Figure 6C). Error bars are 95% confidence intervals. Boxed section: Principal time point day 14. *: Figures include data for respondents who achieved Grade 1 or 2 (mild) and at least 2-grade improvement (ITT) as defined below.

[0048] Figures 7A to 7B In the ITT populations of the M21-309 and M21-310 studies, the time from day 14 to day 120 at maximum contraction was based on investigator assessment using C-APPS ( Figure 7A ) or the subject's self-assessment using P-APPS ( Figure 7B The response rate (%) of participants with mild or mild platysma protrusion is shown in the box. The error bar is the 95% confidence interval. The boxed section shows the principal time point on day 14.

[0049] Figures 8A to 8B In the study of M21-309 ( Figure 8A) and M21-310 research ( Figure 8B In the ITT population, from day 14 to day 120 at maximum contraction, the responder rate (%) of participants achieving mild or mild platysma protrusion was based on investigator's assessment using C-APPS (…dotted line) or participant's self-assessment using P-APPS (- - - dashed line), or the responder rate (%) of participants achieving mild or mild platysma protrusion and at least grade 2 improvement was based on both investigator's assessment using C-APPS and participant's self-assessment using P-APPS (combined, solid line).

[0050] Figures 9A to 9C In the ITT groups of studies M21-309 and M21-310, the percentage (%) of participants who gave the following responses were: (1) Over time, their satisfaction with the treatment outcome on item 5 of the “Neck and Lower Face Appearance Questionnaire (ANLFQ): Satisfaction” questionnaire was “Satisfied” or “Very Satisfied”. Figure 9A (2) Over time, the patient's level of discomfort with the jawline was "not bothered at all" or "somewhat bothered" in the "Discomfort Assessment Scale - Platysma Prominence (BAS-PP)" questionnaire (item 2). Figure 9B ); or (3) over time, the vertical neckband was described as "not bothersome at all" or "somewhat bothersome" in the BAS-PP questionnaire (item 1). Figure 9C The error bar is the 95% confidence interval. Boxed section: Key time points on day 14. Detailed Implementation

[0051] Although botulinum toxin has been used in investigational studies to improve the appearance of the lower face and treat platysma band, there is still a need for improved methods of botulinum toxin administration that can effectively and safely treat the undesirable aesthetic effects of platysma contraction.

[0052] Developing a novel platysma protrusion assessment scale or patient selection criterion is crucial for improving the safety and efficacy of botulinum toxin treatment. It allows for personalized treatment planning, enhances safety by reducing the risk of complications, and improves treatment outcomes, while providing a standardized framework for practice in this field. The anatomy and activity levels of the platysma can vary significantly between individuals. Creating a new, effective scale or patient selection criterion that accommodates this diversity while remaining simple and practical is a complex task. The platysma is dynamic, and its activity changes with facial expressions and movements. It interconnects with other facial muscles, and its function is interrelated to them. Developing a scale that considers this dynamic and interactive nature, as well as static muscle protrusion, is challenging. Furthermore, assessing platysma protrusion often involves a degree of subjectivity, as different practitioners may interpret muscle protrusion differently based on visual or palpation examinations. There is a great need in the field for a platysma protrusion scale that facilitates objectivity and consistency in assessment, is practical for clinical use, and can be easily integrated into practitioners' workflows and administration methods. This disclosure addresses such a need and provides relevant treatment methods.

[0053] Specifically, if the patient's neck has only one or two consecutive vertical neck bands, the method provided herein applies the botulinum toxin type A composition to one side of the patient's neck. Such patients may also have one or more non-consecutive vertical neck bands. Preferably, the method involves injecting a mandibular dose of the botulinum toxin composition below the patient's mandibular line on that side of the patient's neck and injecting a neck band dose of the botulinum toxin composition along one or two consecutive bands. More preferably, the mandibular dose and the neck band dose are each distributed among several injection sites, and the neck band dose is lower than the mandibular dose. For example, the mandibular dose may be a total of eight units of botulinum toxin type A distributed among four injection sites, preferably about two units per injection, while the neck band dose may be a total of five units of botulinum toxin type A distributed among five injection sites, preferably about one unit per injection. A further detailed description of the method and specific injection examples can be found in Section 5.3 below. The various methods described in this disclosure provide a holistic approach with a favorable benefit / risk profile in treating the undesirable aesthetic effects of platysma muscle contraction (see further details below).

[0054] The platysma complex consists of two separate superficial muscle layers that originate from the fascia in the upper chest region and ascend along both sides of the neck, across the mandibular border, and insert into the overlying skin of the lower face. When relaxed, the platysma smoothly covers the mandibular line, neck, and clavicle, resulting in a firm, close-fitting, and symmetrical appearance.

[0055] As the largest facial and neck muscle, the platysma plays a role in conveying personal emotional states during social interactions. Specifically, platysma contraction may be associated with a variety of facial expressions conveying negative emotions such as fear, disgust, and aggression. Functionally, the platysma works in conjunction with the risorius muscle to retract the corners of the mouth and assist in pulling down the corners of the lips, which may result in resting skin tension lines at the corners of the lips. Below the mandibular border, platysma contraction tightens the skin along the lower edge of the jaw, creating a blunting effect as the concavity between the jaw and that side of the neck decreases. Along the length of the neck, platysma contraction may produce noticeable vertical striations, which typically become more pronounced with age.

[0056] Over time, repeated contractions of the platysma muscle, coupled with degenerative changes due to aging (e.g., thinning of neck skin, loss of neck fat tissue, and platysma muscle separation), may result in a poor appearance of the platysma muscle, primarily manifested as a vertical band on the neck, and may include jawline blunting (Le Louarn et al., 2007, Aesthetic Plast Surg31(3):213-218; Brandt and Bellman, 1998, Dermatol Surg 24(11):1232-1234; Hwang et al., 2017, J Craniofac Surg 28(2):539-542; and Le Louarn, 2016, Ann Chir PlastEsthet 61(2):101-109).

[0057] "Platysalis protrusion" is used in this article to describe the undesirable aesthetic effects of platysalis muscle contraction, including, for example, a vertical band on the neck (also known as the platysalis band or platysalis band) and jawline blunting. Platysalis protrusion is primarily caused by the activity of the platysalis muscle. It occurs when the platysalis contracts during normal movements such as speaking or smiling, creating an aged appearance. Forceful contraction of the platysalis tightens the skin of the neck, which can lead to jawline blunting and a vertical neck band. Platysalis protrusion can work in conjunction with other degenerative changes, causing a misperception of an individual's emotional state during social interactions. For individuals whose facial appearance might otherwise appear symmetrical, firm, smooth, and attractive, platysalis protrusion is perceived as a sign of aging. The location, size, and manifestation of platysalis protrusion vary among individuals.

[0058] The platysma protrusion described in this disclosure can be classified into multiple grades according to a platysma protrusion scale, which are assessed at maximal contraction. In various embodiments, the multiple grades of the platysma protrusion scale include at least a grade corresponding to moderate platysma protrusion and a grade corresponding to severe platysma protrusion. In some embodiments, the multiple grades of the platysma protrusion scale include at least a grade corresponding to mild platysma protrusion, a grade corresponding to slight platysma protrusion, a grade corresponding to moderate platysma protrusion, and a grade corresponding to severe platysma protrusion. In some embodiments, the multiple grades of the platysma protrusion scale include a grade corresponding to mild platysma protrusion, a grade corresponding to slight platysma protrusion, a grade corresponding to moderate platysma protrusion, a grade corresponding to severe platysma protrusion, and a grade corresponding to very severe platysma protrusion. In one specific embodiment, the multiple grades of the platysma protrusion scale are five grades corresponding to mild platysma protrusion, slight platysma protrusion, moderate platysma protrusion, severe platysma protrusion, and very severe platysma protrusion, respectively. In one specific embodiment, the platysma protrusion described in this disclosure can be classified into 5 grades according to the Allergan Platysma Protrusion Scale (APPS) illustrated in Table 1 below. These grades are assessed at maximal contraction and are illustrated in Table 1 below. Figure 1 The five levels listed in Table 1 increase from level 1 to level 5 according to the severity of platysma protrusion. In the specific implementation plan, the platysma protrusion scale is a severity grading scale for the platysma band. In a preferred embodiment, the platysma protrusion scale is a platysma band severity grading scale, according to which the severity of the platysma band assessed at maximal contraction is classified into 5 levels, where level 1 corresponds to mild platysma band severity, which is associated with no visible neck band and no mandibular line blunting (i.e., no impact on mandibular line clarity); level 2 corresponds to mild platysma band severity, which is associated with visible neck band and no mandibular line blunting (i.e., no impact on mandibular line clarity); level 3 corresponds to moderate platysma band severity, which is associated with one visible continuous neck band causing mandibular line blunting (i.e., affecting mandibular line clarity); level 4 corresponds to severe platysma band severity, which is associated with two visible continuous neck bands causing mandibular line blunting (i.e., affecting mandibular line clarity); and level 5 corresponds to very severe platysma band severity, which is associated with three or more visible neck bands causing mandibular line blunting (i.e., affecting mandibular line clarity).

[0059]

[0060] As used in this disclosure, "maximal contraction" is a technical term reflecting the fact that a patient undergoing an assessment of the severity of platysma protrusion has been given and followed instructions designed to bring their platysma to maximum tension. In a preferred embodiment, the patient undergoing the platysma protrusion severity assessment is instructed to maximally contract their platysma. In some embodiments, the patient is instructed to pronounce the letter "e" (e.g., for at least 5 seconds) while exposing their lower teeth and with their upper lip covering their upper teeth. It is contemplated that any similar instructions designed to bring the patient's platysma to maximum tension may be used. In a specific embodiment, the patient undergoing the platysma protrusion severity assessment is instructed to maximally contract their platysma while pronouncing the letter "e".

[0061] As used in this disclosure, "lower neck" refers to the area of ​​the neck below the thyroid notch and above the clavicle.

[0062] As used herein, "continuous vertical neck band," "continuous neck band," or "continuous platysma band" refers to a platysma band, or a vertical neck band visible at least at maximum contraction, that extends continuously from the mandibular line of a human patient to the lower neck (i.e., the neck region below the thyroid notch and above the clavicle). It should be understood that patients described herein (e.g., patients with only one or two continuous vertical neck bands on one side of the neck) may have one or more discontinuous (or incoherent) neck bands on that side of the neck. Typically, the presence of one, two, or more continuous vertical neck bands results in a blunted mandibular line (i.e., affects mandibular line definition). Mandibular line definition refers to the sharpness of the mandibular line contour. A well-defined mandibular line is generally associated with a youthful appearance and means that the jaw appears more prominent and angular compared to a blunted mandibular line. In a preferred embodiment, the continuous vertical neck band as described herein is a visible vertical neck band that extends continuously from the mandibular line of a human patient to the lower neck region and results in a blunted mandibular line (i.e., affects mandibular line definition).

[0063] As used in this disclosure, "discontinuous band" refers to a non-continuous band, such as a band that does not extend from the patient's jawline to the lower neck, like... Figure 1 As illustrated. The term "small discontinuity" refers to, for example, a less obvious, less prominent discontinuity, such as... Figure 1 As illustrated. Generally, the presence of only discontinuities or small discontinuities will not cause the jawline to become blunt (i.e., it will not affect the clarity of the jawline).

[0064] A “mandibular line dose” or “submandibular dose” is a dose administered at injection sites (e.g., four injection sites) below and parallel to the lower border of the mandible (or mandibular border) on the first or second side of the neck, within the platysma muscle. Such injections are referred to as “submandibular injections” or “mandibular line injections.” Mandibular contour doses may also be referred to as “unilateral mandibular contour doses.” Mandibular line doses are further classified as first mandibular line doses or second mandibular line doses, which are mandibular line doses administered at the first or second side of the neck of a human patient, respectively. In some embodiments, the first mandibular line dose is equal to the second mandibular line dose. In alternative embodiments, the first mandibular line dose is different from the second mandibular line dose.

[0065] A “neck band dose” is a dose applied to a neck band on the first or second side of the neck. Since the methods described herein treat no more than two consecutive neck bands per side, neck band doses injected along consecutive neck bands are further categorized as a first neck band dose injected along a first consecutive neck band or a second neck band dose injected along a second consecutive neck band. A neck band dose applied to the first or second side of the neck may also be referred to as a “unilateral neck band dose.” In some embodiments, the first neck band dose is equal to the second neck band dose. The first and second neck bands may be further specified as being on the first side of the patient’s neck or the second side of the patient’s neck.

[0066] "Single-sided dose" refers to the total dose administered to the first or second side of a human patient's neck. This includes, for example, the mandibular line dose and the neckband dose.

[0067] "Bilateral dose" refers to the total dose administered to both the first and second sides of a human patient's neck. For example, the term "bilateral neckband dose" refers to the total neckband dose administered to both sides of the neck, and the term "bilateral mandibular line dose" refers to the total mandibular line dose administered to both sides of the neck.

[0068] Although botulinum toxin has been used in investigational studies to improve the appearance of the lower face and treat platysma, several adverse events associated with this treatment have been reported, including dysphagia, weakness of the neck flexors, and weakness of the neck muscles (see, for example, Obagi and Golubets, 2017, J Drugs Dermatol 16(9):929-930; Dominguez et al., 2016, Emergency Medicine 48(12):551-556; and Witmanowski and Błochowiak, 2020, Postepy Dermatol Alergol 37(6):853-861). Treatment-related complications have been reported to include transient edema or ecchymosis (both of which have been observed to subside within 1 to 2 days), hematoma formation, muscle soreness, headache, and injection site tingling (Matarasso et al., 1999, Plast Reconstr Surg 103(2):645-652). In a study of over 1500 participants who received platysma muscle BOTOX treatment, bruising was the most common adverse event (AE), occurring in less than 20% of participants; less than 10% reported transient mild neck discomfort; 1% reported neck weakness during movement / head lifting; and one case of dysphagia was reported after a 100U BOTOX injection (Matarasso et al., 1999, Plast Reconstr Surg103(2):645-652). In another study, the incidence of complications from injection of botulinum toxin (i.e., incobotulinumtoxinA or abobotulinumtoxinA) into the platysma band was 15.2%, with ecchymosis / hematoma occurring in 8.9%, mild dysphagia in 5.2%, and neck weakness in 1.3% (Sugrue et al., 2019, Aesthet Surg J 39(2):201-206). There are also isolated case reports of patients experiencing severe dysphagia following neck injections that may involve the platysma band, requiring nasogastric tube feeding for up to 6 weeks (Carruthers J, Carruthers A. Practical cosmetic Botox techniques. J Cutan Med Surg. 1999; 3 Supplement 4: S49-52), or undergoing BOTULAX treatment. ®Progressive dysphagia occurred three days after an injection of a type A botulinum toxin into the platysma band (Phothong et al., 2017, J Cosmet Dermatol 16(1):15-17). Adverse events such as dysphagia may be caused by, for example, the spread of botulinum toxin to anatomical structures below the injection site in the neck, such as deep muscle tissue.

[0069] On the other hand, this disclosure describes data showing that the various methods described herein provide a holistic approach that is both effective and safe in treating the undesirable aesthetic effects of platysma contraction with botulinum toxin type A, and particularly has a favorable benefit / risk profile in treating the aesthetic indication of platysma protrusion (see, for example, Section 7. Examples). Without wishing to be bound by any single theory, the favorable benefit / risk profile of the various methods described herein for platysma protrusion may derive at least in part from one or more of the following factors:

[0070] (1) Only patients with one or two consecutive neck bands on one side of the neck were selected for treatment, and only the side with one or two consecutive neck bands was treated. Therefore, the number of consecutive neck bands injected on each side of the neck was limited to no more than two, thereby reducing the total dose of botulinum toxin type A injected directly into the neck of human patients.

[0071] (2) The dose of botulinum toxin type A is injected only along a continuous neck band that extends continuously from the mandibular line of the human patient to the lower neck (i.e., the neck region below the thyroid notch and above the clavicle), thereby minimizing the dose of botulinum toxin type A injected directly into the neck of the human patient.

[0072] (3) The total dose of botulinum toxin type A injected into one side of the neck is variable and depends on the number of continuous neck bands present on that side of the neck. Therefore, for human patients with lower platysma protrusion, the unilateral and / or bilateral doses injected into the neck can be reduced. This approach recognizes that there are differences in platysma protrusion presentation within the population, including but not limited to those with one continuous neck band on each side (bilateral moderate), those with one continuous neck band on one side and two continuous neck bands on the other side (asymmetric moderate and severe), and those with two continuous neck bands on each side (bilateral severe).

[0073] (4) Injecting a mandibular line dose of botulinum toxin below the lower border of the mandible (or mandibular border) and parallel to the upper segment of the platysma muscle (e.g., a mandibular line dose of approximately 8 units of botulinum toxin type A per side, preferably distributed among 4 injection sites, with each injection being approximately 2 units of botulinum toxin type A) can have a positive effect on the platysma muscle of the neck, thereby allowing for the injection of lower doses of botulinum toxin type A along the neck band without diminishing efficacy (e.g., allowing a neck band dose of approximately 5 units of botulinum toxin type A per neck band, preferably distributed among 5 injection sites, with each injection being approximately 1 unit of botulinum toxin type A). The mandibular line dose is injected near the attachment point of the platysma muscle (at the mandibular line) and can relax the entire muscle layer, allowing the muscle to more smoothly cover the entire mandibular line and extend downwards into the neck.

[0074] (5) The dose of botulinum toxin type A injected along the neck band into the platysma muscle is lower than the dose injected along the mandibular line or submandibular region. Injecting a lower dose of botulinum toxin into the neck band reduces the risk of negative effects on the anatomical structures beneath the injection site, such as deep muscle tissue, and minimizes the risk of adverse events.

[0075] (6) The neckband dose of botulinum toxin type A at each injection site (e.g., 1 unit of botulinum toxin type A per injection site) is low, thereby reducing the risk of negative effects on the anatomical structures below the injection site (such as deep muscle tissue) and minimizing the risk of adverse events.

[0076] In various aspects and implementation methods, the methods described herein reduce the incidence of adverse effects compared to methods for treating platysma protrusion (e.g., for improving the appearance of platysma protrusion) that do not have one, two, three, four, five, or all of the above factors.

[0077] The benefits of the various methods described in this article for treating platysma protrusion include not only aesthetic improvement in the appearance of the neck brace but also aesthetic improvement in the appearance of the jawline. Without being bound by any single theory, the positive effects on the jawline may at least partially stem from incorporating the jawline injections described herein into a holistic treatment approach, or a combination of the jawline injections and neck brace injections described herein into a holistic treatment approach. Therefore, the treatment of platysma protrusion according to the methods described herein encompasses both the treatment of jawline blunting and the improvement of neck brace appearance.

[0078] Further benefits of this disclosure will be apparent to those skilled in the art. The embodiments and aspects described in this disclosure are intended to exemplify the invention and should not be construed as limiting the scope of the invention.

[0079] 5.1. Definition

[0080] As used in this disclosure, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” include plural indicators. Unless the context clearly indicates otherwise, the term “a” (or “an”) and the terms “one or more” and “at least one” are used interchangeably herein.

[0081] As used in this disclosure and unless otherwise stated, the terms "about" or "approximately" mean within an acceptable range of error for a particular value as determined by one of ordinary skill in the art, the range of error depending in part on how the value is measured or determined (i.e., limitations of the measurement system). For example, "about" or "approximately" may mean within one or more standard deviations according to convention in the art, or may mean a variation allowed within 20%, 10%, or 5% of said value. When a particular value is described in this application and claims, unless otherwise stated, the terms "about" or "approximately" mean within an acceptable range of error for that particular value. In specific embodiments, the terms "about" and "approximately" cover the precise values ​​stated. Unless the context clearly indicates otherwise, all numerical values ​​provided herein are modified by the term "about".

[0082] "Administration / to administer" refers to the step of giving (i.e., administering) a composition (e.g., a pharmaceutical composition) to a subject or a subject who alternatively receives the composition (e.g., a pharmaceutical composition). The compositions (e.g., pharmaceutical compositions) disclosed herein can be administered topically by various methods. For example, intramuscular, intradermal, subcutaneous, topical (percutaneous), infusion, and implantation (e.g., implantation of sustained-release devices such as polymeric implants or microosmotic pumps) are all suitable routes of administration.

[0083] The terms “and” and “or” are used interchangeably and, unless the context clearly indicates otherwise, are understood to mean “and / or”.

[0084] “Animal” means mammals (such as humans), birds, reptiles, fish, insects, spiders, or other animal species. “Animal” does not include microorganisms such as bacteria. A “animal protein-free” pharmaceutical composition may contain botulinum toxin. For example, a “animal protein-free” pharmaceutical composition means a pharmaceutical composition that is substantially free of, substantially free of, or completely free of serum albumin, gelatin, and other animal-derived proteins (such as immunoglobulins). Examples of animal protein-free pharmaceutical compositions are those containing botulinum toxin (as the active ingredient) and a suitable polysaccharide as a stabilizer or excipient, or compositions thereof.

[0085] "Bioactivity" describes the beneficial or adverse effects of a drug on living organisms. When a drug is a complex chemical mixture, this activity is exerted by the active ingredient of the substance, but can be altered by other components. Bioactivity can be assessed through in vivo detection of the drug's solvent (LD50). 50 or ED 50 The efficacy or toxicity may be assessed by determination or by in vitro assays (such as cell-based efficacy assays as described, for example, in U.S. Patent Application Publications Nos. 2010 / 0203559 and 2010 / 0233802).

[0086] "Botulinum toxin" refers to a neurotoxin produced by Clostridium botulinum, as well as botulinum toxin (or its light or heavy chains) recombinantly produced from non-clostridium species. As used herein, the phrase "botulinum toxin" encompasses serotype A botulinum neurotoxin (BoNT / A) and / or its subtypes and variants. "Botulinum toxin" as disclosed herein includes, but is not limited to, naturally occurring botulinum toxins, fragments thereof, or chimeras; and non-naturally occurring botulinum toxins, such as recombinant, modified botulinum toxins, fragments thereof, or chimeras. Furthermore, as used herein, "botulinum toxin" also encompasses botulinum toxin complexes (e.g., 300, 500, 600, and 900 kDa complexes), and the neurotoxic component of botulinum toxin (150 kDa) that does not bind to the complex protein. Throughout this disclosure, "botulinum toxin type A," "serotype A botulinum toxin," "botulinum neurotoxin type A," and "serotype A botulinum neurotoxin" are used interchangeably.

[0087] It should be understood that in this disclosure, all aspects and embodiments described using the word "comprising" are also provided with other similar aspects described using "consisting of" and / or "substantially consisting of".

[0088] The “effective amount” applied to bioactive ingredients refers to the amount of the ingredient that is generally sufficient to achieve the desired change in subjects.

[0089] "Topical application" means the direct application of a drug to or near a site on or within the body of an animal in order to produce a biological effect at that site, such as via intramuscular, intradermal, or subcutaneous injection or local administration. Topical application does not include systemic routes of administration, such as intravenous or oral administration. Topical application is a type of application in which the drug is applied to the patient's skin.

[0090] The terms “patient,” “subject,” and “participant” are used interchangeably herein and refer to humans. In one specific implementation, the subject is an adult. In another specific implementation, the subject is under 65 years of age.

[0091] "Pharmaceutical composition" means a composition comprising an active pharmaceutical ingredient (such as, for example, botulinum toxin) and at least one additional ingredient (such as, for example, a stabilizer or excipient). Therefore, a pharmaceutical composition is a formulation suitable for diagnostic or therapeutic administration to a subject (such as a human patient). A pharmaceutical composition may be, for example, a solution formed by reconstitution of a lyophilized or vacuum-dried pharmaceutical composition, or a solution or solid that does not require reconstitution.

[0092] The term "protrusion" is used to describe an anatomical feature that disrupts a normally smooth or well-defined surface due to a bulge or protrusion, similar to a prominent larynx. "Platysalis protrusion" refers to the platysma muscle bulging out when it contracts, thus creating an unsightly disruption of the lines and contours of the lower face and neck. This contraction causes the muscle to bulge over the lower face, blunting the jawline and forming a vertical band along the length of the neck.

[0093] "Improving or improving the appearance of platysma protrusion" means reducing or improving the severity of platysma protrusion, which includes aesthetic improvements to the following appearances: (i) the jawline, and (ii) the vertical neck band. Therefore, improving the appearance of platysma protrusion includes, but is not limited to, treating the jawline, improving the jawline contour, sharpening the jawline, thinning the jawline, reducing jawline blunting, rejuvenating the jawline, reducing drooping corners of the mouth, reshaping the corners of the mouth, and lifting the corners of the mouth. Improving the appearance of platysma protrusion also includes improving the appearance of the platysma band, reducing the protrusion of the platysma band, changing the neck band to be less visible or less noticeable, and improving the neck contour, making the neck firmer, smoother, and more toned. For example (but not limited to), in some embodiments, improving the appearance of platysma protrusion includes at least one grade improvement on the APPS scale (including C-APPS and P-APPS). In some embodiments, improving the appearance of platysma protrusion includes at least a change in patient-reported outcomes (PROs) (such as ANLFQ and / or BAS-PP) relative to baseline. In one specific implementation, the appearance improvement described herein is a temporary appearance improvement.

