GB2418358A - Pharmaceutical composition comprising botulinum neurotoxin - Google Patents
Pharmaceutical composition comprising botulinum neurotoxin Download PDFInfo
- Publication number
- GB2418358A GB2418358A GB0421288A GB0421288A GB2418358A GB 2418358 A GB2418358 A GB 2418358A GB 0421288 A GB0421288 A GB 0421288A GB 0421288 A GB0421288 A GB 0421288A GB 2418358 A GB2418358 A GB 2418358A
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- pharmaceutical composition
- botulinum
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Classifications
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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
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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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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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
- A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
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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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- 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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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
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Abstract
The invention relates to a solid or liquid pharmaceutical composition comprising: <SL> <LI>(a) a botulinum toxin, and <LI>(b) a surfactant </SL> According to a particular variant of the invention, the pharmaceutical composition comprises botulinum toxin type A2 which not only has a biological activity similar to that of the other botulinum neurotoxins, but also can have the advantage of a significantly greater intramuscular safety margin than any other known botulinum toxin, making it preferred over botulinum neurotoxins of other serotypes for any therapeutic use known for botulinum toxin type A1.
Description
Pharmaceutical composition containing botulinum neurotoxin The invention
relates to a pharmaceutical composition containing botulinum neurotoxin.
The presently most used botulinum neurotoxin is botulinum neurotoxin type A. This neurotoxin is produced during fermentation in the presence of Clostridium botulinum s strains. Botulinum neurotoxin type A complexes (which include botulinum neurotoxin type A and at least another non-toxic protein) are active principles widely used in modern medicine. An example of a pharmaceutical composition based on such a complex is the product Dysport0 currently sold by the company of the Applicants.
Among the most common medical indications for which a botulinum neurotoxin type A lo complex could be used, one could mention the treatment of a number of muscle disorders (e.g. blepharospasm, hemifacial spasm, torticollis, spasticity, tension headache, back pain or wrinkles), as well as other disorders such as migraine.
Alternatively, high purity botulinum toxin (i.e. botulinum neurotoxin free from its complexing non-toxic proteins) may replace the corresponding botulinum toxin complex as disclosed in PCT applications WO 96/11699 or WO 97/35604.
Currently, the marketed botulinum neurotoxin compositions contain human serum albumin. However, some concerns have been expressed about albumin (see e.g. in PCT:.
application WO 01/58472). For this reason, the pharmaceutical industry is now....
considering to find alternative stabilising agents to albumin by other stabilising agents in pharmaceutical compositions. ..
-e A possible solution is disclosed in PCT patent application WO01/58472. In this document, albumin is replaced by a polysaccharide, i. e. a polymer of more than two saccharide molecule monomers, which plays the role of the stabiliser in the botulinum neurotoxin composition.
2s An alternative solution is the one described in PCT patent application WO 97/35604 or US patents Nos. 5,512,547 and 5,756,468. In these documents, it is disclosed that pure botulinum neurotoxin (i.e. botulinum neurotoxin free from its complexing non-toxic proteins) can be stabilised by trehalose.
The Applicant has unexpectedly discovered that a surfactant possesses sufficient stabilising effects to replace albumin, the polysaccharide of PCT patent application Cnorth/Client Docs/SCRAS/47984.GBOl.Spec] WO 01/58472 or the trehalose of PCT patent application WO 97/35604 in botulinum neurotoxin compositions The invention therefore pertains to the use of a surfactant for stabilising a solid or liquid pharmaceutical composition that contains as active principle a botulinum toxin s By botulinum toxin should be understood a naturally occurring botulinum toxin or any recombinantly produced botulinum toxin By naturally occurring botulinum toxin should be understood either a high purity botulinum neurotoxin derived from Clostridium spp or a botulinum neurotoxin complex derived from Clostridium spp.
lo By high purity botulinum neurotoxin (type A, B. C, D, E, F or G) is meant, in the present application, botulinum neurotoxin (type A, B. C, D, E, F or G) outside from complexes including at least another protein In other words, a high purity botulinum neurotoxin (type A, B. C, D, E, F or G) does not contain significant quantities of any other Clostridium spp derived protein than botulinum neurotoxin (type A, B. C, D, E, F or G) Preferably, according to the present invention, botulinum neurotoxin complexes and high purity botulinum neurotoxins will be selected from the group consisting of botulinum neurotoxin complex and high purity botulinum neurotoxin of type A, botulinum neurotoxin complex and high purity botulinum neurotoxin of type B and botulinum neurotoxin complex and high purity botulinum neurotoxin of type F. More preferably, botulinum neurotoxin complexes and high purity botulinum neurotoxins will be selected from the group consisting of botulinum neurotoxin complex and high purity botulinum neurotoxin of type A and botulinum neurotoxin complex and high purity botulinum neurotoxin of type F. More particularly, botulinum neurotoxin complexes and high purity botulinum neurotoxins will be botulinum neurotoxin complexes and high purity botulinum neurotoxins of type A By type A botulinum neurotoxin should be understood any botulinum toxin of type A, and notably botulinum neurotoxins of type Al, A2 or A3 The same applies mutatis mutandis to the other serotypes of toxins The classical type A botulinum toxin (i e the active principle of the marketed products Dysport and Botox) is increasingly being referred to by those skilled in the art as type Al botulinum toxin This is to distinguish it from type A2 botulinum toxin originally isolated from infant botulism cases in 1990, which is an immunologically and Cnorth/Client Docs/SCRAS/47984.GB0 1. Spec 2 biochemically distinct botulinum toxin. In the instant patent application, we will therefore be using this nomenclature.
The high purity botulinum neurotoxin (type A, B. C, D, E, F or G) used according to the invention or contained in the above described pharmaceutical compositions can easily be obtained from the corresponding botulinum neurotoxin complex, for example as explained in Current topics in Microbiology and Immunology (1995), 195, p. 151-154.
High purity Clostridium botulinum toxin (type A, B. C, D, E, F or G) is obtained, for example, by purification of an adequate fermentation medium (for example, an enriched meat media broth containing Clostridium Botulinum and left for fermentation - this lo broth may be, for example, the one described in Current topics in Microbiology and Immunology (1995), 195, p. 150 and DasGupta, "Microbialfood toxicants. Clostridium botulinum toxins. CRC handbook of foodborne diseases of biological origin", CRC Boca Raton, p. 25-56). When including high purity botulinum neurotoxin in a composition according to the instant invention, the purity degree of the toxin should preferably be higher than 80%, more preferably higher than 90 or 95% and in a more particularly preferred manner higher than 98% or 99%. It can be assessed, for example, by using the purity assay described in the present application.
