EP4626556A1 - High concentration botulinum toxin treatment for neck rejuvenation - Google Patents

High concentration botulinum toxin treatment for neck rejuvenation

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Publication number
EP4626556A1
EP4626556A1 EP23813385.4A EP23813385A EP4626556A1 EP 4626556 A1 EP4626556 A1 EP 4626556A1 EP 23813385 A EP23813385 A EP 23813385A EP 4626556 A1 EP4626556 A1 EP 4626556A1
Authority
EP
European Patent Office
Prior art keywords
botulinum toxin
platysma
injected
injection
injection point
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23813385.4A
Other languages
German (de)
French (fr)
Inventor
Susanna ROLL
Petra WEISSENBERGER
Iryna HEIDE
Vladimir SUDIMAC
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merz Pharma GmbH and Co KGaA
Original Assignee
Merz Pharma GmbH and Co KGaA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merz Pharma GmbH and Co KGaA filed Critical Merz Pharma GmbH and Co KGaA
Publication of EP4626556A1 publication Critical patent/EP4626556A1/en
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A61K8/66—Enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/91—Injection
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/24—Metalloendopeptidases (3.4.24)
    • C12Y304/24069—Bontoxilysin (3.4.24.69), i.e. botulinum neurotoxin

Definitions

  • a variety of surgical techniques for treating platysma bands are used to improve or restore the definition of the neck.
  • unfavorable surgical outcomes and the understanding that platysma bands are caused by muscular activity during the aging process have shifted treatment towards non-surgical methods like injections of botulinum toxin.
  • Botulinum toxin is a neurotoxin from Clostridium botulinum that blocks the release of acetylcholine into the synaptic cleft, thereby preventing cholinergic neuromuscular innervation.
  • the 150 kDa neurotoxin is synthesized as single chain polypeptide that is proteolytically cleaved into two chains, i.e., a 50 kDa light chain and a 100 kDa heavy chain, which are connected by a disulfide bond.
  • botulinum toxin in the lower face and neck is more complex than its use in the upper face and, thus, fraught with more complications. This is because the muscles of this region are very close together and interface at different levels and depths to perform heterogeneous functions, such as talking, eating, drinking, and expressivity of the face. Injected botulinum toxin may spread or diffuse to muscles of deglutition, the pharynx and neck flexors structures and cause complications like swallowing difficulties (dysphagia), dysphonia, and neck weakness (see, e.g., De Boulle et al., Chapter 15: Neck Rejuvenation, in: Botulinum Toxins: Cosmetic and Clinical Applications, Cohen, J.
  • the doses per injection point were also quite variable, resulting in total doses per band of 6 to 40+ U depending on the number of injection sites (typically three to five) and doses used.
  • the recommended dose for platysma bands is 1 -2 U for incobotulinumtoxin A and onabotulinumtoxin A in 0.025 to 0.05 mL per injection point.
  • the aging neck is not only characterized by platysma bands but also by a loss of the mandibular definition (mandibular part of the platysma).
  • mandibular part of the platysma Following treatment of platysma bands an overall tightening of the neck and a recontouring of the jawline (Brandt and Bellmann, 1998, supra', Tamura 2012, supra) or a lifting of the lower face was observed (Kane et al., 2010, supra).
  • Levy et al. introduced a new technique, called the "Nefertiti lift" (see Levy, P. M., The 'Nefertiti lift': A new technique for specific re-contouring of the jawline, J. Cosm.
  • the present invention relates to the use of botulinum toxin for the rejuvenation of the neck, wherein the botulinum toxin is injected in at least one platysma band of a subject at a concentration of more than 100 ll/rnl, preferably at a concentration of 150 ll/rnl or more.
  • the dose injected in at least one platysma band per injection point is at least 3 U, more preferably 3 U to 5 U, for example 3 U, 4 U or 5 U.
  • the volume per injection point is preferably 0.030 ml or less, in particular 0.010 ml to 0.025 ml.
  • a highly concentrated botulinum toxin solution is used.
  • the administration of high dose botulinum toxin in a low volume is found to be particularly suitable for thin muscles like the platysma muscle.
  • the botulinum toxin may additionally be injected into the platysma muscle at the jawline at both sides of the face to improve the rejuvenation effect of the injections into the platysma band(s).
  • the downward pull of the platysma muscle will be antagonized, and the elevator muscles will prevail resulting in an additional lifting effect and recontouring of the jawline.
  • the present invention relates to a method for the rejuvenation of the neck, wherein the botulinum toxin is injected in at least one platysma band of a subject at a concentration of more than 100 ll/rnl, preferably at a concentration of 150 ll/rnl or more.
  • FIG. 1 depicts the spread of toluidine dye in porcine muscle after intramuscular injection.
  • A injection of 10 pl, 20 pl or 40 pl toluidine dye at 45° injection angle;
  • B injection of 10 pl, 20 pl or 40 pl toluidine dye at 90° injection angle.
  • FIG. 2 shows an exemplary injection pattern according to the present invention for improving platysma bands prominence and sharpness of the jawline contour.
  • the high concentration approach used in the present invention allows the skilled person to safely administer botulinum toxin in higher doses per injection point, resulting in a superior efficacy with a sustained duration of effect in the treatment of platysma.
  • both the platysma along the mandibular border and platysma bands can be treated in one treatment session to achieve a complete relaxation of the platysma.
  • the additional treatment of the platysma muscle in the jawline area is assumed to diminish residual banding and development of compensatory bands.
  • the term “injection in platysma bands”, is intended to refer to injection into the platysma muscle, i.e. , intramuscular injection.
  • the injection of botulinum toxin into platysma bands can relax and flatten the platysma bands to make the bands less pronounced.
  • plaqueysma bands refers to vertical bands, i.e., bands than run vertically across the front of the neck.
  • plaque lines i.e., horizontal bands or lines that run horizontally around the front of the neck.
  • numerical values without decimal places shall be understood to include all numerical values with one or more decimal places that, applying common rules of rounding, give the numerical value without decimal places.
  • the numerical value 3 includes 2.5 or 2.50 (which are rounded up to 3) and 3.4 or 3.49 (which are rounded off to 3), and all numerical values in between.
  • endpoints of ranges the same applies, i.e. , a range of 3 to 5 may mean, e.g., 2.5-3.4 to 4.5-5.4.
  • each numerical value or one or both, preferably both, endpoints of ranges disclosed in this application can be a numerical value with a decimal place that is zero, e.g., 4 may be 4.0.
  • the term "pure botulinum neurotoxin”, as used herein, means the botulinum neurotoxin free of complexing proteins (sometimes also referred to as the "neurotoxic component"), or more precisely, the botulinum neurotoxin without neurotoxin- associated complexing proteins (NAPs).
  • the pure botulinum neurotoxin is the (active) neurotoxic polypeptide that ultimately inhibits acetylcholine release. It is a di-chain protein comprised of a light chain (LC; about 50 kDa) and a heavy chain (HC; about 100 kDa), held together by a disulfide bond.
  • the active neurotoxic polypeptide may therefore also be referred to herein as the "150 kDa neurotoxin", “Clostridium botulinum neurotoxin (150 kD)” or “neurotoxic component”.
  • the botulinum toxin is the (pure) botulinum neurotoxin contained in Xeomin® or is Xeomin®.
  • toxin complex refers to a high-molecular complex of the neurotoxic component and a set of complexing proteins (NAPs), including the 900 kDa, 500 kDa, and 300 kDa C. botulinum type A toxin complexes.
  • the complexing proteins are nontoxic nonhaemagglutinin (NTNHA) and, in strains of serotype A-D, different haemagglutinins (HAs).
  • the 900 kDa complex is included in onabotulinumtoxin A (Botox®A/istabel®, Allergan, Inc., Irvine, CA, USA), and abobotulinumtoxin A (Dysport®, Azzalure®, Ipsen, Paris, France), Alluzience® (Ipsen/Galderma) and Innotox® (Medytox) also contain a toxin complex as active agent.
  • the botulinum toxin is, besides the pure botulinum neurotoxin that is contained in Xeomin® or is Xeomin®, the toxin complex contained in Botox® or Dysport®, or is Botox® or Dysport®.
  • the botulinum toxin is not the toxin complex contained in Dysport® or is not Dysport®.
  • the botulinum toxin may be a natural neurotoxin obtainable from the bacteria Clostridium botulinum or any other botulinum toxin such as a botulinum toxin obtainable from alternative sources, including recombinant technologies and genetic or chemical modification. Chimeric or genetically modified botulinum toxins, i.e., botulinum toxins containing mutations including substitutions, deletions and insertions, are also encompassed by the terms "botulinum toxin", "neurotoxic component” and the like.
  • the mutation does not compromise any of the biological activities of botulinum toxin. However, it is also envisaged to use mutations to modulate the biological activity of the botulinum toxin.
  • botulinum toxins containing chemically modified amino acids for example one or more amino acids which are glycosylated, acetylated or otherwise modified, which may be beneficial to the uptake or stability of the toxin.
  • amino acids which are glycosylated, acetylated or otherwise modified, which may be beneficial to the uptake or stability of the toxin.
  • Particularly preferred is the lipidation of the neurotoxic component.
  • the dose is expressed in biological units because the used botulinum toxin may contain, for example, variable percentages of inactive toxin that contribute to the overall protein load without contributing to efficacy.
  • the biological potency of botulinum toxin is determined using the mouse bioassay (MBA).
  • the MBA determines the median lethal dose (LD50) of toxin/neurotoxin after intraperitoneal injection in mice, i.e. the dose of toxin/neurotoxin capable of killing 50% of a group of mice.
  • LD50 median lethal dose
  • the LD50 mouse bioassay is the gold standard among various biological, chemical or immunological detection methods for botulinum toxin and is known to those skilled in the art (see, e.g., Pearce, L.B.; Borodic, G.E.; First, E.R.; MacCallum, R.D. Measurement of botulinum toxin activity: Evaluation of the lethality assay. Toxicol. Appl. Pharmacol. 1994, 128, 69-77).