[0094] "Treating / treat / treatment" means temporarily or permanently alleviating at least one symptom of a condition (such as, for example, undesirable aesthetic effects), improving the appearance of at least one symptom, or eliminating at least one symptom. As used herein, treating platysma protrusion means temporarily or permanently improving the appearance of platysma protrusion as defined above, or reducing platysma protrusion in a human patient or subject. In some embodiments, treating platysma protrusion includes maximally reducing or alleviating the appearance of the platysma band in a patient. For example (but not limited to), in some embodiments, treating platysma protrusion includes an improvement of at least one grade on the APPS scale (including C-APPS and P-APPS).

[0095] "Unit" or "U" refers to LD 50 Dosage or dosage determined by cell-based potency assay (CBPA). LD 50 The dosage was defined as the amount of botulinum toxin required to kill 50% of mice injected with botulinum toxin. The CBPA dosage was determined as described in U.S. Patent Nos. 8,618,261, 8,198,034, 9,249,216, 10,703,806, 11,261,240, and 11,332,518; details of the determinations in these U.S. Patents are incorporated herein by reference.

[0096] For convenience, certain terms used in the specification, embodiments, and claims are collected herein. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0097] 5.2. Botulinum toxin

[0098] The genus *Clostridium* comprises over 130 species, grouped by morphology and function. The anaerobic, Gram-positive bacterium *Clostridium botulinum* produces a potent polypeptide neurotoxin, botulinum toxin (synonymous with "toxin"), which causes a neuroparalytic disease called botulism in humans and animals. Symptoms of botulism can progress from difficulty walking, swallowing, and speaking to respiratory muscle paralysis and death.

[0099] Although all botulinum toxin serotypes appear to inhibit the release of the neurotransmitter acetylcholine at the neuromuscular junction, they do so by affecting different neurosecretory proteins and / or cleaving these proteins at different sites. Botulinum toxin type A is a zinc endopeptidase that specifically hydrolyzes the peptide bonds of the 25 kDa synaptosome-associated protein (SNAP-25), a vesicle-associated protein (VAMP, also known as small synaptic vesicle protein). Compared to botulinum toxin type A, botulinum toxin type E, while also cleaving SNAP-25, targets a different amino acid sequence within the protein. Botulinum toxin types B, D, F, and G act on VAMP, each serotype cleaving the protein at different sites. Finally, botulinum toxin type C1 has been shown to cleave both the synaptic fusion protein and SNAP-25. These differences in mechanisms of action may affect the relative potency and / or duration of action of various botulinum toxin serotypes.

[0100] For all known botulinum toxin serotypes, the molecular weight of the active botulinum toxin protein molecule (also known as "pure toxin" or "neurotoxic component") derived from a botulinum toxin complex is approximately 150 kDa. Interestingly, botulinum toxin is released by Clostridium in the form of complexes containing a 150 kDa neurotoxic component and one or more associated non-toxin proteins. Therefore, type A botulinum toxin complexes can be produced by Clostridium in 900 kDa, 500 kDa, and 300 kDa forms (approximate molecular weights). These complexes (i.e., with a molecular weight greater than approximately 150 kDa) contain hemagglutinin (HA) proteins and non-toxin non-hemagglutinin (NTNH) proteins. Thus, a botulinum toxin complex may contain a botulinum toxin molecule (neurotoxic component) and one or more HA and / or NTNH proteins. These two types of non-toxin proteins (which can form associated neurotoxic complexes with the botulinum toxin molecule) can be used to provide stability to the botulinum toxin molecule against denaturation and to protect it from digestive acids upon ingestion of the toxin. Additionally, larger botulinum toxin complexes (greater than approximately 150 kDa molecular weight) may result in a slower rate of diffusion of botulinum toxin from the intramuscular injection site.

[0101] Botulinum toxin type A is known to be soluble in dilute aqueous solutions with pH values ​​ranging from 4 to 6.8. At pH values ​​above approximately 7, stabilizing non-toxin proteins dissociate from the neurotoxin, leading to a gradual loss of toxicity, particularly at elevated pH and temperature (Schantz EJ et al., Preparation and characterization of botulinum toxin type A for human treatment, Jankovic, J. et al., Therapy with Botulinum Toxin, Chapter 3, Marcel Dekker, Inc., 1994).

[0102] Like general enzymes, the biological activity of botulinum toxins (which are intracellular peptidases) depends at least in part on their three-dimensional conformation. Diluting the toxin from milligrams to solutions containing nanograms per milliliter presents significant challenges, for example, as the toxin tends to adhere to surfaces, thus reducing the amount of usable toxin. Since the toxin may not be used for months or years after formulation of a pharmaceutical composition containing it, stabilizers or excipients are used to stabilize the toxin. Acceptable excipients or stabilizers include protein excipients, such as albumin or gelatin, or non-protein excipients, including poloxamer, sugars, polyethylene glycol, hyaluronic acid, etc. The use of non-protein excipients in botulinum toxin formulations is disclosed in U.S. Patent Nos. 10,360,190 and 10,973,890; and in International Patent Application Publications Nos. WO2018053021, WO2018053004 and WO2020056371; each of these references is incorporated herein by reference in its entirety.

[0103] Methods for obtaining botulinum toxin without animal protein and / or for chromatographic analysis are disclosed in U.S. Patents 7,160,699, 7,354,740, 7,189,541, 7,445,914, 7,452,697, 7,560,251, 8,409,828, 8,008,044, 8,012,716, 8,841,110, 9,725,705, and 7,189,541, each of which is incorporated herein by reference in its entirety. Processes and systems for obtaining botulinum toxin without animal protein are also disclosed in U.S. Patent Nos. 8,129,139, 8,927,229, 8,357,541, 8,932,827, 8,324,349, 9,206,409, 9,719,076, 10,465,178, 11,124,786, and 11,203,748. References to U.S. Patent Application Publications Nos. 11,326,155, 202 ...

[0104] It is anticipated that any currently available or future commercially available botulinum toxin formulation is suitable for the methods described herein, including but not limited to onabotulinumtoxin A (such as BOTOX). ® BOTOX ®Cosmetic or VISTABEL ® Products with names like these are known to people), abobotulinumtoxinA (as in DYSPORT) ® Products with names such as XEOMIN are known to people. ® (such as the product name known to people), prabotulinumtoxinA (in the name such as JEUVEAU) ® Products with names like DAXXIFY are known to people. ® Products with names such as (e.g., known to the public), letibotulinumtoxinA (e.g., BOTULAX) ® (such as the product name known to people), NEURONOX ® nivobotulinumtoxinA (such as INNOTOX) ® (such as the product name known to people) and gemibotulinumtoxinA.

[0105] In some embodiments, the botulinum toxin used by the methods described herein is type A (or serotype A) botulinum toxin. The botulinum toxin may be a recombinant botulinum toxin, such as botulinum toxin produced by *Escherichia coli*.

[0106] In some implementations, botulinum toxin type A is selected from onabotulinum toxin A, incobotulinum toxin A, abotulinum toxin A, daxibotulinum toxin A, prabotulinum toxin A, letibotulinum toxin A, lanbotulinum toxin A, nivobotulinum toxin A, gemibotulinum toxin A, and NEURONOX. ® In one implementation, botulinum toxin type A is onabotulinumtoxin A.

[0107] In some embodiments, botulinum toxin is a pure neurotoxin without complex proteins. In some embodiments, the pure neurotoxin is selected from incobotulinumtoxin A and daxibotulinumtoxin A.

[0108] In some embodiments, botulinum toxin is in the form of a formulation free of animal protein. In some embodiments, the botulinum toxin is gemibotulinumtoxin A. In another embodiment, the botulinum toxin is nivobotulinumtoxin A. In yet another embodiment, the botulinum toxin is daxibotulinumtoxin A.

[0109] The botulinum toxin used according to the method of the present invention can be stored in a vacuum pressure vessel in the form of lyophilization, vacuum drying, or as a stable liquid. Prior to lyophilization, the botulinum toxin can be combined with pharmaceutically acceptable excipients, stabilizers, and / or carriers (such as, for example, albumin). Acceptable excipients or stabilizers include protein excipients, such as albumin or gelatin, or non-protein excipients, including poloxamer, sugars, polyethylene glycol, etc. In embodiments containing albumin, the albumin can be, for example, human serum albumin or recombinant human albumin. The lyophilized material can be reconstituted with a suitable liquid (such as, for example, saline, water, etc.) to prepare a solution or composition containing botulinum toxin to be administered to a subject.

[0110] The effective dose of botulinum toxin administered according to the method of the present invention can vary depending on the potency of the toxin and the specific characteristics of the condition being treated, including its severity and various other subject variables, including body size, weight, age, and response to treatment. The potency of the toxin is expressed as the LD50 in mice. 50 A multiple of the value, where one unit (U) of toxin can be defined as the equivalent amount of toxin that kills 50% of a group of 18 to 20 female Swiss-Webster mice (each weighing about 20 grams), or defined by cell-based potency assays, as described in U.S. Patent Application Publication Nos. 2010 / 0203559 and US2010 / 0233802.

[0111] The effective dose of botulinum toxin can vary depending on the potency of the botulinum toxin because commercially available botulinum toxin formulations do not have equivalent potency units. In one embodiment, the effective dose of botulinum toxin type A administered according to this method is about 20 units or less for one side of the patient's neck. In another embodiment, the effective dose of botulinum toxin type A administered according to this method is about 18 units or less for one side of the patient's neck.

[0112] In one embodiment, the applied effective amount of botulinum toxin is in the form of a composition, which may be a stable liquid pharmaceutical composition, such as a stable liquid pharmaceutical composition reconstituted from a stable solid (e.g., lyophilized) pharmaceutical composition. In another embodiment, the applied effective amount of botulinum toxin is in the form of a composition, which may be a solid (e.g., lyophilized) pharmaceutical composition. The composition, liquid pharmaceutical composition, or solid pharmaceutical composition may comprise botulinum toxin and a pharmacologically acceptable excipient. As used herein, "pharmacologically acceptable excipient" is synonymous with "pharmacological excipient" or "excipient" and refers to any excipient that, when administered to mammals, substantially does not have long-term or permanent harmful effects and encompasses compounds such as, for example, stabilizers, swelling agents, cryoprotectants, lyophilization protectants, additives, mediators, carriers, diluents, or adjuvants. Excipients are generally mixed with or allow dilution or encapsulation of the active ingredient and may be solid, semi-solid, or liquid pharmaceutical preparations. In one embodiment, the composition, liquid pharmaceutical composition, or solid pharmaceutical composition comprises botulinum toxin, a disaccharide, a surfactant, and an antioxidant. In another embodiment, the composition, liquid pharmaceutical composition, or solid pharmaceutical composition comprises botulinum toxin, disaccharide, surfactant, and animal protein, such as albumin. In another embodiment, the composition, liquid pharmaceutical composition, or solid pharmaceutical composition comprises botulinum toxin, disaccharide, surfactant, and does not contain animal protein; that is, the composition, liquid pharmaceutical composition, or solid pharmaceutical composition is a composition that does not contain animal protein.

[0113] It is also envisioned that pharmaceutical compositions containing the active ingredient of botulinum toxin may include one or more pharmaceutically acceptable excipients that facilitate the processing of the active ingredient into a pharmaceutically acceptable composition. Any pharmaceutically acceptable excipient may be considered for use in a pharmaceutically acceptable composition, provided that it is not incompatible with the active ingredient of botulinum toxin. Non-limiting examples of pharmacologically acceptable excipients can be found in, for example, Pharmaceutical Dosage Forms and Drug Delivery Systems (edited by Howard C. Ansel et al., Lippincott Williams & Wilkins Publishers, 7th ed., 1999); Remington: The Science and Practice of Pharmacy (edited by Alfonso R. Gennaro, Lippincott, Williams & Wilkins, 20th ed., 2000); Goodman & Gilman's The Pharmacological Basis of Therapeutics (edited by Joel G. Hardman et al., McGraw-Hill Professional, 10th ed., 2001); and Handbook of Pharmaceutical Excipients (Raymond C. Rowe et al., APhA Publications, 4th ed., 2003), each of which is incorporated herein by reference in its entirety.

[0114] The components of a pharmaceutical composition may be included in a single composition (i.e., all components are present in the initial mixing of the pharmaceutical composition except for any desired reconstitution liquid) or may be included as a two-component system, such as a vacuum-dried composition reconstituted with a reconstitution medium, which may, for example, contain components not present in the initial mixing of the pharmaceutical composition. Two-component systems can provide several advantages, including allowing the incorporation of components that are not sufficiently compatible with the first component of the two-component system for long-term storage. For example, the reconstitution medium may contain a preservative that provides sufficient protection against microbial growth during use (e.g., one week of refrigerated storage), but is absent during two years of frozen storage, during which time the preservative may degrade toxins. Other components that may not be compatible with botulinum toxin or other components for extended periods can be incorporated in this way; i.e., added to a second medium (e.g., the reconstitution medium) approximately at the time of use.

[0115] The pharmaceutical composition may also contain preservatives such as benzyl alcohol, benzoic acid, phenol, parabens, and sorbic acid. The pharmaceutical composition may contain, for example, excipients such as surfactants; dispersants; inert diluents; granulating agents and disintegrants; binders; lubricants; preservatives; physiologically degradable compositions such as gelatin; aqueous mediators and solvents; oily mediators and solvents; suspending agents; dispersants or wetting agents; emulsifiers, modifiers; buffers; salts; thickeners; fillers; antioxidants; stabilizers; and pharmaceutically acceptable polymeric or hydrophobic materials and other ingredients known in the art and described, for example, in Genaro, 1985, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., which is incorporated herein by reference.

[0116] In one embodiment, botulinum toxin is provided in the form of a lyophilized powder in a single-use vial. For example, in some embodiments, the vial contains between about 10 units and 750 units, or between about 100 units and 240 units, of type A botulinum toxin and any excipients. Prior to use, the lyophilized material can be reconstituted with, for example, sterile, preservative-free 0.9% sodium chloride injection USP. In one embodiment, the vial contains 50, 100, or 200 units of lyophilized botulinum toxin for reconstitution with sterile, preservative-free 0.9% sodium chloride USP.

[0117] In other embodiments, botulinum toxin is provided in a disposable pre-filled syringe. The pre-filled syringe is pre-reconstructed with sterile, preservative-free 0.9% sodium chloride injection solution USP. The pre-filled syringe may contain between about 1 mL and 5 mL, or preferably about 3 mL, and may contain between about 10 units and 150 units, or about 20 units and 100 units, 20 units and 60 units, or 25 units and 50 units of botulinum toxin type A. In one embodiment, the pre-filled syringe contains 3 mL of 50 units or 200 units of botulinum toxin type A.

[0118] 5.3. Usage Method

[0119] This disclosure provides a method for improving the appearance of a patient with platysma protrusion, the patient having only one or only two consecutive vertical neck bands on at least one side of the patient's neck. Preferably, the method involves injecting a mandibular dose of botulinum toxin type A composition below the patient's mandibular line on that side of the patient's neck and injecting a neck band dose of botulinum toxin type A composition along one or two consecutive bands.

[0120] Some methods for improving the appearance of platysma protrusion, as provided herein, involve determining the number of consecutive vertical neck bands a patient has and selecting patients accordingly for treatment. Therefore, in one aspect, this document provides a method for improving (e.g., temporarily improving) the appearance of platysma protrusion (e.g., moderate to severe platysma protrusion) associated with platysma activity in a human patient, the method comprising quantifying the number of consecutive vertical neck bands on a first side of the human patient's neck at maximum contraction, wherein the consecutive vertical neck bands are vertical neck bands that extend continuously from the mandibular line of the human patient to the lower neck region; and then applying a composition comprising botulinum toxin type A to the first side of the neck of a human patient identified as having only one or only two consecutive vertical neck bands at maximum contraction.

[0121] In specific embodiments, the methods described herein for improving (e.g., temporarily improving) the appearance of platysma protrusions (e.g., moderate to severe platysma protrusions) associated with platysma activity are for improving (e.g., temporarily improving) the appearance of platysma bands (e.g., moderate to severe platysma bands) associated with platysma activity. In specific embodiments, the methods described herein for improving (e.g., temporarily improving) the appearance of platysma protrusions (e.g., moderate to severe platysma protrusions) associated with platysma activity are for improving (e.g., temporarily improving) the appearance of platysma protrusions (e.g., moderate to severe platysma protrusions) seen at maximal contraction. In specific embodiments, the methods described herein for improving (e.g., temporarily improving) the appearance of platysma protrusions (e.g., moderate to severe platysma protrusions) associated with platysma activity are for improving (e.g., temporarily improving) the appearance of platysma band protrusions (e.g., moderate to severe platysma band protrusions) seen at maximal contraction. In specific implementations, the methods described herein for improving (e.g., temporarily improving) the appearance of platysma protrusion (e.g., moderate to severe platysma protrusion) associated with platysma activity are for improving (e.g., temporarily improving) the appearance of the vertical band connecting the mandible and neck (e.g., moderate to severe vertical band connecting the mandible and neck) as seen at maximal contraction.

[0122] In one specific embodiment, the method provided herein for improving the appearance of platysma protrusion associated with platysma activity in a human patient comprises: identifying a human patient suffering from platysma protrusion characterized by at least one continuous vertical neck band at maximal contraction on one side of the human patient's neck; quantifying the number of continuous vertical neck bands on that side of the human patient's neck at maximal contraction; classifying that side of the human patient's neck as: (i) having moderate platysma protrusion if that side of the human patient's neck has only one continuous vertical neck band at maximal contraction; or (ii) having severe platysma protrusion if that side of the human patient's neck has only two continuous vertical neck bands at maximal contraction; and if that side of the human patient's neck is classified as having moderate or severe platysma protrusion, applying a composition comprising botulinum toxin type A to that side of the human patient's neck.

[0123] If it is determined that a human patient has only one continuous vertical neck band on one side of the patient's neck, the composition is applied to that side of the human patient's neck by injecting the following doses: a mandibular line dose in the upper segment of the platysma muscle below and parallel to the lower border of the patient's mandible (or mandibular border) on that side (e.g., distributed among 4 injection sites), and the injection sites (e.g., 4 injection sites) may include an anterior injection site consistent with the corner of the mouth and a posterior injection site anterior to the angle of the mandible (e.g., slightly anterior); and a neck band dose along the only continuous vertical neck band (e.g., distributed among 5 injection sites).

[0124] If it is determined that a human patient has only two consecutive vertical neck bands on one side of the patient's neck, the composition is applied to that side of the human patient's neck by injecting the following doses: a mandibular line dose (e.g., distributed among 4 injection sites) below and parallel to the lower border of the patient's mandible (or mandibular border) on that side, and the injection sites (e.g., 4 injection sites) may include an anterior injection site consistent with the corner of the mouth and a posterior injection site anterior (e.g., slightly anterior) to the angle of the mandible; and a first neck band dose (e.g., distributed among 5 injection sites) along the first consecutive vertical neck band and a second neck band dose (e.g., distributed among 5 injection sites) along the second consecutive vertical neck band.

[0125] Whether the injection site is "slightly in front" of the angle of the mandible can be determined by the attending physician, or based on industry-recognized standards or standards established by ordinary technicians in the field.

[0126] The method may also include the steps of repeated quantification and application to a second side of the neck of a human patient.

[0127] This disclosure provides a specific dosing regimen for human patients identified as having only one or two consecutive vertical neckbands on either side of the patient's neck.

[0128] For example, when a human patient has only one continuous vertical neck band on the first side of their neck, the composition can be administered to the first side of the human patient's neck by injecting the following doses: (i) a first mandibular line dose (e.g., distributed among 4 injection sites) below and parallel to the lower border of the patient's mandible (or mandibular border) on the first side, wherein optionally the injection sites (e.g., the 4 injection sites) include an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior (e.g., slightly anterior) to the angle of the mandible; and (ii) a first neck band dose (e.g., distributed among 5 injection sites) along the only continuous vertical neck band. In a specific embodiment, this administration step delivers a total unilateral dose of about 10 units to about 15 units of botulinum toxin type A to the first side of the human patient's neck. In another specific embodiment, this administration step delivers a total unilateral dose of about 13 units of botulinum toxin type A to the first side of the human patient's neck. In one specific embodiment, the composition is administered by injecting the following doses: (i) a first mandibular line dose of approximately 8 units of botulinum toxin type A (e.g., approximately 2 units of botulinum toxin type A per injection) distributed between four injection sites below and parallel to the lower border of the patient's mandible (or mandibular border) on the first side, including an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior to (e.g., slightly anterior to) the angle of the mandible; and (ii) a first neck band dose of approximately 5 units of botulinum toxin type A (e.g., approximately 1 unit of botulinum toxin type A per injection) distributed between five injection sites along a single continuous vertical neck band.

[0129] In one specific embodiment where the human patient has only one continuous vertical neck band at maximum contraction on the first side of the neck, the method provided herein includes administering a composition containing botulinum toxin type A to the first side of the human patient's neck by injecting the following doses: (i) a first mandibular line dose of approximately 8 units of botulinum toxin type A distributed among four injection sites below and parallel to the lower border of the patient's mandible (or mandibular border) on the first side, the four injection sites including an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior (e.g., slightly anterior) to the angle of the mandible, wherein each injection of the first mandibular line dose is approximately 2 units of botulinum toxin type A; and (ii) a first neck band dose of approximately 5 units of botulinum toxin type A distributed among five injection sites along a single continuous vertical neck band, wherein each injection of the first neck band dose is approximately 1 unit of botulinum toxin type A; wherein this administration step delivers a total unilateral dose of approximately 13 units of botulinum toxin type A to the first side of the human patient's neck.

[0130] In some cases, when both the first and second sides of a human patient's neck have only one continuous vertical neck band, the composition can be administered to the first and second sides of the human patient's neck by injecting the following doses: (i) a first mandibular line dose (e.g., distributed among 4 injection sites) below and parallel to the lower border of the patient's mandible (or mandibular border) on the first side, wherein optionally the injection sites (e.g., 4 injection sites) include an anterior injection site consistent with the corner of the mouth and a posterior injection site anterior (e.g., slightly anterior) to the angle of the mandible; (ii) along the first side... The administration step delivers a first neck band dose along a single, continuous vertical neck band (e.g., distributed among 5 injection sites); (iii) a second mandibular line dose (e.g., distributed among 4 injection sites) below and parallel to the lower border of the patient's mandible (or mandibular border) on the second side, wherein optionally the injection sites (e.g., 4 injection sites) include an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior (e.g., slightly anterior) to the angle of the mandible; and (iv) a first neck band dose along a single, continuous vertical neck band on the second side (e.g., distributed among 5 injection sites). In a specific embodiment, this administration step delivers a total unilateral dose of approximately 10 to approximately 15 units of botulinum toxin type A to each side of the human patient's neck. In another specific embodiment, this administration step delivers a total bilateral dose of approximately 20 to approximately 30 units of botulinum toxin type A to each side of the human patient's neck. In a specific embodiment, this administration step delivers a total unilateral dose of approximately 13 units of botulinum toxin type A to each side of the human patient's neck. In a specific implementation, the administration step delivers a total bilateral dose of approximately 26 units of botulinum toxin type A to the neck of a human patient.In a more specific embodiment, the composition is administered by injecting the following doses: (i) a first mandibular line dose of approximately 8 units of botulinum toxin type A (e.g., approximately 2 units of botulinum toxin type A per injection) distributed between four injection sites below and parallel to the lower border of the patient's mandible (or mandibular border) on the first side, including an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior to (e.g., slightly anterior to) the angle of the mandible; and (ii) approximately 5 units of botulinum toxin type A (e.g., approximately 1 unit of botulinum toxin type A per injection) distributed between five injection sites along the only continuous vertical neck band on the first side. (iii) a first neck band dose of botulinum toxin type A (e.g., about 2 units of botulinum toxin type A per injection) distributed among four injection sites below and parallel to the lower border of the patient's mandible (or mandibular border) on the second side, including an anterior injection site consistent with the corner of the mouth and a posterior injection site anterior to (e.g., slightly anterior to) the angle of the mandible; and (iv) a first neck band dose of about 5 units of botulinum toxin type A (e.g., about 1 unit of botulinum toxin type A per injection) distributed among five injection sites along a single continuous vertical neck band on the second side.