The instant invention also relates to a solid or liquid pharmaceutical composition comprising: . (a) a botulinum toxin, and (b) a surfactant. . According to a particular variant of the invention, the pharmaceutical composition will be a solid pharmaceutical composition and will essentially consist in: (a) a botulinum toxin, and (b) a surfactant.
According to another particular variant of the invention, the pharmaceutical composition will be a liquid pharmaceutical composition and will essentially consist in: (a) a botulinum toxin, (b) a surfactant, and (c) water.
In the abovementioned pharmaceutical compositions, the surfactant will be such that it stabilises the botulinum toxin.
Cnorth/Client Docs/SCRAS/47984.GBO].Spec 3 A solid pharmaceutical composition according to the invention can be obtained for example by Iyophilising a sterile water solution containing the components (a) and (b) as mentioned previously. A liquid pharmaceutical composition according to the invention will be obtained by mixing the solid (e.g. Iyophilised) mixture of components s (a) and (b) with sterile water.
According to the invention, the concentrations of said components (a) and (b) in the solution to be Iyophilised / the liquid pharmaceutical composition will preferably be as follows: - the solution will contain from 50 to 3,000 LD50 units of botulinum neurotoxin 0 complex (type A, B. C, D, E, F or G) or high purity botulinum neurotoxin (type A, B. C, D, E, F or G) per ml of solution, more preferably from 100 to 2,500 LD5, units of botulinum neurotoxin complex (type A, B. C, D, E, F or G) or high purity botulinum neurotoxin (type A, B. C, D, E, F or G) per ml of solution and most preferably from l OO to 2, 000 LD50 units of botulinum neurotoxin complex (type A, B. C, D, E, F or G) or high purity botulinum neurotoxin (type A, B. C, D, E, F or G) per ml of solution; the concentration of surfactant will be from above critical micellar concentration to a concentration of 1% v/v, and notably from about 0.005% to 0.02% v/v in the case Of polysorbate 80.
Preferably, the surfactant will be a non-ionic surfactant. Non-ionic surfactants include: notably polysorbates and block copolymers like poloxamers (i.e. copolymers of polyethylene and propylene glycol). According to a preferred variant of the invention, the surfactant will be a polysorbate. More preferably, a polysorbate included in a composition according to the instant invention will have a mean polymerization degree of from 20 to 100 monomer units (preferably about 80), and may for example be polysorbate 80. Preferably also, the polysorbate should be vegetable-derived.
According to a preferred execution mode of the invention, the solid or liquid pharrnacoutical composition will also contain a crystalline agent.
By crystalline agent is meant an agent which, inter alla, would maintain a mechanically strong cake structure to Iyophilised botulinum neurotoxin complex (type A, B. C, D, E, F or G) or high purity botulinum neurotoxin (type A, B. C, D, E, F or G). When included in solid formulations, crystalline agents also have a bulking effect. Crystalline agents notably include sodium chloride. Contrarily to what was taught in the prior art (see e.g. Goodnough, M.C. and Johnson, E.A., Applied and Environmental Cnorth/Client Docs/SCRAS/47984.GBOl.Spec 4 Microbiology (1992), 58(10), 3426-3428), the use of sodium chloride for this type of compositions further improves the stability of the botulinum toxin composition.
According to yet another preferred execution mode of the invention, the solid or liquid pharmaceutical composition will also contain a buffer to maintain pH from 5.5 to 7.5.
The buffer can be any buffer able to maintain the adequate pH. Preferably, the buffer for compositions according to the invention will be chosen from the group consisting of succinate and an amino acid like histidine. In particular, the buffer will be histidine.
Preferably, the pH will be at least equal to 5.5 or 5.8, and most preferably at least equal to 6.0 or 6.5. Preferably also, the pH will be equal to or less than 7.5 or 7.0, more lo preferably equal to or less than 6.8.
Preferably, the solid or liquid pharmaceutical composition of the invention may also contain a disaccharide.
The disaccharide used in compositions according to the invention will preferably be chosen from the group consisting of sucrose, trehalose, mannitol and lactose. The disaccharide used in compositions according to the invention will more preferably be chosen from the group consisting of sucrose and trehalose. In particular, the disaccharide used in compositions according to the invention will be sucrose Preferably, the disaccharide will be present in the pharmaceutical compositions of the instant invention, particularly when the compositions are in a solid form.
The instant invention therefore notably relates to a solid or liquid pharmaceutical composition comprising: (a) botulinum neurotoxin complex (type A, B. C, D, E, F or G) or high purity botulinum neurotoxin (type A, B. C, D, E, F or G), (b) a surfactant, (c) a crystalline agent, (d) a buffer to maintain pH between 5.5 to 7.5.
Preferably, a disaccharide will also be included in the pharmaceutical compositions according to the present invention, especially when they are in a solid form.
According to this variant of the invention, a solid pharmaceutical composition can be obtained by Iyophilising a sterile water solution containing the components (a) to (d) as mentioned previously. A liquid pharmaceutical composition according to the invention Cnorth/Clent Docs/SCRAS/47984.GBO 1. Spec 5 will be obtained by mixing a solid (e.g. lyophilized) mixture of said components (a) to (d) with sterile water.
According to the invention, the concentrations of said components (a) to (d) in the solution to be Iyophilised / the liquid pharmaceutical composition will preferably be as follows: - the solution will contain from 50 to 3,000 LD50 units of botulinum neurotoxin complex (type A, B. C, D, E, F or G) or high purity botulinum neurotoxin (type A, B. C, D, E, F or G) per ml of solution, more preferably from 100 to 2,500 LD50 units of botulinum neurotoxin complex (type A, B. C, D, E, F or G) or high purity lo botulinum neurotoxin (type A, B. C, D, E, F or G) per ml of solution and most preferably from 100 to 2,000 LD50 units of botulinum neurotoxin complex (type A, B. C, D, E, F or G) or high purity botulinum neurotoxin (type A, B. C, D, E, F or G) per ml of solution; - the concentration of surfactant will be from above critical micellar concentration to a concentration of 1% v/v, and notably from about 0.005% to 0.02% v/v in the case of polysorbate 80; - the concentration of crystalline agent will be from 0.1 to 0.5 M, more preferably: .
from 0.1 to 0.4 M, notably about 0.15 to 0.3 M; and , ...
