Botulinum toxin in aerosol form and method of facial contouring using the same

Abstract

The present invention provides a composition for facial contouring, comprising a mixture of botulinum toxin and air, and a method of facial contouring using the same. When the mixture of botulinum toxin and air is injected into an SMAS layer, the mixture strengthens the SMAS layer and draws back the galea aponeurotica to effectively lift up the face or change the facial contour, thus effectively enhancing the effect of facial contouring.

Claims

1. A method of facial contouring, comprising: administering a mixture of botulinum toxin and air formulated in an aerosol form into a superficial muscular aponeurotic system (SMAS) layer.

2. The method of facial contouring of claim 1, wherein the botulinum toxin and air are mixed in a volume ratio of 1:0.1 to 1:20.

3. The method of facial contouring of claim 1, wherein the administering of the mixture changes facial contour.

4. The method of facial contouring of claim 1, wherein the administering of the mixture comprises: injecting a first end of a delivery device into the SMAS layer; and applying a high pressure on a second end of the delivery device, while maintaining the first end of the delivery device in the SMAS layer, to spread the mixture in the form of aerosol into the SMAS layer.

5. The method of facial contouring of claim 4, wherein the delivery device is a syringe with a needle.

6. The method of facial contouring of claim 5, wherein the needle is 28-gauge or 31-gauge.

7. The method of facial contouring of claim 1, wherein the botulinum toxin is botulinum toxin serotype A or B.

8. The method of facial contouring of claim 5, wherein the first end of the delivery device is a needle.

9. The method of facial contouring of claim 5, wherein the second end of the delivery device is the plunger of the syringe.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The above and other features and advantages of the present invention will become more apparent by describing in detail exemplary embodiments thereof with reference to the attached drawings in which:

(2) FIG. 1 is a diagram showing the SMAS layer;

(3) FIG. 2 is a diagram showing an effect caused by injection of a composition of the invention into the SMAS;

(4) FIG. 3 is a diagram showing the sites of administration of the composition of the invention in a human head without facial movement;

(5) FIG. 4 is a diagram showing the sites of administration of the composition of the invention in a contracting state of the frontal belly;

(6) FIG. 5 is a diagram showing the sites of administration of the composition of the invention in a contracting state of the orbicularis oris and levator labii superioris muscles;

(7) FIG. 6 is a diagram showing the sites of administration of the composition of the invention in a contracting state of the platysma where the facial skin drops down;

(8) FIG. 7 is a diagram showing the change of facial contouring in patient A before and 6 months after the injection of the composition of the present invention;

(9) FIG. 8 is a diagram showing the change of facial contouring in patient B before and 4 weeks after the injection of the composition of the present invention;

(10) FIG. 9 is a diagram showing the change of facial contouring in patient C before and 2 weeks months after the injection of the composition of the present invention;

(11) FIG. 10 is a diagram showing the change of facial contouring in patient D before and 2 weeks after the injection of the composition of the present invention;

(12) FIG. 11 is a diagram showing the change of facial contouring in patient E before and 4 weeks after the injection of the composition of the present invention;

(13) FIG. 12 is a diagram showing the change of facial contouring in patient F before and after the one-time injection of the composition of the present invention;

(14) FIG. 13 is a diagram showing the change of facial contouring in patient G before and 1 month after the injection of the composition of the present invention; and

(15) FIG. 14 is a diagram showing the change of facial contouring in a female patient (patient H) before and 1 month after the injection of the composition of the present invention.

(16) FIG. 15 is a diagram showing the change of facial contouring in a male patient (patient I) before and 1 month after the injection of the composition of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

(17) Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings.

(18) The present invention provides a composition for facial contouring, comprising a mixture of botulinum toxin and air.

(19) In the present invention, the term botulinum toxin refers to a molecule that has the biological activity of botulinum toxin and may be a protein, polypeptide, peptide, fusion protein, truncated protein, chimeric protein, mutant protein, or recombinant protein.

(20) The biological activity of the toxin refers, within the context of the present invention, to muscular paralysis or inhibition of exocytosis, in particular, inhibition of exocytosis of acetylcholine or other neurotransmitters.

(21) Pure or substantially pure botulinum neurotoxin can be obtained from a protein complex containing botulinum toxin, for example, according to the method described in the literature (Current topics in Microbiology and Immunology (1995), 195, p. 151-154). Pure or substantially pure botulinum neurotoxin can be obtained, for example, by purification of a fermentation medium or culture broth containing Clostridium botulinum and can be enriched, for example, with meat or protein-rich food.

(22) The botulinum toxin may comprise at least one selected from the group consisting of botulinum toxin serotypes A, B, C, D, E, F and G, preferably botulinum toxin serotype A or B. The botulinum toxin may comprise both commercially available Dysport and Botox, botulinum neurotoxin Type A, without limitation. Moreover, commercially available Myobloc, botulinum toxin Type B, may be included in the botulinum toxin.

(23) The botulinum toxin and air may be mixed in a volume ratio of 1:0.1 to 1:20, preferably in a volume ratio of 1:10.