[0131] In one specific embodiment where a human patient has only one continuous vertical neck band during maximal contraction on the first side of the neck and only one continuous vertical neck band during maximal contraction on the second side of the neck, the method provided herein comprises: (A) administering a composition containing botulinum toxin type A to the first and second sides of the neck of a human patient by injecting the following doses: (i) a first mandibular line dose of approximately 8 units of botulinum toxin type A distributed among four injection sites below and parallel to the lower border of the patient's mandible (or mandibular border) on the first side, the four injection sites including an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior (e.g., slightly anterior) to the angle of the mandible, wherein each injection of the first mandibular line dose is approximately 2 units of botulinum toxin type A; and (ii) a first neck band dose of approximately 5 units of botulinum toxin type A distributed among five injection sites along the only continuous vertical neck band on the first side, wherein each injection of the first neck band dose is approximately 2 units of botulinum toxin type A. The first injection is approximately 1 unit of botulinum toxin type A; and (B) the composition is further administered to the neck of a human patient by injecting the following doses: (iii) a second mandibular line dose of approximately 8 units of botulinum toxin type A, distributed among 4 injection sites below and parallel to the lower border of the patient's mandible (or mandibular border) on the second side, the 4 injection sites including an anterior injection site consistent with the corner of the mouth and a posterior injection site anterior (e.g., slightly anterior) to the angle of the mandible, wherein each injection of the second mandibular line dose is approximately 2 units of botulinum toxin type A; and (iv) a first neck band dose of approximately 5 units of botulinum toxin type A, distributed among 5 injection sites along a single continuous vertical neck band on the second side, wherein each injection of the first neck band dose is approximately 1 unit of botulinum toxin type A; wherein the steps of administration to the first side and administration to the second side deliver a total bilateral dose of approximately 26 units of botulinum toxin type A to the neck of the human patient.

[0132] In other cases, when the first side of a human patient's neck has only two consecutive vertical neck bands, the composition can be administered to the first side of the human patient's neck by injecting the following doses: (i) a first mandibular line dose (e.g., distributed among 4 injection sites) below and parallel to the lower border of the patient's mandible (or mandibular border) on the first side, wherein optionally the injection sites (e.g., 4 injection sites) include an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior (e.g., slightly anterior) to the angle of the mandible; and (ii) a first neck band dose (e.g., distributed among 5 injection sites) along the first consecutive vertical neck band and a second neck band dose (e.g., distributed among 5 injection sites) along the second consecutive vertical neck band. In a specific embodiment, this administration step delivers a total unilateral dose of about 15 units to about 20 units of botulinum toxin type A to the first side of the human patient's neck. In a specific embodiment, this administration step delivers a total unilateral dose of about 18 units of botulinum toxin type A to the first side of the human patient's neck. In one specific embodiment, the composition is administered by injecting the following doses: (i) a first mandibular line dose of approximately 8 units of botulinum toxin type A (e.g., approximately 2 units of botulinum toxin type A per injection) distributed between four injection sites below and parallel to the lower border of the patient's mandible (or mandibular border) on a first side, the four injection sites including an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior (e.g., slightly anterior) to the angle of the mandible; and (ii) a first neck band dose of approximately 5 units of botulinum toxin type A (e.g., approximately 1 unit of botulinum toxin type A per injection) distributed between five injection sites along a first continuous vertical neck band and a second neck band dose of approximately 5 units of botulinum toxin type A (e.g., approximately 1 unit of botulinum toxin type A per injection) distributed between five injection sites along a second continuous vertical neck band.

[0133] In one specific embodiment where the human patient has only two consecutive vertical neckbands at maximum contraction on the first side of the neck, the method provided herein includes administering a composition containing botulinum toxin type A to the first side of the neck of a human patient by injecting the following doses: (i) a first mandibular line dose of approximately 8 units of botulinum toxin type A distributed among four injection sites below and parallel to the lower border of the patient's mandible (or mandibular border) on the first side, including an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior (e.g., slightly anterior) to the angle of the mandible, wherein the first mandibular line dose Each injection is approximately 2 units of botulinum toxin type A; and (ii) a first neckband dose of approximately 5 units of botulinum toxin type A distributed between 5 injection sites along a first continuous vertical neckband and a second neckband dose of approximately 5 units of botulinum toxin type A distributed between 5 injection sites along a second continuous vertical neckband, wherein each injection of the first neckband dose is approximately 1 unit of botulinum toxin type A, and each injection of the second neckband dose is approximately 1 unit of botulinum toxin type A; wherein this administration step delivers a total unilateral dose of approximately 18 units of botulinum toxin type A to the first side of the neck of a human patient.

[0134] When a human patient has only two consecutive vertical neck bands on both the first and second sides of their neck, the composition can be administered to the first and second sides of the human patient's neck by injecting the following doses: (i) a first mandibular line dose (e.g., distributed among 4 injection sites) below and parallel to the lower border of the patient's mandible (or mandibular border) on the first side, wherein optionally the injection sites (e.g., 4 injection sites) include an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior (e.g., slightly anterior) to the angle of the mandible; (ii) a first neck band dose (e.g., distributed among 5 injection sites) along the first consecutive vertical neck band on the first side and along the second... The administration steps include: (iii) a second neck band dose (e.g., distributed among 5 injection sites) along a continuous vertical neck band; (iv) a second mandibular line dose (e.g., distributed among 4 injection sites) below and parallel to the lower border of the patient's mandible (or mandibular border) on the second side, wherein optionally the injection sites (e.g., 4 injection sites) include an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior (e.g., slightly anterior) to the angle of the mandible; and (iv) a first neck band dose (e.g., distributed among 5 injection sites) along a first continuous vertical neck band on the second side and a second neck band dose (e.g., distributed among 5 injection sites) along a second continuous vertical neck band on the second side. In a specific embodiment, this administration step delivers a total unilateral dose of approximately 15 units to approximately 20 units of botulinum toxin type A to each side of the human patient's neck. In a specific embodiment, this administration step delivers a total bilateral dose of approximately 30 units to approximately 40 units of botulinum toxin type A to the human patient's neck. In one specific implementation, the administration step delivers a total unilateral dose of approximately 18 units of botulinum toxin type A to each side of a human patient's neck. In another specific implementation, the administration step delivers a total bilateral dose of approximately 36 units of botulinum toxin type A to the neck of a human patient.In one specific embodiment, the composition is administered by injecting the following doses: (i) a first mandibular line dose of approximately 8 units of botulinum toxin type A (e.g., approximately 2 units of botulinum toxin type A per injection) distributed between four injection sites below and parallel to the lower border of the patient's mandible (or mandibular border) on the first side, including an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior (e.g., slightly anterior) to the angle of the mandible; (ii) a first neck band dose of approximately 5 units of botulinum toxin type A (e.g., approximately 1 unit of botulinum toxin type A per injection) distributed between five injection sites along a first continuous vertical neck band on the first side, and approximately 5 units of botulinum toxin type A (e.g., approximately 1 unit of botulinum toxin type A per injection) distributed between five injection sites along a second continuous vertical neck band on the first side. (iii) a second neckband dose of botulinum toxin type A (e.g., about 2 units of botulinum toxin type A per injection) distributed between four injection sites below and parallel to the lower border of the mandible (or mandibular border) on the second side, including an anterior injection site consistent with the corner of the mouth and a posterior injection site anterior to (e.g., slightly anterior to) the angle of the mandible; and (iv) a first neckband dose of about 5 units of botulinum toxin type A (e.g., about 1 unit of botulinum toxin type A per injection) distributed between five injection sites along a first continuous vertical neckband on the second side, and a second neckband dose of about 5 units of botulinum toxin type A (e.g., about 1 unit of botulinum toxin type A per injection) distributed between five injection sites along a second continuous vertical neckband on the second side.

[0135] In one specific embodiment where the human patient has only two consecutive vertical neck bands at maximum contraction on the first side of the neck and only two consecutive vertical neck bands at maximum contraction on the second side of the neck, the method provided herein includes: (A) administering a composition containing botulinum toxin type A to the first side of the neck of a human patient by injecting the following doses: (i) approximately 8 units of botulinum toxin type A first mandibular line dose distributed among four injection sites below the patient's mandibular border (or mandibular margin) and parallel to the upper segment of the platysma muscle on the first side, the four injection sites including those near the corners of the mouth. The injection sites are: (i) anterior injection sites and posterior injection sites anterior to the angle of the mandible (e.g., slightly anterior), wherein each injection of the first mandibular line dose is approximately 2 units of botulinum toxin type A; and (ii) a first neckband dose of approximately 5 units of botulinum toxin type A distributed between 5 injection sites along a first continuous vertical neckband on the first side, and a second neckband dose of approximately 5 units of botulinum toxin type A distributed between 5 injection sites along a second continuous vertical neckband on the first side, wherein each injection of the first neckband dose is approximately 1 unit of botulinum toxin type A, and each injection of the second neckband dose is approximately... Approximately 1 unit of botulinum toxin type A; and (B) further application of the composition to the second side of the neck of a human patient by injecting the following doses: (iii) a second mandibular line dose of approximately 8 units of botulinum toxin type A distributed among 4 injection sites below and parallel to the lower border of the patient's mandible (or mandibular border) on the second side, the 4 injection sites including an anterior injection site consistent with the corner of the mouth and a posterior injection site anterior to the angle of the mandible (e.g., slightly anterior), wherein each injection of the second mandibular line dose is approximately 2 units of botulinum toxin type A; and (iv) along the second mandibular line dose of approximately 8 units of botulinum toxin type A. A first neckband dose of approximately 5 units of botulinum toxin type A is distributed between 5 injection sites using a first continuous vertical neckband on both sides, and a second neckband dose of approximately 5 units of botulinum toxin type A is distributed between 5 injection sites using a second continuous vertical neckband on the second side, wherein each injection of the first neckband dose is approximately 1 unit of botulinum toxin type A, and each injection of the second neckband dose is approximately 1 unit of botulinum toxin type A; wherein the steps of administering the first side and administering the second side deliver a total bilateral dose of approximately 36 units of botulinum toxin type A to the neck of a human patient.

[0136] When a human patient has only one continuous vertical neck band on the first side of the neck and only two continuous vertical neck bands on the second side of the neck, the composition can be administered to the first and second sides of the human patient's neck by injecting the following doses: (i) a first mandibular line dose (e.g., distributed among 4 injection sites) below and parallel to the lower border of the patient's mandible (or mandibular border) on the first side, wherein optionally the injection sites (e.g., 4 injection sites) include an anterior injection site consistent with the corner of the mouth and a posterior injection site anterior to the angle of the mandible (e.g., slightly anterior); (ii) the first neck band along the only continuous vertical neck band on the first side. The dosage is distributed (e.g., among 5 injection sites); (iii) a second mandibular line dosage (e.g., among 4 injection sites) below and parallel to the lower border of the patient's mandible (or mandibular border) on the second side, wherein optionally the injection sites (e.g., 4 injection sites) include an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior (e.g., slightly anterior) to the angle of the mandible; and (iv) a first neck band dosage (e.g., among 5 injection sites) along a first continuous vertical neck band on the second side and a second neck band dosage (e.g., among 5 injection sites) along a second continuous vertical neck band on the second side. In a specific embodiment, this administration step delivers a total unilateral dose of about 10 units to about 15 units of botulinum toxin type A to a first side of the human patient's neck and a total unilateral dose of about 15 units to about 20 units of botulinum toxin type A to a second side of the human patient's neck. In one specific embodiment, the administration step delivers a total bilateral dose of approximately 25 to approximately 35 units of botulinum toxin type A to the neck of a human patient. In another specific embodiment, the administration step delivers a total unilateral dose of approximately 13 units of botulinum toxin type A to the first side of the human patient's neck and approximately 18 units of botulinum toxin type A to the second side of the human patient's neck. In yet another specific embodiment, the administration step delivers a total bilateral dose of approximately 31 units of botulinum toxin type A to the neck of a human patient.In one specific embodiment, the composition is administered by injecting the following doses: (i) a first mandibular line dose of approximately 8 units of botulinum toxin type A (e.g., approximately 2 units of botulinum toxin type A per injection) distributed between four injection sites below the patient's lower mandibular border (or mandibular border) and parallel to the upper segment of the platysma muscle along the lower mandibular border on the first side, the four injection sites including an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior (e.g., slightly anterior) to the angle of the mandible; (ii) a first neck band dose of approximately 5 units of botulinum toxin type A (e.g., approximately 1 unit of botulinum toxin type A per injection) distributed between five injection sites along a single continuous vertical neck band on the first side; and (iii) a dose below the patient's lower mandibular border (or mandibular border) on the second side. The second mandibular line dose consists of approximately 8 units of botulinum toxin type A (e.g., approximately 2 units of botulinum toxin type A per injection) distributed between four injection sites in the upper segment of the platysma muscle parallel to the lower border of the mandible, the four injection sites including an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior to (e.g., slightly anterior to) the angle of the mandible; and (iv) a first neck band dose consisting of approximately 5 units of botulinum toxin type A (e.g., approximately 1 unit of botulinum toxin type A per injection) distributed between five injection sites along a first continuous vertical neck band on the second side, and a second neck band dose consisting of approximately 5 units of botulinum toxin type A (e.g., approximately 1 unit of botulinum toxin type A per injection) distributed between five injection sites along a second continuous vertical neck band on the second side.

[0137] In one specific embodiment where the human patient has only one continuous vertical neck band at maximum contraction on the first side of the neck and only two continuous vertical neck bands at maximum contraction on the second side of the neck, the method provided herein includes administering a composition containing botulinum toxin type A to the neck of a human patient by injecting the following doses: (i) a first mandibular line dose of approximately 8 units of botulinum toxin type A distributed among four injection sites below and parallel to the lower border of the patient's mandible (or mandibular border) on the first side, including an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior (e.g., slightly anterior) to the angle of the mandible, wherein each injection of the first mandibular line dose is approximately 2 units of botulinum toxin type A; (ii) a first neck band dose of approximately 5 units of botulinum toxin type A distributed among five injection sites along the only continuous vertical neck band on the first side, wherein each injection of the first neck band dose is approximately 1 unit of botulinum toxin type A; (iii) (iv) A second mandibular line dose of approximately 8 units of botulinum toxin type A is distributed among four injection sites below and parallel to the lower border of the patient's mandible (or mandibular border) on the second side, in the upper segment of the platysma muscle. The four injection sites include an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior to (e.g., slightly anterior to) the angle of the mandible, wherein each injection of the second mandibular line dose is approximately 2 units of botulinum toxin type A; and (iv) along the first continuous vertical neck band on the second side at five injection sites. The administration procedure involves distributing approximately 5 units of botulinum toxin type A in a first neckband dose and approximately 5 units of botulinum toxin type A in a second neckband dose distributed between 5 injection sites along a second continuous vertical neckband on the second side, wherein each injection of the first neckband dose is approximately 1 unit of botulinum toxin type A, and each injection of the second neckband dose is approximately 1 unit of botulinum toxin type A; wherein this administration step delivers a total bilateral dose of approximately 31 units of botulinum toxin type A to the neck of a human patient.

[0138] The methods described herein for improving the appearance of platysma protrusion can be applied to patients who have been selected based on having only one or two consecutive vertical neck bands on one or both sides of their neck, or patients who are otherwise known to have only one or two consecutive vertical neck bands on one or both sides of their neck.

[0139] It should be understood that, unless the context clearly specifies otherwise, the terms “first” and “second” are used in this disclosure to distinguish different sides or different doses, and not to imply the order in which the two items or actions occur. Thus, for example, if a first neck band dose is injected along a single, continuous vertical neck band present on one side of a human patient’s neck, then in a preferred embodiment, a second neck band dose is not injected on that side.

[0140] In various aspects and embodiments, the mandibular line dose (e.g., a first mandibular line dose on a first side or a second mandibular line dose on a second side) is about 5 units to about 20 units of botulinum toxin type A. In a preferred embodiment, the mandibular line dose is about 8 units of botulinum toxin type A. In a specific embodiment, the mandibular line dose is about 5 units of botulinum toxin type A. In a specific embodiment, the mandibular line dose is about 6 units of botulinum toxin type A. In a specific embodiment, the mandibular line dose is about 7 units of botulinum toxin type A. In a specific embodiment, the mandibular line dose is about 9 units of botulinum toxin type A. In a specific embodiment, the mandibular line dose is about 10 units of botulinum toxin type A.

[0141] In various aspects and embodiments, the mandibular line dose is injected at one injection site. In various aspects and embodiments, the mandibular line dose is distributed among more than one injection site. In a specific embodiment, the mandibular line dose is distributed among 2 to 6 injection sites. In a preferred embodiment, the mandibular line dose is distributed among 4 injection sites. In a specific embodiment, the mandibular line dose is distributed among 2 injection sites. In a specific embodiment, the mandibular line dose is distributed among 3 injection sites. In a specific embodiment, the mandibular line dose is distributed among 5 injection sites. In a specific embodiment, the mandibular line dose is distributed among 6 injection sites. In a specific embodiment, the injection sites are arranged equidistant from each other. In a specific embodiment, the injection sites are arranged to be spaced approximately 1 cm to 2 cm apart.

[0142] In various aspects and implementations, the mandibular line dose is evenly distributed among injection sites. In an alternative implementation, the mandibular line dose is not evenly distributed among injection sites.

[0143] In various aspects and embodiments, the mandibular line dose at each injection site is approximately 1 unit to approximately 10 units of botulinum toxin type A. In a preferred embodiment, the mandibular line dose at each injection site is approximately 2 units of botulinum toxin type A. In a specific embodiment, the mandibular line dose at each injection site is approximately 1 unit of botulinum toxin type A. In a specific embodiment, the mandibular line dose at each injection site is approximately 1.5 units of botulinum toxin type A. In a specific embodiment, the mandibular line dose at each injection site is approximately 2.5 units of botulinum toxin type A. In a specific embodiment, the mandibular line dose at each injection site is approximately 3 units of botulinum toxin type A. In a specific embodiment, the mandibular line dose at each injection site is approximately 3.5 units of botulinum toxin type A. In a specific embodiment, the mandibular line dose at each injection site is approximately 4 units of botulinum toxin type A. In some embodiments, the first mandibular line dose is equal to the second mandibular line dose. In an alternative implementation, the first mandibular line dose differs from the second mandibular line dose.

[0144] In various aspects and embodiments, the mandibular line dose is injected into the upper segment of the platysma muscle below and parallel to the lower border of the mandible (or mandibular border) on the first or second side of the neck. In various aspects and embodiments, the mandibular line dose is injected into four injection sites approximately 1 to 5 cm below and parallel to the lower border of the mandible (or mandibular border) of the upper platysma muscle. In a specific embodiment, the mandibular line dose is injected into four injection sites approximately 1 to 2 cm below and parallel to the lower border of the mandible (or mandibular border) of the upper platysma muscle. In some embodiments, the anterior injection site of the four injection sites coincides with the corner of the mouth, and the posterior injection site is anterior to the angle of the mandible (e.g., slightly anterior). In some embodiments, the remaining two mandibular line injections are equidistant between the anterior and posterior injection points. In some embodiments, the remaining two mandibular line injections are spaced approximately 1 to 2 cm apart from each other.

[0145] The mandibular line dose can be administered via any route suitable for injecting a composition of botulinum toxin type A into the injection site. In a preferred embodiment, the mandibular line dose is administered via intramuscular injection (e.g., superficial intramuscular injection). In a specific embodiment, the mandibular line dose is administered via intradermal injection. In a specific embodiment, the mandibular line dose is administered via subcutaneous injection. In some embodiments, the injection into the platysma muscle is both superficial and intramuscular. In a specific embodiment, the injection depth does not exceed approximately 0.5 inches into the muscle. In one embodiment, the intramuscular and superficial injection is administered with a needle perpendicular to the skin surface. In some embodiments, the injection is not administered above the lower border of the mandible (or mandibular border) and / or into the deep structures of the platysma muscle. In some embodiments, a 0.5-inch needle is used to administer the dose. In some embodiments, a 1-inch needle is used to administer the dose. In a specific embodiment, a sterile 30-gauge syringe with a 0.5-inch needle is used to administer the dose. In a specific embodiment, a sterile 30-gauge syringe with a 1-inch needle is used to administer the dose. In some embodiments, the injection is guided by ultrasound or an alternative imaging device. In a preferred embodiment, the injection is administered at least 1 cm below the lower border of the mandible (or mandibular border). In a preferred embodiment, the injection must not penetrate the deep structures of the platysma muscle, particularly in the anterior neck region.

[0146] In various aspects and implementations, the neck band dose (e.g., a first or second neck band dose on a first or second side of the patient's neck) is about 2 units to about 8 units of botulinum toxin type A. In a preferred embodiment, the neck band dose is about 5 units of botulinum toxin type A. In a specific embodiment, the neck band dose is about 2 units of botulinum toxin type A. In a specific embodiment, the neck band dose is about 3 units of botulinum toxin type A. In a specific embodiment, the neck band dose is about 4 units of botulinum toxin type A. In a specific embodiment, the neck band dose is about 6 units of botulinum toxin type A. In a specific embodiment, the neck band dose is about 7 units of botulinum toxin type A. In a specific embodiment, the neck band dose is about 8 units of botulinum toxin type A.

[0147] In various aspects and embodiments, the neck band dose is injected at one injection site. In various aspects and embodiments, the neck band dose is distributed among more than one injection site. In a specific embodiment, the neck band dose is distributed among 2 to 7 injection sites. In a preferred embodiment, the neck band dose is distributed among 5 injection sites. In a specific embodiment, the neck band dose is distributed among 2 injection sites. In a specific embodiment, the neck band dose is distributed among 3 injection sites. In a specific embodiment, the neck band dose is distributed among 4 injection sites. In a specific embodiment, the neck band dose is distributed among 6 injection sites. In a specific embodiment, the neck band dose is distributed among 7 injection sites. In a specific embodiment, the injection sites are arranged to be spaced approximately 1 cm to 2 cm apart from each other. In some embodiments, both the first and second neck band doses on the same side of the patient's neck are equal. In another alternative embodiment, the first and second neck band doses on the same side of the neck are different. In some embodiments, the first or second neck band dose on one side of the neck is equal to the first or second neck band dose on the other side of the neck. In an alternative embodiment, the dose of the first or second neck band on one side of the neck is not equal to the dose of the first or second neck band on the other side of the neck.

[0148] In various aspects and implementations, the neck band dose is evenly distributed among injection sites. In an alternative implementation, the neck band dose is not evenly distributed among injection sites.

[0149] In various aspects and embodiments, the neckband dose at each injection site is approximately 0.5 units to approximately 2 units of botulinum toxin type A. In a preferred embodiment, the neckband dose at each injection site is approximately 1 unit of botulinum toxin type A. In a specific embodiment, the neckband dose at each injection site is approximately 0.5 units of botulinum toxin type A. In a specific embodiment, the neckband dose at each injection site is approximately 0.75 units of botulinum toxin type A. In a specific embodiment, the neckband dose at each injection site is approximately 1.5 units of botulinum toxin type A. In a specific embodiment, the neckband dose at each injection site is approximately 1.25 units of botulinum toxin type A. In a specific embodiment, the neckband dose at each injection site is approximately 2 units of botulinum toxin type A.

[0150] Preferably, the neckband dose injected along the neckband is lower than the dose injected along the mandibular line on the same side of the patient's neck. Preferably, for the same side of the patient's neck, the neckband dose at each injection site is lower than the mandibular line dose at each injection site.

[0151] In various aspects and implementations, the uppermost injection site for the neckband dose is approximately 1 to 2 cm below the mandibular line on the same side.

[0152] The neck band dose can be administered via any route suitable for injecting a composition of botulinum toxin type A into the injection site. In a preferred embodiment, the neck band dose is administered via intramuscular injection (e.g., superficial intramuscular injection). In a specific embodiment, the neck band dose is administered via intradermal injection. In a specific embodiment, the neck band dose is administered via subcutaneous injection. In some embodiments, the injection into the platysma muscle is both superficial and intramuscular. In a specific embodiment, the injection depth does not exceed approximately 0.5 inches into the muscle. In one embodiment, the intramuscular and superficial injections are administered with a needle perpendicular to the skin surface. In some embodiments, the injection is not administered above the submandibular border (or mandibular border) and / or into the deep structures of the platysma muscle. In some embodiments, the dose is administered using a 0.5-inch needle. In some embodiments, the dose is administered using a 1-inch needle. In a specific embodiment, the dose is administered using a sterile 30-gauge syringe with a 0.5-inch needle. In a specific embodiment, the dose is administered using a sterile 30-gauge syringe with a 1-inch needle. In some embodiments, the injection is guided by ultrasound or an alternative imaging device. In some embodiments, for neck band injections, each band is identified as the patient contracts their platysma muscle, and the band is gently pinched during administration to separate the muscle from nearby anatomical structures. In a preferred embodiment, the injection is made at least 1 cm below the lower border of the mandible (or mandibular border). In a preferred embodiment, the injection must not penetrate the deep structures of the platysma muscle, particularly in the anterior neck region.