- the concentration of buffer will be from I to 50 mM, more preferably from 5 to.... :.
20 mM, notably about 10 mM. .. . ..
As mentioned earlier, me solid or liquid pharmaceutical formulation according to the invention may contain a disaccharide. In that case, the concentration of disaccharide in the solution to be lyophilised / the liquid pharmaceutical composition will be for example from 5 to 50 mM, preferably from 5 to 25 mM, more preferably from 10 to 2s 20 mM, and notably about 11.7 mM.
According to a preferred execution mode of the invention, the mixture of the different components of the pharmaceutical composition (i.e. botulinum neurotoxin complex (type A, B. C, D, E, F or G) or high purity botulinum neurotoxin (type A, B. C, D, E, F or G), the surfactant and the optional excipients such as the crystalline agent, the buffer or the disaccharide) is lyophilised. The solid compositions thus obtained, which are also part of this invention, should preferably be stable for at least 12 months, more preferably for at least 18 months and in a more particularly preferred manner for at least 24 or even 36 months.
CnorWClient Docs/SCRAS/47984.GBOl.Spec 6 A composition according to the invention is considered stable during a certain period of time if at least 70% of the initial toxicity, as evaluated by assessing the LD50 in mice or by any method validated with respect to the LDso mouse assay (i e a method allowing a conversion of its results into LD50 units), is maintained over said period of time (cf. the s part entitled "mouse toxicity assay" concerning the LD50 mouse assay) Pharmaceutical compositions according to the invention can be used for preparing medicaments intended to treat a disease / a condition / a syndrome chosen from the following : ophtalmological disorders selected from the group consisting of blepharospasm, 0 strabismus (including restrictive or myogenic strabismus), amblyopia, oscillopsia, protective ptosis, therapeutic ptosis for corneal protection, nystagmus, estropia, diplopia, entropion, eyelid retraction, orbital myopathy, heterophoria, concomitant misalignment, nonconcomitant misalignment, primary or secondary esotropia or exotropia, internuclear ophthalmoplegia, skew deviation, Duane's syndrome and upper eyelid retraction; : movement disorders including hemifacial spasm, torticollis, spasticity of the child or of the adult (e g in cerebral palsy, post-stroke, multiple sclerosis, traumatic brain injury or spinal cord injury patients) , idiopathic focal dystonias, muscle stiffness, Writer's cramp, hand dystonia, Vl nerve palsy, oromandibular dystonia, head tremor, tardive dyskinesia, tardive dystonia, occupational cramps (including musicians' cramp), facial nerve palsy, jaw closing spasm, facial spasm, synkinesia, tremor, primary writing tremor, myoclonus, stiff-person-syndrome, foot dystonia, facial paralysis, painful-arm-and-moving-fingers-syndrome, tic disorders, dystonic tics, Tourette's syndrome, neuromyotonia, trembling chin, lateral rectus palsy, dystonic foot inversion, jaw dystonia, Rabbit syndrome, cerebellar tremor, III nerve palsy, palatal myoclonus, akasthesia, muscle cramps, IV nerve palsy, freezing-of gait, extensor truncal dystonia, post-facial nerve palsy synkinesis, secondary dystonia, Parkinson's disease, Huntington's chorea, epilepsy, off period dystonia, cephalic tetanus, myokymia and benign cramp-fasciculation syndrome; : otorhinolaryngological disorders including spasmodic dysphonia, hypersalivation, sialorrhoea, otic disorders, hearing impairment, ear click, tinnitus, vertigo, Meniere's disease, cochlear nerve dysfunction, stuttering, cricopharyngeal dysphagia, bruxism, closure of larynx in chronic aspiration, vocal fold granuloma, ventricular dystonia, ventricular dysphonia, mutational dysphonia, trismus, snoring, voice tremor, aspiration, tongue protrusion dystonia, palatal tremor, deep bite of lip and laryngeal dystonia; Cnorth/Client Docs/SCRAS/47984.GBO 1. Spec 7 : gastrointestinal disorders including achalasia, anal fissure, constipation, temperomandibular joint dysfunction, sphincter of Oddi dysfunction, sustained sphincter of Oddi hypertension, intestinal muscle disorders, puborectalis syndrome, anismus, pyloric spasm, gall bladder dysfunction, gastrointestinal or oesophageal motility dysfunction, diffuse oesophageal spasm, oesophageal diverticulosis and gastroparesis; : urogenital disorders including detrusor sphincter dyssynergia, detrusor hyperreflexia, neurogenic bladder dysfunction (e g in Parkinson's disease, spinal cord injury, stroke or multiple sclerosis patients), bladder spasms, urinary lo incontinence, urinary retention, hypertrophied bladder neck, voiding dysfunction, interstitial cystitis, vaginismus, endometriosis, pelvic pain, prostate gland enlargement (Benign Prostatic Hyperplasia), prostatodynia, prostate cancer and priapism; : dermatological disorders including hyperhidrosis (including axillary hyperhidrosis, 1 5 palmer hyperhidrosis and Frey's syndrome), bromhidrosis, cutaneous cell proliferative disorders (including psoriasis), skin wounds and acne; : pain disorders including back pain (upper back pain, lower back pain), myofascial pain, tension headache, fibromyalgia, painful syndromes, myalgia, migraine, whiplash, joint pain, post-operative pain, pain not associated with a muscle spasm.
and pain associated with smooth muscle disorders; : inflammatory disorders including pancreatitis, neurogenic inflammatory disorders,...:.
(including gout, tendonitis, bursitis, dermatomyositis and ankylosing spondylitis); .... .
: secretory disorders such as excessive gland secretions, mucus hypersecretion and hyperlacrimation, holocrine gland dysfunction; . ..
