WO2010114828A1 - Methods and compositions for treating skin conditions associated with vascular hyper-reactivity - Google Patents
Methods and compositions for treating skin conditions associated with vascular hyper-reactivity Download PDFInfo
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- WO2010114828A1 WO2010114828A1 PCT/US2010/029183 US2010029183W WO2010114828A1 WO 2010114828 A1 WO2010114828 A1 WO 2010114828A1 US 2010029183 W US2010029183 W US 2010029183W WO 2010114828 A1 WO2010114828 A1 WO 2010114828A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
- A61K38/4893—Botulinum neurotoxin (3.4.24.69)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
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- 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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to the treatment of skin conditions characterized by vascular hyper-reactivity, or hyper-reactive vascular dilation.
- the present invention relates to the use of a topical formulation of botulinum neurotoxin for treating conditions such as rosacea, or for preventing or slowing progression of rosacea.
- Rosacea is a chronic condition characterized by facial redness that can progress into dilated superficial blood vessels in the face, red-domed papules, burning and itching sensations, and a red, bulbous nose. Rosacea affects over 14 million Americans (National Rosacea Society, 2009), and the peak age of onset is between 30 and 60 years.
- Rosacea may be classified into at least four subtypes with varying symptoms, and a patient may concurrently be afflicted with one or more subtypes (Wilkin et al. (2004), J Am Acad Dermatol, Vol. 50 (6): 907-12).
- Erythematotelangiectatic rosacea is characterized by a permanent erythema ⁇ i.e. redness) of the cheeks, forehead, and nose and the patient has a tendency to flush and blush easily.
- small blood vessels are visible near the surface of the skin (e.g. telangiectasias) and the individual may experience burning or itching sensations.
- Papulopustular rosacea can be easily confused with acne due to the presence of some permanent redness across the central face with red papules, some of which are pus filled (pustules).
- Phymatous rosacea is the subtype most commonly associated with rhinophyma, an enlargement of the nose due to sebaceous gland hyperplasia. Symptoms of phymatous rosacea can include thickening skin, irregular surface nodularities, and enlargement, which can also affect the chin, forehead, cheeks, eyelids, and ears (Jansen and Plewig G (1998), Facial Plast Surg, Vol. 14 (4): 241-53).
- a fourth subtype, known as ocular rosacea affects primarily the eyes and is characterized by red, irritated eyes, swollen eyelids, recurrent styes, and sensations of itching and burning.
- rosacea The symptoms of rosacea are socially disabling for many patients and the condition may last for years and rarely reverses itself without treatment. Treatments are typically individually tailored due to the varying type and severity of symptoms.
- Various oral and topical medications including antibiotics, retinoids, benzoyl peroxide, and beta blockers, are initially prescribed to bring the condition under control, which may take up to one to two years. Long term treatment is often necessary to maintain remission of the condition.
- the more advanced stages of rosacea can require laser, intense light source, or surgical treatment to remove visible superficial blood vessels, reduce extensive redness, or ameliorate disfigurements of the nose.
- topical treatments have the advantage of avoiding unwanted systemic toxicity, the effectiveness of topical treatments can be limited by, for example, large areas of affected skin, the varying depths of the skin microvasculature, and individual variations in patient skin.
- the present invention provides methods and compositions for treating, reducing, or ameliorating vasodilation in the cutaneous microvasculature.
- the present invention is useful for treating or ameliorating the vascular hyper-reactivity that characterizes conditions such as rosacea.
- the methods and compositions of the invention may alleviate symptoms such as chronic or episodic flushing and blushing, and prevent their progression to rosacea.
- the present invention provides a method for treating a patient having a skin condition characterized by cutaneous vascular hyper-reactivity, such as chronic or episodic flushing or blushing, or rosacea.
- the method comprises applying a topical composition to the affected area(s) of the patient's skin.
- the topical composition comprises an effective amount of a botulinum neurotoxin for decreasing vasodilation in the cutaneous microvasculature, and a carrier for effectively transporting the botulinum toxin to the cutaneous microvasculature.
- the botulinum neurotoxin is formulated with a positively-charged peptide carrier (e.g., polylysine) having one or more protein transduction domains (or transporter domains), such as HIV-TAT or reverse HIV- TAT amino acid sequences.
- a positively-charged peptide carrier e.g., polylysine
- the method may involve a single application of topical botulinum toxin to the affected regions, or in certain embodiments, may involve repeated application.
- the invention allows for effective amounts of botulinum toxin to be controllably applied to affected regions of the skin, and controllably delivered to the underlying microvasculature.
- the invention thereby provides a safe, effective, and comfortable manner of treating vascular hyper-reactivity in skin, so as to treat, ameliorate, or prevent progression of rosacea, and/or to prevent chronic or episodic vascular hyperreactivity from progressing to a condition such as rosacea.
- the present invention provides compositions, formulations, kits, and/or other vehicles or devices for topically administering botulinum neurotoxin for the treatment of cutaneous vascular hyper-reactivity.
- the invention provides creams, lotions, gels, and patches that allow the botulinum neurotoxin and carrier to be conveniently, safely, comfortably and/or controllably applied to the affected area(s) of the patient's skin.
- the present invention provides methods and compositions for treating, reducing, or ameliorating vasodilation in the cutaneous microvasculature.
- the present invention is useful for treating or ameliorating the vascular hyper-reactivity that characterizes conditions such as rosacea.
- the invention involves applying a topical composition to affected area(s) of the patient's skin.
- the topical composition comprises an effective amount of a botulinum neurtotoxin for decreasing vasodilation in cutaneous microvasculature, and a carrier for effectively transporting the botulinum toxin to the cutaneous microvasculature.