  • Another useful method for determining the biological activity (biological potency) of a botulinum neurotoxin is a cell-based potency assay as it is disclosed, for example, in W02009/114748, WO 2013/049508 or WO 2014/207109.
  • the activity results obtained with such cell-based assays correspond to the activity values obtained in the mouse i.p. LD50 assay because the values are calibrated using the LD50 reference standard.
  • botulinum toxin is abobotulinumtoxinA
  • 2.5 U of abobotulinumtoxinA equal 1 U, with 1 U being preferably one mouse LD50 (1 .0 LD50), measured using the abovedescribed MBA.
  • the first aspect of the present invention relates to the use of botulinum toxin for the rejuvenation of the neck, wherein the botulinum toxin is injected in at least one platysma band of a subject at a concentration of more than 100 ll/rnl, with the proviso that, if the botulinum toxin is abobotulinumtoxinA, 2.5 U of abobotulinumtoxinA equal 1 U.
  • the first aspect of the present invention relates to the use of botulinum toxin for the rejuvenation of the neck, wherein the botulinum toxin is injected in at least one platysma band of a subject at a concentration of more than 100 ll/rnl, wherein 1 U corresponds to 1 LD50, with LD50 being the median lethal dose as measured using the mouse LD50 bioassay, with the proviso that, if the botulinum toxin is abobotulinumtoxinA, 2.5 U of abobotulinumtoxinA equal 1 U.
  • the first aspect of the present invention relates to the use of botulinum toxin for the rejuvenation of the neck, wherein the botulinum toxin is injected in at least one platysma band of a subject at a concentration of more than 100 ll/rnl, wherein 1 U corresponds to 1 LD50, with LD50 being the median lethal dose as measured using the mouse LD50 bioassay, with the proviso that, if the botulinum toxin is incobotulinumtoxinA or onabotulinumtoxinA, 1 U of incobotulinumtoxinA and 1 U of onabotulinumtoxinA both equal 1 U, and, if the botulinumtoxin is abobotulinumtoxinA, 2.5 U of abobotulinumtoxinA equal 1 U.
  • the term “comprising”, like the terms “including” and containing”, and any variations thereof such as “comprises”, “includes” and “contains”, are intended to refer to a non-exclusive inclusion, such that a process, method, product-by-process, composition or formulation that comprises, includes, or contains an element or list of elements does not include only those elements but can include other elements not expressly listed for such process, method, product-by-process, composition or formulation.
  • the botulinum toxin is injected in at least one platysma band of a subject at a concentration of more than 100 ll/rnl, preferably 125 ll/rnl or more, 150 ll/rnl or more, 175 ll/rnl or more, 200 ll/rnl or more, 225 ll/rnl or more, or 250 ll/rnl or more.
  • the upper limit is preferably 500 ll/rnl.
  • the botulinum toxin is injected at a concentration of more than 100 ll/rnl to 500 ll/rnl or at 125 ll/rnl to 400 ll/rnl, more preferably at a concentration of 125 U/ml to 275 U/ml or 150 U/ml to 350 U/ml or 150 U/ml to 300 U/ml or 150 U/ml to 250 ll/rnl or 175 U/ml to 275 U/ml or 200 U/ml to 250 U/ml.
  • the botulinum toxin is injected at a concentration of 130 U/ml to 170 U/ml, or 180 U/ml to 220 U/ml, or 230 U/ml to 270 U/ml, and most preferably at a concentration of 150 U/ml, 200 U/ml or 250 U/ml.
  • the botulinum toxin is preferably injected at a dose of at least 2 U (e.g., 2 U to 6 U, such as 3 U, 4 U or 5 U) and a volume of 0.03 ml or less per injection point.
  • the botulinum toxin is injected at a dose of at least 3 U, particularly at a dose of 3 U to 6 U (e.g., at a dose of 3 U, 4 U, 5 U or 6 U) and a volume of less than 0.030 ml per injection point.
  • the botulinum toxin may further be injected, and preferably is injected, in the platysma muscle at the jawlines of the subject.
  • the use according to the present invention involves the injection of platysma bands as described above and, optionally, the injection of botulinum toxin in the platysma muscle at the jawline.
  • the injection at the jawline releases the tension on the jawline by reducing the depressor effect of the platysma and thus the elevator muscles prevail, leading to an uplift of the skin and re-contouring of the jawline.
  • the botulinum toxin is preferably injected in the platysma muscle at the jawlines at a volume of 0.005 ml to 0.03 ml per injection point, more preferably at a volume of 0.01 ml to 0.025 ml per injection point, for example at a volume of 0.02 ml or 0.01 ml, and most preferably at a volume of 0.01 ml per injection point.
  • the botulinum toxin is injected in the platysma muscle at the jawlines at a dose of at least 1 U per injection point, particularly 1 U to 4 U per injection point, more particularly 1 U to 3 U or 1 .5 U to 2.5 U per injection point, for example 1 .5 U, 2 U or 2.5 U, in a volume of 0.01 ml to 0.02 ml.
  • the botulinum toxin is injected in the platysma muscle at the jawlines at a dose of at least
  • 1 U per injection point particularly 1 U to 4 U per injection point, more particularly 1 U to 3 U or 1 .5 U to 2.5 U per injection point, for example 1.5 U, 2 U or 2.5 U, most preferably 2 U, in a volume of 0.02 ml.
  • the total volume of the botulinum toxin injected in the platysma muscle at each jawline may be 0.02 ml to 0.20 ml, in particular 0.02 ml to 0.16 ml or 0.04 ml to 0.16 ml, preferably 0.06 ml to 0.12 ml, more preferably 0.08 ml to 0.12 ml, and most preferably 0.08 ml to 0.10 ml.
  • the total dose of the botulinum toxin injected in the platysma muscle at each jawline may be 4 U to 16 U, preferably 5 U to 12 U, more preferably 6 U to 10 U (e.g., 6 U, 8 U or 10 U), and most preferably 8 U.
  • the number of injection point in the platysma muscle at each jawline is at least 2, preferably 2 to 6, more preferably 3 to 5, and most preferably 4. Furthermore, the injection points along the jawline are spaced at a distance of about 0.5 cm to about
  • botulinum toxin is administered into 2 to 4 injection points per side along and under each mandible not anterior to a line drawn from the nasolabial fold down to the mandible.
  • the botulinum toxin may be administered in consecutive treatment cycles. It is understood that a treatment cycle is the time interval between two administrations of the botulinum neurotoxin, i.e., a treatment cycle consists of one administration of the botulinum neurotoxin and a follow-up period until the next botulinum neurotoxin injection is administered.
  • the said administration of botulinum toxin occurs in a treatment session (or "injection session").
  • the time interval between two consecutive administrations of the botulinum neurotoxin can vary between about 5 and 10 months, in particular between about 6 and 9 months or between about 7 and 8 months This prolonged treatment interval is enabled by the longer duration of effect achieved by the present invention.
  • the aqueous botulinum toxin solution or composition may include other carriers or non-toxic, non-therapeutic, non-immunogenic stabilizers and the like.
  • the aqueous botulinum toxin composition may contain glycerol, protein stabilizers (HSA) or non-protein stabilizers such as polyvinyl pyrrolidone (PVP), hyaluronic acid or free amino acids, e.g., methionine or histidine.
  • the aqueous botulinum toxin composition can be free of amino acids. In one embodiment, it may be free of stabilizing peptides (e.g., consisting of 5 to 50 amino acids, 10 to 40 amino acids or 15 to 30 amino acids).
  • Suitable non-proteinaceous stabilizers for use herein are disclosed in WO 2005/007185 or WO 2006/020208.
  • the botulinum toxin composition can also include non-ionic or ionic surfactant, e.g., polysorbate or poloxamer.
  • a suitable formulation for HSA-stabilized formulation comprising a botulinum toxin according to the present invention is for example disclosed in US 8,398,998 B2.
  • the botulinum toxin used within the present invention is present in the form of an aqueous solution comprising sodium chloride (NaCI), more preferably in the form of a physiological saline solution (i.e. a solution including sodium chloride in physiological concentration, e.g., about 9 g/l NaCI), wherein the aqueous botulinum toxin solution comprises (i) no other excipient (except NaCI), (ii) human serum albumin (HSA) and a sugar, in particular a monosaccharide or a disaccharide, (iii) human serum albumin (HSA) and lactose, (iv) human serum albumin (HSA) and sucrose, (v) a monosaccharide and/or a disaccharide (e.g.
  • NaCI sodium chloride
  • a physiological saline solution i.e. a solution including sodium chloride in physiological concentration, e.g., about 9 g/l NaCI
  • the present invention relates to a method for the rejuvenation of the neck, the method comprising injecting botulinum toxin in at least one platysma band of a subject at a concentration of more than 100 U/ml.
  • This method of treatment is used for purely aesthetic purposes, i.e. , for the rejuvenation of the neck or the neck and lower face and is therefore a cosmetic method.
  • the botulinum toxin is generally intramuscularly injected using a suitable injection device, for example a syringe equipped with a 30G, 32 G or 33 G needle.
  • the syringe is not particularly limited and any conventional syringe may be used.
  • a particularly suited syringe for use in accordance with the present invention is, for example, a 3DoseTM high precision syringe (vlow medical).
  • FIG. 2 An exemplary injection pattern is shown in FIG. 2, according to which five injections spaced 1 -2 cm apart are made into the left and right medial and lateral bands, resulting in a total of 20 platysma band injections.
  • 4 injections into the platysma muscle at the left and right jawline, i.e., 8 injections in total, are used.
  • an improvement in platysma bands prominence and sharpness of the jawline contour are obtained.