: respiratory disorders including rhinitis (including allergic rhinitis), COPD, asthma and tuberculosis; : hypertrophic disorders including muscle enlargement, masseteric hypertrophy, acromegaly and neurogenic tibialis anterior hypertrophy with myalgia; : articular disorders including tennis elbow (or epicondilytis of the elbow), inflammation of joints, coxarthrosis, hip osteoarthritis, rotator muscle cap pathology of the shoulder, rheumatoid arthritis and carpal tunnel syndrome; : endocrine disorders like type 2 diabetes, hyperglucagonism, hyperinsulinism, hypoinsulinism, hypercalcemia, hypocalcemia, thyroid disorders (including Grave's disease, thyroiditis, Hashimoto's thyroiditis, hyperthyroidism and hypothyroidism), Cnorth/Client Docs/SCRAS/47984.GBOl.Spec parathyroid disorders (including hyperparathyroidism and hypoparathyroidism), Cushing's syndrome and obesity; : autoimmune diseases like systemic lupus erythemotosus; . proliferative diseases including paraganglioma tumors, prostate cancer and bone tumors; : traumatic injuries including sports injuries, muscle injuries, tendon wounds and bone fractures; and : veterinary disorders (e g immobilization of mammals, equine colic, animal achalasia or animal muscle spasms) lo Pharmaceutical compositions according to the invention can also be used for cosmetic treatments including cosmetic treatments of the following cosmetic disorders : skin defects; : facial asymmetry; : wrinkles including glabellar frown lines and facial wrinkles; is : downturned mouth; : hair loss; and.....
: body odours .
Preferably, pharmaceutical compositions according to the invention will be used forth.
preparing medicaments intended to treat a disease / a condition / a syndrome chosen. .
from the following . : ophtalmological disorders selected from the group consisting of blepharospasm, strabismus (including restrictive or myogenic strabismus), amblyopia, protective ptosis, therapeutic ptosis for corneal protection and upper eyelid retraction; : movement disorders selected from the group consisting of hemifacial spasm, torticollis, cerebral palsy spasticity of the child, spasticity of the adult in post-stroke, multiple sclerosis, traumatic brain injury or spinal cord injury patients, idiopathic focal dystonias, muscle stiffness, Writer's cramp, hand dystonia, VI nerve palsy, oromandibular dystonia, head tremor, tardive dyskinesia, tardive dystonia, occupational cramps (including musicians' cramp), facial nerve palsy, jaw closing spasm, facial spasm, synkinesia, tremor, primary writing tremor, myoclonus, stiff person-syndrome, foot dystonia, facial paralysis, painful-arm-andmoving-fingers syndrome, tic disorders, dystonic tics, Tourette's syndrome, neuromyotonia, trembling chin, lateral rectus palsy, dystonic foot inversion, jaw dystonia, Rabbit Cnorth/Cltent Docs/SCRAS/47984.GBO l. Spec 9 syndrome, cerebellar tremor, III nerve palsy, palatal myoclonus, akasthesia, muscle cramps, IV nerve palsy, freezing-of-gait, extensor truncal dystonia, post-facial nerve palsy synkinesis, secondary dystonia, off period dystonia, cephalic tetanus, myokyrnia and benign crampfasciculation syndrome; : otorhinolaryugological disorders selected from the group consisting of spasmodic dysphonia, hypersalivation, sialorrhoea, ear click, tinnitus, vertigo, Meniere's disease, cochlear nerve dysfunction, stuttering, cricopharyngeal dysphagia, bruxism, closure of larynx in chronic aspiration, vocal fold granuloma, ventricular dystonia, ventricular dysphonia, mutational dysphonia, trismus, snoring, voice tremor, 0 aspiration, tongue protrusion dystonia, palatal tremor and laryngeal dystonia; : gastrointestinal disorders selected from the group consisting of achalasia, anal fissure, constipation, ternperomandibular joint dysfunction, sphincter of Oddi dysfunction, sustained sphincter of Oddi hypertension, intestinal muscle disorders, puborectalis syndrome, anismus, pyloric spasm, gall bladder dysfunction, gastrointestinal or oesophageal motility dysfunction, diffuse oesophageal spasm, oesophageal diverticulosis and gastroparesis; : urogenital disorders selected from the group consisting of detrusor sphincter dyssynergia, detrusor hyperreflexia, neurogenic bladder dysfunction in Parkinson's disease, spinal cord injury, stroke or multiple sclerosis patients, bladder spasms, urinary incontinence, urinary retention, hypertrophied bladder neck, voiding dysfunction, interstitial cystitis, vaginismus, endometriosis, pelvic pain, prostate gland enlargement (Benign Prostatic Hyperplasia), prostatodynia, prostate cancer and priapism; : dermatological disorders selected from the group consisting of axillary hyperhidrosis, palmer hyperhidrosis, Frey's syndrome, bromhidrosis, psoriasis, skin.
: pain disorders selected from the group consisting of upper back pain, lower back pain, myofascial pain, tension headache, fibromyalgia, myalgia, migraine, whiplash, joint pain, post-operative pain and pain associated with smooth muscle disorders; : inflammatory disorders selected from the group consisting of pancreatitis, gout, tendonitis, bursitis, derrnatomyositis and ankylosing spondylitis; : secretory disorders selected from the group consisting of excessive gland secretions, mucus hypersecretion and hyperlacrimation and holocrine gland dysfunction; : respiratory disorders selected from the group consisting of non- allergic rhinitis, 35allergic rhinitis, COPD and asthma; CnorWClient Docs/SCRAS/47984.GBOl. Spec 10 : hypertrophic disorders selected from the group consisting of muscle enlargement, masseteric hypertrophy, acromegaly and neurogenic tibialis anterior hypertrophy with mya]gia; : articular disorders selected from the group consisting of tennis elbow (or epicondilytis of the elbow), inflammation of joints, coxarthrosis, hip osteoarthritis, rotator muscle cap pathology of the shoulder, rheumatoid arthritis and carpal tunnel syndrome; : endocrine disorders selected from the group consisting of type 2 diabetes, hypercalcemia, hypocalcemia, thyroid disorders, Cushing's syndrome and obesity; lo : prostate cancer; and : traumatic injuries selected from the group consisting of sports injuries, muscle injuries, tendon wounds and bone fractures; or for performing cosmetic treatments wherein the cosmetic disorder to be treated is selected from the group consisting of: is : skin defects; : facial asymmetry; : wrinkles selected from glabellar frown lines and facial wrinkles; .