[0153] In various aspects and embodiments where the mandibular line dose and neck band dose are administered on the first or second side of the neck, the mandibular line dose is injected before the neck band dose. In an alternative embodiment, the mandibular line dose is administered after the neck band dose. In embodiments where there are two neck bands on the first or second side, the mandibular line dose may be administered first, followed by the neck band dose. In an alternative embodiment, the neck band dose is administered before the mandibular line dose. In an alternative embodiment, the mandibular line dose is administered between the first and second neck band doses. In embodiments where the mandibular line dose on the first side of the neck, the mandibular line dose on the second side, the first neck band dose on the first side, and the first neck band dose on the second side are administered before the first neck band dose on the first side and the first neck band dose on the second side. In some embodiments, the administration sequence is as follows: mandibular line dose on the first side, mandibular line dose on the second side, first neck band dose on the first side, and first neck band dose on the second side. In an alternative implementation, the sequence is as follows: mandibular line dose on the first side, first neck band dose on the first side, mandibular line dose on the second side, and first neck band dose on the second side.

[0154] In various aspects and embodiments of administering the mandibular line dose, the first neck band dose, and / or the second neck band dose on the first, second, or both sides of the neck, the mandibular line dose, the first neck band dose, and / or the second neck band dose are administered within 24 hours of each other. In a specific embodiment, the mandibular line dose, the first neck band dose, and / or the second neck band dose are administered within 12 hours of each other. In a specific embodiment, the mandibular line dose, the first neck band dose, and / or the second neck band dose are administered within 6 hours of each other. In a specific embodiment, the mandibular line dose, the first neck band dose, and / or the second neck band dose are administered within 4 hours of each other. In a specific embodiment, the mandibular line dose, the first neck band dose, and / or the second neck band dose are administered within 2 hours of each other. In a specific embodiment, the mandibular line dose, the first neck band dose, and / or the second neck band dose are administered within 1 hour of each other. In a specific embodiment, the mandibular line dose, the first neck band dose, and / or the second neck band dose are administered within 0.5 hours of each other. In one embodiment, the mandibular line dose, the neck band dose, and / or the second neck band dose are administered within 20 minutes of each other. In another embodiment, the mandibular line dose, the first neck band dose, and / or the second neck band dose are administered within 10 minutes of each other. In yet another embodiment, the mandibular line dose, the first neck band dose, and / or the second neck band dose are administered within 5 minutes of each other.

[0155] In various aspects and implementations, the methods or application steps described herein deliver a total unilateral dose of about 10 units to about 40 units of botulinum toxin type A to a first or second side of the neck of a human patient. In specific implementations, the methods or application steps deliver a total unilateral dose of about 10 units to about 20 units of botulinum toxin type A. In specific implementations, the methods or application steps deliver a total unilateral dose of about 10 units to about 15 units of botulinum toxin type A. In one specific implementation, the methods or application steps deliver a total unilateral dose of about 13 units of botulinum toxin type A. In one specific implementation, the methods or application steps deliver a total unilateral dose of about 18 units of botulinum toxin type A. In one specific implementation, the methods or application steps deliver a total unilateral dose of about 10 units of botulinum toxin type A. In one specific implementation, the methods or application steps deliver a total unilateral dose of about 11 units of botulinum toxin type A. In one specific implementation, the methods or application steps deliver a total unilateral dose of about 12 units of botulinum toxin type A. In one embodiment, the method or application step delivers a total one-sided dose of about 14 units of botulinum toxin type A. In one embodiment, the method or application step delivers a total one-sided dose of about 15 units of botulinum toxin type A. In one embodiment, the method or application step delivers a total one-sided dose of about 16 units of botulinum toxin type A. In one embodiment, the method or application step delivers a total one-sided dose of about 17 units of botulinum toxin type A. In one embodiment, the method or application step delivers a total one-sided dose of about 19 units of botulinum toxin type A. In one embodiment, the method or application step delivers a total one-sided dose of about 20 units of botulinum toxin type A.

[0156] In various aspects and implementations, the methods or administration steps described herein deliver a total bilateral dose of about 20 units to about 80 units of botulinum toxin type A to both sides of the neck of a human patient. In specific implementations, the methods or administration steps deliver a total bilateral dose of about 20 units to about 40 units of botulinum toxin type A to both sides of the neck of a human patient. In specific implementations, the methods or administration steps deliver a total bilateral dose of about 20 units to about 30 units of botulinum toxin type A to both sides of the neck of a human patient. In specific implementations, the methods or administration steps deliver a total bilateral dose of about 30 units to about 40 units of botulinum toxin type A to both sides of the neck of a human patient. In specific implementations, the methods or administration steps deliver a total bilateral dose of about 25 units to about 35 units of botulinum toxin type A to both sides of the neck of a human patient. In one specific implementation, the methods or administration steps deliver a total bilateral dose of about 26 units of botulinum toxin type A to both sides of the neck of a human patient. In one embodiment, the method or administration step delivers a total bilateral dose of approximately 31 units of botulinum toxin type A to both sides of the neck of a human patient. In another embodiment, the method or administration step delivers a total bilateral dose of approximately 36 units of botulinum toxin type A to both sides of the neck of a human patient.

[0157] In various aspects and embodiments of the methods described herein, the severity grade of platysma herniation, including the number of consecutive vertical neck bands on one side of the human patient's neck, is determined by a physician (e.g., the attending physician of the human patient) or an investigator. In other embodiments, the severity grade of platysma herniation, including the number of consecutive vertical neck bands on one side of the human patient's neck, is determined by a human patient, subject, or participant. In some embodiments, the severity grade of platysma herniation, including the number of consecutive vertical neck bands on one side of the human patient's neck, is determined by both a physician and a human patient, subject, or participant.

[0158] In various aspects and embodiments, the cosmetic effect of the methods described herein is obtained within 14 days (including day 14) after the administration of botulinum toxin type A, wherein the cosmetic effect includes a change in the platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade, assessed by a physician and / or a human patient, from moderate or severe before the administration of botulinum toxin type A to slight or mild after the administration of botulinum toxin type A. In some embodiments, the change in the platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade is assessed by a physician. In some embodiments, the change in the platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade is assessed by a human patient. In some embodiments, the change in the platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade is assessed by both a physician and a human patient. In some embodiments in which the methods described herein are used to treat both sides of the neck of a human patient, the cosmetic effect includes achieving the aforementioned effect on both sides of the neck of the human patient. In other embodiments in which the methods described herein are used to treat both sides of the neck of a human patient, the cosmetic effect includes achieving the aforementioned effect on at least one side of the neck of the human patient.

[0159] In various aspects and embodiments, the cosmetic effect of the methods described herein is obtained within 14 days (including day 14) after application of botulinum toxin type A, wherein the cosmetic effect includes a grade 2 or better improvement in platysma protrusion as assessed by a physician and / or a human patient on a platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale), ranging from moderate or severe before application of botulinum toxin type A to slight or mild improvement after application. In some embodiments, a grade 2 or better improvement is assessed by a physician. In some embodiments, a grade 2 or better improvement is assessed by a human patient. In some embodiments, a grade 2 or better improvement is assessed by both a physician and a human patient. In some embodiments in which the methods described herein are used to treat both sides of the neck of a human patient, the cosmetic effect includes achieving the aforementioned effect on both sides of the neck of the human patient. In other embodiments in which the methods described herein are used to treat both sides of the neck of a human patient, the cosmetic effect includes achieving the aforementioned effect on at least one side of the neck of the human patient.

[0160] In various aspects and embodiments, the cosmetic effect of the methods described herein is obtained within 14 days (including day 14) after application of botulinum toxin type A, wherein the cosmetic effect includes a Grade 1 or better improvement in platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) as assessed by a physician and / or a human patient, from moderate or severe before application of botulinum toxin type A to mild or moderate after application of botulinum toxin type A. In some embodiments, a Grade 1 or better improvement is assessed by a physician. In some embodiments, a Grade 1 or better improvement is assessed by a human patient. In some embodiments, a Grade 1 or better improvement is assessed by both a physician and a human patient. In some embodiments in which the methods described herein are used to treat both sides of the neck of a human patient, the cosmetic effect includes achieving the aforementioned effect on both sides of the neck of the human patient. In other embodiments in which the methods described herein are used to treat both sides of the neck of a human patient, the cosmetic effect includes achieving the aforementioned effect on at least one side of the neck of the human patient.

[0161] In various aspects and implementations, the cosmetic effects described herein are obtained within 14 days (including on day 14) following the application of botulinum toxin type A, wherein the cosmetic effects include: (1) a change in platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade, assessed by a physician and / or a human patient, from moderate or severe before the application of botulinum toxin type A to slight or mild after the application; and (2) a grade 2 or better improvement in platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale), assessed by a physician and / or a human patient, from moderate or severe before the application of botulinum toxin type A to slight or mild after the application. In some implementations, the change in platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade is assessed by a physician. In some implementations, the change in platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade is assessed by a human patient. In some embodiments, changes in the platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade are assessed by both a physician and a human patient. In some embodiments, a grade 2 or better improvement is assessed by a physician. In some embodiments, a grade 2 or better improvement is assessed by a human patient. In some embodiments, a grade 2 or better improvement is assessed by both a physician and a human patient. In some embodiments, changes in the platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade and a grade 2 or better improvement are assessed by a physician. In some embodiments, changes in the platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade and a grade 2 or better improvement are assessed by both a physician and a human patient. In some embodiments where the methods described herein are used to treat both sides of the neck of a human patient, the cosmetic effect includes achieving the aforementioned effect on both sides of the neck of the human patient. In other embodiments in which the methods described herein are used to treat both sides of the neck of a human patient, the cosmetic effect includes achieving the aforementioned effect on at least one side of the neck of the human patient.

[0162] In various aspects and implementations, the cosmetic effects of the methods described herein are obtained within 14 days (including on day 14) after administration of botulinum toxin type A, wherein the cosmetic effects include achieving a mild or slight grade and at least 2-grade improvement relative to baseline on a platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) as assessed by a physician and / or a human patient. The baseline is assessed prior to the administration of botulinum toxin type A. In specific implementations, the baseline is assessed on the day of administration of botulinum toxin type A but prior to administration. In specific implementations, the baseline is a moderate or severe grade on a platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale). In some implementations, achieving a mild or slight grade and at least 2-grade improvement is assessed by a physician. In some implementations, achieving a mild or slight grade and at least 2-grade improvement is assessed by a human patient. In some implementations, achieving a mild or slight grade and at least 2-grade improvement is assessed by both a physician and a human patient. In some implementations in which the methods described herein are used to treat both sides of the neck of a human patient, the cosmetic effects include achieving the aforementioned effects on both sides of the neck of the human patient. In other embodiments in which the methods described herein are used to treat both sides of the neck of a human patient, the cosmetic effect includes achieving the aforementioned effect on at least one side of the neck of the human patient.

[0163] The Allergan platysma protrusion scale, as described herein, is listed in Table 1 above and... Figure 1 Example in.

[0164] In some implementations, the cosmetic effect is achieved within 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 day after the application of botulinum toxin type A.

[0165] In some embodiments, the duration of the cosmetic effect ranges from approximately 60 to approximately 90 days after the application of botulinum toxin type A. In some embodiments, the duration of the cosmetic effect ranges from approximately 60 to approximately 120 days after the application of botulinum toxin type A. In some embodiments, the duration of the cosmetic effect ranges from approximately 90 to approximately 120 days after the application of botulinum toxin type A. In some embodiments, the duration of the cosmetic effect is at least 120 days. In some embodiments, the duration of the cosmetic effect is at least 60 days. In some embodiments, the duration of the cosmetic effect is at least 30 days. In some embodiments, the duration of the cosmetic effect is at least 90 days. In some embodiments, the duration of the cosmetic effect is assessed at the population level based on whether the percentage of human patients treated with this method who have achieved and maintained a cosmetic effect is above a set threshold (e.g., 5%, 10%, 15%, or 20%).

[0166] In some embodiments, the methods described herein are superior (preferably statistically superior) to comparable methods in which a placebo is administered instead of botulinum toxin type A in terms of physician-assessed and / or human patient-assessed mild or slight grades on a platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) at 14, 30, 60, 90, or 120 days post-administration. In some embodiments, the grades on the platysma protrusion scale are assessed by a physician. In some embodiments, the grades on the platysma protrusion scale are assessed by a human patient. In some embodiments, the grades on the platysma protrusion scale are assessed by both a physician and a human patient.

[0167] In some embodiments, the methods described herein are superior (preferably statistically superior) to comparable methods in achieving changes in platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grades, assessed by physicians and / or human patients, from moderate or severe before administration of botulinum toxin type A or placebo to slight or mild changes at 14, 30, 60, 90, or 120 days after administration, where placebo is used instead of botulinum toxin type A. In some embodiments, the grade change is assessed by a physician. In some embodiments, the grade change is assessed by a human patient. In some embodiments, the grade change is assessed by both a physician and a human patient.

[0168] In some embodiments, the methods described herein are superior (preferably statistically superior) to comparable methods in achieving physician-assessed and / or patient-assessed Grade 1 or better improvement on a platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) from moderate or severe before administration of botulinum toxin type A or placebo to mild or moderate improvement at 14, 30, 60, 90, or 120 days after administration, where placebo is administered instead of botulinum toxin type A. In some embodiments, Grade 1 or better improvement is assessed by a physician. In some embodiments, Grade 1 or better improvement is assessed by a human patient. In some embodiments, Grade 1 or better improvement is assessed by both a physician and a human patient.

[0169] In some embodiments, the methods described herein are superior (preferably statistically superior) to comparable methods in achieving a grade 2 or better improvement on a platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) assessed by physicians and / or human patients, ranging from moderate or severe before administration of botulinum toxin type A or placebo to mild or slight improvement at 14, 30, 60, 90, or 120 days after administration, where placebo is administered instead of botulinum toxin type A. In some embodiments, the grade 2 or better improvement is assessed by a physician. In some embodiments, the grade 2 or better improvement is assessed by a human patient. In some embodiments, the grade 2 or better improvement is assessed by both a physician and a human patient.

[0170] In some embodiments, the methods described herein are superior (preferably statistically superior) to comparable methods in which a placebo is administered instead of botulinum toxin type A: (1) a physician-assessed and / or human patient-assessed change in platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade from moderate or severe before administration of botulinum toxin type A or placebo to slight or mild improvement at 14, 30, 60, 90, or 120 days after administration; and (2) a physician-assessed and / or human patient-assessed improvement of grade 2 or better on the platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) from moderate or severe before administration of botulinum toxin type A or placebo to slight or mild improvement at 14, 30, 60, 90, or 120 days after administration. In some embodiments, the change in platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade is assessed by a physician. In some embodiments, changes in the platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade are assessed by human patients. In some embodiments, changes in the platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade are assessed by both a physician and a human patient. In some embodiments, a grade 2 or better improvement is assessed by a physician. In some embodiments, a grade 2 or better improvement is assessed by both a physician and a human patient. In some embodiments, both grade changes and grade 2 or better improvements are assessed by a physician. In some embodiments, both grade changes and grade 2 or better improvements are assessed by human patients. In some embodiments, both grade changes and grade 2 or better improvements are assessed by both a physician and a human patient.

[0171] In some embodiments, the methods described herein are superior (preferably statistically superior) to comparable methods in which a mild or slight grade of platysma protrusion (e.g., Allergan Platysma Protrusion Scale) and at least a 2-grade improvement relative to baseline are achieved at 14, 30, 60, 90, or 120 days post-administration, as assessed by a physician and / or a human patient. The baseline is assessed prior to the administration of botulinum toxin type A. In a specific embodiment, the baseline is assessed on the day of but prior to the administration of botulinum toxin type A. In a specific embodiment, the baseline is a moderate or severe grade on a platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale). In some embodiments, achieving a mild or slight grade and at least a 2-grade improvement is assessed by a physician. In some embodiments, achieving a mild or slight grade and at least a 2-grade improvement is assessed by a human patient. In some embodiments, achieving a mild or slight grade and at least a 2-grade improvement is assessed by both a physician and a human patient.

[0172] In some implementations, the comparison of the methods described herein with comparable methods is assessed at the population level based on the percentage of human patients who have achieved and maintained cosmetic effects treated with the method (or comparable methods, as appropriate).

[0173] In various aspects and embodiments, the cosmetic effects of the methods described herein peak approximately 30 days or within 30 days after application of botulinum toxin type A, wherein the cosmetic effect includes a change in platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade, assessed by a physician and / or a human patient, from moderate or severe before application of botulinum toxin type A to slight or mild after application. In some embodiments, the cosmetic effects of the methods described herein peak approximately 14 days or within 14 days (inclusive) after application of botulinum toxin type A. In some embodiments in which the methods described herein are used to treat both sides of the neck of a human patient, the cosmetic effect includes achieving the aforementioned effect on both sides of the neck of the human patient. In other embodiments in which the methods described herein are used to treat both sides of the neck of a human patient, the cosmetic effect includes achieving the aforementioned effect on at least one side of the neck of the human patient. In some embodiments, the grade change is assessed by a physician. In other embodiments, the grade change is assessed by a human patient. In some embodiments, the grade change is assessed by both a physician and a human patient.

[0174] In various aspects and embodiments, the cosmetic effects of the methods described herein peak approximately 30 days or within 30 days after application of botulinum toxin type A, wherein the cosmetic effects include a grade 2 or better improvement in platysma protrusion (e.g., Allergan Platysma Protrusion Scale) as assessed by a physician and / or a human patient, ranging from moderate or severe before application of botulinum toxin type A to slight or mild improvement after application. In some embodiments, the cosmetic effects of the methods described herein peak approximately 14 days or within 14 days (inclusive) after application of botulinum toxin type A. In some embodiments in which the methods described herein are used to treat both sides of the neck of a human patient, the cosmetic effects include achieving the aforementioned effects on both sides of the neck of the human patient. In other embodiments in which the methods described herein are used to treat both sides of the neck of a human patient, the cosmetic effects include achieving the aforementioned effects on at least one side of the neck of the human patient. In some embodiments, a grade 2 or better improvement is assessed by a physician. In other embodiments, a grade 2 or better improvement is assessed by a human patient. In some embodiments, a grade 2 or better improvement is assessed by both a physician and a human patient.

[0175] In various aspects and embodiments, the cosmetic effects of the methods described herein peak approximately 30 days or within 30 days after application of botulinum toxin type A, wherein the cosmetic effects include a Grade 1 or better improvement in platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) as assessed by a physician and / or a human patient, from moderate or severe before application of botulinum toxin type A to mild or moderate after application. In some embodiments, the cosmetic effects of the methods described herein peak approximately 14 days or within 14 days after application of botulinum toxin type A. In some embodiments in which the methods described herein are used to treat both sides of the neck of a human patient, the cosmetic effects include achieving the aforementioned effects on both sides of the neck of the human patient. In other embodiments in which the methods described herein are used to treat both sides of the neck of a human patient, the cosmetic effects include achieving the aforementioned effects on at least one side of the neck of the human patient. In some embodiments, a Grade 1 or better improvement is assessed by a physician. In other embodiments, a Grade 1 or better improvement is assessed by a human patient. In some embodiments, a Grade 1 or better improvement is assessed by both a physician and a human patient.

[0176] In various aspects and implementations, the cosmetic effects of the methods described herein peak approximately 30 days or within 30 days after application of botulinum toxin type A, wherein the cosmetic effects include: (1) a change in platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade, assessed by a physician and / or a human patient, from moderate or severe before application of botulinum toxin type A to slight or mild after application; and (2) a grade 2 or better improvement in platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale), assessed by a physician and / or a human patient, from moderate or severe before application of botulinum toxin type A to slight or mild after application. In some implementations, the cosmetic effects of the methods described herein peak approximately 14 days or within 14 days (inclusive) after application of botulinum toxin type A. In some implementations, the change in platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade is assessed by a physician. In some embodiments, changes in the platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade are assessed by human patients. In some embodiments, changes in the platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade are assessed by both a physician and a human patient. In some embodiments, a grade 2 or better improvement is assessed by a physician. In some embodiments, a grade 2 or better improvement is assessed by both a physician and a human patient. In some embodiments, changes in the platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade and a grade 2 or better improvement are assessed by a physician. In some embodiments, changes in the platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade and a grade 2 or better improvement are assessed by both a physician and a human patient. In some embodiments where the methods described herein are used to treat both sides of a human patient's neck, the cosmetic effect includes achieving the aforementioned effect on both sides of the human patient's neck. In other embodiments where the methods described herein are used to treat both sides of a human patient's neck, the cosmetic effect includes achieving the aforementioned effect on at least one side of the human patient's neck.

[0177] In various aspects and implementations, the cosmetic effects of the methods described herein peak approximately 30 days or within 30 days after application of botulinum toxin type A, wherein the cosmetic effects include achieving a mild or slight grade and at least 2-grade improvement relative to baseline, as assessed by a physician and / or human patient on a platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale). The baseline is assessed prior to application of botulinum toxin type A. In specific implementations, the baseline is assessed on the day of application of botulinum toxin type A but prior to application. In specific implementations, the baseline is a moderate or severe grade on a platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale). In some implementations, the cosmetic effects of the methods described herein peak approximately 14 days or within 14 days (inclusive) after application of botulinum toxin type A. In some implementations, achieving a mild or slight grade and at least 2-grade improvement is assessed by a physician. In some implementations, achieving a mild or slight grade and at least 2-grade improvement is assessed by a human patient. In some implementations, achieving a mild or slight grade and at least 2-grade improvement is assessed by both a physician and a human patient. In some embodiments where the methods described herein are used to treat both sides of a human patient's neck, the cosmetic effect includes achieving the aforementioned effect on both sides of the human patient's neck. In other embodiments where the methods described herein are used to treat both sides of a human patient's neck, the cosmetic effect includes achieving the aforementioned effect on at least one side of the human patient's neck.

[0178] In some implementations, the peak time of cosmetic effect is assessed at the population level based on the percentage of human patients treated with the method who have achieved and maintained cosmetic effects.

[0179] In various aspects and embodiments, the duration of the cosmetic effect of the methods described herein is at least 30 days, at least 60 days, at least 90 days, or at least 120 days after the application of botulinum toxin type A, or within the range of approximately 30 to approximately 60 days, approximately 30 to approximately 90 days, approximately 30 to approximately 120 days, approximately 60 to approximately 90 days, approximately 60 to approximately 120 days, or approximately 90 to approximately 120 days after the application of botulinum toxin type A, wherein the cosmetic effect includes a change in platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade, assessed by a physician and / or a human patient, from moderate or severe before the application of botulinum toxin type A to slight or mild after the application of botulinum toxin type A. In some embodiments, the grade change is assessed by a physician. In some embodiments, the grade change is assessed by a human patient. In some embodiments, the grade change is assessed by both a physician and a human patient. In some embodiments in which the methods described herein are used to treat both sides of the neck of a human patient, the cosmetic effect includes achieving the aforementioned effect on both sides of the neck of the human patient. In other embodiments in which the methods described herein are used to treat both sides of the neck of a human patient, the cosmetic effect includes achieving the aforementioned effect on at least one side of the neck of the human patient.

[0180] In various aspects and implementations, the duration of the cosmetic effect of the methods described herein is at least 30 days, at least 60 days, at least 90 days, or at least 120 days after application of botulinum toxin type A, or within the range of approximately 30 to approximately 60 days, approximately 30 to approximately 90 days, approximately 30 to approximately 120 days, approximately 60 to approximately 90 days, approximately 60 to approximately 120 days, or approximately 90 to approximately 120 days after application of botulinum toxin type A, wherein the cosmetic effect includes a grade 2 or better improvement in platysma protrusion as assessed by a physician and / or a human patient on a platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale), ranging from moderate or severe before application of botulinum toxin type A to slight or mild improvement after application of botulinum toxin type A. In some implementations, the grade 2 or better improvement is assessed by a physician. In some implementations, the grade 2 or better improvement is assessed by a human patient. In some implementations, the grade 2 or better improvement is assessed by both a physician and a human patient. In some embodiments where the methods described herein are used to treat both sides of a human patient's neck, the cosmetic effect includes achieving the aforementioned effect on both sides of the human patient's neck. In other embodiments where the methods described herein are used to treat both sides of a human patient's neck, the cosmetic effect includes achieving the aforementioned effect on at least one side of the human patient's neck.

[0181] In various aspects and implementations, the duration of the cosmetic effect of the methods described herein is at least 30 days, at least 60 days, at least 90 days, or at least 120 days after application of botulinum toxin type A, or within the range of approximately 30 to approximately 60 days, approximately 30 to approximately 90 days, approximately 30 to approximately 120 days, approximately 60 to approximately 90 days, approximately 60 to approximately 120 days, or approximately 90 to approximately 120 days after application of botulinum toxin type A, wherein the cosmetic effect includes a grade 1 or better improvement in platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) as assessed by a physician and / or a human patient, from moderate or severe before application of botulinum toxin type A to mild or moderate after application of botulinum toxin type A. In some implementations, a grade 1 or better improvement is assessed by a physician. In some implementations, a grade 1 or better improvement is assessed by a human patient. In some implementations, a grade 1 or better improvement is assessed by both a physician and a human patient. In some embodiments where the methods described herein are used to treat both sides of a human patient's neck, the cosmetic effect includes achieving the aforementioned effect on both sides of the human patient's neck. In other embodiments where the methods described herein are used to treat both sides of a human patient's neck, the cosmetic effect includes achieving the aforementioned effect on at least one side of the human patient's neck.