- Botulinum toxin is known to mediate the effects of acetylcholine in soft tissue
- botulinum toxin is administered topically to decrease vasodilation in the cutaneous microvasculature, to thereby reduce vascular hyper-reactivity in skin.
- the invention decreases or eliminates chronic or episodic flushing or blushing as solitary conditions, and/or, delays or prevents the progressive disease of rosacea, e.g., flushing, papules, and eventual rhinophyma.
- Vasoconstriction may be mediated by inhibiting the release of vasoactive intestinal peptide (VIP), calcitonin gene-related-peptide (CGRP) or other peptides contained in presynaptic vesicles.
- VIP vasoactive intestinal peptide
- CGRP calcitonin gene-related-peptide
- Vasodilator neuropeptides are involved in vascular tone of the peripheral circulation by enhancing nitric oxide formation in the microvasculature of the human dermis.
- botulinum neurotoxin may decrease vasodilation in cutaneous microvasculature by blocking the release of vasodilator neuropeptides, such as CGRP and VIP that are co-released with acetylcholine from sudomotor nerve terminals.
- vasodilators with botulinum neurotoxin can lead to vasoconstriction or the avoidance of vasodilation and the avoidance of blushing and flushing of the skin, and thus the subsequent development of the progressive disease of rosacea.
- Existing treatments for rosacea include topical and oral antibiotics, benzoyl peroxide, retinoids, beta blockers, cortisone cream, and laser or intense pulse light treatments. All of these treatments are associated with one or more disadvantages.
- Topical and oral antibiotics have the risk of promoting bacterial multidrug resistance and allergic reactions, which can result in death.
- Benzoyl peroxide and retinoids can be irritating to the skin, and cortisone creams are limited to short-duration uses and can cause a rebound flare up when discontinued.
- Beta blockers can produce unwanted side effects, such as fatigue and sexual dysfunction.
- Associated risks with laser and intense pulse light treatments include scarring, bruising, longer recovery, higher cost, and pain.
- the topical botulinum neurotoxin compositions and associated treatments as described herein overcome disadvantages associated with the existing treatments for rosacea.
- the compositions can be applied over a large area, do not cause pain, provide a prolonged period of relief, and eliminate the risk of overuse of antibiotics in a chronic condition.
- the topical formulation overcomes some of the technical difficulties of using injectable botulinum neurotoxin. For instance, administration of injectable botulinum neurotoxin is operator dependent and can be injected too deeply into facial nerves and muscles resulting in a functional impairment and facial asymmetry.
- compositions of the invention offer a dilute topical form of botulinum toxin that is designed to target the superficial layers of skin, and which can be applied evenly over large areas.
- the invention thereby provides a safe, effective, comfortable, and/or convenient manner of treating vascular hyper-reactivity in skin, including chronic or episodic vascular hyper-reactivity, so as to treat or ameliorate rosacea, and/or to prevent the chronic or episodic vascular hyper-reactivity from progressing to a condition such as rosacea.
- the patient to be treated has a skin condition associated with cutaneous vascular hyper-reactivity, such as, without limitation, flushing, blushing, and rosacea.
- Flushing is an episodic attack of redness of the skin together with a sensation of warmth or burning of the face, neck, and less frequently the upper trunk and abdomen. It is the transient nature of the attacks that distinguishes flushing from the persistent erythema of photosensitivity, acute contact reactions, or solar elastosis (Greaves (1998) Flushing and flushing syndromes, rosacea and perioral dermatitis. In: Champion RH, et al, eds. Rook/Wilkinson/Ebling textbook of dermatology, 6th ed., Vol. 3: 2099-2104).
- the flushing or blushing may result from an underlying condition or disease including, but not limited to, social phobia (e.g. generalized anxiety disorder, panic disorder), alcoholism, menopause and premenstrual syndrome, diabetes, lung disorders or diseases (e.g.
- emphysema chronic bronchitis
- insect sting allergies pregnancy, mastocytosis, Soto's Syndrome, Zollinger-Ellison syndrome, Cushing's syndrome
- Hodgkin's disease septicemia, yellow fever, niacin derivatives, acipimox, Acute Stress Disorder, adrenal cancer, anticholinergic syndrome, hemorrhagic fever, autonomic dysreflexia syndrome, carcinoid syndrome, hyperadrenalism, hyperemia, hyperglycemia, hypergonadotropic ovarian failure, gastro-enteropancreatic neuroendocrine tumor, hypermagnesaemia, hyperthyroidism, medullary thyroid carcinoma, mitral valve disease, opioid withdrawal, neuroblastoma, niacin toxicity, paraneoplastic autoimmune syndromes, pituitary gland diseases, spinal autonomic dysreflexia, thymus cancer, and thyroid cancer.
- the patient has (e.g., has been diagnosed with) rosacea, such as one or more of erythematotelangiectatic rosacea, papulopustular rosacea, phymatous rosacea, and/or ocular rosacea.
- rosacea such as one or more of erythematotelangiectatic rosacea, papulopustular rosacea, phymatous rosacea, and/or ocular rosacea.
- the patient has one or more symptoms of rosacea.
- the one or more symptoms of rosacea include erythema, flushing, blushing, telangiectasias, papules, pustules, rhinophyma, burning sensations, and itching sensations.
- Such one or more symptoms are improved or ameliorated in accordance with the invention.
- the patient has rosacea, but does not yet have rhinophyma, which frequently occurs with phymatous rosacea or in advanced stages of rosacea.
- Rhinophyma is a slow growing benign tumor on the nose caused by the hypertrophy of sebaceous glands at the tip of the nose.
- the compositions and methods of the present invention may prevent the development of rhinophyma.
- Botulinum toxins or botulinum neurotoxins are neurotoxins produced by the gram-positive bacteria Clostridium botulinum and are one of the most lethal substances known to man.