: downturned mouth; and e' : hair loss. - oe More preferably, pharmaceutical compositions according to the invention will be used. for preparing medicaments intended to treat a disease / a condition / a syndrome chosen....
from the following: t : ophtalmological disorders selected from the group consisting of blepharospasm and strabismus; : movement disorders selected from the group consisting of hemifacial spasm, torticollis, cerebral palsy spasticity of the child and arm or leg spasticity of the adult in post-stroke, multiple sclerosis, traumatic brain injury or spinal cord injury patients; : otorhinolaryngological disorders selected from the group consisting of spasmodic dysphonia, hypersalivation, sialorrhoea, cricopharyngeal dysphagia, bruxism, closure of larynx in chronic aspiration, ventricular dystonia, ventricular dysphonia, mutational dysphonia, trismus, snoring, voice tremor, tongue protrusion dystonia, palatal tremor and laryngeal dystonia; Cnorth/Client Docs/SCRAS/47984.GBOI.Spec I I : gastrointestinal disorders selected from the group consisting of achalasia, anal fissure, constipation, temperomandibular joint dysfunction, sphincter of Oddi dysfunction, sustained sphincter of Oddi hypertension, intestinal muscle disorders, anismus, pyloric spasm, gall bladder dysfunction, gastrointestinal or oesophageal s motility dysfunction and gastroparesis; : urogenital disorders selected from the group consisting of detrusor sphincter dyssynergia, detrusor hyperreflexia, neurogenic bladder dysfunction in Parkinson's disease, spinal cord injury, stroke or multiple sclerosis patients, bladder spasms, urinary incontinence, urinary retention, hypertrophied bladder neck, voiding 0 dysfunction, interstitial cystitis, vaginismus, endometriosis, pelvic pain, prostate gland enlargement (Benign Prostatic Hyperplasia), prostatodynia, prostate cancer and priapism; : dermatological disorders selected from the group consisting of axillary hyperhidrosis, palmer hyperhidrosis, Frey's syndrome, bromhidrosis, psoriasis, skin wounds and acne; : pain disorders selected from the group consisting of upper back pain, lower back pain, myofascial pain, tension headache, fibromyalgia, myalgia, migraine, whiplash, joint pain, post-operative pain and pain associated with smooth muscle disorders; : inflammatory disorders selected from the group consisting of pancreatitis and gout; . . : hyperlacrimation; :-: : respiratory disorders selected from the group consisting of non- allergic rhinitis, allergic rhinitis, COPD and asthma; .
: masseteric hypertrophy; . , : articular disorders selected from the group consisting of tennis elbow (or;. :..
2s epicondilytis of the elbow), inflammation of joints, coxarthrosis, hip osteoarthritis, rotator muscle cap pathology of the shoulder, rheumatoid arthritis and carpal tunnel syndrome; : obesity; : traumatic injuries selected from the group consisting of muscle injuries, tendon so woundsand bone fractures; or for performing cosmetic treatments wherein the cosmetic disorder to be treated is selected from the group consisting of: : skin defects; : facial asymmetry; Cnorth/Client Docs/SCRAS/47984.GBOI.Spec 12 : wrinkles selected from glabellar frown lines and facial wrinkles; : downtuned mouth; and : hair loss.
In a particularly preferred manner, pharmaceutical compositions according to the s invention will be used for preparing medicaments intended to treat a disease / a condition / a syndrome chosen from the following: blepharospasm, hemifacial spasm, torticollis, cerebral palsy spasticity of the child and arm or leg spasticity of the adult in post-stroke, multiple sclerosis, traumatic brain injury or spinal cord injury patients, axillary hyperhidrosis, palmer hyperhidrosis, Frey's syndrome, skin wounds, acne, lo upper back pain, lower back pain, myofascial pain, migraine, tension headache, joint pain, tennis elbow (or epicondilytis of the elbow), inflammation of joints, coxarthrosis, hip osteoarthritis, rotator muscle cap pathology of the shoulder, muscle injuries, tendon or for performing cosmetic treatments wherein the cosmetic disorder to be treated is is selected from the group consisting of: : skin defects; : facial asymmetry; and......
: wrinkles selected from glabellar frown lines and facial wrinkles. . ... .
The dose of botulinum neurotoxin complex (type A, B. C, D, E, F or G) or high purity... . botulinum neurotoxin (type A, B. C, D, E, F or G) which shall be needed for the. . treatment of the diseases / disorders mentioned above varies depending on the disease / disorder to be treated, administration mode, age and body weight of the patiert"'.. e
to be treated and health state of the latter, and it is the treating physician or veterinary that will eventually make the decision. Such a quantity determined by the treating physician or veterinary is called here "therapeutically efficient quantity".
For botulinum neurotoxin complex (type A, B. C, D, E, F or G) or high purity botulinum neurotoxin (type A, B. C, D, E, F or G), this therapeutically efficient dose is often expressed as a function of the corresponding LD50. By LDso should be understood in the present application the median intraperitoneal dose in mice injected with botulinum neurotoxin complex (type A, B. C, D, E, F or G) or high purity botulinum neurotoxin (type A, B. C, D, E, F or G) that causes death of half of said mice within 96 hours.
Another aspect of this invention relates to botulinum toxin type A2.
Cnor:h/CIIent Docs/SCRAS/47984.GBOl.Spec 13 Clostridium botulinum type A2 toxin-producing organisms were first identified in 1990 in Japan, from multiple cases of infant botulism (Sakaguchi et al., Int. J. Food Microbiol. (1990), 11, 231-242). Infant botulism, or intestinal colonization botulism is unlike food-borne botulism in that the toxin is produced after infection of the patient, s rather than pre-forrned in food. The clinical isolate strains most closely associated with type A2 toxin are Kyoto-F, Chiba-H, Y-8036, 7103-H, 7105-H and KZ1828, although several others have been characterized as type A2 by molecular methods (Cordoba et al., System. Appl. Microbiol. (1995), 18, 13-22, Franciosa et al., abstract presented at 40"' Interagency Botulism Research Coordinating Committee (IBRCC) Meeting, lo November 2003).
Botulinum type A2 toxin is a unique neurotoxin which has been shown to be a distinct toxin type when compared with other botulinum toxin types A G. Botulinum type A2 toxin differs from type Al toxin in its molecular genetic characteristics, its biochemical characteristics and in its immunological characteristics.
At the molecular genetic level, the organization of the type A2 neurotoxin gene cluster is distinct from all other botulinum toxin types. Many botulinum toxin types, including type A botulinum toxins, are found as neurotoxin complexes with haemagglutinin (HA) proteins as components of the complex. The genes encoding these HA proteins (HA17 HA34 and HA70) are contained in the neurotoxin gene cluster of type A, B. C, D and G organisms, but are entirely absent in the type A2 neurotoxin gene cluster. The type A2 neurotoxin gene cluster also contains regulatory genes such as p47, which are absent i' type Al neurotoxin gene clusters. Additionally, the sequence of the NTNH protein of type A2 toxin complex has been shown to be a mosaic of type C and type Al NTN11 gene sequences (Kubota et al., Biochem. Biophys. Res. Commun. (1996), 224(31 2s 843-848).