[0182] In various aspects and implementations, the duration of the cosmetic effect of the methods described herein is at least 30 days, at least 60 days, at least 90 days, or at least 120 days after the application of botulinum toxin type A, or within the range of about 30 days to about 60 days, about 30 days to about 90 days, about 30 days to about 120 days, about 60 days to about 90 days, about 60 days to about 120 days, or about 90 days to about 120 days after the application of botulinum toxin type A, wherein the cosmetic effect includes: (1) a change in platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade assessed by a physician and / or by a human patient from moderate or severe before the application of botulinum toxin type A to slight or mild after the application of botulinum toxin type A; and (2) a grade 2 or better improvement on the platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) assessed by a physician and / or by a human patient from moderate or severe before the application of botulinum toxin type A to slight or mild after the application of botulinum toxin type A. In some embodiments, changes in the platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade are assessed by a physician. In some embodiments, changes in the platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade are assessed by a human patient. In some embodiments, changes in the platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade are assessed by both a physician and a human patient. In some embodiments, a grade 2 or better improvement is assessed by a physician. In some embodiments, a grade 2 or better improvement is assessed by a human patient. In some embodiments, a grade 2 or better improvement is assessed by both a physician and a human patient. In some embodiments, changes in the platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade and a grade 2 or better improvement are assessed by a physician. In some embodiments, changes in the platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade and a grade 2 or better improvement are assessed by a human patient. In some embodiments, changes in platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grades and improvements of grade 2 or better are assessed by both a physician and a human patient. In some embodiments in which the methods described herein are used to treat both sides of a human patient's neck, the cosmetic effect includes achieving the aforementioned effect on both sides of the human patient's neck. In other embodiments in which the methods described herein are used to treat both sides of a human patient's neck, the cosmetic effect includes achieving the aforementioned effect on at least one side of the human patient's neck.

[0183] In various aspects and implementations, the duration of the cosmetic effect of the methods described herein is at least 30 days, at least 60 days, at least 90 days, or at least 120 days after application of botulinum toxin type A, or within the range of approximately 30 to approximately 60 days, approximately 30 to approximately 90 days, approximately 30 to approximately 120 days, approximately 60 to approximately 90 days, approximately 60 to approximately 120 days, or approximately 90 to approximately 120 days after application of botulinum toxin type A, wherein the cosmetic effect includes achieving a mild or slight grade and at least 2-grade improvement relative to baseline on a platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) as assessed by a physician and / or by a human patient. The baseline is assessed prior to application of botulinum toxin type A. In specific implementations, the baseline is assessed on the day of application of botulinum toxin type A but prior to application. In specific implementations, the baseline is a moderate or severe grade on a platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale). In some implementations, achieving a mild or slight grade and at least 2-grade improvement is assessed by a physician. In some embodiments, achieving a slight or mild improvement of at least grade 2 is assessed by a human patient. In some embodiments, achieving a slight or mild improvement of at least grade 2 is assessed by both a physician and a human patient. In some embodiments where the methods described herein are used to treat both sides of a human patient's neck, the cosmetic effect includes achieving the aforementioned effect on both sides of the human patient's neck. In other embodiments where the methods described herein are used to treat both sides of a human patient's neck, the cosmetic effect includes achieving the aforementioned effect on at least one side of the human patient's neck.

[0184] In some implementations, the duration of the cosmetic effect is assessed at the population level based on whether the percentage of human patients treated with the method who have achieved and maintained the cosmetic effect is above a set threshold (e.g., 5%, 10%, 15%, or 20%).

[0185] In various aspects and embodiments, the methods described herein are superior (preferably statistically superior) to comparable methods in which a placebo is administered instead of botulinum toxin type A in terms of achieving a mild or slight grade on a platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) as assessed by a physician and / or by a human patient at 14, 30, 60, 90, or 120 days after administration. In some embodiments, the grade on the platysma protrusion scale is assessed by a physician. In some embodiments, the grade on the platysma protrusion scale is assessed by a human patient. In some embodiments, the grade on the platysma protrusion scale is assessed by both a physician and a human patient. In some embodiments in which the methods described herein are used to treat both sides of the neck of a human patient, the cosmetic effect includes achieving the aforementioned effect on both sides of the neck of the human patient. In other embodiments in which the methods described herein are used to treat both sides of the neck of a human patient, the cosmetic effect includes achieving the aforementioned effect on at least one side of the neck of the human patient.

[0186] In various aspects and implementations, the methods described herein are superior (preferably statistically superior) to comparable methods in which a platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade, assessed by a physician and / or a human patient, changes from moderate or severe pre-treatment with botulinum toxin type A or placebo to slight or mild changes at 14, 30, 60, 90, or 120 days post-treatment, where placebo is used instead of botulinum toxin type A. In some implementations, the grade change is assessed by a physician. In some implementations, the grade change is assessed by a human patient. In some implementations, the grade change is assessed by both a physician and a human patient. In some implementations in which the methods described herein are used to treat both sides of a human patient's neck, the cosmetic effect includes achieving the aforementioned effect on both sides of the human patient's neck. In other implementations in which the methods described herein are used to treat both sides of a human patient's neck, the cosmetic effect includes achieving the aforementioned effect on at least one side of the human patient's neck.

[0187] In various aspects and implementations, the methods described herein are superior (preferably statistically superior) to comparable methods in achieving grade 2 or better improvement in platysma protrusion (e.g., Allergan Platysma Protrusion Scale) assessed by physicians and / or human patients, ranging from moderate or severe before application of botulinum toxin type A or placebo to mild or slight improvement at 14, 30, 60, 90, or 120 days after application, where placebo is used instead of botulinum toxin type A. In some implementations, grade 2 or better improvement is assessed by a physician. In some implementations, grade 2 or better improvement is assessed by a human patient. In some implementations, grade 2 or better improvement is assessed by both a physician and a human patient. In some implementations in which the methods described herein are used to treat both sides of the neck of a human patient, the cosmetic effect includes achieving the aforementioned effect on both sides of the neck of the human patient. In other implementations in which the methods described herein are used to treat both sides of the neck of a human patient, the cosmetic effect includes achieving the aforementioned effect on at least one side of the neck of the human patient.

[0188] In various aspects and implementations, the methods described herein are superior (preferably statistically superior) to comparable methods in achieving Grade 1 or better improvement in platysma protrusion (e.g., Allergan Platysma Protrusion Scale) assessed by physicians and / or human patients, ranging from moderate or severe before application of botulinum toxin type A or placebo to mild or moderate improvement at 14, 30, 60, 90, or 120 days after application, where placebo is used instead of botulinum toxin type A. In some implementations, Grade 1 or better improvement is assessed by a physician. In some implementations, Grade 1 or better improvement is assessed by a human patient. In some implementations, Grade 1 or better improvement is assessed by both a physician and a human patient. In some implementations in which the methods described herein are used to treat both sides of the neck of a human patient, the cosmetic effect includes achieving the aforementioned effect on both sides of the neck of the human patient. In other implementations in which the methods described herein are used to treat both sides of the neck of a human patient, the cosmetic effect includes achieving the aforementioned effect on at least one side of the neck of the human patient.

[0189] In various aspects and implementations, the methods described herein are superior (preferably statistically superior) to comparable methods in which a placebo is administered instead of botulinum toxin type A: (1) a physician-assessed and / or human patient-assessed change in platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade from moderate or severe before administration of botulinum toxin type A or placebo to slight or mild improvement at 14, 30, 60, 90, or 120 days after administration; and (2) a physician-assessed and / or human patient-assessed improvement of grade 2 or better on the platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) from moderate or severe before administration of botulinum toxin type A or placebo to slight or mild improvement at 14, 30, 60, 90, or 120 days after administration. In some implementations, the change in platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade is assessed by a physician. In other embodiments, changes in the platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade are assessed by human patients. In some embodiments, changes in the platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade are assessed by both a physician and a human patient. In some embodiments, a grade 2 or better improvement is assessed by a physician. In some embodiments, a grade 2 or better improvement is assessed by both a physician and a human patient. In some embodiments, changes in the platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade and a grade 2 or better improvement are assessed by a physician. In some embodiments, changes in the platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade and a grade 2 or better improvement are assessed by human patients. In some embodiments, changes in the platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale) grade and a grade 2 or better improvement are assessed by both a physician and a human patient. In some embodiments where the methods described herein are used to treat both sides of a human patient's neck, the cosmetic effect includes achieving the aforementioned effect on both sides of the human patient's neck. In other embodiments where the methods described herein are used to treat both sides of a human patient's neck, the cosmetic effect includes achieving the aforementioned effect on at least one side of the human patient's neck.

[0190] In various aspects and implementations, the methods described herein are superior (preferably statistically superior) to comparable methods in which a mild or slight grade of platysma protrusion (e.g., Allergan Platysma Protrusion Scale) and at least a 2-grade improvement relative to baseline, as assessed by a physician and / or a human patient, are achieved at 14, 30, 60, 90, or 120 days after administration, where a placebo is administered instead of botulinum toxin type A. The baseline is assessed prior to the administration of botulinum toxin type A. In specific implementations, the baseline is assessed on the day of but prior to the administration of botulinum toxin type A. In specific implementations, the baseline is a moderate or severe grade on a platysma protrusion scale (e.g., Allergan Platysma Protrusion Scale). In some implementations, achieving a mild or slight grade and at least a 2-grade improvement is assessed by a physician. In some implementations, achieving a mild or slight grade and at least a 2-grade improvement is assessed by a human patient. In some implementations, achieving a mild or slight grade and at least a 2-grade improvement is assessed by both a physician and a human patient. In some embodiments where the methods described herein are used to treat both sides of a human patient's neck, the cosmetic effect includes achieving the aforementioned effect on both sides of the human patient's neck. In other embodiments where the methods described herein are used to treat both sides of a human patient's neck, the cosmetic effect includes achieving the aforementioned effect on at least one side of the human patient's neck.

[0191] In a preferred embodiment, the comparison of the methods described herein with comparable methods is evaluated 14 days after application. In some embodiments, the comparison of the methods described herein with comparable methods is evaluated 30 days after application. In some embodiments, the comparison of the methods described herein with comparable methods is evaluated 60 days after application.

[0192] In some embodiments, the comparison of the methods described herein with comparable methods is assessed at the population level based on the percentage of human patients treated with the method (or comparable methods, as appropriate) who have achieved and maintained cosmetic effects. In some embodiments, the methods described herein are at least 25% better than comparable methods, for example, at least 50%, at least 75%, or at least 90% better. In some embodiments, the methods described herein are at least 100% better than comparable methods. In some embodiments, the methods described herein are at least 2 times better than comparable methods, for example, at least 3 times better, at least 5 times better, at least 10 times better, at least 50 times better, or at least 90 times better.

[0193] In various aspects and implementation methods, when assessed by the Neck and Lower Facial Appearance Questionnaire (ANLFQ – Satisfaction, Follow-up, Item 5), the method described herein is superior (preferably statistically superior) to comparable methods in which a placebo is administered instead of botulinum toxin type A, the questionnaire assessing patient satisfaction with treatment efficacy at 7, 14, 30, 60, 90, or 120 days post-administration. In various aspects and implementation methods, when assessed by the Distress Assessment Scale – Platysma Prominence (BAS-PP) Items 1 and 2, the method described herein is superior (preferably statistically superior) to comparable methods in which a placebo is administered instead of botulinum toxin type A, the scale assessing the degree of distress patients experience with the appearance of their platysma band and jawline at 7, 14, 30, 60, 90, or 120 days post-administration. In some embodiments, the comparison of the methods described herein with comparable methods is assessed at the population level based on the percentage of human patients treated with the method (or comparable methods, as appropriate) who answered “satisfied” or “very satisfied” on the “ANLFQ – Satisfaction, Follow-up, Item 5”; or the percentage who answered “not bothered at all” or “somewhat bothered” on the “BAS-PP, Items 1 and 2” questionnaire (as appropriate). In some embodiments, the methods described herein are at least 25% better than comparable methods, for example, at least 50%, at least 75%, or at least 90% better than comparable methods. In some embodiments, the methods described herein are at least 100% better than comparable methods. In some embodiments, the methods described herein are at least 2 times better than comparable methods, for example, at least 3 times better, at least 5 times better, at least 10 times better, at least 50 times better, or at least 90 times better than comparable methods.

[0194] "Treatment-induced adverse event" or "TEAE" are technical terms understood by those skilled in the art. In a specific embodiment, a TEAE is an adverse event that begins after a first dose of the composition containing botulinum toxin type A, or an adverse event that existed before a first dose of the composition containing botulinum toxin type A but became more severe or serious after a first dose of the composition containing botulinum toxin type A. In a specific embodiment, a TEAE is an adverse event that occurs after a first dose of the composition containing botulinum toxin type A.

[0195] In various aspects and implementations, the methods described herein are associated with less than 25% of treatment-induced adverse events (TEAEs), less than 30% of TEAEs, less than 35% of TEAEs, or less than 40% of TEAEs (e.g., when assessed at the population level). In specific implementations, the above safety results are obtained after one treatment cycle. In specific implementations, the above safety results are obtained after two treatment cycles. In specific implementations, the above safety results are obtained after three treatment cycles. In specific implementations, the above safety results are obtained after four treatment cycles. See the description of treatment cycles below.

[0196] In various aspects and embodiments, the methods described herein result in a TEAE incidence of less than 2%, less than 3%, less than 4%, less than 5%, less than 10%, or less than 16% (e.g., when assessed at the population level). In various aspects and embodiments, the methods described herein result in a TEAE incidence of less than 5% or less than 2% (e.g., when assessed at the population level). In a specific embodiment, the above safety results are obtained after one treatment cycle. In a specific embodiment, the above safety results are obtained after two treatment cycles. In a specific embodiment, the above safety results are obtained after three treatment cycles. In a specific embodiment, the above safety results are obtained after four treatment cycles. See the description of treatment cycles below.

[0197] Determining the severity of an adverse event can be based on criteria established by those skilled in the art. In a specific implementation, a serious adverse event is one that interferes with the normal activities of daily life or significantly affects a clinical condition or may require intensive therapeutic intervention. In a specific implementation, a serious adverse event is one that causes considerable disruption to a subject's normal activities and may result in incapacitation or life-threatening situations.

[0198] In various aspects and implementations, the methods described herein result in an incidence of treatment-related serious TEAEs of less than 1% or less than 0.5%, or no treatment-related serious TEAEs. In various aspects and implementations, the methods described herein result in an incidence of treatment-related serious TEAEs of less than 1%, less than 0.9%, less than 0.8%, less than 0.7%, or less than 0.6%.

[0199] In various aspects and implementations, the methods described herein result in an incidence of treatment-related serious TEAEs of less than 0.5%, for example, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1%. In various aspects and implementations, the methods described herein result in no treatment-related serious TEAEs occurring. In a specific implementation, the above safety results are obtained after one treatment cycle. In a specific implementation, the above safety results are obtained after two treatment cycles. In a specific implementation, the above safety results are obtained after three treatment cycles. In a specific implementation, the above safety results are obtained after four treatment cycles. See the description of treatment cycles below.

[0200] In various aspects and implementations, the methods described herein result in an incidence of adverse events of particular concern (AESIs) of less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.3%, or less than 0.1%, or no AESIs. In specific implementations, AESIs include aspiration, aspiration pneumonia, dry mouth, dysphagia, dyspnea, facial paralysis, and myasthenia gravis (i.e., neck muscle weakness). In one specific implementation, the AESI is aspiration. In another specific implementation, the AESI is aspiration pneumonia. In another specific implementation, the AESI is dry mouth. In another specific implementation, the AESI is dysphagia. In another specific implementation, the AESI is dyspnea. In another specific implementation, the AESI is facial paralysis. In another specific implementation, the AESI is myasthenia gravis (i.e., neck muscle weakness). In specific implementations, the above safety results are obtained after one treatment cycle. In specific implementations, the above safety results are obtained after two treatment cycles. In specific implementations, the above safety results are obtained after three treatment cycles. In specific implementations, the above safety results are obtained after four treatment cycles. See the description of treatment cycles below.

[0201] In various aspects and implementations, the methods described herein result in an incidence of injection site bruising of less than 10%, less than 5%, less than 2%, or less than 1.5%. In a specific implementation, the above safety results were obtained after one treatment cycle. In a specific implementation, the above safety results were obtained after two treatment cycles. In a specific implementation, the above safety results were obtained after three treatment cycles. In a specific implementation, the above safety results were obtained after four treatment cycles. See the description of treatment cycles below.

[0202] In various aspects and implementations, the methods described herein result in an incidence of neck muscle weakness of less than 1%, less than 0.5%, or less than 0.1%, or no neck muscle weakness. In a specific implementation, the above safety results are obtained after one treatment cycle. In a specific implementation, the above safety results are obtained after two treatment cycles. In a specific implementation, the above safety results are obtained after three treatment cycles. In a specific implementation, the above safety results are obtained after four treatment cycles. See the description of treatment cycles below.

[0203] In various aspects and implementations, the methods described herein result in an incidence of dysphagia of less than 2%, less than 1%, less than 0.5%, or less than 0.1%, or no dysphagia. In a specific implementation, the above safety results are obtained after one treatment cycle. In a specific implementation, the above safety results are obtained after two treatment cycles. In a specific implementation, the above safety results are obtained after three treatment cycles. In a specific implementation, the above safety results are obtained after four treatment cycles. See the description of treatment cycles below.

[0204] In various aspects and implementations, the methods described herein result in an injection site hematoma incidence of less than 5%, less than 2%, less than 1%, or less than 0.5%, or no injection site hematoma. In a specific implementation, the above safety results are obtained after one treatment cycle. In a specific implementation, the above safety results are obtained after two treatment cycles. In a specific implementation, the above safety results are obtained after three treatment cycles. In a specific implementation, the above safety results are obtained after four treatment cycles. See the description of treatment cycles below.

[0205] In various aspects and implementations, the methods described herein result in a lower incidence of adverse effects compared to comparable methods for treating platysma protrusion (e.g., for improving the appearance of platysma protrusion, such as the appearance of platysma bands), which include injecting one or more neckband doses of botulinum toxin type A into one or more neckbands in the neck of a human subject, but do not include injecting a mandibular line dose of botulinum toxin type A into the neck of a human subject.

[0206] In various aspects and implementations, the methods described herein result in a lower incidence of adverse effects compared to comparable methods for treating platysma protrusion (e.g., for improving the appearance of platysma protrusion, such as the appearance of platysma bands), which include injecting one or more neckband doses of botulinum toxin type A into one or more neckbands in the neck of a human subject, and injecting one or more mandibular line doses of botulinum toxin type A into one or both sides of the mandibular line in the neck of a human subject, wherein at least one neckband dose is higher than at least one mandibular line dose.

[0207] In various aspects and implementations, the methods described herein result in a lower incidence of adverse effects compared to comparable methods used to treat platysma protrusion (e.g., to improve the appearance of platysma protrusion, such as the appearance of platysma bands), which involve injecting a higher dose of botulinum toxin type A than the dose injected according to the methods described herein (e.g., a neck band dose of more than 5 units of botulinum toxin type A injected per neck band).

[0208] In various aspects and implementations, the methods described herein result in a lower incidence of adverse effects compared to comparable methods used to treat platysma protrusion (e.g., to improve the appearance of platysma protrusion, such as the appearance of the platysma band), which include injecting a neck band dose having a higher per-injection-site dose of botulinum toxin type A than the neck band dose injected according to the methods described herein (e.g., injecting a neck band dose having a per-injection-site dose of more than 1 unit of botulinum toxin type A).

[0209] In various aspects and implementations, the methods described herein result in a lower incidence of adverse effects compared to comparable methods used to treat platysma protrusion (e.g., to improve the appearance of platysma protrusion, such as the appearance of the platysma band), which involve injecting a higher dose of botulinum toxin type A than the dose injected according to the methods described herein (e.g., a mandibular line dose of more than 8 units of botulinum toxin type A injected per side of the mandibular line).

[0210] In various aspects and implementations, the methods described herein result in a lower incidence of adverse effects compared to comparable methods used to treat platysma protrusion (e.g., to improve the appearance of platysma protrusion, such as the appearance of the platysma band), which involve injecting a mandibular line dose having a higher per-injection-site dose of botulinum toxin type A than the mandibular line dose injected according to the methods described herein (e.g., injecting a mandibular line dose having a per-injection-site dose of more than 2 units of botulinum toxin type A).

[0211] In various aspects and implementations, the method described herein involves injecting a total dose of 18 units or less of botulinum toxin type A as a mandibular line dose and one or two neck band doses into one side of the neck of a human patient, and this method results in a lower incidence of adverse effects compared to comparable methods for treating platysma protrusion (e.g., for improving the appearance of platysma protrusion, such as the appearance of platysma bands), in which more than 18 units of botulinum toxin type A are injected into one side of the neck of a human subject (e.g., as a mandibular line dose and one or more (e.g., one or two) neck band doses).

[0212] In various aspects and implementations, the method described herein injects a total dose of 18 units of botulinum toxin type A as a mandibular line dose and two neckband doses into one side of the neck of a human patient, and reduces the incidence of adverse effects compared to comparable methods for treating platysma protrusion (e.g., for improving the appearance of platysma protrusion, such as the appearance of platysma bands), in which more than 18 units of botulinum toxin type A are injected into one side of the neck of a human subject (e.g., as a mandibular line dose and one or more (e.g., one or two) neckband doses).

[0213] In various aspects and implementations, the method described herein involves injecting a total dose of 13 units of botulinum toxin type A as a mandibular line dose and a neckband dose into one side of the neck of a human patient, and this method results in a lower incidence of adverse effects compared to comparable methods for treating platysma protrusion (e.g., for improving the appearance of platysma protrusion, such as the appearance of a platysma band), in which more than 13 units of botulinum toxin type A are injected into one side of the neck of a human subject (e.g., as a mandibular line dose and one or more (e.g., one) neckband doses).

[0214] In various aspects and implementations, the methods described herein result in a lower incidence of adverse effects compared to comparable methods for treating platysma protrusion (e.g., for improving the appearance of platysma protrusion, such as the appearance of platysma bands), which involve injecting one or more neckband doses of botulinum toxin type A into one or more neckbands in the neck of a human subject, wherein the one or more neckbands into which the one or more neckband doses are injected are not limited to continuous vertical neckbands extending from the mandibular line of the human subject into the lower neck region.

[0215] In various aspects and implementations, the methods described herein result in a lower incidence of adverse effects compared to comparable methods for treating platysma protrusion (e.g., for improving the appearance of platysma protrusion, such as the appearance of platysma bands), in which a neck band dose of botulinum toxin type A is injected into the neck of a human subject, but whether or not the neck band dose is injected does not depend on whether the neck band is a continuous vertical neck band.

[0216] In various aspects and implementations, the methods described herein result in a lower incidence of adverse effects compared to comparable methods for treating platysma protrusion (e.g., for improving the appearance of platysma protrusion, such as the appearance of the platysma band), in which a neck band dose of botulinum toxin type A is injected into the neck of a human subject, but not a fixed dose injected only along a continuous vertical neck band.

[0217] In various aspects and implementations, the methods described herein result in a lower incidence of adverse effects compared to comparable methods used to treat platysma protrusion (e.g., to improve the appearance of platysma protrusion, such as the appearance of the platysma band), which involve injecting a neckband dose of botulinum toxin type A along more than two consecutive neckbands on one side of the neck of a human subject.

[0218] In various aspects and implementations, the methods described herein result in a lower incidence of adverse effects compared to comparable methods for treating platysma protrusion (e.g., for improving the appearance of platysma protrusion, such as the appearance of the platysma band), which involve injecting three or more neckband doses of botulinum toxin type A into one side of the neck of a human subject, wherein each neckband dose is injected along different neckbands. In some implementations, three or more neckband doses are injected along three or more consecutive vertical neckbands. In some implementations, three or more neckband doses are injected along two consecutive vertical neckbands and one or more discontinuous neckbands. In some implementations, three or more neckband doses are injected along one consecutive vertical neckband and two or more discontinuous vertical neckbands. In some implementations, three or more neckband doses are injected along three or more discontinuous neckbands.

[0219] In various aspects and implementations, the methods described herein result in a lower incidence of adverse effects compared to comparable methods used to treat platysma protrusion (e.g., to improve the appearance of platysma protrusion, such as the appearance of the platysma band), which do not classify platysma protrusion according to platysma protrusion scales.

[0220] In various aspects and implementations, the methods described herein result in a lower incidence of adverse effects compared to comparable methods for treating platysma protrusion (e.g., for improving the appearance of platysma protrusion, such as the appearance of the platysma band), which are not based on Table 1 ( Figure 1 The Allergan Platysma Protrusion Scale (APPS) (as illustrated) classifies platysma protrusion.