  • dosing regimen used in connection with the method according to the second aspect of the present invention is as disclosed herein above in relation to the use according to the first aspect of the present invention. More specifically, dosing regimens that are particularly preferred for use within the present invention (i.e., for the use according to the first aspect and the method according to the second aspect) are as follows:
  • BTX concentration 125-300 U/ml 100-300 U/ml
  • botulinum toxin is injected at 150 U/ml to 250 U/ml in 4 to 6 injection points per platysma band, wherein the dose per injection point is in the range of 3 U to 5 U and/or wherein the injection volume per injection point is in the range of 0.015 ml to 0.025 ml, and optionally botulinum toxin is injected at 150 ll/rnl to 250 ll/rnl in 3 to 5 injection points per jawline, wherein the dose per injection point is in the range of 1 .5 U to 2.5 U and/or wherein the injection volume per injection point is in the range of 0.005 ml to 0.015 ml.
  • botulinum toxin is injected at 150 ll/rnl to 250 ll/rnl in 4 to 6 injection points per platysma band, wherein the dose per injection point is in the range of 3 U to 5 U and wherein the injection volume per injection point is in the range of 0.015 ml to 0.025 ml, and optionally botulinum toxin is injected at 150 ll/rnl to 250 ll/rnl in 3 to 5 injection points per jawline, wherein the dose per injection point is in the range of 1 .5 U to 2.5 U and wherein the injection volume per injection point is in the range of 0.005 ml to 0.015 ml.
  • botulinum toxin is injected at 150 ll/rnl to 250 ll/rnl in in 4 to 6 injection points per platysma band, wherein the injection volume per injection point is 0.02 ml, and optionally botulinum toxin is injected at 150 ll/rnl to 250 ll/rnl in 3 to 5 injection points per jawline, wherein the injection volume per injection point is 0.01 ml.
  • the botulinum toxin may be injected in platysma for the improvement of platysma bands prominence and sharpness of the jawline contour using an injection pattern as shown in FIG. 2.
  • the exemplary injection scheme includes five injections spaced 1-2 cm apart into the left and right medial and lateral bands (20 injections in total) and 4 injections into the platysma muscle of the left and right jawline (8 injections in total).
  • the injected botulinum toxin is typically a 0.9% saline solution.
  • Any suitable injection device such as a syringe equipped with a 32G needle, may be used to administer the botulinum toxin solution by intramuscular injection in platysma bands.
  • the botulinum toxin solution is administered using the "high concentration approach” (high dose/low volume approach) underlying the present invention.
  • high concentration approach high dose/low volume approach
  • Exemplary dosing schemes using the high concentration approach of the present invention are shown in Table 1. Table 1. Injection and dosing regimens

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Abstract

The present invention generally relates to the use of botulinum toxin for neck rejuvenation by injection of highly concentrated botulinum toxin into the platysma muscle. Specifically, the botulinum toxin is injected in at least one platysma band of a subject at a concentration of more than 100 U/ml. Furthermore, the present invention relates to a method for neck rejuvenation involving injection of botulinum toxin at high concentration.

Description

HIGH CONCENTRATION BOTULINUM TOXIN TREATMENT FOR NECK REJUVENATION
FIELD OF THE INVENTION
[001 ] The present invention generally relates to the use of botulinum toxin for neck rejuvenation by injection of highly concentrated botulinum toxin into the platysma muscle. Specifically, the botulinum toxin is injected in at least one platysma band of a subject at a concentration of more than 100 U/ml, and optionally is injected in the platysma muscle at the jawlines. Furthermore, the present invention relates to a method for neck rejuvenation involving injection of botulinum toxin at high concentration.
BACKGROUND OF THE INVENTION
[002] Restoring volume to the m id-face and treating wrinkles in the upper face have been the focus of facial rejuvenation for many years. However, over the past few years, the lower face and the neck have become the focus of facial rejuvenation, especially in the higher age group. A sharp, defined jawline is associated with a youthful appearance and a slender, streamlined neck is perceived as a sign of health and youth. With aging, however, the jawline loses its sharpness resulting in a less defined or sagging jawline and the neck begins to show platysma bands, sagging skin, and prominent folds or jowls.
[003] The platysma is a thin sheet of muscle that envelopes the entire neck. It arises from the fascia that covers the upper segments of the deltoid and pectoralis muscles. Its thin muscle fibers cross over the clavicle and proceed obliquely superiorly, laterally and medially over the neck. The platysma crosses the mandible, with some fibers being inserted into the bone below the oblique line and others extending approximately 4 cm above the mandibular border into the cheek and inserting into the skin and subcutaneous tissue. In addition, some muscle fibers insert in the mentalis muscle and the depressor anguli oris. [004] In terms of function, the platysma is a mimetic muscle that contributes to facial expression. It distends the skin of the neck and pulls it downward. Laterally, it acts in synergy with the depressor anguli oris (DAO) and lowers the corner of the lower lips by pulling down the lateral corner of the mouth. It is also involved in the formation of transversal lines of the neck. Thus, contraction of the platysma pulls down the mandible, the corner of the mouth and the lower lip. During the aging process the muscle begins to separate and bunch into cords or bands usually in the midline para median at each side of the neck, but also at the side of the neck. These cords or bands are called platysma bands (or platysmal bands) and are characteristic of an aging neck.
[005] A variety of surgical techniques for treating platysma bands are used to improve or restore the definition of the neck. However, unfavorable surgical outcomes and the understanding that platysma bands are caused by muscular activity during the aging process (see, e.g., Trevidic, P. and Criollo-Lam ilia, G., Plast. Reconstr. Surg. 2017; 139(1 ):41 -47) have shifted treatment towards non-surgical methods like injections of botulinum toxin. Botulinum toxin is a neurotoxin from Clostridium botulinum that blocks the release of acetylcholine into the synaptic cleft, thereby preventing cholinergic neuromuscular innervation. It exists in different serotypes (types A-H) and is produced as non-covalent macromolecular protein complexes consisting of the active 150 kDa neurotoxin and nontoxic neurotoxin-associated proteins (NAPs or non-toxic "complexing proteins"). The 150 kDa neurotoxin is synthesized as single chain polypeptide that is proteolytically cleaved into two chains, i.e., a 50 kDa light chain and a 100 kDa heavy chain, which are connected by a disulfide bond.
[006] Botulinum toxin can relax and flatten the platysma bands to make the bands less pronounced. It also improves transversal (horizontal) neck lines. Furthermore, by reducing the degree of downward pull, injection of the platysma can also be used in the treatment of the lower face contour, e.g., the contour of the jawline, for global facial rejuvenation. In addition, the reduced downward pull of botulinum toxin-injected platysma can improve lateral cheek lines and marionette lines, lifting the lower face (see, e.g., Tamura, B. M., The Effect of Botulinum Toxin on the Platysma Muscle, Curr. Derm. Rep. 2012, 1 :89-95; Kane et al., Expanding the Use of Neurotoxins in Facial Aesthetics: A Consensus Panel’s Assessment and Recommendations, J. Drugs Dermatol. 2010, 9(1 ):s7-s25).
[007] However, the use of botulinum toxin in the lower face and neck is more complex than its use in the upper face and, thus, fraught with more complications. This is because the muscles of this region are very close together and interface at different levels and depths to perform heterogeneous functions, such as talking, eating, drinking, and expressivity of the face. Injected botulinum toxin may spread or diffuse to muscles of deglutition, the pharynx and neck flexors structures and cause complications like swallowing difficulties (dysphagia), dysphonia, and neck weakness (see, e.g., De Boulle et al., Chapter 15: Neck Rejuvenation, in: Botulinum Toxins: Cosmetic and Clinical Applications, Cohen, J. L., Ozog, D. M., and Porto, D. A. (eds.), Wiley-Blackwell, 2017; Chen, D. L. and Cohen, J. L., Botulinum Toxin-A Chemical Denervation for Platysmal Bands: Maximal Dosing Considerations, J. Drugs Dermatol.
2015, 14(9):931 ; Carruthers et al., Consensus Recommendations on the Use of Botulinum Toxin Type A in Facial Aesthetics, Plast. Reconstr. Surg. 2004, 114(6 Suppl): 1 S-22S)).
[008] These undesirable side effects can be reduced by using lower doses. However, low doses are less effective and may lead to residual banding and development of compensatory bands due to incomplete paralysis of the platysma muscle. In addition, when using low doses, the duration of effect is shorter and more frequent treatments are needed.
[009] In several studies the relationship between toxin dilution (concentration, volume) and efficacy and safety has been studied, but with controversial results. For example, it was found that dilution increased the incidence of adverse effects observed in the treatment of glabellar rhytides, but had no significant effect on efficacy or duration (Carruthers et al., Dilution volume of botulinum toxin type A for the treatment of glabellar rhytides: does it matter?, Dermatol. Surg. 2007, 33:S97-S104). In another study directed to dynamic forehead lines (Hsu et al., Effect of volume and concentration on the diffusion of botulinum exotoxin A, Arch. Dermatol. 2004, 140(11 ): 1351 -1354), it was found that larger volumes are beneficial in that they resulted in a greater diffusion and a larger affected area. The authors concluded that for treating larger, confluent areas, such as the forehead, a larger volume can be used to achieve more spread. This also means that fewer injections are required, which decreases pain on injection and increases patient comfort and satisfaction. On the other hand, the authors pointed out that greater dilutions tend to have a shorter duration of effect and bear the risk of migration to unintended muscles.
[0010] Regarding the treatment of platysma bands, several studies showed that botulinum toxin treatment is an alternative, effective, non-invasive method for the treatment of platysma bands (see, e.g., Brandt, F. S. and Bellman, B., Cosmetic Use of Botulinum A Exotoxin for the Aging Neck, Dermatol. Surg. 1998, 24:1232-1234; Matarasso et al., Botulinum A Exotoxin for the Management of Platysma Bands, Plast. Reconstr. Surg. 1999, 103(2):645-652; Kane, M., Nonsurgical Treatment of Platysmal Bands with Injection of Botulinum Toxin A, Plast. Reconstr. Surg. 1999, 103:656-665; Brandt, F. S. and Boker, A., Botulinum Toxin for Rejuvenation of the Neck, Clin. Dermatology 2003, 21 :515-520; Kane et al., Expanding the Use of Neurotoxins in Facial Aesthetics: A Consensus Panel’s Assessment and Recommendations, J. Drugs Dermatol. 2010, 9(1 ):s7-s25; Gubanova et al., Efficacy and Safety of IncobotulinumtoxinA for the Treatment of Platysmal Bands of the Aging Neck: An Open-Label, Prospective Pilot Study, J. Drugs Dermatol. 2013, 12(12): 1461 -1466; Prager et al., IncobotulinumtoxinA for the Treatment of Platysmal Bands: A SingleArm, Prospective Proof-of-Concept Clinical Study, Dermatol. Surg. 2015, 41 :S88-S92; see also review of Sugrue et al., Botulinum Toxin Treatment for Mild to Moderate Platysma Bands: A Systematic Review of Efficacy, Safety, and Injection Technique, Aesthet. Surg. J. 2019, 39(2):201 -206).