Type A2 toxin and type Al toxin also differ markedly in the biochemical characteristics of the purified toxin complex. While type Al toxin complex contains the NTNH protein, and at least three HA proteins (HA17, HA34 and HA70), type A2 toxin complex contains only an NTNH protein and lacks the HA proteins (Sakaguchi et al., Int. J. Food Microbiol. (]990), 11, 231-242). The neurotoxin molecule itself differs in molecular weight, the heavy chain being 101 kDa in type A2 toxin and 93 kDa in type Al toxin, and shows differing sensitivity to proteases (Kozaki et al., Microbiol.
Immunol. (1995), 39(10), 767-74). The amino acid sequence of the type A2 and type A I toxins are markedly different, particularly in the heavy chain region, where 109 of the 3s 847 amino acids are different between the two toxin types (13% difference) (Cordoba et al., System. Appl. Microbiol. (1995), 18, 13-22). The heavy chain sequences of isolates CnorWClientDocs/SCRAS/47984.GBOl. Spec 14 of type Al toxins, by contrast, typically differ by less than 2%. Heavy chain of botulinum neurotoxins are responsible for key biological functions of the molecule, including receptor binding on target cells and intracellular trafficking (Zhang et al., Gene (2003), 315, 21-32). Indeed, studies of binding of neurotoxins A2 and Al have s shown different binding characteristics of the two toxins to purified synaptosomes (Kozaki et al., Microbiol. Immunol. (1995), 39(10), 767-74).
Botulinum type A2 toxin is also immunologically distinct. Antibodies raised against type A toxin have been shown not to recognise type A2 botulinum toxin (and vice versa) in immunodiffusion experiments, ELISA and Western blots (Sakaguchi et al., loInt. J. Food Microbiol. (1990), 11, 231-242; Kozaki et al., Microbiol. Immunol. (1995), 39(10), 767-74). Most significantly, however, antibodies raised to type Al toxins, while able to neutralize toxicity of type Al toxin in mice, could not neutralize type A2 toxins in parallel mouse toxicity experiments (Kozaki et al., Microbiol. Immunol. (1995), 39(10), 767-74) In summary, it can be seen from the state of the art that type A2 botulinum toxin is biochemically and immunologically different from other botulinum toxin types, and particularly from type Al botulinum toxin.
The Applicant has now surprisingly found that botulinum toxin type A2 not only had 'a biological activity similar to that of the other botulinum neurotoxins, but also had the A.: major advantage of a significantly greater intramuscular safety margin than any other known botulinum toxin (as shown for example by the intramuscular safety margin assay . . described in the part entitled "Pharmacological study"), making it preferred over....
botulinum neurotoxins of other serotypes for any therapeutic use known for botulinurn....
toxin type Al. .. - ë:
The intramuscular safety margin of botulinum toxin preparations has been defined (Aoki KR, Toxicon (2002), 40, 923-928) as "the ratio of the intramuscular median lethal dose to the intramuscular dose that produced half-maximal muscle weakness". This ratio is considered a measure of the separation between therapeutic, locally effective dose of botulinum toxin and a dose capable of having systemic adverse effects (Aoki KR, Toxicon (2001), 39, 1815-1820).
Accordingly, the invention firstly relates to botulinum toxin type A2 as a medicament.
The invention also relates to a pharmaceutical composition comprising, as active principle, botulinum toxin type A2. It also relates to a pharmaceutical composition comprising, as active ingredient, botulinum toxin type A2.
Cnorth/CIIent Docs/SCRAS/47984.GBO I. Spec 15 Moreover, the invention relates to the use of botulinum toxin type A2 for the preparation of a medicament intended to treat the diseases / conditions / syndromes mentioned previously (i.e. for the pharmaceutical compositions mentioned in the other aspect of the invention).
It also relates to a method of treating cosmetic disorders selected from the group consisting of: : skin defects; facial asymmetry; : wrinkles selected from glabellar frown lines and facial wrinkles; lo downturned mouth; and hair loss; said method comprising the administration of botulinum toxin type A2 to the area affected by the cosmetic disorder.
The preferences indicated for the therapeutic and cosmetic indications for the botulinum toxin pharmaceutical compositions mentioned in the other aspect of the invention apply mutatis mutandis to the uses of botulinum toxin type A2. .... :.
The term "about" refers to an interval around the considered value. As used in this A..
patent application, "about X" means an interval from X minus 10% of X to X plus 1 09/.0 of X, and preferably an interval from X minus 5% of X to X plus 5% of X. -:.
Unless they are defined differently, all the technical and scientific terms used here have the same meaning as that usually understood by an ordinary specialist in the field to which this invention belongs. Similarly, all publications, patent applications, all patents:.
and all other references mentioned here are incorporated by way of reference.
The following examples are presented to illustrate the above and must in no case be considered as a limit to the scope of the invention.
Cnorth/ClientDocs/SCRAS/47984.GBOl.Spec 16
EXAMPLES
Example 1:
A liquid pharmaceutical composition containing the following components is prepared: Clostridium botulinum type Al neurotoxin complex 2,000 LD50 units/ml Sucrose 11.7 mM Histidine 10 mM Sodium chloride 0.3 M Polysorbate 80 0.01 % v/v pH 6.5 The mixture containing nominally 2,000 LD50 units of botulinum toxin per ml is s Iyophilised in a sterilised vial which is then sealed. The solid composition obtained is stable for at least 12 months when stored at a temperature between 2 and C and at least 6 months at 23 to 27 C.
Example 2: . . Be..
A liquid pharmaceutical composition containing the following components is prepared' A.. .
l Clostridium botulinum type Al neurotoxin complex 500 LD50 units/ml.....
Sucrose 11.7 mM:. ..
Histidine l O mM Sodium chloride 0.3 M.... .
Polysorbate 80 0.01% v/v.. :: pH 6.5.. . lo The liquid composition thus prepared is sealed in a syringe type device with no liquid/gaseous interface. Stored in these conditions, it is stable for at least one month at 23 to 27 C and at least six months at 2-S C.
Cnorth/Client Docs/SCRAS/47984.GBO 1. Spec 17
Example 3:
A liquid pharmaceutical composition containing the following components is prepared: Clostridium botulinum type Al neurotoxin complex 500 LDso units/ml Sucrose 11.7 mM Histidine 10 mM Sodium chloride 0.15 M Polysorbate 80 0.01 /0 v/v pH 6.5 The liquid composition composition thus prepared is sealed in a syringe type device with no liquid/gaseous interface. Stored in these conditions, it is stable for at least one month at 23 to 27 C and at least six months at 2-S C.