[0221] In specific implementations, the methods described herein reduce the incidence of adverse effects compared to comparable methods for treating platysma protrusion (e.g., for improving the appearance of platysma protrusion, such as the appearance of the platysma band), which have one, two, three, four, five or more of the aforementioned features that distinguish them from the methods described herein.

[0222] In specific implementations, the method described herein reduces the incidence of adverse effects compared to injection techniques or examples known in the art for treating platysma herniation.

[0223] In some implementations, adverse effects are treatment-induced adverse events or TEAEs (e.g., treatment-related serious TEAEs).

[0224] In some implementations, the adverse effects are those described herein.

[0225] In some implementation schemes, adverse effects are selected from the group consisting of aspiration, aspiration pneumonia, dry mouth, dysphagia, dyspnea, facial paralysis, muscle weakness, bruising at the injection site, and hematoma at the injection site.

[0226] In various aspects and implementations, the methods described herein achieve one or more of the aforementioned efficacy effects. In various aspects and implementations, the methods described herein achieve one or more of the aforementioned safety effects. In various aspects and implementations, the methods described herein achieve one or more of the aforementioned efficacy and safety effects. In various aspects and implementations, the methods described herein achieve one or more of the aforementioned efficacy effects and one or more of the aforementioned safety effects.

[0227] In specific implementations, in the context of describing the efficacy and / or safety effects of the methods described herein, human patients are subjects of clinical trials, particularly when assessing such efficacy and / or safety effects at the population level.

[0228] In the specific implementation, in the context of describing the efficacy and / or safety effects of the methods described herein, the physician (e.g., the attending physician) is the investigator of a clinical trial, particularly when assessing such efficacy and / or safety effects at the population level.

[0229] In various respects and implementations, the compositions comprising botulinum toxin type A described herein are pharmaceutical compositions (see Sections 5.1 and 5.2 for further description).

[0230] In various aspects and embodiments, the concentration of botulinum toxin type A in the composition is from about 10 units / mL to about 100 units / mL. In a specific embodiment, the concentration of botulinum toxin type A in the composition is from about 20 units / mL to about 60 units / mL. In one specific embodiment, the concentration of botulinum toxin type A in the composition is about 40 units / mL.

[0231] In various aspects and embodiments, the volume of botulinum toxin type A composition applied to each mandibular line injection site is from about 0.02 mL to about 0.10 mL. In a specific embodiment, the volume of botulinum toxin type A composition applied to each mandibular line injection site is from about 0.04 mL to about 0.08 mL. In a specific embodiment, the volume of botulinum toxin type A composition applied to each mandibular line injection site is from about 0.04 mL to about 0.06 mL. In one specific embodiment, the volume of botulinum toxin type A composition applied to each mandibular line injection site is about 0.05 mL.

[0232] In various aspects and embodiments, the volume of botulinum toxin type A composition applied to each neckband injection site is from about 0.01 mL to about 0.05 mL. In a specific embodiment, the volume of botulinum toxin type A composition applied to each neckband is from about 0.02 mL to about 0.04 mL. In a specific embodiment, the volume of botulinum toxin type A composition applied to each neckband injection site is from about 0.02 mL to about 0.03 mL. In one specific embodiment, the volume of botulinum toxin type A composition applied to each neckband injection site is about 0.025 mL.

[0233] In various aspects and embodiments, the botulinum toxin type A used in the methods described herein is the botulinum toxin type A as described in Section 5.1 or Section 5.2. In a particular embodiment, the botulinum toxin type A used in the methods described herein is a 900 kDa serum-type botulinum toxin type A neurotoxin (BoNT / A) complex. In a preferred embodiment, the botulinum toxin type A used in the methods described herein is onabotulinumtoxin A.

[0234] In a specific embodiment, the composition comprises a powdered BoNT / A pharmaceutical composition reconstituted with physiological saline, wherein prior to reconstitution, the powdered BoNT / A pharmaceutical composition consists of a 900 kDa BoNT / A complex (e.g., about 100 units or 200 units of the 900 kDa BoNT / A complex), human albumin (e.g., about 0.5 mg of human albumin per 100 units of the 900 kDa BoNT / A complex), and sodium chloride (e.g., about 0.9 mg of sodium chloride per 100 units of the 900 kDa BoNT / A complex).

[0235] In a specific embodiment, the composition is a liquid. In one specific embodiment, the composition is a liquid pharmaceutical composition reconstituted from a powdered BoNT / A pharmaceutical composition with physiological saline, wherein prior to reconstitution, the powdered BoNT / A pharmaceutical composition consisted of a 900 kDa BoNT / A complex (e.g., about 100 units or 200 units of the 900 kDa BoNT / A complex), human albumin (e.g., about 0.5 mg of human albumin per 100 units of the 900 kDa BoNT / A complex), and sodium chloride (e.g., about 0.9 mg of sodium chloride per 100 units of the 900 kDa BoNT / A complex).

[0236] In all aspects and implementation methods, the injection depth does not exceed approximately 0.5 inches into the muscle.

[0237] In various aspects and implementation schemes, injections are administered superficially and intramuscularly using a needle perpendicular to the skin surface.

[0238] In various aspects and embodiments, no additional dose of botulinum toxin type A is injected into the neck of a human patient (e.g., during the same treatment cycle). In various aspects and embodiments, no additional dose of botulinum toxin type A is injected into the neck of a human patient (e.g., during the same treatment cycle). In various aspects and embodiments, no additional dose of botulinum toxin type A is injected into the neck of a human patient (e.g., during the same treatment cycle). In various aspects and embodiments, no additional dose of botulinum toxin type A and no additional dose of botulinum toxin type A are injected into the neck of a human patient (e.g., during the same treatment cycle).

[0239] In various aspects and embodiments, the composition is administered to human patients using a sterile 30-gauge syringe with a 0.5-inch needle. In various aspects and embodiments, the composition is administered to human patients using a sterile 30-gauge syringe with a 1-inch needle.

[0240] In a specific implementation scheme, the composition is applied in the following manner:

[0241] 1. Take 100 units of onabotulinumtoxin A (BOTOX) from each vial. ® BOTOX ® Cosmetic or VISTABEL ® Dilute with 2.5 mL of sterile, preservative-free saline solution to make BOTOX ® It reaches 4 units / 0.1mL.

[0242] 2. Using an appropriately sized sterile syringe, needle, and aseptic technique, dispense 2 units / 0.05 mL of reconstituted BOTOX. ® Inject into four sites in the upper segment of the platysma muscle below the mandibular line on each side. Additionally, administer 1 unit / 0.025 mL of reconstituted BOTOX. ® Inject into 5 sites along each vertical neck band, 1 to 2 vertical neck bands per side (Figures 2A and 2B). Depending on the severity of platysma protrusion, the total dose may be 26 units (1 band / side), 31 units (1 band on one side and 2 bands on the other side), or 36 units (2 bands / side).

[0243] 3. For each side, the four mandibular line injections of the platysma muscle should be approximately 1 to 2 cm below the lower border of the mandible and parallel to it. The anterior injection site should align with the corner of the mouth, and the posterior injection site should be slightly anterior to the angle of the mandible. The remaining two injections should be equidistant from the anterior and posterior injection points (approximately 1 to 2 cm apart). For each identified vertical neck band (1 to 2 on each side), five injections should be vertically distributed, spaced approximately 1 to 2 cm apart. The uppermost injection site should be approximately 1 to 2 cm below the mandibular line injections.

[0244] 4. The platysma is a thin layer of muscle located directly beneath the skin surface. Therefore, all platysma injections should be administered superficially and intramuscularly using a needle perpendicular to the skin surface. For vertical neck band injections, each band should be identified when the patient contracts their platysma. Gently pinch the band during administration to separate the muscle from nearby anatomical structures.

[0245] 5. To reduce injection-related complications, injections should be made at least 1 cm below the lower border of the mandible. Avoid injecting into the deep structures of the platysma muscle, especially in the anterior neck region.

[0246] In various aspects and implementation schemes, the above method is repeated multiple times. In some implementation schemes, the above method is repeated once. In some implementation schemes, the above method is repeated twice. In some implementation schemes, the above method is repeated three times. In specific implementation schemes, the above method is repeated no less than once every 3 months. In specific implementation schemes, the above method is repeated no less than once every 12 weeks. In specific implementation schemes, the above method is repeated no less than once every 84 days. In specific implementation schemes, the above method is repeated approximately once every 3 months. In specific implementation schemes, the above method is repeated approximately once every 12 weeks. In specific implementation schemes, the above method is repeated approximately once every 84 days.

[0247] In various aspects and implementations, the steps of one or more of the above methods constitute a treatment cycle, and this document provides an extended treatment method comprising more than one treatment cycle from one or more of the above methods. In some implementations, the extended treatment method comprises two treatment cycles. In some implementations, the extended treatment method comprises three treatment cycles. In some implementations, the extended treatment method comprises four treatment cycles. In a specific implementation, a subsequent treatment cycle is provided at least three months after the previous treatment cycle. In a specific implementation, a subsequent treatment cycle is provided at least 12 weeks after the previous treatment cycle. In a specific implementation, a subsequent treatment cycle is provided at least 84 days after the previous treatment cycle. In a specific implementation, a subsequent treatment cycle is provided approximately three months after the previous treatment cycle. In a specific implementation, a subsequent treatment cycle is provided approximately 12 weeks after the previous treatment cycle. In a specific implementation, a subsequent treatment cycle is provided approximately 84 days after the previous treatment cycle.

[0248] This article also provides a composition comprising botulinum toxin type A, which is used in the methods described herein for improving (e.g., temporarily improving) the appearance of platysma protrusion (e.g., moderate to severe platysma protrusion) associated with platysma muscle activity in human patients.

[0249] This document also provides the use of compositions comprising botulinum toxin type A for manufacturing a medicament for improving (e.g., temporarily improving) the appearance of platysma protrusion (e.g., moderate to severe platysma protrusion) associated with platysma activity in human patients, according to the methods described herein. In a specific embodiment, improving (e.g., temporarily improving) the appearance of platysma protrusion associated with platysma activity (e.g., moderate to severe platysma protrusion) is improving (e.g., temporarily improving) the appearance of platysma band associated with platysma activity (e.g., moderate to severe platysma band). In a specific embodiment, improving (e.g., temporarily improving) the appearance of platysma protrusion associated with platysma activity (e.g., moderate to severe platysma protrusion) is improving (e.g., temporarily improving) the appearance of platysma protrusion seen at maximal contraction (e.g., moderate to severe platysma protrusion seen at maximal contraction). In a specific implementation, improving (e.g., temporarily improving) the appearance of platysma protrusion associated with platysma activity (e.g., moderate to severe platysma protrusion) is improving (e.g., temporarily improving) the appearance of platysma band protrusion seen at maximal contraction (e.g., moderate to severe platysma band protrusion seen at maximal contraction). In a specific implementation, improving (e.g., temporarily improving) the appearance of platysma protrusion associated with platysma activity (e.g., moderate to severe platysma protrusion) is improving (e.g., temporarily improving) the appearance of the vertical band connecting the mandible and neck seen at maximal contraction (e.g., moderate to severe vertical band connecting the mandible and neck seen at maximal contraction).

[0250] This document also provides a composition substantially as described herein for improving the appearance of platysma protrusion. In a specific embodiment, the improvement (e.g., temporary improvement) in the appearance of platysma protrusion associated with platysma activity (e.g., moderate to severe platysma protrusion) is an improvement (e.g., temporary improvement) in the appearance of platysma band associated with platysma activity (e.g., moderate to severe platysma band). In a specific embodiment, the improvement (e.g., temporary improvement) in the appearance of platysma protrusion associated with platysma activity is an improvement (e.g., temporary improvement) in the appearance of platysma protrusion seen at maximal contraction (e.g., moderate to severe platysma protrusion seen at maximal contraction). In a specific embodiment, the improvement (e.g., temporary improvement) in the appearance of platysma protrusion associated with platysma activity is an improvement (e.g., temporary improvement) in the appearance of platysma band protrusion seen at maximal contraction (e.g., moderate to severe platysma band protrusion seen at maximal contraction). In a specific implementation, the improvement (e.g., temporary improvement) in the appearance of platysma protrusion (e.g., moderate to severe platysma protrusion) associated with platysma activity is the improvement (e.g., temporary improvement) in the appearance of the vertical band connecting the mandible and neck (e.g., moderate to severe vertical band connecting the mandible and neck as seen at maximal contraction).

[0251] Use of compositions comprising botulinum toxin type A, substantially as described herein, is also provided.

[0252] 6. Exemplary Implementation Plan

[0253] This disclosure includes the following non-limiting exemplary embodiments:

[0254] Implementation Scheme 1: A method for improving the appearance of platysma protrusion associated with platysma muscle activity in human patients, the method comprising:

[0255] (A) Quantifying the number of consecutive vertical neck bands on the first side of the neck of the human patient during maximum contraction, wherein the consecutive vertical neck bands are vertical neck bands that extend continuously from the mandibular line of the human patient to the lower neck region; and

[0256] (B) The composition comprising botulinum toxin type A is applied to the first side of the neck of the human patient identified as having only one or two consecutive vertical neck bands at maximal contraction.

[0257] Implementation Scheme 2: The method according to Implementation Scheme 1, wherein the composition is applied to the first side of the neck of the human patient by injecting the following dose:

[0258] (i) A first mandibular line dose distributed among four injection sites below the mandibular border of the patient on the first side and parallel to the upper segment of the platysma muscle of the mandibular border; and

[0259] (ii)(a) If the first side of the human patient's neck has only one continuous vertical neck band, then a first neck band dose is distributed along the only continuous vertical neck band among the five injection sites; or (b) If the first side of the human patient's neck has only two continuous vertical neck bands, then a first neck band dose is distributed along the first continuous vertical neck band among the five injection sites and a second neck band dose is distributed along the second continuous vertical neck band among the five injection sites.

[0260] Implementation Scheme 3: The method according to Implementation Scheme 1 or 2, wherein the first side of the human patient's neck has only one continuous vertical neck band, and the administration step delivers a total unilateral dose of approximately 13 units of botulinum toxin type A to the first side of the human patient's neck.

[0261] Implementation Scheme 4: The method according to Implementation Scheme 1 or 2, wherein the first side of the human patient's neck has only two consecutive vertical neck straps, and the administration step delivers a total unilateral dose of approximately 18 units of botulinum toxin type A to the first side of the human patient's neck.

[0262] Implementation Scheme 5: The method according to any one of Implementation Schemes 2 to 4, wherein:

[0263] (1) The first mandibular line dose is about 8 units of botulinum toxin type A, and optionally, each injection of the first mandibular line dose is about 2 units of botulinum toxin type A.

[0264] (2) The first neckband dose is approximately 5 units of botulinum toxin type A, and optionally, each injection of the first neckband dose is approximately 1 unit of botulinum toxin type A; and / or

[0265] (3) The second neckband dose is about 5 units of botulinum toxin type A, and optionally, each injection of the second neckband dose is about 1 unit of botulinum toxin type A.

[0266] Implementation Scheme 6: The method according to any one of Implementation Schemes 1 to 5, the method further comprising the steps of repeatedly quantifying and applying to a second side of the neck of the human patient.

[0267] Implementation Scheme 7: The method according to Implementation Scheme 6, wherein the steps of applying to the first side and applying to the second side deliver a total bilateral dose to the neck of the human patient, the total bilateral dose being selected from the group consisting of about 26 units, about 31 units, and about 36 units of botulinum toxin type A.

[0268] Implementation Scheme 8: A method for improving the appearance of platysma protrusion associated with platysma muscle activity in a human patient having only one continuous vertical neckband at maximum contraction on a first side of the neck, the method comprising administering a composition comprising botulinum toxin type A to the first side of the human patient's neck by injecting the following dose:

[0269] (i) A first mandibular line dose distributed among four injection sites below the mandibular border of the patient on the first side and parallel to the upper segment of the platysma muscle of the mandibular border; and

[0270] (ii) The first neck band dose is distributed among five injection sites along a single continuous vertical neck band;

[0271] The continuous vertical neck band is a vertical neck band that extends continuously from the mandibular line to the lower neck region of the human patient.

[0272] Implementation Scheme 9: The method according to Implementation Scheme 8, wherein the administration step delivers a total unilateral dose of approximately 13 units of botulinum toxin type A to the first side of the neck of the human patient.

[0273] Implementation Scheme 10: The method according to Implementation Scheme 8 or 9, wherein:

[0274] (1) The first mandibular line dose is approximately 8 units of botulinum toxin type A, and optionally, each injection of the first mandibular line dose is approximately 2 units of botulinum toxin type A; and

[0275] (2) The first neckband dose is about 5 units of botulinum toxin type A, and optionally, each injection of the first neckband dose is about 1 unit of botulinum toxin type A.

[0276] Implementation Scheme 11: The method according to any one of Implementation Schemes 8 to 10, the method further comprising the step of repeatedly applying to a second side of the neck of the human patient, wherein the second side of the neck of the human patient has only one continuous vertical neck band at maximum contraction.

[0277] Implementation Scheme 12: The method according to Implementation Scheme 11, wherein the steps of applying to the first side and applying to the second side deliver a total bilateral dose of approximately 26 units of botulinum toxin type A to the neck of the human patient.

[0278] Implementation Scheme 13: A method for improving the appearance of platysma protrusion associated with platysma muscle activity in a human patient having only two consecutive vertical neckbands at maximum contraction on a first side of the neck, the method comprising administering a composition comprising botulinum toxin type A to the first side of the human patient's neck by injecting the following dose:

[0279] (i) A first mandibular line dose is distributed among four injection sites below the lower border of the patient's mandible and parallel to the upper segment of the platysma muscle on the first side;

[0280] (ii) The first neckband dose is distributed along the first continuous vertical neckband among five injection sites; and

[0281] (iii) The second neck band dose is distributed among five injection sites along the second continuous vertical neck band;

[0282] The continuous vertical neck band extends continuously from the mandibular line of the human patient to the lower neck region, and the administration step delivers a total unilateral dose of botulinum toxin type A ranging from about 15 units to about 20 units to the first side of the human patient's neck.

[0283] Implementation Scheme 14: The method according to Implementation Scheme 13, wherein the administration step delivers a total unilateral dose of approximately 18 units of botulinum toxin type A to the first side of the neck of the human patient.

[0284] Implementation Scheme 15: The method according to Implementation Scheme 13 or 14, wherein:

[0285] (1) The first mandibular line dose is about 8 units of botulinum toxin type A, and optionally, each injection of the first mandibular line dose is about 2 units of botulinum toxin type A.

[0286] (2) The first neckband dose is approximately 5 units of botulinum toxin type A, and optionally, each injection of the first neckband dose is approximately 1 unit of botulinum toxin type A; and

[0287] (3) The second neckband dose is about 5 units of botulinum toxin type A, and optionally, each injection of the second neckband dose is about 1 unit of botulinum toxin type A.

[0288] Implementation Scheme 16: The method according to any one of Implementation Schemes 13 to 15, the method further comprising the step of repeatedly applying to a second side of the neck of the human patient, wherein the second side of the neck of the human patient has only two consecutive vertical neck bands at maximum contraction.

[0289] Implementation Scheme 17: The method according to Implementation Scheme 16, wherein the steps of applying to the first side and applying to the second side deliver a total bilateral dose of approximately 36 units of botulinum toxin type A to the neck of the human patient.

[0290] Implementation Scheme 18: A method for improving the appearance of platysma protrusion associated with platysma muscle activity in a human patient having only one continuous vertical neck band at maximum contraction on a first side of the neck and only two continuous vertical neck bands at maximum contraction on a second side of the neck, the method comprising administering a composition comprising botulinum toxin type A to the neck of the human patient by injecting the following doses:

[0291] (i) A first mandibular line dose is distributed among four injection sites below the lower border of the patient's mandible and parallel to the upper segment of the platysma muscle on the first side;

[0292] (ii) A first neck band dose is distributed among five injection sites along the only continuous vertical neck band on the first side;

[0293] (iii) A second mandibular line dose is distributed among four injection sites in the upper segment of the platysma muscle below the mandibular border of the patient on the second side and parallel to the mandibular border;

[0294] (iv) A first neck band dose is distributed among five injection sites along the first continuous vertical neck band on the second side; and

[0295] (v) A second neck band dose is distributed between five injection sites along the second continuous vertical neck band on the second side;

[0296] The continuous vertical neck band is a vertical neck band that extends continuously from the mandibular line to the lower neck region of the human patient.

[0297] Implementation Scheme 19: The method according to Implementation Scheme 18, wherein the first mandibular line dose is equal to the second mandibular line dose.

[0298] Implementation Scheme 20: The method according to Implementation Scheme 18, wherein the first mandibular line dose is not equal to the second mandibular line dose.

[0299] Implementation Scheme 21: The method according to any one of Implementation Schemes 18 to 20, wherein:

[0300] (1) The first mandibular line dose is about 8 units of botulinum toxin type A, and optionally, each injection of the first mandibular line dose is about 2 units of botulinum toxin type A.

[0301] (2) The second mandibular line dose is about 8 units of botulinum toxin type A, and optionally, each injection of the second mandibular line dose is about 2 units of botulinum toxin type A.

[0302] (3) The first neckband dose on the first side is about 5 units of botulinum toxin type A, and optionally, each injection of the first neckband dose on the first side is about 1 unit of botulinum toxin type A.

[0303] (4) The first neckband dose on the second side is approximately 5 units of botulinum toxin type A, and optionally, each injection of the first neckband dose on the second side is approximately 1 unit of botulinum toxin type A; and

[0304] (5) The second neck band dose on the second side is about 5 units of botulinum toxin type A, and optionally, each injection of the second neck band dose on the second side is about 1 unit of botulinum toxin type A.

[0305] Implementation Scheme 22: The method according to any one of Implementation Schemes 18 to 21, wherein the administration step delivers a total bilateral dose of about 31 units of botulinum toxin type A to the neck of the human patient.

[0306] Implementation Scheme 23: The method according to any one of Implementation Schemes 1 to 22, wherein the cosmetic effect of the method is obtained within 14 days after the application of the type A botulinum toxin, and wherein:

[0307] (1) The cosmetic effect includes a change in platysma protrusion scale grade, assessed by a physician or human patient, from moderate or severe before the application of the botulinum toxin type A to slight or mild after the application of the botulinum toxin type A; wherein optionally, the duration of the cosmetic effect is in the range of about 30 days to about 120 days after the application of the botulinum toxin type A, or the duration of the cosmetic effect is at least 120 days; and wherein optionally, the method is statistically superior to comparable methods in which a placebo is used instead of the botulinum toxin type A in achieving a slight or mild grade on the platysma protrusion scale assessed by a physician or human patient 14 days after application.

[0308] (2) The cosmetic effect includes a grade 2 or better improvement in platysma protrusion as assessed by physicians and human patients on the platysma protrusion scale, from moderate or severe before the application of the botulinum toxin type A to slight or mild improvement after the application of the botulinum toxin type A.

[0309] (3) The cosmetic effect includes a change in platysma protrusion scale rating, assessed by physicians and human patients, from moderate or severe before the application of the botulinum toxin type A to slight or mild changes after the application of the botulinum toxin type A; or

[0310] (4) The cosmetic effect includes achieving a slight or mild grade of improvement relative to baseline, as assessed by physicians and human patients on the platysma protrusion scale; wherein optionally, the duration of the cosmetic effect is at least 120 days after the administration of the botulinum toxin type A, or the duration of the cosmetic effect is in the range of about 60 days to about 120 days after the administration of the botulinum toxin type A; and wherein optionally, the method is statistically superior to comparable methods in which a placebo is administered instead of the botulinum toxin type A in achieving a slight or mild grade of improvement relative to baseline, as assessed by physicians and human patients on the platysma protrusion scale, 14 days after administration;

[0311] Optionally, the platysma protrusion scale is a platysma band severity grading scale.

[0312] Implementation Scheme 24: The method according to any one of Implementation Schemes 1 to 23, wherein the concentration of botulinum toxin type A in the composition is about 40 units / mL.

[0313] Implementation Scheme 25: The method according to any one of Implementation Schemes 1 to 24, wherein the type A botulinum toxin is a 900 kD serum type A botulinum neurotoxin (BoNT / A) complex.

[0314] Implementation Scheme 26: The method according to Implementation Scheme 25, wherein the type A botulinum toxin is onabotulinumtoxin A.

[0315] Implementation Scheme 27: The method according to Implementation Scheme 25 or 26, wherein the composition comprises a powdered BoNT / A drug composition reconstituted with physiological saline, wherein prior to the reconstitution, the powdered BoNT / A drug composition consists of the 900 kDa BoNT / A complex, human albumin and sodium chloride.

[0316] Implementation Scheme 28: The method according to any one of Implementation Schemes 1 to 27, wherein the composition is a liquid.