[0011 ] In the published literature, significantly varying botulinum toxin doses have been reported for the treatment of platysma bands. Total doses of between 10 U and 100 U onabotulinumtoxinA (BOTOX®) (see Brandt and Bellman, 1998, supra', Kane, 1999, supra', Brandt and Boker, 2003, supra', Tamura, 2012, supra', Chen and Cohen, 2015, supra) and up to 250 U (see Matarasso et al., 1999, supra) have been used for a successful treatment of platysma bands. Furthermore, total doses of 30 U to 60 U have been described for incobotulinumtoxin A (Xeomin®) (see Gubanova et al., 2013; supra', Prager et al., 2015, supra', see also review of Sugrue et al., supra), and a total dose of 5-20 U per band has been described for abobotulinumtoxinA (Dysport™) (Kane et al., 2010, supra). Moreover, according to the consensus recommendation on the use of botulinum toxin type A in facial aesthetics (see Carruthers et al., 2004, supra), the doses per injection point were also quite variable, resulting in total doses per band of 6 to 40+ U depending on the number of injection sites (typically three to five) and doses used.
[0012] In addition, a variety of different dilutions was used in the art. For example, Matarasso et al., 1999 (supra) used 5-10 U onabotulinumtoxin A in 0.1 -0.2 mL per injection point. Prager et al., 2015 (supra) injected 2.5 U incobotulinumtoxin A in a volume of 0.0625 mL per injection point (total amount of 60 U). Gubanova et al., 2013 (supra) injected 5 U incobotulinumtoxin A in 0.1 mL per injection point and a total amount of 60 U. Furthermore, as disclosed in the textbook "Illustrated Guide to Aesthestic Botulinum Toxin Injections" (Kane M. and Sattler, G., 2013, Quintessence Publishing Co Ltd), the recommended dose for platysma bands is 1 -2 U for incobotulinumtoxin A and onabotulinumtoxin A in 0.025 to 0.05 mL per injection point.
[0013] The aging neck is not only characterized by platysma bands but also by a loss of the mandibular definition (mandibular part of the platysma). Following treatment of platysma bands an overall tightening of the neck and a recontouring of the jawline (Brandt and Bellmann, 1998, supra', Tamura 2012, supra) or a lifting of the lower face was observed (Kane et al., 2010, supra). With special focus on the jawline, Levy et al. introduced a new technique, called the "Nefertiti lift" (see Levy, P. M., The 'Nefertiti lift': A new technique for specific re-contouring of the jawline, J. Cosm. Laser Then 2007, 9:249-252). In addition to treating platysma bands, Levy injected botulinum toxin A in the part of the platysma along and under the mandible posterior to the nasolabial fold. Injection with botulinum toxin A releases the tension on the jawline by reducing the depressor effect of the platysma and thus the elevator muscles prevail, leading to an uplift of the skin and re-contouring of the jawline. [0014] Another injection pattern was published by de Almeida et al. (de Almeida et al., The Facial Platysma and Its Underappreciated Role in Lower Face Dynamics and Contour, Dermatol. Surg. 2017, 43:1042-1049) which not only addresses the lateral mandibular part of the platysma as described by Levy et al. (supra) but also treats the anterior fibers of the platysma and the mentalis muscle. This treatment pattern resulted in a redefinition of the jawline as well as an improvement of lateral cheek lines and horizontal lines along and under the mandible. Yet another technique for the improvement of mandibular contour and definition is described in Bravo et al. (Bravo et al., J. Clin. Aesthet. Dermatol. 2019, 12(11 ):32-34).
[0015] Despite these advances, there exists a need in the art for an improved rejuvenation treatment of the neck, optionally together with the lower face, by botulinum toxin that results in highly satisfying cosmetic results without compromising the safety of the patient.
OBJECT OF THE INVENTION
[0016] It is therefore an object of the present invention to provide a botulinum toxin treatment for the rejuvenation of the neck that is highly efficient and safe.
SUMMARY OF THE INVENTION
[0017] The present invention is based on the finding that administration of a highly concentrated botulinum toxin formulation to the platysma, more specifically to platysma bands and optionally the platysma muscle at the jawline, allows for the efficient and safe rejuvenation of the neck, or optionally the neck and the lower face. This mode of administration localizes the toxin to the targeted platysma muscle to provide the desired cosmetic effect and prevents migration of the toxin to non-intended muscles. In the neck where anatomic structures like the deglutition muscles, the larynx and the neck flexors are in very close vicinity, a small migration potential is of utmost importance to avoid spread to these vital anatomic structures. The "high concentration" (or "low volume-high dose") approach of the present invention avoids such complications while at the same time providing a high efficacy.
[0018] In a first aspect, the present invention relates to the use of botulinum toxin for the rejuvenation of the neck, wherein the botulinum toxin is injected in at least one platysma band of a subject at a concentration of more than 100 ll/rnl, preferably at a concentration of 150 ll/rnl or more.
[0019] Preferably, the dose injected in at least one platysma band per injection point is at least 3 U, more preferably 3 U to 5 U, for example 3 U, 4 U or 5 U. The volume per injection point is preferably 0.030 ml or less, in particular 0.010 ml to 0.025 ml. This is, within the present invention, a highly concentrated botulinum toxin solution is used. The administration of high dose botulinum toxin in a low volume is found to be particularly suitable for thin muscles like the platysma muscle.
[0020] In accordance with the present invention, the botulinum toxin may additionally be injected into the platysma muscle at the jawline at both sides of the face to improve the rejuvenation effect of the injections into the platysma band(s). By relaxing the platysma along the jawline, the downward pull of the platysma muscle will be antagonized, and the elevator muscles will prevail resulting in an additional lifting effect and recontouring of the jawline.
[0021 ] In a second aspect, the present invention relates to a method for the rejuvenation of the neck, wherein the botulinum toxin is injected in at least one platysma band of a subject at a concentration of more than 100 ll/rnl, preferably at a concentration of 150 ll/rnl or more.
[0022] Preferred embodiments are set forth in the appended dependent claims and in the following detailed description taken in connection with the examples provided therein and the accompanying figures. BRIEF DESCRIPTION OF THE FIGURES
[0023] FIG. 1 depicts the spread of toluidine dye in porcine muscle after intramuscular injection. (A): injection of 10 pl, 20 pl or 40 pl toluidine dye at 45° injection angle; (B) injection of 10 pl, 20 pl or 40 pl toluidine dye at 90° injection angle.
[0024] FIG. 2 shows an exemplary injection pattern according to the present invention for improving platysma bands prominence and sharpness of the jawline contour.
DETAILED DESCRIPTION OF THE INVENTION
[0025] The high concentration approach (or high dose/low volume concept) used in the present invention allows the skilled person to safely administer botulinum toxin in higher doses per injection point, resulting in a superior efficacy with a sustained duration of effect in the treatment of platysma.
[0026] The low volume is believed to prevent spreading of the toxin to adjacent muscles, thus preventing complications and unwanted side effects. This is particularly important in case of platysma because the platysma is a rather thin muscle and in anatomical vicinity to vital structures. Special care is therefore required to prevent complications associated with the treatment of platysma bands with botulinum toxin. The small volumes used in accordance with the present invention reduces the risk of migration/spread to unintended muscles, thereby removing the main concern with the use of botulinum toxin in aesthetic indications, in particular in the treatment of the platysma.
[0027] The low volume approach allows for the use of higher toxin doses per injection point as well as in total, which improves the efficacy of the treatment. In addition, the higher doses will prolong the duration of effect which leads to longer treatment intervals, thereby enhancing patient satisfaction. Further, in accordance with the present invention, both the platysma along the mandibular border and platysma bands can be treated in one treatment session to achieve a complete relaxation of the platysma. The additional treatment of the platysma muscle in the jawline area is assumed to diminish residual banding and development of compensatory bands.
[0028] Overall, the present invention allows for the treatment of the platysma as an anatomic and cosmetic entity and leads to a balanced and harmonious appearance of the neck, enhancing patient satisfaction without increasing side effects. Furthermore, it enables the use of longer treatment intervals, resulting in a lower immunogenic risk of neutralizing antibody formation which is known to lead to secondary treatment failure, thereby adding to patient convenience and satisfaction. Hence, the botulinum toxin treatment at low volumes and high doses (i.e., using botulinum toxin at high concentrations) provides high efficacy, excellent aesthetic outcome and long duration of effect, while preventing or minimizing unwanted side effects.
[0029] In a first aspect, the present invention relates to the use of botulinum toxin for the rejuvenation of the neck, wherein the botulinum toxin is injected in at least one platysma band of a subject at a concentration of more than 100 ll/rnl, preferably at a concentration of 150 ll/rnl or more.
[0030] As used herein, the term "rejuvenation" broadly means restoring a youthful appearance. Further, the term "rejuvenation" when used in connection with the use and method of the present invention refers to a purely aesthetic application. This is, in accordance with the present invention, botulinum toxin is only used for cosmetic purposes.
[0031 ] The term "lower face", as used herein, refers to the area from the subnasale to the menton, comprising jawline including jowls and marionette lines. The term "neck", as used herein, refers to the region extending from the lower part of the mandible (lower jawbone) down to the clavicle and sternum.