Example 4:
A liquid pharmaceutical composition containing the following components is prepared: - ë Clostridium botulinum type A2 neurotoxin complex 500 LD50 units/ml. . Sucrose 1 1.7 mM A.: Histidine 10 mM Sodium chloride 0.15 M.....
Polysorbate 80 0.01% v/v. .
pH 6.5 ... .e
The liquid composition composition thus prepared is sealed in a syringe type devices: with no liquid/gaseous interface.
lo Example 5:
A patient in his fifties suffers from cervical dystonia. He receives by intramuscular injection the liquid pharmaceutical composition of Example 4 (I ml; 500 LDso units) is injected, the total dose being divided into the most active muscles of his neck. Relief of his symptoms is observed for more than 20 weeks.
Cnorth/Client Docs/SCRAS/47984.GBO 1.Spec I
ANALYTICAL METHODS
Mouse toxicity assay A mouse toxicity assay can be used to measure the toxicity of botulinum neurotoxin complex (type A, B. C, D, E, F or G) or high purity botulinum neurotoxin (type A, B. C, D, E, F or G). In the assay, a standard diluent will be used to prepare a range of dilutions at or about the estimated LD50 value. The range and scale of dilutions is arranged so as to establish an accurate LD50 value.
Mice are injected intraperitoneally with a known and standardised volume of diluted toxin. After 96 hours, the number of deaths and survivors in each dilution group will be lo recorded. The LD5, value is the median dose which kills half of the injected animals within 96 hours.
A composition according to the invention is considered stable over a certain period of time if at least 70% of the initial toxicity is maintained over said period of time relative to a reference preparation. ë
PHAR1VIACOLOGICAL STUDY.
Intramuscular safety margin assay.
For determination of intramuscular LD50, CDI mice are randomly assigned to group. . containing 8 animals each. The gastrocnemius muscle of the left leg is injected with formulated botulinum toxin in 0.1 ml gelatine phosphate buffer. Groups receive equimolar amounts of either botulinum type A2 toxin or type Al toxin, each group: receiving one of a range of doses. The i.m. LD50 is calculated (Spearmann-Karber analysis) as the dose at which 50% of the mice died following i.m. injection.
For determination of half maximal muscle weakness (ED50), the Digit Abduction Scoring assay (DAS) assay is used (Aoki KR, Toxicon (2001), 39, 1815-]820). CD1 2s mice are assigned randomly into groups of 10 each. The gastrocnemius muscle of the left leg is injected with formulated botulinum toxin in 0.1 ml gelatine phosphate buffer.
Groups receive equimolar amounts of either botulinum type A2 toxin or botulinum typeA1 toxin, each group receiving one of a range of doses. After a fixed period following injection, mice are briefly suspended by the tail to generate digit abduction as part of the characteristic startle response in this position. The abduction of the digits of the limb injected is scored on a scale of 0 to 4, where 0 is normal abduction and 4 is the Cnorth/Client Docs/SCRAS/47984.GBOl.Spec I 9 maximal reduction in abduction of the digits and extension of the limb. ED50 was calculated as the dose resulting in a digit abduction score of 2.
Measurement of intramuscular LD50 to intramuscular EDso ratio from results obtained using these two methods shows that intramuscular safety margin of muscle weaking produced by botulinum type A2 toxin is greater when compared to onset of paralysis of muscles induced by botulinum type Al toxin.
- .... .
ace.. ë e. - . A.
Cnorth/Client Docs/SCRAS/47984.GB0 1. Spec 20
Claims (14)
- Claims 1. A solid or liquid pharmaceutical composition comprising: (a)botulinum neurotoxin complex (type A, B. C, D, E, F or G) or high purity botulinum neurotoxin (type A, B. C, D, E, F or G), and s (b) a surfactant,
- 2. A solid or liquid pharmaceutical composition according to claim I further comprising a crystalline agent.
- 3. A solid or liquid pharmaceutical composition according to claim 2 wherein the crystalline agent is sodium chloride.lo
- 4. A solid or liquid pharmaceutical composition according to one of claims l to 3 further comprising a buffer to maintain pH between 5.5 to 7. 5.
- 5. A solid or liquid pharmaceutical composition according claim 4 wherein the buffer is maintaining a pH from 5.8 to 7.0. ^ ^
- 6. A solid or liquid pharmaceutical composition according to any of claims I to 5 .further comprising a disaccharide. ... :.
- 7. A solid or liquid pharmaceutical composition according to claim 6 wherein thy '..' disaccharide is chosen from the group consisting of sucrose, trehalose, lactose and....mannitol. 'a.... e
- 8. A solid or liquid pharmaceutical composition according to any of claims I to 7 which contains botulinum neurotoxin complex type A.
- 9. A pharmaceutical composition according to any of claims l to 7 which contains high purity botulinum neurotoxin type A.
- 10. A pharmaceutical composition according to any of claims I to 9 in which the surfactant is polysorbate 80.
- 11. As a medicament, botulinum toxin type A2.
- 12. Pharmaceutical composition comprising, as active principle, botulinum toxin type A2.Cnorth/Client Docs/SCRAS/47984.GBO 1. Spec 21
- 13. Use of botulinum toxin type A2 for the manufacture of a medicament intended to treat a disease / a condition / a syndrome chosen from the following: ophtalmological disorders, movement disorders, otorhinolaryngological disorders, gastrointestinal disorders, urogenital disorders, dermatological disorders, pain disorders, inflammatory disorders, secretory disorders, respiratory disorders, hypertrophic disorders, articular disorders, endocrine disorders, autoimmune diseases, proliferative diseases, traumatic injuries and veterinary disorders.