- the neurotoxins are well known to produce paralysis of muscles by preventing release of acetylcholine from pre-synaptic nerve terminals at the neuromuscular junction.
- the neurotoxins can inhibit synaptic transmission at cholinergic synapses of the autonomic nervous system as well.
- Botulinum toxin is classified into eight neurotoxins that are serologically related, but distinct. Of these, seven can cause paralysis, namely botulinum neurotoxin serotypes A, B, C, D, E, F and G. Each of these serotypes is distinguished by neutralization with type-specific antibodies. Each serotype can be isolated from the bacteria or produced recombinantly. The molecular weight of the purified, active botulinum toxin protein molecule for all seven of the toxin serotypes is about 150 kDa, which includes a 100 kDa heavy chain and a 50 kDa light chain.
- the botulinum toxins are complexes comprising the 150 kDa botulinum toxin protein molecule along with associated non-toxic proteins.
- the botulinum toxin type A complex can be produced by Clostridia as 900 kDa, 500 kDa and 300 kDa forms.
- Botulinum toxin types B and C can be produced as a 700 kDa or 500 kDa complex.
- Botulinum toxin type D is produced as both 300 kDa and 500 kDa complexes, while botulinum toxin types E and F are produced as only approximately. 300 kDa complexes.
- the nontoxic proteins associated with the 150 kDa botulinum toxin are thought to provide stability against denaturation and provide protection against digestive acids when toxin is ingested. While the complexed forms of the botulinum neurotoxins described above may be used in connection with the compositions and methods described herein, in certain embodiments of the invention, the botulinum toxin is purified ⁇ e.g. not associated with accessory proteins) and has a molecular weight of about 150 kDa.
- the botulinum toxin may be selected from botulinum toxin serotypes A, B, C,
- the botulinum toxin is botulinum toxin serotype A, including Types Al, A2 and/or Type A3.
- Exemplary Type A producing strains include the Hall Strain (Type Al), Kyoto F (Type A2), and NCTC 2916 (Type Al). See Jacobson et al., Analysis of Neurotoxin Cluster Genes in Clostridium botulinum Strains Producing Botulinum Neurotoxin Serotype A Subtypes, Appl. Environ. Microbiol. 74(9):2778-2786 (2008).
- Botulinum toxin suitable for use in the methods and compositions of the invention can be produced by the Clostridia bacteria and purified, or alternatively produced by recombinant or synthetic techniques.
- the toxin may be a recombinant peptide, a fusion protein, or a hybrid neurotoxin, as prepared from subunits or domains of different botulinum toxin serotypes (see, e.g., U.S. patent 6,444,209, which is hereby incorporated by reference).
- botulinum toxin serotypes All seven botulinum toxin serotypes (A, B, C, D, E, F, and G) are commercially available from Sigma-Aldrich and from Metabiologics, Inc. (Madison, Wisconsin), as well as from other sources. At least two types of botulinum toxin, types A and B, are available commercially in formulations for treatment of certain human conditions. Type A, for example, is contained in BOTOX® (Allergan) and DYSPORT® (Ipsen), and Type B is contained in MYOBLOC® (Elan).
- the botulinum toxin may alternatively be a botulinum toxin derivative, e.g., a compound that has botulinum toxin activity but contains one or more chemical or functional alterations relative to naturally occurring or recombinant native botulinum toxins.
- the botulinum toxin can be a modified neurotoxin, e.g., a neurotoxin which has at least one of its amino acids deleted, modified or replaced, as compared to a native, or a recombinantly produced neurotoxin.
- the botulinum toxin may be a Type A (including type A2 or Type A3) or Type B toxin having from 1 to about 20, or from 1 to about 10, or from 1 to about 5, amino acid substitutions, deletions, and/or insertions (collectively).
- the botulinum toxin may be a portion of the overall molecule that possesses the necessary botulinum toxin activity, and in such case may be used per se or as part of a combination or conjugate molecule, for instance a fusion protein.
- the botulinum toxin is a combination of botulinum toxin serotypes.
- the invention may employ a combination of botulinum toxin serotype A and serotype B.
- botulinum toxin is formulated with a carrier for effectively transporting the botulinum toxin to the cutaneous microvasculature.
- the invention allows for effective amounts of botulinum toxin to be controllably applied to affected regions of the skin (which may be large areas), and controllably delivered to the underlying microvasculature.
- the carrier is a peptide carrier or a non-peptide polymeric carrier, and is generally positively charged.
- the carrier may comprise at least one protein transduction domain or transport domain, such as an HIV-TAT or reverse HIV-TAT amino acid sequence, as described in WO 2008/082885, which is hereby incorporated by reference.
- exemplary transport domains have an amino acid sequence that corresponds to the reverse sequence of the HIV-TAT basic region (amino acids 49-57 of naturally-occurring HIV-TAT protein).
- the reverse sequence of the HIV-TAT basic region (RRRQRRKKR (SEQ ID NO: I)) is hereafter referred to as "reverse HIV-TAT.”
- Exemplary carriers thus include the peptides described in WO 2009/015385, which is hereby incorporated by reference in its entirety.
- the carrier may be a cationic peptide that comprises an HIV-TAT sequence or reverse HIV-TAT sequence at the N- or C-terminus, or both the N-terminus and the C-terminus.
- the peptide carrier may have an HIV-TAT sequence, such as Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg (SEQ ID NO:2), or a reverse HIV TAT sequence, such as Arg-Arg-Arg-Gln-Arg-Arg-Lys- Lys-Arg (SEQ ID NO:1), at the N- or C-terminus or both the N-terminus and the C-terminus.
- HIV-TAT sequence such as Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg (SEQ ID NO:2)
- a reverse HIV TAT sequence such as Arg-Arg-Arg-Gln-Arg-Arg-Lys- Lys-Arg (SEQ ID NO:1), at the N- or C-terminus or both the N-terminus and the C-terminus.
