Injectable Botulinum Toxin Formulations And Methods Of Use Thereof Having Long Duration Of Therapeutic Or Cosmetic Effect

Abstract

This invention provides novel injectable compositions comprising botulinum toxin that may be administered to a subject for various therapeutic, aesthetic and / or cosmetic purposes. The injectable compositions embraced by the invention exhibit one or more advantages over conventional botulinum toxin formulations, including reduced antigenicity, a reduced tendency to undergo unwanted localized diffusion following injection, increased duration of clinical efficacy or enhanced potency relative, faster onset of clinical efficacy, and / or improved stability. According to the invention, single treatment of the compositions by injection affords significant clinical responses and at least a 6-month duration of effect in a subject undergoing treatment, as provided by the described treatment methods.

Description

FIELD OF THE INVENTION[0001]This invention relates to novel injectable compositions comprising botulinum toxin that may be administered to a subject for various therapeutic, aesthetic and / or cosmetic purposes. The injectable compositions and methods in which these compositions are used provide advantageous treatments which result in high responder rates and long duration of effect, for example, a duration of effect for over 20 to 24 weeks and longer.BACKGROUND OF THE INVENTION[0002]Skin protects the body's organs from external environmental threats and acts as a thermostat to maintain body temperature. It consists of several different layers, each with specialized functions. The major layers include the epidermis, the dermis and the hypodermis. The epidermis is a stratifying layer of epithelial cells that overlies the dermis, which consists of connective tissue. Both the epidermis and the dermis are further supported by the hypodermis, an internal layer of adipose tissue.[0003]The e...

AI Technical Summary

Benefits of technology

[0015]In one of its aspects, this invention provides injectable compositions comprising botulinum toxin non-covalently associated with a positively charged carrier molecule. In preferred embodiments, the compositions of the invention possess one or more advantages over conventional commercial botulinum toxin formulations, such as BOTOX® or MYOBLOC®. For instance, in certain embodiments, the compositions may exhibit one or more advantages over conventional injectable botulinum formulations, including reduced antigenicity, a reduced tendency to undergo diffusion into surrounding tissue following injection, increased duration of clinical efficacy or enhanced potency relative to conventional botulinum toxin formulations, faster onset of clinical efficacy, and / or improved stability.

[0016]Another aspect of this invention is the recognition that certain non-native molecules (i.e., molecules not found in botulinum toxin complexes obtained from Clostridium botulinum bacteria) can be added to botulinum toxin, botulinum toxin complexes, and in particular reduced botulinum toxin complexes (as defined herein), to improve toxin diffusion through tissues. The non-native molecules associate non-covalently with the toxin and act as penetration enhancers that improve the ability of the toxin to reach target structures after injection. Furthermore, the non-native molecules may increase the stability of the toxin prior to and after injection. By way of example, the penetration enhancers may be positively charged carriers, such as cationic peptides, which have no inherent botulinum-toxin-like activity and which also contain one or more protein transduction domains as described herein.

[0019]In another aspect, the invention provides effective doses and amounts of the compositions of this invention that afford a long-lasting, sustained efficacy e.g., a response rate of long duration, following administration by injection to a subject or patient in need of treatment. Such doses and amounts are preferably therapeutically or cosmetically effective doses and amounts that produce or result in a desired therapeutic or cosmetic effect in a subject to whom the doses and amounts are administered. In an embodiment, the effect of reducing wrinkles and lines of the face, particularly, glabellar lines, provided by a dose of a composition of the invention administered by injection as a single treatment to the subject or patient in need, lasted several weeks to several months compared with conventional treatment, such as BOTOX® Cosmetic injection. In particular embodiments, and as described in the Examples herein, a single treatment of a subject or patient with a composition of the invention comprising a botulinum toxin, such as botulinum toxin A, and a positively charged carrier, as described herein, in therapeutically effective amounts of 20 U to 60 U, afforded a response rate of wrinkle and facial line reduction for at least 20 weeks, at least 24 weeks, or about 6 to 10 months, or even longer, compared with conventional BOTOX® injection. Moreover, the compositions of the invention provide an attribute of reduced diffusion or spread from the injection site following injection, thereby localizing the toxin and its effect where desired and decreasing nonspecific or unwanted effects of the toxin at sites or locations distant from the site of injection for treatment.