- 14. Use of botulinum toxin type A2 for treating cosmetic disorders selected from the group consisting of: lo skin defects; : facial asymmetry; : wrinkles selected from glabellar frown lines and facial wrinkles; : downturned mouth; and : hair loss; said method comprising the administration of botulinum toxin type A2 to the area affected by the cosmetic disorder. A. . . @- . a. seeCnorth/Client Docs/SCRAS/47984.GBOl.Spec 22
Priority Applications (21)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0421288A GB2418358A (en) | 2004-09-24 | 2004-09-24 | Pharmaceutical composition comprising botulinum neurotoxin |
| ES05767871.6T ES2526912T3 (en) | 2004-08-04 | 2005-08-03 | Pharmaceutical composition containing botulinum neurotoxin A2 |
| US11/659,449 US20080102090A1 (en) | 2004-08-04 | 2005-08-03 | Pharmaceutical Compositon Containing Botulinum Neurotoxin A2 |
| PL14180875T PL2813239T3 (en) | 2004-08-04 | 2005-08-03 | Pharmaceutical composition containing botulinum neurotoxin A2 |
| ES05767945.8T ES2526913T3 (en) | 2004-08-04 | 2005-08-03 | Pharmaceutical composition containing botulinum neurotoxin 2 |
| HUE14180875A HUE032950T2 (en) | 2004-08-04 | 2005-08-03 | Pharmaceutical composition containing botulinum neurotoxin A2 |
| EP17161071.0A EP3210620A1 (en) | 2004-08-04 | 2005-08-03 | Pharmaceutical composition containing botulinum neurotoxin a2 |
| PT141808758T PT2813239T (en) | 2004-08-04 | 2005-08-03 | Pharmaceutical composition containing botulinum neurotoxin a2 |
| US11/659,448 US20080069841A1 (en) | 2004-08-04 | 2005-08-03 | Pharmaceutical Compositions Containing Botulinum Neurotoxin A2 |
| EP14180875.8A EP2813239B1 (en) | 2004-08-04 | 2005-08-03 | Pharmaceutical composition containing botulinum neurotoxin A2 |
| EP05767871.6A EP1776137B1 (en) | 2004-08-04 | 2005-08-03 | Pharmaceutical composition containing botulinum neurotoxin a2 |
| PCT/GB2005/003057 WO2006013370A1 (en) | 2004-08-04 | 2005-08-03 | Pharmaceutical composition containing botulinum neurotoxin a2 |
| PT57678716T PT1776137E (en) | 2004-08-04 | 2005-08-03 | Pharmaceutical composition containing botulinum neurotoxin a2 |
| ES14180875.8T ES2627627T3 (en) | 2004-08-04 | 2005-08-03 | Pharmaceutical composition containing botulinum neurotoxin A2 |
| EP05767945.8A EP1778279B1 (en) | 2004-08-04 | 2005-08-03 | Pharmaceutical composition containing botulinum neurotoxin a2 |
| DK14180875.8T DK2813239T3 (en) | 2004-08-04 | 2005-08-03 | Pharmaceutical composition containing botulinum neurotoxin A2 |
| TR2017/08749T TR201708749T4 (en) | 2004-08-04 | 2005-08-03 | PHARMACEUTICAL COMPOSITION CONTAINING BOTULINUM NEUROTOXIN A2 |
| PCT/GB2005/003036 WO2006013357A1 (en) | 2004-08-04 | 2005-08-03 | Pharmaceutical composition containing botulinum neurotoxin a2 |
| DK05767871.6T DK1776137T3 (en) | 2004-08-04 | 2005-08-03 | A pharmaceutical composition comprising botulinum neurotoxin A2 |
| PL05767871T PL1776137T3 (en) | 2004-08-04 | 2005-08-03 | Pharmaceutical composition containing botulinum neurotoxin a2 |
| US12/748,733 US20100184689A1 (en) | 2004-08-04 | 2010-03-29 | Pharmaceutical Composition Containing Botulinum Neurotoxin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0421288A GB2418358A (en) | 2004-09-24 | 2004-09-24 | Pharmaceutical composition comprising botulinum neurotoxin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB0421288D0 GB0421288D0 (en) | 2004-10-27 |
| GB2418358A true GB2418358A (en) | 2006-03-29 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB0421288A Withdrawn GB2418358A (en) | 2004-08-04 | 2004-09-24 | Pharmaceutical composition comprising botulinum neurotoxin |
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| GB (1) | GB2418358A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10201594B2 (en) | 2012-10-28 | 2019-02-12 | Revance Therapeutics, Inc. | Compositions and methods for safe treatment of rhinitis |
| US11484580B2 (en) | 2014-07-18 | 2022-11-01 | Revance Therapeutics, Inc. | Topical ocular preparation of botulinum toxin for use in ocular surface disease |
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|---|---|---|---|---|
| WO1999037326A1 (en) * | 1998-01-26 | 1999-07-29 | University Of Massachusetts | Biologically active hemagglutinin from type a clostridium botulinum and methods of use |
| US20020197278A1 (en) * | 2001-06-21 | 2002-12-26 | Surromed, Inc. | Covalent coupling of botulinum toxin with polyethylene glycol |
| US20030138437A1 (en) * | 2000-02-08 | 2003-07-24 | Allergan, Inc. | Reduced toxicity clostridial toxin pharmaceutical compositions |
| US20040033241A1 (en) * | 2000-06-02 | 2004-02-19 | Allergan, Inc. | Controlled release botulinum toxin system |
| WO2004019905A1 (en) * | 2002-08-29 | 2004-03-11 | Novadel Pharma Inc. | Buccal, polar and non-polar spray or capsule containing drugs for treating muscular and skeletal disorders |
-
2004
- 2004-09-24 GB GB0421288A patent/GB2418358A/en not_active Withdrawn
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999037326A1 (en) * | 1998-01-26 | 1999-07-29 | University Of Massachusetts | Biologically active hemagglutinin from type a clostridium botulinum and methods of use |
| US20030138437A1 (en) * | 2000-02-08 | 2003-07-24 | Allergan, Inc. | Reduced toxicity clostridial toxin pharmaceutical compositions |
| US20040033241A1 (en) * | 2000-06-02 | 2004-02-19 | Allergan, Inc. | Controlled release botulinum toxin system |
| US20020197278A1 (en) * | 2001-06-21 | 2002-12-26 | Surromed, Inc. | Covalent coupling of botulinum toxin with polyethylene glycol |
| WO2004019905A1 (en) * | 2002-08-29 | 2004-03-11 | Novadel Pharma Inc. | Buccal, polar and non-polar spray or capsule containing drugs for treating muscular and skeletal disorders |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10201594B2 (en) | 2012-10-28 | 2019-02-12 | Revance Therapeutics, Inc. | Compositions and methods for safe treatment of rhinitis |
| US11484580B2 (en) | 2014-07-18 | 2022-11-01 | Revance Therapeutics, Inc. | Topical ocular preparation of botulinum toxin for use in ocular surface disease |
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| GB0421288D0 (en) | 2004-10-27 |
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