(24) The composition of the present invention may be used in various forms for facial contour and may be injected into a superficial muscular aponeurotic system (SMAS) layer.

(25) As used herein, the term superficial muscular aponeurotic system (SMAS) refers to a tough muscular layer under the facial skin, which is located about 4.5 mm from the skin between the subcutaneous fat layer and the muscular layer. The SMAS has a structure in which some thin layer of muscular fascia connects to fibrous septa of the subcutaneous tissue to deliver the movement of facial muscles to the skin, and thus is also known as the muscles of facial expression. With age, the SMAS layer is weakened and pulled down by gravity, causing wrinkles.

(26) As shown in FIG. 1, the SMAS may be imagined as a thin plastic bag covering the entire head, composed of thin muscle fibers of the facial muscles. The SMAS has an obvious layer in the outer part of the face. However, the layer becomes obscure in the inner part of the face and is absent in the center of the face such as perioral area. The network of the SMAS acts as a distributor of force for various facial muscles, and thus a blended smooth expression of the face is made.

(27) When the composition of the present invention is injected into a specific plane of the SMAS, it partially paralyzes the SMAS, strengthens the contraction of adjacent SMAS to adjust the equilibrium point of the whole SMAS in a normal static state, which causes the movement or contraction of the SMAS, which in turn draws back the galea aponeurotica to lift up the scalp backwards as shown in FIG. 2.

(28) As such, the effect of drawing back the galea aponeurotica lifts up the face or change the facial contour.

(29) The composition of the present invention may further comprise appropriate carriers, excipients, and diluents which are generally used in the preparation of pharmaceutical compositions.

(30) The composition of the present invention may preferably be formulated in the form of liquid, aerosol, and sterile injection, and most preferably, the mixture of botulinum toxin and air may be formulated in the form of aerosol. When the composition is formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc. may be used.

(31) The composition of the present invention may optionally comprise a dispersant. As used herein, the dispersant refers to any substance or additive capable of preventing or minimizing undesired or uncontrolled agglomeration between the botulinum toxin and the carrier of the present invention. The dispersant is useful when a concentrated botulinum toxin solution is to be employed due to capacity limit, for example. In these cases, the dispersant allows the botulinum toxin to be dispersed, thus preventing the agglomeration of toxins which may occur in the absence of the dispersant. In general, the dispersant (1) is non-irritating, (2) does not destroy the botulinum toxin, (3) does not cause an increase in permeability, (4) has a reliable and stable particle size, (5) does not have a charge, and (6) does not interfere with complexes of toxins and transdermal carriers.

(32) The injection of the present invention refers to the administration of a predetermined composition of the present invention to a subject by any suitable route.

(33) The preferred dosage of the pharmaceutical composition of the present invention depends on the condition and weight of a patient, the severity of disease, the type of drug, the route and duration of administration, etc., but may be appropriately selected by those skilled in the art. For the desired effect, the composition of the present invention may be administered in an amount of 0.1 unit to 3000 units per injection, preferably 1 unit to 10 units, based on the content of botulinum toxin type A. The composition of the present invention may be administered once or several times a day.

(34) The sites of administration of the composition of the invention are shown in FIGS. 3 to 6.

(35) FIG. 3 shows a human head without facial movement, FIG. 4 shows a contracting state of the frontal belly, FIG. 5 shows a contracting state of the orbicularis oris and levator labii superioris muscles, and FIG. 6 shows a contracting state of the platysma where the facial skin drops down.

(36) As shown in FIG. 4, the skins marked with yellow spots and red spots are gathered in red posts just above the eyebrows. When the composition of the present invention is injected into three yellow spots in the immediate vicinity of the red spot, the contraction of the superficial fascia in the occipital region is strengthened, and as a result, the facial skin in the frontal region is pulled toward the occipital region, which in turn lifts up the entire upper face.

(37) Moreover, as shown in FIG. 5, there are muscles that contract towards the occipital region in a direction opposite to the blue arrow indicating muscles that contract from the ear to the cheekbone, and when the composition of the present invention is injected into the yellow spots and red spots around the cheekbone, the contraction in the direction of the yellow arrow is strengthened, and thus the cheekbone is reduced.

(38) Furthermore, as shown in FIG. 6, when the composition of the present invention is injected into the region along the red line indicating the jawline to selectively paralyze the platysma SMAS, the contraction of the SMAS is strengthened along the yellow spots in the occipital region, and as a result, the lower face is reduced, exhibiting the lifting effect.

(39) The composition of the present invention may be used alone or in conjunction with surgery, radiation therapy, hormone therapy, chemical therapy, and methods using biological response modifiers for facial contouring.

(40) Moreover, the present invention provides an aerosol spray kit comprising the composition formulated in the form of aerosol.

(41) The aerosol form can control the spread of botulinum toxin to limit its effects on cut planes. Moreover, aerosol form can deliver a tiny amount of botulinum toxin to the target SMAS to adjust the tug-of-war between muscle fibers in SMAS.