- the carrier comprises an N-terminal portion that is an
- HIV-TAT or reverse HIV-TAT sequence a C-terminal portion that is an HIV-TAT or reverse HIV-TAT sequence, and one or more cationic residues (e.g., Lys or Arg) between the N- terminal portion and the C-terminal portion.
- the peptide may have from 5 to 20 cationic residues such as Lys between the N-terminal portion and the C-terminal portion, such as about 12, about 15, or about 17 cationic residues.
- Exemplary carriers thus include Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Gly-(Lys)n-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg- Arg-Arg (SEQ ID NO:3), or Arg-Arg-Arg-Gln-Arg-Arg-Lys-Lys-Arg-Gly-(Lys)n- Gly-Arg- Arg-Arg-Gln-Arg-Arg-Lys-Lys-Arg (SEQ ID NO:4), where n is from about 5 to about 20, such as from about 10 to about 20.
- the N-terminal portion of the peptide is an HIV-TAT sequence and the C-terminal portion of the peptide is an HIV-TAT sequence.
- the carrier may comprise peptides where the N-terminal portion is a reverse HIV-TAT sequence and the C-terminal portion is a reverse HIV-TAT sequence.
- the peptide may have the following amino acid sequence: Arg-Lys-Lys-Arg- Arg-Gln-Arg-Arg-Arg-Arg-Gly-(Lys)l 5-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg (SEQ ID NO:5).
- the carrier is characterized as having a particularly high content of
- the carrier may contain at least about 50%, collectively, of Arg and Lys amino acid residues, but may contain at least about 75%, or at least about 80%, Arg and Lys residues.
- such derivatives may have the amino acid sequence of SEQ ID NO: 3, 4, or 5 with from 1 to 5 amino acid substitutions, insertions, or deletions (collectively), including 1, 2, 3, or 4 amino acid substitutions, insertions, or deletions with respect to SEQ ID NO: 3, 4, or 5.
- substitutions, insertions, or deletions are located within the HIV-TAT or reverse HIV-TAT sequence.
- the carrier may be a peptide having a length of from about 15 amino acids to about 100 amino acids. In certain embodiments, the carrier is from about 25 to about 50, or from about 25 to about 40 amino acids in length. In an exemplary embodiment of the invention, the carrier peptide is about 35 amino acids in length.
- the length of the carrier can be designed to carry botulinum neurotoxin to different depths of penetration in the skin by varying the length of the carrier. For example, longer polymeric carriers will penetrate to deeper layers of the skin.
- Other carriers suitable for use in connection with the invention include a positively charged polymeric carrier to deliver the botulinum toxin across the skin barrier to desired depths of the underlying dermis.
- a positively charged polymeric carrier to deliver the botulinum toxin across the skin barrier to desired depths of the underlying dermis.
- Such carriers include the polymeric carriers disclosed in U.S. Patent Publication No. 2004/0220100 and WO 2005/084410, both of which are hereby incorporated by reference in their entireties.
- the positively charged polymeric carrier comprises positively charged branching groups attached to a polymeric backbone.
- positively charged means that the carrier has a positive charge under physiologically compatible conditions.
- the positively-charged polymeric carrier is a linear chain of atoms, either with groups in the chain carrying a positive charge at physiological pH, or with groups carrying a positive charge attached to side chains extending from the backbone.
- the positively charged backbone itself need not have a defined enzymatic or therapeutic biologic activity.
- the linear backbone is a hydrocarbon backbone which is, in some embodiments, interrupted by heteroatoms selected from nitrogen, oxygen, sulfur, silicon and phosphorus. The majority of backbone chain atoms are carbon.
- the backbone can be a polymer of repeating units (e.g., amino acids, poly(ethyleneoxy), poly(propyleneamine), polyalkyleneimine, and the like), but may alternatively be a heteropolymer.
- the polymeric backbone is a positively charged polypeptide (e.g., polylysine).
- the positively charged backbone is a polypropyleneamine wherein a number of the amine nitrogen atoms are present as ammonium groups (tetra-substituted) carrying a positive charge.
- the positively charged backbone may be a nonpeptidyl polymer, which may be a hetero- or homo-polymer such as a polyalkyleneimine, for example a polyethyleneimine or polypropyleneimine, having a molecular weight of from about 10,000 to about 2,500,000, or from about 100,000 to about 1,800,000, or from about 500,000 to about 1,400,000.
- the length of the polymeric carrier can be designed to carry botulinum neurotoxin to different depths of penetration in the skin by varying the length of the carrier. For example, longer polymeric carriers will penetrate to deeper layers of the skin.
- the backbone has attached a plurality of side-chain moieties that include positively charged groups (e.g., ammonium groups, pyridinium groups, phosphonium groups, sulfonium groups, guanidinium groups, or amidinium groups).
- the sidechain moieties may be spaced along the backbone in a consistent or variable manner. Additionally, the length of the sidechains can be similar or dissimilar.
- the sidechains can be linear or branched hydrocarbon chains having from one to twenty carbon atoms and terminating at the distal end (away from the backbone) in one of the above-noted positively charged groups.
- the association between the carrier and the biologically active agent is generally by non-covalent interaction, such as by ionic interactions, hydrogen bonding, van der Waals forces, or combinations thereof.
- the positively charged backbone is a polypeptide having multiple positively charged sidechain groups (e.g., lysine, arginine, ornithine, homoarginine, and the like).
- the polypeptide has a molecular weight of from about 10,000 to about 1,500,000, or from about 25,000 to about 1,200,000, or from about 100,000 to about 1,000,000.
- the sidechains can have either the D- or L-form (R or S configuration) at the center of attachment.