[0032] As used herein, the term "platysma" has the same meaning as the term "platysma muscle" and these terms are therefore interchangeably used herein. The platysma is a thin sheet of muscle that envelopes the entire neck. It arises from the fascia that covers the upper segments of the deltoid and pectoralis muscles and a portion of the platysma muscle extends over the mandibular border and inserts into the lower face just above the mandible. Thus, since only the platysma is targeted in this invention, injections into the jawline should be understood to refer to injections into the platysma muscle at the jawline. Since this part of the platysma muscle inserts on the lower face, these injections are intended to result in a rejuvenation of the lower face.
[0033] The term "platysma band" or "platysmal bands", as used herein, has the meaning known in the art, and refers to cords or bands of the neck. The platysma bands are covered by the term "platysma" or the term "platysma muscle" as used herein. Platysma bands are characteristic of an ageing neck. In the ageing process the platysma muscle begins to separate and bunch into cords or bands, usually in the midline para median at each side of the neck but also at the side of the neck. Hence, platysma bands may be, and usually are, medial and lateral, with two medial and two lateral bands. In the context of the present invention, the term "injection in platysma bands", is intended to refer to injection into the platysma muscle, i.e. , intramuscular injection. The injection of botulinum toxin into platysma bands can relax and flatten the platysma bands to make the bands less pronounced. It should be noted that the term "platysma bands", as used herein, refers to vertical bands, i.e., bands than run vertically across the front of the neck. Thus, "platysma bands" are different to necklace lines, i.e., horizontal bands or lines that run horizontally around the front of the neck.
[0034] The term "subject", as used herein, is not particularly limited and refers to a human, who is in the need of cosmetic treatment of the neck or the neck and lower face. The term "subject" may be interchangeably used with the term patient in the context of the present invention.
[0035] Within the meaning of the present invention, numerical values without decimal places shall be understood to include all numerical values with one or more decimal places that, applying common rules of rounding, give the numerical value without decimal places. For example, the numerical value 3 includes 2.5 or 2.50 (which are rounded up to 3) and 3.4 or 3.49 (which are rounded off to 3), and all numerical values in between. As regards endpoints of ranges, the same applies, i.e. , a range of 3 to 5 may mean, e.g., 2.5-3.4 to 4.5-5.4. It is also contemplated that each numerical value or one or both, preferably both, endpoints of ranges disclosed in this application, if they have no decimal places, can be a numerical value with a decimal place that is zero, e.g., 4 may be 4.0.
[0036] The term "botulinum toxin", as used herein, is not particularly limited and includes botulinum toxin of any serotype (BoNT/A-H). For example, the botulinum toxin may be of serotype A or B (BoNT/A, BoNT/B). Preferably, the botulinum toxin is of serotype A, more preferably of serotype A1 (BoNT/A1 ), and most preferably BoNT/A1 produced by Clostridium botulinum Hall strain. Furthermore, as used herein, the term "botulinum toxin" ("BT") and the synonymously used term "botulinum neurotoxin" ("BoNT") are intended to refer to the pure botulinum neurotoxin and/or any complex thereof, i.e., any complex of the pure botulinum neurotoxin and complexing proteins (referred to as the "toxin complex"). Preferably, the botulinum toxin is the pure botulinum neurotoxin of serotype A.
[0037] The term "pure botulinum neurotoxin", as used herein, means the botulinum neurotoxin free of complexing proteins (sometimes also referred to as the "neurotoxic component"), or more precisely, the botulinum neurotoxin without neurotoxin- associated complexing proteins (NAPs). The pure botulinum neurotoxin is the (active) neurotoxic polypeptide that ultimately inhibits acetylcholine release. It is a di-chain protein comprised of a light chain (LC; about 50 kDa) and a heavy chain (HC; about 100 kDa), held together by a disulfide bond. The active neurotoxic polypeptide may therefore also be referred to herein as the "150 kDa neurotoxin", "Clostridium botulinum neurotoxin (150 kD)" or "neurotoxic component". Preferably, the botulinum toxin is the (pure) botulinum neurotoxin contained in Xeomin® or is Xeomin®.
[0038] The term "toxin complex", as used herein, refers to a high-molecular complex of the neurotoxic component and a set of complexing proteins (NAPs), including the 900 kDa, 500 kDa, and 300 kDa C. botulinum type A toxin complexes. The complexing proteins are nontoxic nonhaemagglutinin (NTNHA) and, in strains of serotype A-D, different haemagglutinins (HAs). For example, the 900 kDa complex is included in onabotulinumtoxin A (Botox®A/istabel®, Allergan, Inc., Irvine, CA, USA), and abobotulinumtoxin A (Dysport®, Azzalure®, Ipsen, Paris, France), Alluzience® (Ipsen/Galderma) and Innotox® (Medytox) also contain a toxin complex as active agent. Preferably, the botulinum toxin is, besides the pure botulinum neurotoxin that is contained in Xeomin® or is Xeomin®, the toxin complex contained in Botox® or Dysport®, or is Botox® or Dysport®. In another preferred embodiment, the botulinum toxin is not the toxin complex contained in Dysport® or is not Dysport®.
[0039] The botulinum toxin may be a natural neurotoxin obtainable from the bacteria Clostridium botulinum or any other botulinum toxin such as a botulinum toxin obtainable from alternative sources, including recombinant technologies and genetic or chemical modification. Chimeric or genetically modified botulinum toxins, i.e., botulinum toxins containing mutations including substitutions, deletions and insertions, are also encompassed by the terms "botulinum toxin", "neurotoxic component" and the like. Preferably, the mutation does not compromise any of the biological activities of botulinum toxin. However, it is also envisaged to use mutations to modulate the biological activity of the botulinum toxin. Also included are botulinum toxins containing chemically modified amino acids, for example one or more amino acids which are glycosylated, acetylated or otherwise modified, which may be beneficial to the uptake or stability of the toxin. Particularly preferred is the lipidation of the neurotoxic component.
[0040] Within the present invention, the dose is expressed in biological units because the used botulinum toxin may contain, for example, variable percentages of inactive toxin that contribute to the overall protein load without contributing to efficacy. Within the context of the present invention, the biological potency of botulinum toxin is determined using the mouse bioassay (MBA). The MBA determines the median lethal dose (LD50) of toxin/neurotoxin after intraperitoneal injection in mice, i.e. the dose of toxin/neurotoxin capable of killing 50% of a group of mice. On this basis, 1 unit (U) of toxin/neurotoxin, as used herein, is defined as one mouse LD50 (1.0 LD50 = 1.0 U). The LD50 mouse bioassay is the gold standard among various biological, chemical or immunological detection methods for botulinum toxin and is known to those skilled in the art (see, e.g., Pearce, L.B.; Borodic, G.E.; First, E.R.; MacCallum, R.D. Measurement of botulinum toxin activity: Evaluation of the lethality assay. Toxicol. Appl. Pharmacol. 1994, 128, 69-77).
[0041 ] Another useful method for determining the biological activity (biological potency) of a botulinum neurotoxin is a cell-based potency assay as it is disclosed, for example, in W02009/114748, WO 2013/049508 or WO 2014/207109. The activity results obtained with such cell-based assays correspond to the activity values obtained in the mouse i.p. LD50 assay because the values are calibrated using the LD50 reference standard.
[0042] Due to differences in the LD50 tests used by manufacturers of commercial botulinum toxin formulations, the unit potencies indicated by the manufacturers for their commercial botulinum toxin formulations is proprietary and cannot easily be compared. Therefore, within the framework of the present invention, the conversion rates provided below are used to establish the comparative potencies of incobotulinumtoxinA ("INCO"; Xeomin®, Bocouture®; botulinum toxin serotype A, free of complexing proteins; Merz Pharmaceuticals GmbH), onabotulinumtoxinA ("ONA"; Botox®, Vistabel®; botulinum toxin complex of serotype A; Allergan Inc.), abobotulinumtoxinA ("ABO"; Dysport®, Azzalure®; botulinum toxin complex of serotype A; Medicis Pharmaceutical Corp., Galderma Lab.), rimabotulinumtoxinB ("RIM"; Myobloc®, NeuroBloc®; botulinum toxin serotype B; Solstice Neurosciences Inc.), and PurTox® ("TBD"; botulinum toxin serotype A; Mentor Worldwide LLC). For use herein, the conversion rate of ONA and INCO is 1 :1. The conversion rate of ONA/INCO:ABO is 1 :2.5. The conversion rate of ONA/INCO:RIM is 1 :50, and the conversion rate of ONA/INCO:TBD is 1 : 1 .5. Furthermore, and preferably, within the context of the present invention, 1 U of INCO (Xeomin®) and 1 U of onabotulinumtoxinA ("ONA"; Botox®) shall be deemed to correspond to one mouse LD50 (1.0 LD50), or 1 U, measured as described above, i.e. using the MBA. It is further preferred within the present invention that, if the botulinum toxin is abobotulinumtoxinA, 2.5 U of abobotulinumtoxinA equal 1 U, with 1 U being preferably one mouse LD50 (1 .0 LD50), measured using the abovedescribed MBA.
[0043] In a preferred embodiment, the first aspect of the present invention relates to the use of botulinum toxin for the rejuvenation of the neck, wherein the botulinum toxin is injected in at least one platysma band of a subject at a concentration of more than 100 ll/rnl, with the proviso that, if the botulinum toxin is abobotulinumtoxinA, 2.5 U of abobotulinumtoxinA equal 1 U. In another preferred embodiment, the first aspect of the present invention relates to the use of botulinum toxin for the rejuvenation of the neck, wherein the botulinum toxin is injected in at least one platysma band of a subject at a concentration of more than 100 ll/rnl, wherein 1 U corresponds to 1 LD50, with LD50 being the median lethal dose as measured using the mouse LD50 bioassay, with the proviso that, if the botulinum toxin is abobotulinumtoxinA, 2.5 U of abobotulinumtoxinA equal 1 U. In yet another preferred embodiment, the first aspect of the present invention relates to the use of botulinum toxin for the rejuvenation of the neck, wherein the botulinum toxin is injected in at least one platysma band of a subject at a concentration of more than 100 ll/rnl, wherein 1 U corresponds to 1 LD50, with LD50 being the median lethal dose as measured using the mouse LD50 bioassay, with the proviso that, if the botulinum toxin is incobotulinumtoxinA or onabotulinumtoxinA, 1 U of incobotulinumtoxinA and 1 U of onabotulinumtoxinA both equal 1 U, and, if the botulinumtoxin is abobotulinumtoxinA, 2.5 U of abobotulinumtoxinA equal 1 U.