(42) The present invention provides a kit comprising a device for injecting the botulinum toxin into the skin and a carrier as well as a liquid, gel, cream, etc. suitable for use in the skin or epithelium of a subject. The kit for administration of the composition of the present invention under the instructions of a medical practitioner or by a patient or subject may comprise a custom applicator suitable for that purpose.

(43) Moreover, the present invention provides a method of facial contouring, comprising injecting a mixture of botulinum toxin and air into a superficial muscular aponeurotic system (SMAS) layer.

(44) In the above step, when the mixture of botulinum toxin and air is injected into the SMAS layer, the mixture draws back the galea aponeurotica to effectively lift up the face or change the facial contour.

(45) The botulinum toxin and air may be mixed in a volume ratio of 1:0.1 to 1:20, preferably in a volume ratio of 1:10.

(46) The injection may be performed by administering the mixture to the SMAS layer through a 28-gauge to 31-gauge syringe needle, and the mixture may preferably be sprayed through a 31-gauge syringe needle and may be sprayed and injected into the SMAS layer at a very high pressure by Bernoulli's fluid dynamics. Moreover, a BD insulin syringe with a 28-gauge to 31-gauge syringe needle may be used.

(47) The injection may preferably be performed by spraying the mixture in the form of aerosol.

(48) Unlike conventional botulinum toxin injections that paralyze the target muscles, the method of facial contouring using the composition of the present invention can exhibit longer treatment duration lasting more than a year, because it partially paralyzes the muscles treated to induce strengthened untreated adjacent muscles, generating muscle tone shift. Accordingly, the method of the present invention can be an excellent substitute for various facial contouring procedures such as double jaw surgery, reduction mandibuloplasty, and reduction zygoplasty.

(49) Hereinafter, the present invention will be described in detail with reference to Examples. However, the following Examples are merely illustrative of the present invention and the present invention is not limited by the following Examples.

Example 1: Preparation of Composition Comprising Mixture of Botulinum Toxin and Air

(50) A 0.5 U/cc botulinum toxin solution was prepared by adding 10 cc saline solution to a bottle containing 100 U Botox, botulinum toxin Type A. The prepared botulinum toxin solution was loaded in a BD Ultra-Fine II Short Needle Insulin Syringe 3/10 cc 31 G8 mm ( 5/16 in), and air was drawn into the corresponding syringe to prepare a mixture of botulinum toxin and air in a volume ratio of 1:10 and 1:20, respectively.

Example 2: Determination of Effect of Facial Contouring

(51) The effect of facial contouring was determined by injecting the composition in the form of aerosol prepared in Example 1 into the SMAS layer of each of eight patients (A to H). The appearance after the treatment was compared to that before the treatment, and the results are shown in FIGS. 7 to 15.

(52) Cheekbones of patient A were reduced using a 1:10 mixture of allergan botox, botulinum toxin Type A, and face reduction and lifting surgery was performed on patient B using a 1:20 mixture of allergan botox.

(53) 1:10 mixtures, each comprising Dysport, Xeomin, Meditoxin, and BTX-A, botulinum toxin Type B, respectively, were used in patients C to F, and 1:10 and 1:20 mixtures of Myobloc, botulinum toxin Type, were used in patients G and H, respectively.

(54) As shown in FIGS. 3 to 6, all of the patients subjected to the treatment of the present invention had the effect of facial contouring and, in particular, severe asymmetries of patients E and F were corrected by injecting the composition into the right face only.

(55) In the following, formulation examples of the composition of the present invention will be illustrated.

Formulation Example 1: Pharmaceutical Composition

(56) 1.1 Preparation of Injection

(57) TABLE-US-00001 Mixture of botulinum toxin and air of the present invention 10 mg Mannitol 180 mg Sterile distilled water for injection 2974 mg Na.sub.2HPO.sub.42H.sub.2O 26 mg

(58) An injection is prepared with the above ingredients per ampoule (2 ml) according to a conventional method for preparing injections.

(59) 1.2 Preparation of Liquid Formulation

(60) TABLE-US-00002 Mixture of botulinum toxin and air of the present invention 10 mg Isomerized sugar 10 g Mannitol 5 mg Purified water Proper quantity

(61) A liquid formulation is prepared according to a conventional method for preparing liquid formations by dissolving each ingredient in purified water, adding a proper quantity of lemon flavor, mixing the ingredients, adding purified water to the resulting mixture to regulate the total mixture to 100 ml, filling the mixture in a brown bottle, and sterilizing the mixture.

(62) As described above, when the mixture of botulinum toxin and air the injection of is injected into the SMAS layer, the mobility of untreated adjacent SMAS layer is strengthened, and thus the SMAS layer contracts, which in turn draw back the galea aponeurotica to effectively lift up the face or change the facial contour, thus effectively enhancing the effect of facial contouring.

(63) While the invention has been shown and described with reference to certain preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the scope of the invention is defined not by the detailed description of the invention but by the appended claims, and all differences within the scope will be construed as being included in the present invention.