- the backbone can be an analog of a polypeptide such as a peptoid. See, for example, Kessler, Angew. Chem. Int.
- a peptoid is a polyglycine in which the sidechain is attached to the backbone nitrogen atoms rather than the ⁇ -carbon atoms. A portion of the sidechains can terminate in a positively charged group to provide a positively charged backbone component. Synthesis of peptoids is described in, for example, U.S. Patent No. 5,877,278, which is hereby incorporated by reference in its entirety. As the term is used herein, positively charged backbones that have a peptoid backbone construction are considered "non-peptide" as they are not composed of amino acids having naturally occurring sidechains at the ⁇ -carbon locations.
- sidechain groups can be appended that carry a positively charged group.
- the sulfonamide-linked backbones (- SO 2 NH- and -NHSO 2 -) can have sidechain groups attached to the nitrogen atoms.
- the hydroxyethylene (-CH(OH)CH 2 -) linkage can bear a sidechain group attached to the hydroxy substituent.
- One of skill in the art can readily adapt the other linkage chemistries to provide positively charged sidechain groups using standard synthetic methods.
- the positively charged polymeric carrier is a polypeptide having branching groups (also referred to as efficiency groups).
- an efficiency group or branching group is any agent that has the effect of promoting the translocation of the positively charged polymeric carrier through a tissue or cell membrane.
- branching or efficiency groups include HIV-TAT or reverse HIV-TAT (as described) or fragments thereof, the protein transduction domain of Antennapedia, or a fragment thereof, or -(gly) n ]-(arg) n2 , wherein nl is an integer of from about O to about 20, or O to about 8, or 2 to about 5.
- n2 is independently an odd integer of from about 5 to about 25, or about 7 to about 17, or about 7 to about 13.
- Other embodiments employ HIV-TAT fragment or reverse HIV-TAT sequences having the formula (gly) p -RGRDDRRQRRR-(gly) q (SEQ ID NO: 6), (gly) p - YGRKKRRQRRR-(gly) q (SEQ ID NO: 7), or (gly) p -RKKRRQRRR-(gly) q (SEQ ID NO: 8) wherein p and q are each independently an integer of from 0 to 20 and the fragment is attached to the backbone via either the C-terminus or the N-terminus of the fragment.
- HIV- TAT fragments include those in which p and q are each independently integers of from 0 to about 8, such as from 2 to about 5.
- the positively charged side chain or branching group may be the
- the positively charged polymeric carrier may include positively charged branching groups in an amount of at least about 0.05%, as a percentage of the total carrier weight, such as from about 0.05 to about 45%, or about 0.1 to about 30%.
- the amount may be from about 0.1 to about 25 %.
- the backbone portion of the carrier is a polylysine and positively charged branching groups (as described above) are attached to the lysine sidechain amino groups.
- the polylysine may have a molecular weight of from about 10,000 to about 1,500,000, such as from about 25,000 to about 1,200,000, or from about 100,000 to about 1,000,000. It can be any of the commercially available polylysines (Sigma Chemical Company, St. Louis, Missouri, USA) such as, for example, polylysine having MW > 70,000, polylysine having MW of 70,000 to 150,000, polylysine having MW 150,000 to 300,000 and polylysine having MW > 300,000.
- the selection of an appropriate polylysine will depend on the remaining components of the composition and will be sufficient to provide an overall net positive charge to the composition and provide a length that is preferably from one to four times the combined length of the negatively charged components.
- the carrier is a relatively short polylysine or polyethyleneimine (PEI) backbone (which may be linear or branched) and which has positively charged branching groups.
- PEI polyethyleneimine
- Such carriers may be useful for minimizing uncontrolled aggregation of the backbones and botulinum toxin in a therapeutic composition, which causes the transport efficiency to decrease dramatically.
- the carrier is a relatively short linear polylysine or PEI backbone
- the backbone will have a molecular weight of less than about 75,000, or less than about 30,000, or less than about 25,000.
- the carrier is a relatively short branched polylysine or PEI backbone
- the backbone will have a molecular weight less than about 60,000, or less than about 55,000, or less than about 50,000. If, however, partitioning agents as described herein are included in the composition, the molecular weight of the branched polylysine and PEI backbones can be up to about 75,000, while the molecular weight of the linear polylysine and PEI backbones can be up to about 150,000.
- compositions used in the methods of the invention preferably comprise an effective amount of a botulinum toxin.
- An "effective amount” is an amount sufficient to affect a beneficial or desired clinical result, e.g. an amount sufficient to reduce vascular hyper-reactivity in the skin.
- An effective amount in each embodiment will be based on the serotype of botulinum toxin, the form of toxin used ⁇ e.g. complex or purified di-chains), and in some embodiments, factors individual to the patient, including age, condition to be treated ⁇ e.g. flushing, blushing, particular subtype of rosacea), size of skin area to be treated, and severity of symptoms.
- an effective amount is from about 0.1 ng to about 2.0 ng of purified botulinum neurotoxin (e.g., serotype A).
- the effective amount may be from about 0.2 ng to about 1.5 ng, or from about 0.5 ng to about 1.0 ng of purified botulinum neurotoxin (e.g., serotype A or botulinum neurotoxin Type A complex).
- the effective amount may be combined in about 0.5 ml to about 10 mis of cream or gel, as described herein, depending on the size of the area needing treatment.
- compositions for use in the methods of the invention are formulated for application to the skin or epithelium of subjects or patients, i.e. humans or other mammals in need of the particular treatment.
- the compositions are prepared by mixing the botulinum toxin with the carrier (described above), and optionally with one or more additional pharmaceutically acceptable diluents or excipients.
- the ratio of carrier to botulinum toxin may be in the range of about 10:1 to about 1 :10 by mass (e.g., about 1 :1). The ratio may be from about 6:1 to about 1.5:1 respectively.