[0044] As used herein, the term "comprising", like the terms "including" and containing", and any variations thereof such as "comprises", "includes" and "contains", are intended to refer to a non-exclusive inclusion, such that a process, method, product-by-process, composition or formulation that comprises, includes, or contains an element or list of elements does not include only those elements but can include other elements not expressly listed for such process, method, product-by-process, composition or formulation. In addition, within the framework of the present invention, it is intended that each of the terms "comprise," "comprising", "includes", "including", "contains", "containing", and any variations thereof, can be replaced by the term "consists" or "consisting", or any variation thereof, which will be understood to refer to an exclusive inclusion of the elements indicated.
[0045] The terms "a" and "an" and "the" and similar reference used in the context of the present invention are to be construed to cover both the singular and the plural and, thus, may also relate to "at least one" or "more than one", unless otherwise indicated herein or clearly contradicted by the context.
[0046] In accordance with the first aspect of the present invention, the botulinum toxin is injected in at least one platysma band of a subject at a concentration of more than 100 ll/rnl, preferably 125 ll/rnl or more, 150 ll/rnl or more, 175 ll/rnl or more, 200 ll/rnl or more, 225 ll/rnl or more, or 250 ll/rnl or more. The upper limit is preferably 500 ll/rnl. Preferably, the botulinum toxin is injected at a concentration of more than 100 ll/rnl to 500 ll/rnl or at 125 ll/rnl to 400 ll/rnl, more preferably at a concentration of 125 U/ml to 275 U/ml or 150 U/ml to 350 U/ml or 150 U/ml to 300 U/ml or 150 U/ml to 250 ll/rnl or 175 U/ml to 275 U/ml or 200 U/ml to 250 U/ml. More preferably, the botulinum toxin is injected at a concentration of 130 U/ml to 170 U/ml, or 180 U/ml to 220 U/ml, or 230 U/ml to 270 U/ml, and most preferably at a concentration of 150 U/ml, 200 U/ml or 250 U/ml.
[0047] Furthermore, in addition to injecting the botulinum toxin concentrations disclosed herein, the botulinum toxin is preferably injected at a dose of at least 2 U (e.g., 2 U to 6 U, such as 3 U, 4 U or 5 U) and a volume of 0.03 ml or less per injection point. Preferably, the botulinum toxin is injected at a dose of at least 3 U, particularly at a dose of 3 U to 6 U (e.g., at a dose of 3 U, 4 U, 5 U or 6 U) and a volume of less than 0.030 ml per injection point. More preferably, the botulinum toxin is injected at a dose of at least 3 U, particularly at a dose of 3 U to 6 U (e.g., at a dose of 3 U, 4 U, 5 U or 6 U), and a volume of 0.010 ml to 0.025 ml, per injection point, and more particularly at a dose of at least 3 U, particularly at a dose of 3 U to 6 U (e.g., at a dose of 3 U, 4 U, 5 U or 6 U), and a volume of 0.015 ml to 0.025 ml per injection point. [0048] Most preferably, the botulinum toxin is injected at a dose of 3 U to 5 U and a volume of less than 0.030 ml per injection point, particularly at a dose of 3 U to 5 U and a volume of 0.010 to less than 0.030 ml per injection point, more particularly at a dose of 3 U to 5 U and a volume of 0.010 ml to 0.025 ml per injection point, and most particularly at a dose of 3 U to 5 U and a volume of 0.015 ml to 0.025 ml per injection point.
[0049] In accordance with the present invention, the botulinum toxin is injected in one or more platysma bands, preferably in 2 or 4 platysma bands, more preferably in the two left and right medial bands or the two left and right lateral bands, most preferably in 4 platysma bands, i.e. , each of the left and right medial and lateral bands. In other cases, e.g., asymmetrical bands, the botulinum toxin may also be injected in 3 platysma bands.
[0050] Generally, the botulinum toxin is injected in at least three injection points per platysma band, preferably in 4, 5 or 6 injection points per platysma band. The total number of injection points in the (i.e., all the) platysma bands is typically 6 to 24, preferably 8 to 22, more preferably 14 to 20, and most preferably 16 to 20.
[0051 ] The total volume of the botulinum toxin injected in said at least one platysma band (i.e., all the platysma bands treated) is usually 0.15 ml to 0.60 ml, preferably 0.20 ml to 0.50 ml, more preferably 0.30 ml to 0.45 ml or 0.35 ml to 0.40 ml, most preferably 0.40 ml.
[0052] The total dose of botulinum toxin injected in said at least one platysma band (i.e., all the platysma bands treated) is usually 25 U to 200 U, preferably 30 U to 150 U or 40 U to 120 U, more preferably 50 U to 120 U or 60 U to 110 U, and most preferably 60 U to 100 U or 80 U to 100 U.
[0053] As used herein, the terms "total dose" and "total volume" refers to the total dose and total volume of botulinum toxin, respectively, generally administered in a treatment session (or "injection session") and administered by multiple injections at different injection points, in a single area. A treatment session typically lasts less than one hour, e.g., around 30 minutes. The single area is the platysma bands, and optionally the platysma muscle at the jawlines, to be treated.
[0054] The injection points along the platysma band(s) are spaced at a distance of about 1 cm to about 3 cm, preferably about 1 .5 cm to about 2.5 cm, more preferably about 2 cm. This spacing refers to the distance between adjacent injection points on the platysma bands.
[0055] In accordance with the present invention, the botulinum toxin may further be injected, and preferably is injected, in the platysma muscle at the jawlines of the subject. In other words, the use according to the present invention involves the injection of platysma bands as described above and, optionally, the injection of botulinum toxin in the platysma muscle at the jawline. The injection at the jawline releases the tension on the jawline by reducing the depressor effect of the platysma and thus the elevator muscles prevail, leading to an uplift of the skin and re-contouring of the jawline.
[0056] As mentioned above, the platysma crosses the mandible, with some fibers being inserted into the bone below the oblique line and others extending approximately 4 cm above the mandibular border into the cheek and inserting into the skin and subcutaneous tissue. Hence, the terms "injected in the jawlines" or "injection at the jawline" or similar terms, as used herein, are intended to mean that the platysma muscle is injected. As a result, the platysma muscle will be antagonized, and the elevator muscles will prevail resulting in an additional lifting effect and recontouring of the jawline. Furthermore, the term "injected in the jawlines" or "injection at the jawline" or similar terms preferably means in each, or both, jawlines of a subject’s face, unless otherwise stated.
[0057] Preferably the botulinum toxin is injected in the platysma muscle at the jawlines at a concentration of at least 50 ll/rnl, preferably at least 100 ll/rnl or at least 150 ll/rnl or at least 200 ll/rnl per injection point. Most preferably the botulinum toxin is injected in the platysma muscle at the jawlines at a concentration of 100 ll/rnl to 250 ll/rnl, e.g., at a concentration of 150 ll/rnl, 200 ll/rnl or 250 ll/rnl.
[0058] Further, in addition to or alternatively to the botulinum toxin concentration described above in relation to the jawlines, it is preferred within the context of the present invention that the botulinum toxin is injected in the platysma muscle of the jawlines at a dose of at least 1 U per injection point, particularly 1 U to 4 U per injection point, more particularly 1 U to 3 U or 1 .5 U to 2.5 U (e.g., 1.5 U, 2 U or 2.5 U) per injection point, and most particularly 2 U per injection point.
[0059] In particular, the botulinum toxin is injected in the platysma muscle at the jawlines at a dose of at least 1 U per injection point, preferably 1 U to 4 U per injection point, more preferably 1 U to 3 U or 1 .5 U to 2.5 U per injection point, for example 1 .5 U, 2 U or 2.5 U, and most preferably 2 U per injection point, and at a concentration of at least 100 ll/rnl per injection point. More preferably, the botulinum toxin is injected in the platysma muscle at the jawlines at a dose of at least 1 U per injection point, preferably 1 U to 4 U per injection point, more preferably 1 U to 3 U or 1 .5 U to 2.5 U per injection point, for example 1 .5 U, 2 U or 2.5 U and most preferably 2 U per injection point, and at a concentration of at least 150 ll/rnl per injection point. Most preferably, the botulinum toxin is injected in the platysma muscle at the jawlines at a dose of at least 1 U, preferably 1 U to 4 U, more preferably 1 U to 3 U or 1 .5 U to 2.5 U per injection point, for example 1.5 U, 2 U or 2.5 U, and most preferably 2 U, and at a concentration of at least 200 ll/rnl (e.g., at 200 ll/rnl, or 250 ll/rnl). The upper limit of all the open-ended ranges mentioned above is preferably 500 ll/rnl, most preferably 400 ll/rnl. An appropriate concentration can be readily selected by the skilled person depending on the dose to be injected and taking into account that the injection volume should not be too low for practicability reasons and to avoid dosing inaccuracies.
[0060] The botulinum toxin is preferably injected in the platysma muscle at the jawlines at a volume of 0.005 ml to 0.03 ml per injection point, more preferably at a volume of 0.01 ml to 0.025 ml per injection point, for example at a volume of 0.02 ml or 0.01 ml, and most preferably at a volume of 0.01 ml per injection point. [0061 ] Further, it is preferred within the context of the present invention that the botulinum toxin is injected in the platysma muscle at the jawlines at a dose of at least 1 U per injection point, particularly 1 U to 4 U per injection point, more particularly 1 U to 3 U or 1 .5 U to 2.5 U per injection point, for example 1 .5 U, 2 U or 2.5 U, in a volume of 0.01 ml to 0.02 ml.