[0020]The duration of effect provided by compositions of the invention, e.g., RT002 of Example 5, as well as by the described treatment methods and uses, affords significant advantages compared to the art. By way of example, subjects undergoing treatment, such as aesthetic treatment, with compositions containing botulinum toxin consider that duration of effect following treatment is of high importance to them. Such a long, sustained duration of effect, which is achieved by even a single treatment with an effective dose of a product of the invention, for example, RT002, permits fewer injections per treatment course for a subject, which is extremely important for the subject. A prolonged duration effect from a single treatment with a product which has clear efficacy and safety, as provided by the inventive compositions and methods described herein, offer less discomfort, less cost and more convenience to subjects undergoing a course of treatment. Furthermore, a product that affords significant and sustained effects, which are maintained for at least a 20 or 24 week period, or for at least a 6-month period, or for greater than a 6-month period, following the single injectable treatment of the product to a subject, provides a solution to an unmet need in the art for both practitioners and patients alike. Thus, the compositions and methods of the invention provide a solution to the problem of too frequent treatments and improve patients' overall well-being. Such prolonged duration of action provides for fewer treatments over an entire treatment course.

[0022]In another aspect, the invention provides a method of reducing wrinkles, lines, or furrows in an individual in need thereof, the method comprising administering to the individual as a single dose injection a composition comprising: a botulinum toxin, a botulinum toxin complex, or a reduced botulinum toxin complex and a positively charged carrier comprising a positively charged polylysine backbone having covalently attached thereto one or more positively charged efficiency groups having an amino acid sequence of (gly)p-RGRDDRRQRRR-(gly)q, (gly)p-YGRKKRRQRRR-(gly)q or (gly)p-RKKRRQRRR-(gly)q, wherein the subscripts p and q are each independently an integer of from 0 to 20; and a pharmaceutically acceptable diluent for injection; wherein the botulinum toxin is administered to the individual in an amount of 20 U to 60 U; wherein the positively charged carrier is non-covalently associated with the botulinum toxin, botulinum toxin complex, or reduced botulinum toxin complex component; and wherein the single dose injection of the composition provides a single treatment having at least about a six month to about a 10 month duration of effect in reducing the wrinkles, lines, or furrows in the individual, thereby extending treatment interval duration for the individual. In an embodiment, the composition reduces, or reduces the severity of, glabellar lines in the face of the individual.

[0024]In some embodiments of these above methods and composition, the composition comprises botulinum toxin of serotype A, preferably a serotype A botulinum toxin having a molecular weight of 150 kDa. In an embodiment, the positively charged carrier has the amino acid sequence RKKRRQRRRG-(K)15-GRKKRRQRRR. In an embodiment, the botulinum toxin is present in the composition in a dosage amount of 20 U. In an embodiment, the botulinum toxin is present in the composition in a dosage amount of 40 U. In an embodiment, the botulinum toxin is present in the composition in a dosage amount of 60 U. In an embodiment, the composition reduces the severity of glabellar lines in an individual who has undergone a single treatment by injection of the composition. In certain embodiments, the duration of the treatment effect comprises greater than 6 months; greater than 7 months; greater than 8 months; greater than 9 months; or at least 6 months through 10 months.

Problems solved by technology

When the horny layer loses its softness and flexibility it becomes rough and brittle, resulting in dry skin.

Spores of C. botulinum are found in soil and can grow in improperly sterilized and sealed food containers.

Botulism, which may be fatal, may be caused by the ingestion of the bacteria.

Its action essentially blocks signals that normally would cause muscle spasms or contractions, resulting in paralysis.

However, there are several problems associated with this approach.

The botulinum toxin may migrate from these subdermal wells to cause unwanted paralysis in surrounding areas of the body.

This problem is exacerbated when the area to be treated is large and many injections of toxin are required to treat the area.

Moreover, because the injected toxin complexes contain non-toxin proteins and albumin that stabilize the botulinum toxin and increase the molecular weight of the toxin complex, the toxin complexes have a long half-life in the body and may cause an undesirable antigenic response in the patient.

For example, some patients will, over time, develop an allergy to the albumin used as a stabilizer in current commercial formulations.

When this happens, subsequent injections must be carefully placed so that they do not release a large amount of toxin into the bloodstream of the patient, which could lead to fatal systemic poisoning, especially since the non-toxin proteins and albumin stabilize the botulinum toxin in blood.

Images