- the carrier may be the peptide of SEQ ID NO: 3, 4, or 5.
- compositions may contain other ingredients typical in topical pharmaceutical or cosmeceutical compositions, including a dermatologically or pharmaceutically acceptable carrier, vehicle or medium, (i.e. a carrier, vehicle or medium that is compatible with the tissues to which they will be applied).
- a dermatologically or pharmaceutically acceptable carrier i.e. a carrier, vehicle or medium that is compatible with the tissues to which they will be applied.
- the term "dermatologically or pharmaceutically acceptable,” as used herein, means that the compositions or components thereof so described are suitable for use in contact with these tissues or for use in patients in general without undue toxicity, incompatibility, instability, allergic response, and the like.
- compositions suitable for use in the methods of the invention can comprise any ingredient conventionally used in the fields under consideration, and particularly in cosmetics and dermatology.
- the compositions can also include a quantity of a small anion, preferably a polyvalent anion, for example, phosphate, aspartate, or citrate.
- the topical botulinum toxin compositions can include solutions, emulsions (including microemulsions), suspensions, creams, lotions, gels, powders, ointments or other typical solid or liquid compositions used for application to skin and other tissues where the compositions may be used.
- compositions may contain, in addition to the botulinum toxin and carrier, other ingredients typically used in such products, such as antimicrobials, moisturizers and hydration agents, penetration agents, preservatives, emulsifiers, natural or synthetic oils, solvents, surfactants, detergents, emollients, antioxidants, fragrances, fillers, thickeners, waxes, odor absorbers, dyestuffs, coloring agents, powders, and optionally include anesthetics, anti-itch additives, botanical extracts, conditioning agents, darkening or lightening agents, glitter, humectants, mica, minerals, polyphenols, silicones or derivatives thereof, sunblocks, vitamins, and phytomedicinals.
- other ingredients typically used in such products such as antimicrobials, moisturizers and hydration agents, penetration agents, preservatives, emulsifiers, natural or synthetic oils, solvents, surfactants, detergents, emollients, antioxidants, fragrances, fillers,
- the compositions include gelling agents and/or viscosity-modifying agents. These agents are generally added to increase the viscosity of the composition, so as to make the application of the composition easier and more accurate. Additionally, these agents help to prevent the aqueous botulinum toxin/carrier solution from drying out, which tends to cause a decrease in the activity of the botulinum toxin. Exemplary agents are those that are uncharged and do not interfere with the botulinum toxin activity or the efficiency of the toxin-carrier complexes in crossing skin.
- the gelling agents may be certain cellulose-based gelling agents, such as hydroxypropylcellulose (HPC) for example.
- the botulinum toxin/carrier complex is formulated in a composition having 2-4% HPC.
- the viscosity of a solution containing a botulinum toxin/carrier complex may be altered by adding polyethylene glycol (PEG).
- the botulinum toxin/carrier solution is combined with pre-mixed viscous agents, such as Cetaphil® moisturizer.
- the composition further comprises a poloxamer-based diluent.
- the poloxamer diluent is a copolymer surfactant amenable to diluting lyophilized protein, and then gelling to a viscosity sufficient to be applied and remain in a defined cutaneous area.
- the poloxamer may be present at about 10% to 20%, for example, in 0.9% saline.
- the poloxamer is thermal-sensitive. That is, the composition will remain liquid at temperatures of 2O 0 C or less, with a gel product forming at temperatures in the range of 20-35°C for local application.
- the botulinum toxin compositions can optionally include partitioning agents.
- a "partitioning agent” is any substance or additive that has the property of preventing or minimizing unwanted or uncontrolled aggregation of the botulinum toxin with the positively charged polymeric carriers. Partitioning agents are particularly useful, for example, when a concentrated botulinum toxin solution is employed due to volume constraints. In such embodiments, the partitioning agent keeps the botulinum toxin dispersed, thereby preventing aggregation of the toxin that would otherwise occur without the partitioning agent.
- a partitioning agent is (1) non-irritating, (2) does not destroy the botulinum toxin, (3) does not confer any increase in permeability, (4) affords reliable and stable particle sizes, (5) is uncharged, and (6) does not interfere with complexes of the toxin and the polymeric carrier.
- EtOH ethanol
- the EtOH may be present at less than 20% of the composition, such as less than about 5% of the composition.
- volume constraints require reconstituting 100 U of botulinum toxin in 0.5 ml of solution, rather than 2.5 ml, one typically observes that the botulinum toxin will exhibit undesirable aggregation, and thus lowered activity.
- 1 % EtOH as a dispersing agent, full activity is maintained even after 24 hours at this concentration.
- Botox® at 1.0 ml 0.9% NaCl reconstitution has full activity, while reconstitution at 0.5 ml in 1% and 5% EtOH plus 0.9% NaCI produces solutions with full activity.
- oligo- or polyanion bridges are added to the botulinum toxin compositions to improve the complexation of the toxin with a positively charged carrier. Such bridges are particularly useful when the botulinum toxin complexes are used in the compositions. Some of the complex proteins are positively charged, and others are negatively charged. Because the exact distribution of the components of the toxin varies depending on the source of the toxin, it may be that botulinum toxin from certain sources has a lower propensity for complexation with the positively charged polymeric carriers described herein. However, by adding an oligo- or polyanion bridge to such botulinum toxin complexes, the efficiency and efficacy of topical administration is increased dramatically. Suitable examples of such oligo-/polyanion bridges include sodium phosphate (5%), PBS or 5% poly-L-aspartate (e.g., with a MW of 3000).
- compositions according to this invention can be in the form of controlled- release or sustained-release compositions, wherein the botulinum toxin and the carrier are encapsulated or otherwise contained within a material such that they are released onto the skin in a controlled manner over time.