[0317] Implementation Scheme 29: The method according to any one of Implementation Schemes 2 to 28, wherein the injection depth does not exceed about 0.5 inches into the muscle; and / or wherein the injection is performed superficially and intramuscularly with a needle perpendicular to the skin surface.

[0318] Implementation Scheme 30: The method according to any one of Implementation Schemes 1 to 29, wherein the human patient also has one or more discontinuous neck bands on the first and / or second side of the human patient's neck; and / or wherein no additional dose of the botulinum toxin type A is injected into the human patient's neck.

[0319] Implementation Scheme 31: The method according to any one of Implementation Schemes 1 to 30, wherein the method is repeated approximately every 12 weeks.

[0320] Implementation Scheme 32: The method according to any one of Implementation Schemes 1 to 31, wherein the method causes at least one occurrence rate selected from the group consisting of:

[0321] (1) The incidence of treatment-induced adverse events (TEAEs) associated with the composition containing the botulinum toxin type A is less than 5%;

[0322] (2) The incidence of treatment-related serious TEAEs is less than 1%, and optionally no treatment-related serious TEAEs occur;

[0323] (3) The incidence of adverse events of particular concern (AESI) is less than 5%, and optionally no AESI occurs, including aspiration, aspiration pneumonia, dry mouth, dysphagia, dyspnea, facial paralysis and muscle weakness.

[0324] (4) The incidence of bruising at the injection site is less than 10%;

[0325] (5) The incidence of neck muscle weakness is less than 1%, and optionally no neck muscle weakness occurs.

[0326] (6) An incidence of dysphagia of less than 2%, with optional absence of dysphagia; and

[0327] (7) The incidence of injection site hematoma is less than 5%, and optionally no injection site hematoma occurs.

[0328] Implementation Scheme 33: The method according to any one of Implementation Schemes 2 to 32, wherein the method reduces the incidence of adverse effects compared to comparable methods, the comparable methods comprising:

[0329] (1) Injecting one or more neckband doses of the type A botulinum toxin into one or more neckbands of a human subject, but excluding injecting a mandibular dose of the type A botulinum toxin into the neck of the human subject.

[0330] (2) Injecting one or more neckband doses of the type A botulinum toxin into one or more neckbands in the neck of a human subject, wherein the one or more neckbands into which the one or more neckband doses were injected are not limited to continuous vertical neckbands extending from the jawline of the human subject to the lower neck region; and / or

[0331] (3) Three or more neckband doses of the type A botulinum toxin were injected into one side of the neck of a human subject, wherein each neckband dose was injected along a different neckband.

[0332] Implementation Scheme 34: The method described in Implementation Scheme 33, wherein the adverse effects are selected from the group consisting of aspiration, aspiration pneumonia, dry mouth, dysphagia, dyspnea, facial paralysis, muscle weakness, bruising at the injection site, and hematoma at the injection site.

[0333] Implementation Scheme 35: The method according to any one of Implementation Schemes 1 to 34, the method being used to improve the appearance of the platysma band associated with platysma muscle activity.

[0334] Implementation Scheme 36: The method according to any one of Implementation Schemes 1 to 35, wherein a continuous vertical neck band is a visible vertical neck band that extends continuously from the mandibular line of the human patient to the lower neck region and causes blunting of the mandibular line.

[0335] Implementation Scheme 37: The method according to any one of Implementation Schemes 2 to 36, wherein the four injection sites in the upper segment of the platysma muscle include an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior to the angle of the mandible.

[0336] Implementation Scheme 38: A composition comprising botulinum toxin type A, said composition being used in the method according to any one of Implementation Schemes 1 to 37.

[0337] Implementation Scheme 39: Use of a composition comprising botulinum toxin type A for manufacturing a medicament for providing an improvement in the appearance of platysma protrusion associated with platysma muscle activity in a human patient, according to the method of any one of Implementation Schemes 1 to 37.

[0338] Implementation Scheme 40: Use of a composition comprising botulinum toxin type A, substantially as described herein.

[0339] Implementation Scheme 41: A composition substantially as described herein for improving the appearance of platysma protrusion.

[0340] Implementation Scheme 42: A method for treating the appearance of the platysma band associated with platysma muscle activity in a human patient using a composition comprising botulinum toxin type A, wherein the treatment comprises intramuscular administration to the first side of the neck of the human patient:

[0341] a) A first mandibular line dose distributed among four injection sites in the upper platysma muscle on the first side of the neck of the human patient, wherein the first mandibular line dose is approximately 8 units of botulinum toxin type A; and

[0342] b) A first neck band dose distributed among five injection sites along the first platysma band on the first side of the neck of the human patient, wherein the first neck band dose is approximately five units of botulinum toxin type A.

[0343] Furthermore, the appearance of the platysma band in the human patient is safely and effectively treated.

[0344] Implementation Scheme 43: The method according to Implementation Scheme 42, wherein the method further includes administering the following to the second side of the patient's neck muscles:

[0345] a) A second mandibular line dose distributed among four injection sites in the upper platysma muscle on the second side of the neck of the human patient, wherein the second mandibular line dose is approximately 8 units of botulinum toxin type A; and

[0346] b) A second neck band dose, distributed among five injection sites along the second side of the neck of the human patient, consisting of approximately five units of botulinum toxin type A.

[0347] Implementation Scheme 44: The method according to Implementation Scheme 43, wherein the method further comprises administering intramuscularly to at least one side of the first or second side of the neck of the human patient a third neck band dose distributed among five injection sites along the third platysma band, wherein the third neck band dose is approximately five units of botulinum toxin type A.

[0348] Implementation Scheme 45: The method according to any one of Implementation Schemes 42 to 44, the method further comprising administering a fourth neck band dose distributed between five injection sites along the fourth platysma band, wherein the fourth neck band dose is about five units of botulinum toxin type A, and wherein the human patient has two platysma bands located on each of the first and second sides of the human patient's neck.

[0349] Implementation Scheme 46: The method according to Implementation Scheme 43, wherein the administration step delivers a total two-sided dose of 26 units of botulinum toxin type A.

[0350] Implementation Scheme 47: The method according to Implementation Scheme 44, wherein the administration step delivers a total bilateral dose of 31 units of botulinum toxin type A.

[0351] Implementation Scheme 48: The method according to Implementation Scheme 44 or 45, wherein the administration step delivers a total bilateral dose of 36 units of botulinum toxin type A.

[0352] Implementation Scheme 49: The method according to any one of Implementation Schemes 42 to 48, wherein the first platysma band on the first side of the neck of the human patient, the first platysma band on the second side, the third platysma band on at least one of the first or second sides, and / or the fourth platysma band are visible continuous vertical neck bands at maximum contraction, which extend continuously from the mandibular line of the human patient to the lower neck region and cause blunting of the mandibular line.

[0353] Implementation Scheme 50: The method according to any one of Implementation Schemes 42 to 49, wherein the four mandibular line injection sites are applied below and parallel to the lower mandibular margin of the patient.

[0354] Implementation Scheme 51: According to the method of Implementation Scheme 50, the four mandibular line injection sites are applied approximately 1 to 2 cm below the lower edge of the patient's mandible and parallel to the lower edge of the mandible.

[0355] Implementation Scheme 52: The method according to Implementation Scheme 50 or 51, wherein the first mandibular line injection site is an anterior injection site aligned with the corner of the patient's mouth, the fourth mandibular line injection site is a posterior injection site anterior to the angle of the mandible, and the second mandibular line injection site and the third mandibular line injection site are equidistant from the first mandibular line injection site and the fourth mandibular line injection site.

[0356] Implementation Scheme 53: The method according to any one of Implementation Schemes 42 to 52, wherein the first injection site of the first neck band dose, the second neck band dose, the third neck band dose, or the fourth neck band dose is applied approximately 1 to 2 cm below the mandibular line injection site.

[0357] Implementation Scheme 54: The method according to Implementation Scheme 53, wherein the neckband injection sites are spaced approximately 1 cm to 2 cm apart.

[0358] Implementation Scheme 55: The method according to any one of Implementation Schemes 42 to 54, wherein the treatment provides a temporary improvement in the appearance of the platysma band.

[0359] 7. Example

[0360] Certain embodiments provided herein are illustrated by the following non-limiting examples, which describe a holistic approach to treating platysma herniation using botulinum toxin and demonstrate that the holistic approach has a favorable benefit / risk profile.

[0361] 7.1. Example 1: Type A botulinum toxin (BOTOX) ® Used to treat platysma herniation

[0362] A multicenter, randomized, double-blind, placebo-controlled, dose-range-determined phase 2 study was conducted to evaluate the purified neurotoxin complex of botulinum toxin type A (BOTOX). ® The safety and efficacy of treating platysma herniation.

[0363] The purpose of this placebo-controlled phase 2 trial was to evaluate high-dose and low-dose BOTOX. ® The safety and efficacy of platysma bulging in reducing the appearance of platysma bulging in adult participants with moderate to severe platysma bulging compared to placebo. The total duration of the study was 4 months, with 171 participants enrolled. Participants were screened from day -14 to day -7 (screening period). Participants were men and women 18 years of age and older with moderate (grade 3) or severe (grade 4) platysma bulging on both left and right sides (the severity on both sides did not have to be the same), which was determined by the investigator at screening using C-APPS at maximal contraction and by the investigator and participants on day 1 using C-APPS and P-APPS, respectively (see [link to study]). Figure 1 (See Table 3). Exclusion criteria included certain medical conditions (including dysphagia, pregnancy, and conditions that might expose participants to increased medical risks due to BOTOX exposure), and exposure to botulinum toxin within 6 months prior to Day 1. Follow-up visits were scheduled on days 7, 14, 30, 60, and 90, as well as at study exit (day 120).

[0364] Following the screening period, on day 1, participants who met the inclusion criteria were randomly assigned to groups in a 1:1:1 ratio for admission.

[0365] • High dose of BOTOX (52U, 62U, or 72U, depending on the investigator-assessed baseline (day 1) C-APPS rating)

[0366] • Low dose of BOTOX (26U, 31U, or 36U, depending on the investigator-assessed baseline (day 1) C-APPS rating)

[0367] • Placebo (0U)

[0368] For each participant, a superficial intramuscular injection was administered into the platysma muscle above the mandibular line on each side of the neck (0.1 mL per injection, spaced approximately 1 cm apart) and along each consecutive vertical neck band (up to two bands per side, 0.05 mL per injection, spaced approximately 1 to 2 cm apart). Dosage was determined based on the investigator's C-APPS score at baseline on day 1 (Figures 2A to 2B and Table 2).

[0369] • Participants with grade 3 platysma protrusion on both sides received a total of 18 injections (9 injections per side: 4 injections in the upper segment of the platysma below the mandibular line and 5 injections along the continuous vertical neck band on each side).

[0370] • Participants with grade 3 platysma protrusion on one side and grade 4 platysma protrusion on the other side received a total of 23 injections (as mentioned above, 9 injections on the side with grade 3 platysma protrusion and 14 injections on the side with grade 4 platysma protrusion).

[0371] • Participants with grade 4 platysma protrusion on both sides received a total of 28 injections (14 injections per side: 4 injections in the upper segment of the platysma below the mandibular line, 5 injections along the anterior vertical neck band, and 5 injections along the posterior vertical neck band).

[0372] For illustration, participants randomly assigned to a high dose of BOTOX who have grade 4 platysma on both sides will receive 28 injections or a total dose of 72U, as detailed below:

[0373] • Dosage administered to the upper platysma muscle below the mandibular line = (2 sides) × (4 injections below each mandibular line) × (4U) = 32U

[0374] • Dosage administered to continuous vertical neck straps = (2 sides) × (2 vertical neck straps per side) × (5 injections per vertical neck strap) × (2U) = 40U

[0375]

[0376] When implementing this embodiment, medical practitioners should follow the instructions below: Dispense 100 units of onabotulinumtoxin A (BOTOX) per vial. ® Dilute with 2.5 mL or 5 mL of sterile, preservative-free saline to obtain a high dose of BOTOX (2 U / 0.05 mL) or a low dose of BOTOX (1 U / 0.05 mL), and dilute each vial of placebo with 2.5 mL of sterile, preservative-free saline.

[0377] The primary efficacy endpoint was defined as at least a grade 1 improvement on both the left and right sides on day 14, as assessed by the investigator using APPS at maximal contraction. Secondary efficacy endpoints were defined as at least a grade 1 improvement on both the left and right sides on day 14, as assessed by the participant using APPS at maximal contraction.

[0378] Researchers or participants independently assessed platysma protrusion on the left and right sides at maximal contraction using C-APPS and P-APPS (1=mild, 2=mild, 3=moderate, 4=severe, 5=very severe; Table 3). Figure 1 ).

[0379]

[0380] Any adverse events (AEs) were reported by the participant (or, where appropriate, by a caregiver or agent) and assessed according to the classification shown in Table 4.

[0381]

[0382] Data for the primary and secondary efficacy endpoints are shown in the figures below. Figure 3A and Figure 3B middle. Figure 3A The results showed that the high-dose and low-dose BOTOX groups had a statistically significant higher rate of responders than the placebo group in achieving at least a grade 1 improvement on both the left and right sides on day 14 (p < 0.0001), as assessed by the investigators using C-APPS at maximal contraction (i.e., the primary efficacy endpoint). Figure 3B The data showed that both the high-dose and low-dose BOTOX groups had statistically significantly higher rates of response to at least Grade 1 improvement on both the left and right sides on day 14 than the placebo group (p < 0.0001), as assessed by participants using P-APPS at maximal contraction (i.e., the secondary efficacy endpoint). Therefore, the data indicate that both the high-dose and low-dose BOTOX groups achieved both the primary and secondary endpoints.

[0383] Safety data are summarized in Table 5 below. Most treatment-related adverse events (AEs) were of mild severity. The incidence of treatment-related AEs was significantly higher in the high-dose BOTOX group. Most investigational drug-related treatment-induced adverse events (TEAEs) occurred in the high-dose BOTOX group (AEs are considered TEAEs if they begin after the first dose of the study intervention, or if they were present before the first dose of the study intervention but became more severe or serious after the first dose). Furthermore, the reported treatment-related AEs were not unexpected. All of this is consistent with known BOTOX pharmacology and literature findings.

[0384]

[0385] In summary, the results of this phase 2 study indicate that BOTOX is more effective than placebo in treating platysma herniation (as determined by clinicians and participants using APPS), and that the treatment has an ideal safety profile following a single treatment in the dose range of 26U to 36U.

[0386] 7.2. Example 2: Type A botulinum toxin (BOTOX) ® Used to treat platysma herniation

[0387] Two phase 3, multicenter, randomized, double-blind, placebo-controlled studies were conducted to evaluate the purified neurotoxin complex (BOTOX) of botulinum toxin type A. ® Safety and efficacy in improving the appearance of moderate to severe platysma protrusion. The first clinical study (Study 1) was also known as the M21-309 study, and the second clinical study (or Study 2) was also known as the M21-310 study.

[0388] Subjects were randomly assigned to receive BOTOX based on the severity of the condition on the left and right sides. ® A single treatment of 26, 31, or 36 units or placebo. The total duration of each study in the two studies was 4 months. Participants were screened from day -14 to day -7 (screening period). Participants were males and females at least 18 years of age with moderate (grade 3) or severe (grade 4) platysma protrusion on both left and right sides, as independently determined by the investigator using the Level 5 Clinician Allergan Platysma Protrusion Scale (C-APPS) at screening and at maximal contraction on day 1, and by the participant using the Level 5 Participant Allergan Platysma Protrusion Scale (P-APPS) (see [link to study]). Figure 1 (See Table 3). The severity of platysma protrusion on the left and right sides need not be the same. Exclusion criteria include certain medical conditions (including dysphagia, pregnancy, and possible exposure to BOTOX). ® Conditions that increase medical risk to participants, and exposure to botulinum toxin within 6 months prior to Day 1. Follow-up visits are scheduled on days 14, 30, 60, and 90, and at study exit (day 120). After exiting Study 1, eligible participants may choose to participate in an 8-month open-label extension study (see Example 3 and...). Figure 4 To further evaluate long-term safety and efficacy.

[0389] Following the screening period, eligible participants were randomly assigned to receive BOTOX in a 1:1 ratio on day 1. ® Or a placebo.

[0390] For each subject, a superficial intramuscular injection was administered in the upper platysma muscle below the mandibular line on each side (0.05 mL injected per injection, spaced approximately 1 cm apart) and along each consecutive vertical neck band on each side of the neck (up to 2 bands per side, 0.025 mL injected per injection, spaced approximately 1 to 2 cm apart). Dosage was determined based on the baseline C-APPS score assessed by the investigator on day 1. Depending on the severity of platysma protrusion, the total dose could be 26 units (1 band / side), 31 units (1 band on one side, 2 bands on the other side), or 36 units (2 bands / side) (Tables 6A to 6B and Figures 2A to 2B):

[0391] • Subjects with grade 3 platysma protrusion on both sides received a total of 26U or 18 injections (9 injections per side: 4 injections in the upper platysma muscle below the mandibular line and 5 injections along the continuous vertical neck band on each side).

[0392] • Subjects with grade 3 platysma protrusion on one side and grade 4 platysma protrusion on the other side received a total of 31U or 23 injections (9 injections on the side with grade 3 platysma protrusion and 14 injections on the side with grade 4 platysma protrusion).

[0393] • Subjects with grade 4 platysma protrusion on both sides received a total of 36U or 28 injections (14 injections per side: 4 injections in the upper segment of the platysma muscle below the mandibular line, 5 injections along the anterior vertical neck band, and 5 injections along the posterior vertical neck band).

[0394] For illustration, subjects randomly assigned to receive BOTOX with bilateral grade 4 platysma will receive 28 injections or a total dose of 36U, as detailed below:

[0395] • Dosage administered to the upper platysma muscle below the mandibular line = (2 sides) × (4 injections below each mandibular line) × (2U) = 16U

[0396] • Dosage administered to continuous vertical neck straps = (2 sides) × (2 vertical neck straps per side) × (5 injections per vertical neck strap) × (1U) = 20U

[0397]

[0398]

[0399] Each vial contains 100 units of onabotulinumtoxin A (BOTOX) ® BOTOX ® Cosmetic or VISTABEL ® Dilute with 2.5 mL of sterile, preservative-free saline solution to make BOTOX® The dosage was 4 units / 0.1 mL, and each placebo was diluted with 2.5 mL of sterile, preservative-free saline.

[0400] Using an appropriately sized sterile syringe, needle, and aseptic technique, administer 2 units / 0.05 mL of reconstituted BOTOX. ® Inject into four sites in the upper segment of the platysma muscle below the mandibular line on each side. Additionally, administer 1 unit / 0.025 mL of reconstituted BOTOX. ® Inject into 5 sites along each vertical neck band, 1 to 2 vertical neck bands per side. Depending on the severity of platysma protrusion, the total dose may be 26 units (1 band / side), 31 units (1 band on one side and 2 bands on the other side), or 36 units (2 bands / side) (Figures 2A and 2B and Table 6B).

[0401] For each side, the four mandibular line injections of the platysma muscle should be placed approximately 1 to 2 cm below the lower border of the mandible and parallel to it. The anterior injection site should align with the corner of the mouth, and the posterior injection site should be slightly anterior to the angle of the mandible. The remaining two injections should be equidistant from the anterior and posterior injection points (approximately 1 to 2 cm apart) (Figures 2A and 2B). For each identified vertical neck band (1 to 2 on each side) (Figures 2A and 2B), five injections are distributed vertically, spaced approximately 1 to 2 cm apart. The uppermost injection site should be approximately 1 to 2 cm below the mandibular line injection.

[0402] The platysma is a thin layer of muscle located directly beneath the skin surface. Therefore, all platysma injections should be administered superficially and intramuscularly using a needle perpendicular to the skin surface. For vertical neck band injections, each band should be identified when the patient contracts their platysma. The band should be gently pinched during administration to separate the muscle from nearby anatomical structures.

[0403] To minimize injection-related complications, injections should be made at least 1 cm below the lower border of the mandible. Avoid injecting into the deep structures of the platysma muscle, especially in the anterior neck region.

[0404] For the U.S. regulatory agency (i.e., the FDA), the combined primary efficacy endpoint is a grade 1 or 2 (mild or slight) improvement relative to baseline at day 14 at maximum contraction, based on investigator assessment using C-APPS and subject self-assessment using P-APPS.

[0405] For EU regulatory authorities, the co-primary efficacy endpoint is based on achieving at least a grade 2 improvement relative to baseline by: (1) investigator assessment using C-APPS at the time of maximum contraction on day 14, and (2) subject self-assessment using P-APPS at the time of maximum contraction on day 14.

[0406] Secondary endpoints include:

[0407] • Based on the researcher's assessment using C-APPS at maximum contraction over time, a grade 1 or 2 (mild or mild) condition is achieved.

[0408] • Based on the subject's self-assessment using P-APPS at maximum contraction over time, a grade 1 or 2 (mild or mild) was achieved.

[0409] • On day 14, the response to item 5 of the “Neck and Lower Face Appearance Questionnaire (ANLFQ): Satisfaction (Follow-up)” was either “Satisfied” or “Very Satisfied”. The response range for item 5 is from “Very Satisfied” to “Very Dissatisfied”.

[0410] • On day 14, the response to item 2 (mandibular line) of the "Distress Assessment Scale - Platysma Prominence (BAS-PP)" was either "not bothered at all" or "somewhat bothered".

[0411] • On day 14, the answer to "BAS-PP item 1 (vertical neck brace)" was either "not bothered at all" or "somewhat bothered".

[0412] • The “ANLFQ: Impact” summary score changed relative to baseline on day 14.

[0413] • Based on the investigator's assessment using C-APPS at maximum contraction over time, achieve at least one grade improvement relative to baseline.

[0414] • Based on the subject's self-assessment using P-APPS at maximal contraction over time, achieving at least one grade improvement relative to baseline.

[0415] Researchers regularly monitored clinical evidence of adverse events (AEs) for each subject throughout the study and assessed AEs according to the classification shown in Table 7. In studies M21-309 and M21-310, the adverse events of particular concern (AESIs) monitored included aspiration, aspiration pneumonia, dry mouth, dysphagia, dyspnea, facial paralysis, and muscle weakness (i.e., neck muscle weakness).

[0416]

[0417] Treatment was not discontinued due to death, adverse events (AEs), or COVID-19.

[0418] The primary efficacy endpoint was defined as the combined achievement of a grade 1 or 2 (mild or mild) improvement in platysma protrusion severity at maximal contraction relative to baseline, assessed by both investigator and participant on day 14. (See Table 8 and...) Figure 5 Figure 6A Figure 8A and Figure 8BAs shown, on day 14, compared with placebo, BOTOX ® The proportion of respondents in the group was larger (p<0.0001 for both studies).

[0419]

[0420] The efficacy results obtained in the first study showed that BOTOX ® The treatment significantly reduced the severity of platysma herniation (see Table 8). Figure 5 For the first study, the response rates at the primary time point of day 14 were: (1) for the US primary endpoint (i.e., achieving grade 1 or 2 (mild or slight) improvement relative to baseline at maximum contraction based on investigator's assessment using C-APPS and subject's self-assessment using P-APPS), the rates for BOTOX and placebo were 32.3% and 1.9%, respectively, in the ITT population; (2) for the EU co-primary endpoint based on investigator's assessment (i.e., ≥2-grade improvement relative to baseline at maximum contraction based on investigator's assessment using C-APPS), the rates for BOTOX and placebo were 1.9% in the mITT population. ® The rates of BOTOX in the mITT population were 43.8% and 3.9% for the placebo population, respectively; and (3) for the EU common primary endpoint based on subject assessment (i.e., ≥2 grade improvement relative to baseline at day 14 at maximum contraction based on subject assessment using P-APPS). ® The efficacy rates were 45.6% and 3.9% for the control and placebo, respectively; comparable efficacy results were also obtained in the second study (see Table 8 and Figures 6A to 6C).

[0421] The primary endpoints indicated that efficacy peaked around day 14 (see Figures 6A through 6C). Figure 6A shows the response rates in the ITT populations of the M21-309 and M21-310 studies for achieving the US primary endpoint (i.e., achieving grade 1 or 2 (mild or slight) improvement relative to baseline based on investigator's assessment using C-APPS and subject's self-assessment using P-APPS at day 14, at maximum contraction). Figures 6B and 6C show the response rates in the mITT populations of the M21-309 and M21-310 studies for achieving the EU common primary endpoint (i.e., achieving at least 2-grade improvement relative to baseline based on investigator's assessment using C-APPS at day 14 (Figure 6B), and achieving at least 2-grade improvement relative to baseline based on subject's self-assessment using P-APPS at day 14 (Figure 6C)).