[0062] Further, it is preferred within the context of the present invention that the botulinum toxin is injected in the platysma muscle at the jawlines at a dose of at least 1 U per injection point, particularly 1 U to 4 U per injection point, more particularly 1 U to 3 U or 1 .5 U to 2.5 U per injection point, for example 1 .5 U, 2 U or 2.5 U, in a volume of 0.01 ml.
[0063] Further, it is preferred within the context of the present invention that the botulinum toxin is injected in the platysma muscle at the jawlines at a dose of at least
1 U per injection point, particularly 1 U to 4 U per injection point, more particularly 1 U to 3 U or 1 .5 U to 2.5 U per injection point, for example 1.5 U, 2 U or 2.5 U, most preferably 2 U, in a volume of 0.02 ml.
[0064] The total volume of the botulinum toxin injected in the platysma muscle at each jawline may be 0.02 ml to 0.20 ml, in particular 0.02 ml to 0.16 ml or 0.04 ml to 0.16 ml, preferably 0.06 ml to 0.12 ml, more preferably 0.08 ml to 0.12 ml, and most preferably 0.08 ml to 0.10 ml. The total dose of the botulinum toxin injected in the platysma muscle at each jawline may be 4 U to 16 U, preferably 5 U to 12 U, more preferably 6 U to 10 U (e.g., 6 U, 8 U or 10 U), and most preferably 8 U.
[0065] The number of injection point in the platysma muscle at each jawline is at least 2, preferably 2 to 6, more preferably 3 to 5, and most preferably 4. Furthermore, the injection points along the jawline are spaced at a distance of about 0.5 cm to about
2 cm, preferably about 1 .0 cm to about 1 .5 cm, more preferably about 1 cm. Preferably, botulinum toxin is administered into 2 to 4 injection points per side along and under each mandible not anterior to a line drawn from the nasolabial fold down to the mandible. [0066] In accordance with the use according to the first aspect of the present invention, the botulinum toxin may be administered in consecutive treatment cycles. It is understood that a treatment cycle is the time interval between two administrations of the botulinum neurotoxin, i.e., a treatment cycle consists of one administration of the botulinum neurotoxin and a follow-up period until the next botulinum neurotoxin injection is administered. The said administration of botulinum toxin occurs in a treatment session (or "injection session"). The time interval between two consecutive administrations of the botulinum neurotoxin can vary between about 5 and 10 months, in particular between about 6 and 9 months or between about 7 and 8 months This prolonged treatment interval is enabled by the longer duration of effect achieved by the present invention.
[0067] In accordance with the present invention, the botulinum toxin (i.e., the neurotoxic component or toxin complex) may be of serotype A, B, C1 , D, E, F, G or H. Due to its longer lasting effects compared to the other serotypes, botulinum toxin type A is preferably used herein. Furthermore, within the framework of the present invention, the term "botulinum toxin" may refer to a natural neurotoxin obtainable from the bacteria Clostridium botulinum or to a botulinum toxin obtainable from alternative sources, including from recombinant technologies or from genetic or chemical modification.
[0068] Generally, the botulinum toxin used within the present invention is present in the form of a liquid composition. The liquid composition can be formulated by various techniques dependent on the desired application, as known in the art. It may be provided as a ready-to-use liquid formulation or in the form of a lyophilized powder that is to be reconstituted, typically in physiological saline, prior to use. Preferably, the botulinum toxin used within the present invention is in the form of an aqueous solution, more preferably a saline solution or a physiological saline solution, and most preferably a phosphate buffered physiological saline solution. The aqueous solution may additionally comprise one or more pharmaceutically acceptable substances. Suitable pharmaceutically acceptable substances comprise those well known in the art, see, e.g., Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.
[0069] In particular, the aqueous botulinum toxin solution or composition may include other carriers or non-toxic, non-therapeutic, non-immunogenic stabilizers and the like. Thus, the aqueous botulinum toxin composition may contain glycerol, protein stabilizers (HSA) or non-protein stabilizers such as polyvinyl pyrrolidone (PVP), hyaluronic acid or free amino acids, e.g., methionine or histidine. The aqueous botulinum toxin composition can be free of amino acids. In one embodiment, it may be free of stabilizing peptides (e.g., consisting of 5 to 50 amino acids, 10 to 40 amino acids or 15 to 30 amino acids). Suitable non-proteinaceous stabilizers for use herein are disclosed in WO 2005/007185 or WO 2006/020208. The botulinum toxin composition can also include non-ionic or ionic surfactant, e.g., polysorbate or poloxamer. A suitable formulation for HSA-stabilized formulation comprising a botulinum toxin according to the present invention is for example disclosed in US 8,398,998 B2.
[0070] Preferably, the botulinum toxin used within the present invention is present in the form of an aqueous solution comprising sodium chloride (NaCI), more preferably in the form of a physiological saline solution (i.e. a solution including sodium chloride in physiological concentration, e.g., about 9 g/l NaCI), wherein the aqueous botulinum toxin solution comprises (i) no other excipient (except NaCI), (ii) human serum albumin (HSA) and a sugar, in particular a monosaccharide or a disaccharide, (iii) human serum albumin (HSA) and lactose, (iv) human serum albumin (HSA) and sucrose, (v) a monosaccharide and/or a disaccharide (e.g. lactose and/or sucrose), (vi) no buffer, (vii) no single amino acids, (viii) no human serum albumin (HSA), sodium chloride and lactose or no HSA, sodium chloride and sucrose, or (ix) no HSA and sodium chloride, or any combination of (i) to (ix).
[0071 ] In a second aspect, the present invention relates to a method for the rejuvenation of the neck, the method comprising injecting botulinum toxin in at least one platysma band of a subject at a concentration of more than 100 U/ml. [0072] This method of treatment is used for purely aesthetic purposes, i.e. , for the rejuvenation of the neck or the neck and lower face and is therefore a cosmetic method. The botulinum toxin is generally intramuscularly injected using a suitable injection device, for example a syringe equipped with a 30G, 32 G or 33 G needle. The syringe is not particularly limited and any conventional syringe may be used. A particularly suited syringe for use in accordance with the present invention is, for example, a 3Dose™ high precision syringe (vlow medical).
[0073] The location, number and spacing of injection points suited for used within the framework of the present invention are as disclosed herein above. An exemplary injection pattern is shown in FIG. 2, according to which five injections spaced 1 -2 cm apart are made into the left and right medial and lateral bands, resulting in a total of 20 platysma band injections. In addition, 4 injections into the platysma muscle at the left and right jawline, i.e., 8 injections in total, are used. Following this exemplary injection pattern, an improvement in platysma bands prominence and sharpness of the jawline contour are obtained.
[0074] The dosing regimen used in connection with the method according to the second aspect of the present invention is as disclosed herein above in relation to the use according to the first aspect of the present invention. More specifically, dosing regimens that are particularly preferred for use within the present invention (i.e., for the use according to the first aspect and the method according to the second aspect) are as follows:
Platysma bands Jawlines (optionally)
BTX concentration: 125-300 U/ml 100-300 U/ml
Number of injection points: 16-24 (total) 6-10 (total)
Dose per injection point: 3-5 U 1 -3 U
[0075] In a preferred embodiment, botulinum toxin is injected at 150 U/ml to 250 U/ml in 4 to 6 injection points per platysma band, wherein the dose per injection point is in the range of 3 U to 5 U and/or wherein the injection volume per injection point is in the range of 0.015 ml to 0.025 ml, and optionally botulinum toxin is injected at 150 ll/rnl to 250 ll/rnl in 3 to 5 injection points per jawline, wherein the dose per injection point is in the range of 1 .5 U to 2.5 U and/or wherein the injection volume per injection point is in the range of 0.005 ml to 0.015 ml.
[0076] Preferably, botulinum toxin is injected at 150 ll/rnl to 250 ll/rnl in 4 to 6 injection points per platysma band, wherein the dose per injection point is in the range of 3 U to 5 U and wherein the injection volume per injection point is in the range of 0.015 ml to 0.025 ml, and optionally botulinum toxin is injected at 150 ll/rnl to 250 ll/rnl in 3 to 5 injection points per jawline, wherein the dose per injection point is in the range of 1 .5 U to 2.5 U and wherein the injection volume per injection point is in the range of 0.005 ml to 0.015 ml.
[0077] Preferably, botulinum toxin is injected at 150 ll/rnl to 250 ll/rnl in in 4 to 6 injection points per platysma band, wherein the injection volume per injection point is 0.02 ml, and optionally botulinum toxin is injected at 150 ll/rnl to 250 ll/rnl in 3 to 5 injection points per jawline, wherein the injection volume per injection point is 0.01 ml.
[0078] Preferably, botulinum toxin is injected at 150 ll/rnl to 250 ll/rnl in 20 injection points on 4 platysma bands, wherein the dose per injection point is in the range of 3 U to 5 U and/or wherein the injection volume per injection point is in the range of 0.015 ml to 0.025 ml, and optionally botulinum toxin is injected at 100 ll/rnl to 250 ll/rnl or 150 ll/rnl to 250 ll/rnl in 4 injection points in the platysma muscle at each jawline, wherein the dose per injection point is in the range of 1.5 U to 2.5 U and/or wherein the injection volume per injection point is in the range of 0.005 ml to 0.015 ml.
[0079] Preferably, botulinum toxin is injected at 150 ll/rnl to 250 ll/rnl in 20 injection points on 4 platysma bands, wherein the dose per injection point is in the range of 3 U to 5 U and wherein the injection volume per injection point is in the range of 0.015 ml to 0.025 ml, and optionally botulinum toxin is injected at 150 ll/rnl to 250 ll/rnl in 4 injection points in the platysma muscle at each jawline, wherein the dose per injection point is in the range of 1.5 U to 2.5 U and wherein the injection volume per injection point is in the range of 0.005 ml to 0.015 ml.