- the botulinum toxin and carrier may be contained within matrixes, liposomes, vesicles, microcapsules, microspheres and the like, or within a solid particulate material, all of which is selected and/or constructed to provide release of the botulinum toxin over time.
- the botulinum toxin and the carrier may be encapsulated together (e.g., in the same capsule) or separately (in separate capsules).
- compositions are administered according to the methods of the invention by or under the direction of a physician or other health care professional.
- the compositions can be administered in a single treatment or in a series of periodic treatments over time. It is expected that the effect of the treatment will last for about 3, 4, 5, or 6 months.
- the topical composition may be administered once, or may be administered repeatedly, or routinely.
- the frequency of the treatment can vary, but may be, for example, once a month, or two to ten times per year, such as two to five times per year. Because the treatment is non- irritating and does not exacerbate the underlying condition, long term treatment for 1, 2, 3, or 4 or more years is possible if necessary.
- a composition as described above is applied topically to the skin at a location or locations where the effect is desired (e.g. affected areas of the skin).
- a composition as described above is applied directly to the skin, it is preferable to cover the treated area (e.g., with Cetaphil® moisturizer) or occlude the treated area with a barrier (e.g., Telfa), in order to prevent the solution from drying out, which would lead to a decrease in toxin activity.
- a barrier e.g., Telfa
- topical compositions of the invention should be applied at a rate of from about IU to about 20,00OU, preferably from about IU to about 10,000U botulinum toxin per cm 2 of skin surface. Higher dosages within these ranges could preferably be employed in conjunction with controlled release materials (e.g. patches and the like), for instance, or allowed a shorter dwell time on the skin prior to removal.
- controlled release materials e.g. patches and the like
- the method for treating a patient having a skin condition characterized by vascular hyper-reactivity further comprises preparing the skin surface prior to application of the topical botulinum toxin composition.
- preparation of the skin surface prior to the application of the botulinum toxin/carrier composition promotes the efficacy of the solution.
- the introduction of surfactants on the surface of the skin for the purpose of cleaning off surface oils on the skin prior to application may be counterproductive, because the surfactants appear to destroy the activity of the botulinum toxin. This occurs even if the skin is subsequently washed with water several times before application of the botulinum toxin/carrier solution.
- the skin is pre-cleaned using water alone. Washing with only water also appears to improve the transdermal transport of the botulinum toxin moderately.
- the present invention provides transdermal devices for treating a patient having a skin condition characterized by vascular hyper-reactivity.
- Such devices contain botulinum toxin and a carrier as described herein.
- Such devices can be as simple in construction as a skin patch, or may be more complicated devices that include means for dispensing and monitoring the dispensing of the composition, and optionally means for monitoring the condition of the subject (e.g., monitoring the reaction of the subject to the substances being dispensed).
- the present invention provides a skin patch comprising an effective amount of a botulinum toxin and a carrier as described.
- the materials for the construction of delivery devices may be those that do not lead to a loss of activity of the botulinum toxin/carrier solution, either through degradation or unwanted adsorption of the botulinum toxin on a surface of the device.
- Such undesired behavior has been observed, for example, when botulinum toxin/carrier in an aqueous solution contacts polypropylene surfaces, but not when the botulinum toxin/carrier solution contacts polyvinyl chloride (PVC) surfaces.
- PVC polyvinyl chloride
- compositions can be pre-formulated and/or pre-installed in a device or can be prepared later, for example using a kit comprising the two ingredients (botulinum toxin and carrier) separately, but providing a mechanism for combining them at or prior to the time of application.
- kit comprising the two ingredients (botulinum toxin and carrier) separately, but providing a mechanism for combining them at or prior to the time of application.
- in conjunction with is meant that the two components (botulinum toxin and carrier) are administered in a combination procedure, which may involve either combining them in a composition, which is subsequently administered to the subject, or administering them separately, but in a manner such that they act together to provide the requisite delivery of an effective amount of the botulinum toxin.
- a composition containing the carrier may first be applied to the skin of the patient, followed by applying a skin patch or other device containing the botulinum toxin.
- the botulinum toxin can be incorporated in dry form in a skin patch or other dispensing device, while the positively charged polymeric carrier can be applied to the skin surface in a cream or lotion before application of the patch so that the two act together, resulting in the desired transdermal delivery.
- the two substances carrier and botulinum toxin
- the present invention also provides a kit for treating a skin condition characterized by vascular hyper-reactivity.
- the kit comprises an effective amount of a botulinum toxin, a carrier, and a diluent, such as a poloxamer diluent as described herein.
- the skin condition is rosacea.
- the botulinum toxin is packaged separately from the other components in the kit.
- the botulinum toxin can be lyophilized and stored in a separate vial than the carrier and/or diluent.
- the botulinum toxin is packaged within a device, e.g. a skin patch.
- the positively charged polymeric carrier is pre- formulated in a liquid, gel, cream, or the like for application to the skin or epithelium of a patient.
- the kit can further comprise utensils and/or an applicator for mixing the botulinum toxin with the positively charged polymeric carrier and diluent and applying the topical mixture to an affected area of the patient's skin.
- the kit can comprise components for maintaining the treated area between or after neurotoxin treatments.
- the kit may comprise a gentle skin cleanser(s) for removing the excess botulinum toxin composition following treatment, a redness reducing lotion, one or more additional topical treatments for rosacea, and/or sun protection products with an SPF of 15 or greater.
- kits for maintaining the treated area.
- the kit comprises a gentle skin cleanser (which the patient may apply in the morning and/or evening), a topical redness reducing lotion (for example, Eucerin® Anti-Redness system or other lotions containing licorice), which may be applied after the gentle skin cleanser, and a broad spectrum sunblock of SPF 15 or greater (to protect the treated area during the day).