[0422] Figure 7AThe figure shows the rate of improvement to grade 1 or 2 (mild or mild) response for BOTOX in the ITT population of the M21-309 study at the time of maximum contraction on day 14, based on investigator assessment using C-APPS. ® The response rates for BOTOX were 56.9% and 5.8% for placebo, respectively (p < 0.0001, unadjusted), and the response rates in the ITT population of the M21-310 study were significantly higher than those for BOTOX. ® The rates of benefit were 48.3% for the control group and 3.0% for the placebo group (p < 0.0001). Figure 7B The figure shows the rate of improvement to grade 1 or 2 (mild or mild) response for BOTOX in the ITT population of the M21-309 study, based on the subjects' assessment using P-APPS at maximal contraction on day 14. ® The response rates for BOTOX were 51.7% and 5.1% for placebo, respectively (p < 0.0001, unadjusted), and the response rates in the ITT population of the M21-310 study were significantly higher than those for BOTOX. ® The rates of 47.1% and 5.1% were observed in the placebo and placebo, respectively (p < 0.0001).

[0423] Figure 8A The following response rates (%) were shown in the ITT population of the M21-309 study: (i) the rate of participants achieving improvement to grade 1 or 2 (mild or mild) response at the time of maximum contraction on day 14, based on investigator assessment using C-APPS for BOTOX. ® The rates of improvement to grade 1 or 2 (mild or mild) at day 14 at maximal contraction, compared with placebo, were 56.9% and 5.8%, respectively (p < 0.0001, unadjusted); (ii) the rate of responders achieving improvement to grade 1 or 2 (mild or mild) at day 14 at maximal contraction, based on the subject's assessment using P-APPS. ® The rates of response to BOTOX were 51.7% and 5.1% for placebo, respectively (p < 0.0001, unadjusted); and (iii) the rate of responders achieving at least a grade 2 improvement on day 14 based on investigator assessments using C-APPS and subject self-assessments using P-APPS. ® The rates of benefit were 32.3% for the control group and 1.9% for the placebo group (p < 0.0001). Figure 8B The following response rates (%) were shown in the ITT population of the M21-310 study: (i) a response rate of improvement to grade 1 or 2 (mild or mild) at the time of maximum contraction on day 14, based on investigator assessment using C-APPS for BOTOX. ®The rates of improvement to grade 1 or 2 (mild or mild) at maximal contraction on day 14, as assessed by subjects using P-APPS, were 48.3% and 3.0%, respectively (p < 0.0001); (ii) the rate of responders achieving improvement to grade 1 or 2 (mild or mild) at maximal contraction on day 14, based on subjects' assessment using P-APPS. ® The rates of response to BOTOX were 47.1% and 5.1% for placebo, respectively (p < 0.0001); and (iii) the rate of responders achieving at least a grade 2 improvement on day 14 based on investigator assessments using C-APPS and subject self-assessments using P-APPS. ® The rates of benefit from the placebo were 31.4% and 0.0%, respectively (p < 0.0001).

[0424] For the primary endpoint in the United States (i.e., achieving Grade 1 or 2 (mild or slight) improvement relative to baseline at the time of maximum systole on day 14 based on investigator assessment using C-APPS and subject self-assessment using P-APPS), BOTOX ® The treatment showed a statistically higher response rate than placebo (see [link]). Figure 5 Figure 6A Figures 8A to 8B (and Table 8). Regarding the achievement of Grade 1 or 2 (mild or mild) systolic contraction at maximum contraction on day 14 based on investigator assessment using C-APPS, BOTOX... ® The treatment also showed a higher response rate than placebo (see Figure 7A , Figures 8A to 8B Regarding the achievement of Grade 1 or 2 (mild or mild) systole at maximal contraction on day 14 based on the subject's assessment using P-APPS, BOTOX... ® The treatment also showed a higher response rate than placebo (see Figure 7B , Figures 8A to 8B ).

[0425] Secondary efficacy measures included the Neck and Lower Face Appearance Questionnaire (ANLFQ): Satisfaction (Follow-up) and the Distress Assessment Scale – Platysma Protrusion (BAS-PP).

[0426] On day 14, participants assessed their satisfaction with the treatment effect using the "ANLFQ: Satisfaction (Follow-up) Item 5" using a 5-point scale (1 = Very satisfied, 2 = Satisfied, 3 = Neither satisfied nor dissatisfied, 4 = Dissatisfied, 5 = Very dissatisfied).

[0427] Participants used the BAS-PP to assess how much they were bothered by the appearance of their platysma muscles. Specifically, on day 14, participants used a 5-point response scale (1 = not bothered at all, 2 = somewhat bothered, 3 = somewhat bothered, 4 = very bothered, 5 = extremely bothered) to assess how much they were bothered by the appearance of their vertical neck band (BAS-PP item 1) and jawline (BAS-PP item 2).

[0428] The results of the secondary efficacy endpoints for studies 1 and 2 are presented in Tables 9A and 9B.

[0429]

[0430] On day 14, based on the "ANLFQ: Satisfaction (Follow-up) Item 5 (Satisfaction with Treatment Outcome)," compared to subjects receiving placebo (10.1% in Study 1, 11.5% in Study 2), the percentage of subjects reporting "very satisfied" or "satisfied" with the treatment outcome for BOTOX was [not specified]. ® The percentage of subjects receiving treatment was higher (66.4% in Study 1 and 63.1% in Study 2) [p<0.0001 for both studies] (see [link to study 2]). Figure 9A ).

[0431] Based on BAS-PP item 2 (jawline) on day 14, compared with placebo-treated subjects (13.9% in Study 1, 21.6% in Study 2), those reporting "no problem at all" or "some problem" with their jawline appearance after using BOTOX reported the following: ® The percentage of subjects receiving treatment was higher (55.3% in Study 1 and 49.8% in Study 2) [p<0.0001 for both studies] (see [link to study 2]). Figure 9B ).

[0432] Based on BAS-PP item 1 (vertical neck band) on day 14, compared with placebo-treated subjects (6.6% in Study 1, 13.4% in Study 2), those reporting "no discomfort" or "some discomfort" with the appearance of their vertical neck band after BOTOX treatment... ® The percentage of subjects receiving treatment was higher (52.2% in Study 1 and 50.7% in Study 2) [p<0.0001 for both studies] (see [link to study 2]). Figure 9C ).

[0433] The primary endpoints in the United States (comprehensive) and the European Union (co-primary) met statistical significance, indicating that BOTOX... ® Superior to placebo (p < 0.0001). All secondary endpoints in the US and EU also met statistical significance on day 14, indicating that BOTOX was superior to placebo. ®Superior to placebo (p < 0.0001). Compared to placebo, receiving BOTOX... ® Subjects who received the treatment were more satisfied with the results and less bothered by the appearance of their jawline and neckband. Therefore, 26U to 36U of BOTOX... ® Treatment has shown to significantly improve platysma protrusion.

[0434] Regarding safety, most treatment-induced adverse events (TEAEs) were mild in severity, and the frequency of TEAEs was similar between treatment groups (TEAEs are defined as any AE that occurs after the first dose of the study drug). No new safety signals were identified. TEAE data are summarized in Table 10 below.

[0435]

[0436] The most common treatment-induced adverse events (TEAEs) reported were COVID-19, injection site bruising, and injection site bleeding (see Table 11 below, which shows TEAEs reported at a frequency of ≥1.5% in the first study and at a frequency of ≥1.0% in the second study). Results showed that the incidence of treatment-induced adverse events (TEAEs) was similar to or lower in subjects treated with BOTOX compared to the placebo group.

[0437]

[0438]

[0439] Most treatment-associated adverse events (TEAEs) were mild in severity and occurred at a balanced frequency across treatment groups. The most common treatment-related AEs were related to the study procedure (injection site bleeding and injection site bruising), were mild in severity, and typically resolved within 7 days. No treatment-related serious TEAEs or TESAEs were reported. No TEAEs leading to study discontinuation or death occurred, and there was no evidence of long-distance toxin diffusion. It should be noted that no adverse events of particular concern (AESIs) were reported: aspiration, aspiration pneumonia, dry mouth, dysphagia, dyspnea, facial paralysis, and muscle weakness (i.e., neck muscle weakness).

[0440] Data shows that 26U to 36U of BOTOX is effective for platysma muscle protrusion. ® The treatment was well tolerated, no new safety signals were identified, and the treatment demonstrated a favorable benefit / risk profile.

[0441] In summary, the results from two key studies support the use of 26U to 36U of BOTOX. ® Treatment provides safe and effective treatment for platysma protrusion to improve the appearance of moderate (grade 3) to severe (grade 4) platysma protrusion in adults.

[0442] In the pivotal study, 3.6% (30 / 834) of the participants were 65 years of age or older. The responder rate appeared to be higher among participants under 65 years of age than among those 65 years of age or older.

[0443] In a double-blind, placebo-controlled clinical study aimed at improving platysma protrusion, a total of 466 BOTOX patients were included. ® The treated subjects and 481 placebo-treated subjects underwent BOTOX treatment. ® Safety evaluation of 26U, 31U, or 36U. ≥1% BOTOX ® No adverse reactions were reported in the treated subjects, and the frequency of adverse reactions was higher than in the placebo-treated subjects.

[0444] 7.3. Example 3: Type A botulinum toxin (BOTOX) ® Used to treat platysma herniation

[0445] After withdrawing from the first phase 3 study described in Example 2, eligible participants may choose to participate in the 8-month phase 3 open-label extension study (see Example 2). Figure 4 To further evaluate the purified neurotoxin complex (BOTOX type A botulinum toxin) ® The long-term safety and efficacy of this treatment for platysma herniation were assessed. Therefore, Day 1 of this Phase 3 open-label extension study was the exit date of the first Phase 3 clinical trial described in Example 2. The design of this Phase 3 open-label extension study is similar to the two Phase 3 clinical trials described in Example 2, but it lasts for 8 months, is open-label, and allows participants to receive up to 3 additional BOTOX treatments. ® (Botulinum toxin type A) treatment (26 units, 31 units, or 36 units) was administered at least 3 months (84 days) after the previous study treatment. In these subjects, each subsequent BOTOX treatment... ® Similar efficacy profiles were observed in treatment outcomes regarding the severity of platysma protrusion, treatment satisfaction, and distress caused by the appearance of the jawline and vertical neck girdle. In 350 patients undergoing BOTOX treatment... ® Among treated subjects, adverse events occurring in ≤1% of subjects included mild dysphagia in 3 subjects (0.9%) and mild facial paralysis in 2 subjects (0.6%). Specifically, no adverse events of dysphagia or facial paralysis occurred during the placebo-controlled period (cycle 1). Dysphagia was reported in 3 subjects (1.1%) in cycle 2 and in 1 subject (0.6%) in cycle 3. Facial paralysis was reported in 1 subject (0.4%) in cycle 2 and in 1 subject (1.9%) in cycle 4. These adverse events were reported to be mild in severity and usually resolved without intervention. (Using BOTOX) ®The overall safety profile remained unchanged after repeated dosing of up to four treatments.

[0446] *****

[0447] All references cited in this article are incorporated herein by reference in their entirety and for all purposes, to the extent that each individual publication or patent or patent application is specifically and individually indicated as incorporated herein by reference in its entirety for all purposes.

[0448] As will be apparent to those skilled in the art, many modifications and variations can be made to this invention without departing from its spirit and scope. The specific embodiments described herein are provided by way of example only, and the invention is limited only by the terms of the appended claims and the full scope of their equivalents.

Claims

1. A method for improving the appearance of platysma protrusion associated with platysma muscle activity in human patients, the method comprising: (A) Quantify the number of continuous vertical neck bands on the first side of the neck of the human patient at maximum contraction, wherein the continuous vertical neck bands are vertical neck bands that extend continuously from the mandibular line of the human patient to the lower neck region. as well as (B) The composition comprising botulinum toxin type A is applied to the first side of the neck of the human patient identified as having only one or two consecutive vertical neck bands at maximal contraction.

2. The method of claim 1, wherein the composition is administered to the first side of the neck of the human patient by injection of the following dose: (i) A first mandibular line dose distributed among four injection sites below the mandibular border of the patient on the first side and parallel to the upper segment of the platysma muscle of the mandibular border; and (ii)(a) If the first side of the human patient's neck has only one continuous vertical neck band, then a first neck band dose is distributed along the only continuous vertical neck band among five injection sites; or (b) If the first side of the human patient's neck has only two continuous vertical neck bands, then a first neck band dose is distributed along the first continuous vertical neck band among five injection sites and a second neck band dose is distributed along the second continuous vertical neck band among five injection sites.

3. The method of claim 1 or 2, wherein the first side of the human patient's neck has only one continuous vertical neckband, and the administration step delivers a total unilateral dose of approximately 13 units of botulinum toxin type A to the first side of the human patient's neck.

4. The method of claim 1 or 2, wherein the first side of the human patient's neck has only two consecutive vertical neckbands, and the administration step delivers a total unilateral dose of approximately 18 units of botulinum toxin type A to the first side of the human patient's neck.

5. The method according to any one of claims 2 to 4, wherein: (1) The first mandibular line dose is about 8 units of botulinum toxin type A, and optionally, each injection of the first mandibular line dose is about 2 units of botulinum toxin type A. (2) The first neckband dose is approximately 5 units of botulinum toxin type A, and optionally, each injection of the first neckband dose is approximately 1 unit of botulinum toxin type A; and / or (3) The second neckband dose is about 5 units of botulinum toxin type A, and optionally, each injection of the second neckband dose is about 1 unit of botulinum toxin type A.

6. The method according to any one of claims 1 to 5, the method further comprising the steps of repeatedly quantifying and applying to a second side of the neck of the human patient.

7. The method of claim 6, wherein the steps of administering to the first side and administering to the second side deliver a total bilateral dose to the neck of the human patient, the total bilateral dose being selected from the group consisting of about 26 units, about 31 units, and about 36 units of botulinum toxin type A.

8. A method for improving the appearance of platysma protrusion associated with platysma muscle activity in a human patient having only one continuous vertical neckband at maximum contraction on a first side of the neck, the method comprising administering a composition comprising botulinum toxin type A to the first side of the human patient's neck by injecting the following dose: (i) A first mandibular line dose distributed among four injection sites below the mandibular border of the patient on the first side and parallel to the upper segment of the platysma muscle of the mandibular border; and (ii) The first neck band dose is distributed among five injection sites along a single continuous vertical neck band; The continuous vertical neck band is a vertical neck band that extends continuously from the mandibular line to the lower neck region of the human patient.

9. The method of claim 8, wherein the administration step delivers a total unilateral dose of about 13 units of botulinum toxin type A to the first side of the neck of the human patient.

10. The method according to claim 8 or 9, wherein: (1) The first mandibular line dose is approximately 8 units of botulinum toxin type A, and optionally, each injection of the first mandibular line dose is approximately 2 units of botulinum toxin type A; and (2) The first neckband dose is about 5 units of botulinum toxin type A, and optionally, each injection of the first neckband dose is about 1 unit of botulinum toxin type A.

11. The method according to any one of claims 8 to 10, the method further comprising the step of repeatedly applying to a second side of the neck of the human patient, wherein the second side of the neck of the human patient has only one continuous vertical neck band at maximum contraction.

12. The method of claim 11, wherein the steps of administering to the first side and administering to the second side deliver a total bilateral dose of approximately 26 units of botulinum toxin type A to the neck of the human patient.

13. A method for improving the appearance of platysma protrusion associated with platysma muscle activity in a human patient having only two consecutive vertical neckbands at maximum contraction on a first side of the neck, the method comprising administering a composition comprising botulinum toxin type A to the first side of the human patient's neck by injecting the following dose: (i) A first mandibular line dose is distributed among four injection sites below the lower border of the patient's mandible and parallel to the upper segment of the platysma muscle on the first side; (ii) The first neckband dose is distributed along the first continuous vertical neckband among five injection sites; and (iii) The second neck band dose is distributed among five injection sites along the second continuous vertical neck band; The continuous vertical neck band extends continuously from the mandibular line of the human patient to the lower neck region, and the administration step delivers a total unilateral dose of botulinum toxin type A ranging from about 15 units to about 20 units to the first side of the human patient's neck.

14. The method of claim 13, wherein the administration step delivers a total unilateral dose of about 18 units of botulinum toxin type A to the first side of the neck of the human patient.

15. The method according to claim 13 or 14, wherein: (1) The first mandibular line dose is about 8 units of botulinum toxin type A, and optionally, each injection of the first mandibular line dose is about 2 units of botulinum toxin type A. (2) The first neckband dose is about 5 units of botulinum toxin type A, and optionally, each injection of the first neckband dose is about 1 unit of botulinum toxin type A. as well as (3) The second neckband dose is about 5 units of botulinum toxin type A, and optionally, each injection of the second neckband dose is about 1 unit of botulinum toxin type A.

16. The method of any one of claims 13 to 15, further comprising the step of repeatedly applying the method to a second side of the neck of the human patient, wherein the second side of the neck of the human patient has only two consecutive vertical neck bands at maximum contraction.

17. The method of claim 16, wherein the steps of administering to the first side and administering to the second side deliver a total bilateral dose of approximately 36 units of botulinum toxin type A to the neck of the human patient.

18. A method for improving the appearance of platysma protrusion associated with platysma muscle activity in a human patient having only one continuous vertical neck band at maximum contraction on a first side of the neck and only two continuous vertical neck bands at maximum contraction on a second side of the neck, the method comprising administering a composition comprising botulinum toxin type A to the neck of the human patient by injecting the following doses: (i) A first mandibular line dose is distributed among four injection sites below the lower border of the patient's mandible and parallel to the upper segment of the platysma muscle on the first side; (ii) A first neck band dose is distributed among five injection sites along the only continuous vertical neck band on the first side; (iii) A second mandibular line dose is distributed among four injection sites in the upper segment of the platysma muscle below the mandibular border of the patient on the second side and parallel to the mandibular border; (iv) A first neck band dose is distributed among five injection sites along the first continuous vertical neck band on the second side; and (v) A second neck band dose is distributed between five injection sites along the second continuous vertical neck band on the second side; The continuous vertical neck band is a vertical neck band that extends continuously from the mandibular line to the lower neck region of the human patient.

19. The method of claim 18, wherein the first mandibular line dose is equal to the second mandibular line dose.

20. The method of claim 18, wherein the first mandibular line dose is not equal to the second mandibular line dose.

21. The method according to any one of claims 18 to 20, wherein: (1) The first mandibular line dose is about 8 units of botulinum toxin type A, and optionally, each injection of the first mandibular line dose is about 2 units of botulinum toxin type A. (2) The second mandibular line dose is about 8 units of botulinum toxin type A, and optionally, each injection of the second mandibular line dose is about 2 units of botulinum toxin type A. (3) The first neckband dose on the first side is about 5 units of botulinum toxin type A, and optionally, each injection of the first neckband dose on the first side is about 1 unit of botulinum toxin type A. (4) The first neckband dose on the second side is about 5 units of botulinum toxin type A, and optionally, each injection of the first neckband dose on the second side is about 1 unit of botulinum toxin type A. as well as (5) The second neck band dose on the second side is about 5 units of botulinum toxin type A, and optionally, each injection of the second neck band dose on the second side is about 1 unit of botulinum toxin type A.

22. The method according to any one of claims 18 to 21, wherein the administration step delivers a total bilateral dose of about 31 units of botulinum toxin type A to the neck of the human patient.

23. The method according to any one of claims 1 to 22, wherein the cosmetic effect of the method is obtained within 14 days after the application of the botulinum toxin type A, and wherein: (1) The cosmetic effect includes a change in platysma protrusion scale grade, assessed by a physician or human patient, from moderate or severe before the application of the botulinum toxin type A to slight or mild after the application of the botulinum toxin type A; wherein optionally, the duration of the cosmetic effect is in the range of about 30 days to about 120 days after the application of the botulinum toxin type A, or the duration of the cosmetic effect is at least 120 days; and wherein optionally, the method is statistically superior to comparable methods in which a placebo is used instead of the botulinum toxin type A in achieving a slight or mild grade on the platysma protrusion scale assessed by a physician or human patient 14 days after application. (2) The cosmetic effect includes a grade 2 or better improvement in platysma protrusion as assessed by physicians and human patients on the platysma protrusion scale, from moderate or severe before the application of the botulinum toxin type A to slight or mild improvement after the application of the botulinum toxin type A. (3) The cosmetic effect includes a change in platysma protrusion scale rating, assessed by physicians and human patients, from moderate or severe before the application of the botulinum toxin type A to slight or mild changes after the application of the botulinum toxin type A; or (4) The cosmetic effect includes achieving a slight or mild grade of improvement relative to baseline, as assessed by physicians and human patients on the platysma protrusion scale; wherein optionally, the duration of the cosmetic effect is at least 120 days after the administration of the botulinum toxin type A, or the duration of the cosmetic effect is in the range of about 60 days to about 120 days after the administration of the botulinum toxin type A; and wherein optionally, the method is statistically superior to comparable methods in which a placebo is administered instead of the botulinum toxin type A in achieving a slight or mild grade of improvement relative to baseline, as assessed by physicians and human patients on the platysma protrusion scale, 14 days after administration; Optionally, the platysma protrusion scale is a platysma band severity grading scale.

24. The method according to any one of claims 1 to 23, wherein the concentration of botulinum toxin type A in the composition is about 40 units / mL.

25. The method according to any one of claims 1 to 24, wherein the botulinum toxin type A is a 900 kD serum botulinum toxin type A neurotoxin (BoNT / A) complex.

26. The method of claim 25, wherein the type A botulinum toxin is onabotulinumtoxin A.

27. The method of claim 25 or 26, wherein the composition comprises a powdered BoNT / A pharmaceutical composition reconstituted with physiological saline, wherein prior to the reconstitution, the powdered BoNT / A pharmaceutical composition comprises the 900 kDa BoNT / A complex, human albumin, and sodium chloride.

28. The method according to any one of claims 1 to 27, wherein the composition is a liquid.

29. The method according to any one of claims 2 to 28, wherein the depth of the injection does not exceed about 0.5 inches into the muscle; and / or wherein the injection is performed superficially and intramuscularly with a needle perpendicular to the skin surface.

30. The method according to any one of claims 1 to 29, wherein the human patient also has one or more discontinuous neck bands on the first side and / or the second side of the human patient's neck; and / or wherein no additional dose of the botulinum toxin type A is injected into the human patient's neck.

31. The method according to any one of claims 1 to 30, wherein the method is repeated approximately every 12 weeks.

32. The method according to any one of claims 1 to 31, wherein the method causes at least one occurrence rate selected from the group consisting of: (1) The incidence of treatment-induced adverse events (TEAEs) associated with the composition containing botulinum toxin type A is less than 5%; (2) The incidence of treatment-related serious TEAEs is less than 1%, and optionally no treatment-related serious TEAEs occur; (3) The incidence of adverse events of particular concern (AESI) is less than 5%, and optionally no AESI occurs, including aspiration, aspiration pneumonia, dry mouth, dysphagia, dyspnea, facial paralysis and muscle weakness. (4) The incidence of bruising at the injection site is less than 10%; (5) The incidence of neck muscle weakness is less than 1%, and optionally no neck muscle weakness occurs. (6) An incidence of dysphagia of less than 2%, with optional absence of dysphagia; and (7) The incidence of injection site hematoma is less than 5%, and optionally no injection site hematoma occurs.

33. The method according to any one of claims 2 to 32, wherein the method reduces the incidence of adverse effects compared to comparable methods, the comparable methods comprising: (1) Injecting one or more neckband doses of the type A botulinum toxin into one or more neckbands of a human subject, but excluding injecting a mandibular dose of the type A botulinum toxin into the neck of the human subject. (2) Injecting one or more neckband doses of the type A botulinum toxin into one or more neckbands in the neck of a human subject, wherein the one or more neckbands into which the one or more neckband doses are injected are not limited to continuous vertical neckbands extending from the jawline of the human subject to the lower neck region. And / or (3) Three or more neckband doses of the type A botulinum toxin were injected into one side of the neck of a human subject, wherein each neckband dose was injected along a different neckband.

34. The method according to claim 33, wherein the adverse effects are selected from the group consisting of aspiration, aspiration pneumonia, dry mouth, dysphagia, dyspnea, facial paralysis, muscle weakness, bruising at the injection site, and hematoma at the injection site.

35. The method according to any one of claims 1 to 34, wherein the method is used to improve the appearance of the platysma band associated with platysma muscle activity.

36. The method according to any one of claims 1 to 35, wherein the continuous vertical neck band is a visible vertical neck band that extends continuously from the mandibular line of the human patient to the lower neck region and causes blunting of the mandibular line.

37. The method according to any one of claims 2 to 36, wherein the four injection sites in the upper segment of the platysma muscle include an anterior injection site aligned with the corner of the mouth and a posterior injection site anterior to the angle of the mandible.

38. A composition comprising botulinum toxin type A, said composition being used in the method according to any one of claims 1 to 37.

39. Use of a composition comprising botulinum toxin type A for manufacturing a medicament for providing, by any one of claims 1 to 37, an improvement in the appearance of platysma protrusion associated with platysma muscle activity in a human patient.

40. Use of compositions comprising botulinum toxin type A, essentially as described herein.

41. A composition substantially as described herein for improving the appearance of platysma protrusion.

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