[0080] More preferably, botulinum toxin is injected at 150 ll/ml to 250 ll/ml in 20 injection points on 4 platysma bands, wherein the injection volume per injection point is 0.02 ml, and optionally botulinum toxin is injected at 150 ll/ml to 250 ll/ml in 4 injection points in the platysma muscle at each jawline, wherein the injection volume per injection point is 0.01 ml.
[0081] In a particularly preferred embodiment, botulinum toxin is injected at 130 ll/ml to 170 ll/ml in 4 to 6 injection points per platysma band, wherein the dose per injection point is in the range of 2.5 U to 3.5 U and/or wherein the injection volume per injection point is in the range of 0.015 ml to 0.025 ml, and optionally botulinum toxin is injected at 130 ll/ml to 170 ll/ml in 3 to 5 injection points per jawline, wherein the dose per injection point is 1 U to 2 U and/or the injection volume per injection point is in the range of 0.005 ml to 0.015 ml.
[0082] Preferably, botulinum toxin is injected at 150 ll/ml in 4 to 6 injection points per platysma band, wherein the injection volume per injection point is 0.02 ml, and optionally botulinum toxin is injected at 150 ll/ml in 3 to 5 injection points per jawline, wherein the injection volume per injection point is 0.01 ml.
[0083] Most preferably, botulinum toxin is injected at 150 ll/ml in 20 injection points on 4 platysma bands, wherein the injection volume per injection point is 0.02 ml, and optionally botulinum toxin is injected at 150 ll/ml in 4 injection points in the platysma muscle at each jawline, wherein the injection volume per injection point is 0.01 ml.
[0084] In another particularly preferred embodiment, botulinum toxin is injected at 180 ll/ml to 220 ll/ml in 4 to 6 injection points per platysma band, wherein the dose per injection point is in the range of 3.5 U to 4.5 U and/or wherein the injection volume per injection point is 0.015 ml to 0.025 ml, and optionally botulinum toxin is injected at 180 ll/ml to 220 ll/ml in 3 to 5 injection points per jawline, wherein the dose per injection point is 1 .5 U to 2.5 U and/or the injection volume per injection point is in the range of 0.005 ml to 0.015 ml
[0085] Preferably, botulinum toxin is injected at 200 ll/ml in 4 to 6 injection points per platysma band, wherein the injection volume per injection point is 0.02 ml, and optionally botulinum toxin is injected at 200 ll/ml in 3 to 5 injection points per jawline, wherein the injection volume per injection point is 0.01 ml.
[0086] Most preferably, botulinum toxin is injected at 200 ll/ml in 20 injection points on 4 platysma bands, wherein the injection volume per injection point is 0.02 ml, and optionally botulinum toxin is injected at 200 ll/ml in 4 injection points in the platysma muscle at each jawline, wherein the injection volume per injection point is 0.01 ml.
[0087] In another particularly preferred embodiment, botulinum toxin is injected at 230 ll/ml to 270 ll/ml in 4 to 6 injection points per platysma band, wherein the dose per injection point is in the range of 4.5 U to 5.5 U and/or wherein the injection volume per injection point is 0.015 ml to 0.025 ml, and optionally botulinum toxin is injected at 230 ll/ml to 270 ll/ml in 3 to 5 injection points per jawline, wherein the dose per injection point is 2 U to 3 U and/or the injection volume per injection point is in the range of 0.005 ml to 0.015 ml.
[0088] Preferably, botulinum toxin is injected at 250 ll/ml in 4 to 6 injection points per platysma band, wherein the injection volume per injection point is 0.02 ml, and optionally botulinum toxin is injected at 250 ll/ml in 3 to 5 injection points per jawline, wherein the injection volume per injection point is 0.01 ml.
[0089] Most preferably, botulinum toxin is injected at 250 ll/ml in 20 injection points on 4 platysma bands, wherein the injection volume per injection point is 0.02 ml, and optionally botulinum toxin is injected at 250 ll/ml in 4 injection points in the platysma muscle at each jawline, wherein the injection volume per injection point is 0.01 ml. [0090] The prolonged duration of effect allows for less frequent administration of botulinum toxin. For example, botulinum neurotoxin may be repeatedly administered at an interval between a first administration and a second administration, or between a second or further administration and another administration following said second or further administration (i.e. , between consecutive administrations of the botulinum toxin) of between about 5 and 10 months, especially between about 6 and 9 months or between about 7 and 8 months.
[0091 ] The method according to the second aspect of the present invention is closely related to the use according to the first aspect of the present invention. Thus, all definitions, explanations and advantages given herein with respect to the use according to the first aspect equally apply to the method according to the second aspect.
EXAMPLES
EXAMPLE 1
Intramuscular injection of dye in porcine muscle
[0092] A staining dye solution of 0.025% toluidine blue and 0.9% NaCI was injected into a pork loin muscle sample (porcine M. psoas major) using a vlow medical syringe equipped with a 30G x 1 " hypodermic needle. Three different injection volumes were used, i.e., 10 pl, 20 pl, and 40 pl, which were each injected in triplicate at 45° angle as well as at 90° angle and allowed to spread. Then, muscle pieces covering the lateral dye spread area were cut from the injected porcine M. psoas major and cross-sectional cuts thereof were also prepared.
[0093] Photographs of the muscle cuts together with an indication of scale are shown in FIG. 1. The muscle cuts injected with 10 pl, 20 pl or 40 pl at 45° or 90° angle showing the lateral dye spread in top view are depicted in (A) and (B), respectively. [0094] As can be seen from FIG. 1 , the spread depends on the injection volume and occurs along the muscle fibers (even if perpendicular injected). The lateral spread of 10 pl and 40 pl toluidine dye solution at 90° injection angle was 10.4 ± 2.2 mm and 23.3 ± 5.4 mm, respectively.
[0095] These results, although obtained in an ex vivo preclinical model using porcine muscle, indicate that the "low volume" injection of highly concentrated botulinum toxin at broadly spaced (e.g., 2 cm distance) injection points in the platysma muscle will provide sufficient distribution for achieving the desired treatment effect.
EXAMPLE 2
Injection scheme and dosing regimen of the present invention
[0096] In accordance with the present invention, the botulinum toxin may be injected in platysma for the improvement of platysma bands prominence and sharpness of the jawline contour using an injection pattern as shown in FIG. 2. As can be seen, the exemplary injection scheme includes five injections spaced 1-2 cm apart into the left and right medial and lateral bands (20 injections in total) and 4 injections into the platysma muscle of the left and right jawline (8 injections in total).
[0097] The injected botulinum toxin is typically a 0.9% saline solution. Any suitable injection device, such as a syringe equipped with a 32G needle, may be used to administer the botulinum toxin solution by intramuscular injection in platysma bands.
[0098] The botulinum toxin solution is administered using the "high concentration approach" (high dose/low volume approach) underlying the present invention. Exemplary dosing schemes using the high concentration approach of the present invention are shown in Table 1. Table 1. Injection and dosing regimens

Claims

CLAIMS Use of botulinum toxin for the rejuvenation of the neck, wherein the botulinum toxin is injected in at least one platysma band of a subject at a concentration of more than 100 U/ml. The use of claim 1 , wherein the botulinum toxin is injected at a concentration of 150 U/ml or more. The use of claim 1 or 2, wherein the botulinum toxin is injected at a dose of at least 3 U, preferably 3 U to 6 U, and a volume of less than 0.030 ml per injection point. The use of any one of claims 1 to 3, wherein the botulinum toxin is injected at a dose of at least 3 U, preferably 3 U to 6 U, and a volume of 0.010 ml to 0.025 ml per injection point. The use of any one of claims 1 to 4, wherein the botulinum toxin is injected in at least 3 injection points per platysma band, preferably in 4 to 6 injection points per platysma band, more preferably in 5 injection points per platysma band. The use of any one of claims 1 to 5, wherein the botulinum toxin is injected in said at least one platysma band in a total number of 6 to 24 injection points, preferably 8 to 22, more preferably 14 to 20, and most preferably 16 to 20. The use of any one of claims 1 to 6, wherein the botulinum toxin is injected in said at least one platysma band in a total volume of 0.15 ml to 0.60 ml, preferably 0.20 ml to 0.50 ml, more preferably 0.30 ml to 0.45 ml, and most preferably 0.35 ml to 0.4 ml. The use of any one of claims 1 to 7, wherein the botulinum toxin is injected in said at least one platysma band in a total dose of 25 U to 200 U, preferably 30 U to 150 U or 40 U to 120 U, more preferably 50 U to 120 U or 60 U to 110 U, most preferably 60 U to 100 U or 80 U to 100 U. The use of any one of claims 1 to 8, wherein the injection points along the platysma band are spaced at a distance of about 1 cm to about 3 cm, preferably about 1 .5 cm to about 2.5 cm, more preferably about 2 cm. The use of any one of claims 1 to 9 for the rejuvenation of the neck and the lower face, wherein the botulinum toxin is further injected in the jawlines of the subject. The use of claim 10, wherein the botulinum toxin is injected in the jawlines at a concentration of at least 50 ll/rnl, preferably at least 100 ll/rnl, more preferably at least 150 ll/rnl, per injection point. The use of claim 10 or 11 , wherein the botulinum toxin is injected in the jawlines at a dose of at least 1 U, preferably 1 U to 4 U, per injection point. The use of any one of claims 10 to 12, wherein the botulinum toxin is injected in at least 2 injection points in each jawline, preferably in 2 to 6 injection points, more preferably 3 to 5 injection points, and most preferably at 4 injection points, per jawline. The use of any one of claims 10 to 13, wherein the injection points along the jawline are spaced at a distance of about 0.5 cm to about 2.0 cm, preferably about 1 .0 cm to about 1 .5 cm, more preferably about 1 cm. The use of any one of claims 10 to 14, wherein the botulinum toxin is injected in each jawline at a total volume of 0.02 ml to 0.16 ml and/or at a total dose of 4 U to 16 U.
EP23813385.4A 2022-11-28 2023-11-27 High concentration botulinum toxin treatment for neck rejuvenation Pending EP4626556A1 (en)

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