- a topical redness reducing lotion for example, Eucerin® Anti-Redness system or other lotions containing licorice
- SPF 15 or greater to protect the treated area during the day.
- topical rosacea treatments such as, for example, metronidazole gel (USP ranging from 0.75% to 1.0%).
- An exemplary formulation comprises: a purified 150 kDa botulinum toxin type A, which is minimally immunogenic and contains no animal or human components; the carrier peptide (R-K-K-R-R-Q-R-R-R-G-(K) I5 -G-R-K-K-R-R-Q-R-R-R SEQ ID NO:5), which enables the transcutaneous delivery of the botulinum toxin to the underlying dermis; and a poloxamer-based diluent, which acts as a vehicle for the carrier.
- the botulinum toxin is produced by Clostridium botulinum (serotype A - Hall strain) in a fermentation culture, and the fully active di-chain comprised of a 100-kDa heavy chain and a 50-kDa light chain is purified from the culture medium.
- the purified 150 kDa neurotoxin is not associated with any of the bacterially-derived accessory proteins or formulated in human serum albumin, hemaglutinin, or other pooled human-derived components.
- the purified botulinum neurotoxin is combined with the peptide carrier in a ratio of about 1 :1 by mass, and diluted with phosphate buffered saline to 200 ⁇ L.
- the resulting mixture is combined with 1.8 mL of poloxamer-based diluent (e.g., Pluronic® F127, NF Grade, BASF Corp.).
- the poloxamer diluent is a copolymer surfactant amenable to diluting lyophilized protein, and then gelling to a viscosity sufficient to be applied and remain in a defined cutaneous area.
- the poloxamer is thermal- sensitive. That is, the composition will remain liquid at temperatures of 20°C or less, with a gel product forming at temperatures in the range of 20-35 0 C for local application.
- Example 2 Treatment of facial flushing with a topical botulinum neurotoxin composition
- a vial containing 1 nanogram of lyophilized botulinum neurotoxin type A is mixed with a second vial containing a liquid diluent containing peptide carrier and the poloxamer-based diluent (see Example 1).
- the components are mixed together to form a smooth viscous gel that is applied topically to affected areas (e.g., a patient's cheeks and nasal fold areas).
- Example 3 Treatment of rosacea with a topical botulinum neurotoxin composition
- 1.2 nanograms of lyophilized botulinum neurotoxin type A is mixed with the carrier peptide and the poloxamer-based diluent (Example 1).
- the composition is applied topically to all the affected areas of the patient's central face.
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CA2757449A CA2757449A1 (en) | 2009-04-01 | 2010-03-30 | Methods and compositions for treating skin conditions associated with vascular hyper-reactivity |
JP2012503602A JP6140445B2 (en) | 2009-04-01 | 2010-03-30 | Methods and compositions for treating skin conditions associated with vascular hypersensitivity reactions |
BRPI1014922A BRPI1014922A2 (en) | 2009-04-01 | 2010-03-30 | methods and compositions for treating skin diseases associated with vascular hyperreactivity |
US13/262,798 US20120148562A1 (en) | 2009-04-01 | 2010-03-30 | Methods and compositions for treating skin conditions associated with vascular hyper-reactivity |
EP10759288.3A EP2413947B1 (en) | 2009-04-01 | 2010-03-30 | Methods and compositions for treating skin conditions associated with vascular hyper-reactivity |
ES10759288T ES2804328T3 (en) | 2009-04-01 | 2010-03-30 | Methods and compositions for treating skin conditions associated with vascular hyperresponsiveness |
DK10759288.3T DK2413947T3 (en) | 2009-04-01 | 2010-03-30 | Methods and compositions for treating skin conditions associated with vascular hyperreactivity |
KR1020117025371A KR101959234B1 (en) | 2009-04-01 | 2010-03-30 | Methods and compositions for treating skin conditions associated with vascular hyper-reactivity |
MX2011010335A MX2011010335A (en) | 2009-04-01 | 2010-03-30 | Methods and compositions for treating skin conditions associated with vascular hyper-reactivity. |
US15/184,025 US20170136105A1 (en) | 2009-04-01 | 2016-06-16 | Methods and compositions for treating skin conditions associated with vascular hyper-reactivity |
CY20201100685T CY1123249T1 (en) | 2009-04-01 | 2020-07-27 | METHODS AND COMPOSITIONS FOR THE THERAPEUTIC TREATMENT OF SKIN DISEASES RELATED TO VASCULAR HYPERACTIVITY |
US16/984,036 US20220347275A1 (en) | 2009-04-01 | 2020-08-03 | Methods and Compositions for Treating Skin Conditions Associated With Vascular Hyper-reactivity |
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2010
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Also Published As
Publication number | Publication date |
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CA2757449A1 (en) | 2010-10-07 |
EP2413947B1 (en) | 2020-04-29 |
US20120148562A1 (en) | 2012-06-14 |
BRPI1014922A2 (en) | 2016-04-19 |
DK2413947T3 (en) | 2020-06-02 |
EP2413947A1 (en) | 2012-02-08 |
MX2011010335A (en) | 2012-01-12 |
KR20120027170A (en) | 2012-03-21 |
CY1123249T1 (en) | 2021-10-29 |
JP6140445B2 (en) | 2017-05-31 |
KR101959234B1 (en) | 2019-03-18 |
JP2012522786A (en) | 2012-09-27 |
ES2804328T3 (en) | 2021-02-05 |
US20220347275A1 (en) | 2022-11-03 |
PT2413947T (en) | 2020-05-28 |
US20170136105A1 (en) | 2017-05-18 |
EP2413947A4 (en) | 2014-02-12 |
JP2017081997A (en) | 2017-05-18 |
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