WO2009008595A1 - Pharmaceutical liquid composition of botulinum toxin with improved stability - Google Patents
Pharmaceutical liquid composition of botulinum toxin with improved stability Download PDFInfo
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- WO2009008595A1 WO2009008595A1 PCT/KR2008/002975 KR2008002975W WO2009008595A1 WO 2009008595 A1 WO2009008595 A1 WO 2009008595A1 KR 2008002975 W KR2008002975 W KR 2008002975W WO 2009008595 A1 WO2009008595 A1 WO 2009008595A1
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- botulinum toxin
- pharmaceutical composition
- liquid pharmaceutical
- polysorbate
- methionine
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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
- 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
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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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
-
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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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
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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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
-
- 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
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
- A61K8/447—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof containing sulfur
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4993—Derivatives containing from 2 to 10 oxyalkylene groups
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
- A61K8/66—Enzymes
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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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q15/00—Anti-perspirants or body deodorants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/52—Stabilizers
Definitions
- the present invention relates, in general, to a more stable liquid pharmaceutical botulinum toxin composition and, more particularly, to a liquid pharmaceutical composition, comprising a botulinum toxin in combination with polysorbate 20 and methionine and optionally isoleucine.
- Botulinum toxin is a neurotoxin protein produced by the bacterium Clostridium botulinum. This toxin blocks the presynaptic release of acetylcholine at the neuromuscular junction, causing flaccid (sagging) paralysis of muscles in mammals.
- the toxin has proven to be effective for treating strabismus, idiopathic blepharospasm and hemifacial spasm.
- it has recently been found to provide relief for a number of motor disturbances of involuntary muscles, including spasmodic torticollis, oro- mandibular dystonia, and spasmodic dyphonia.
- botulinum toxin received FDA approval for temporary improvement in the facial appearance of moderate-to- severe frown lines and for the non-surgical treatment of hyperhidrosis (excessive underarm sweating).
- botulinum toxin proteins serotype A and B are now formulated into dosage forms for use in medical applications such as the treatment of torticollis, blepharospasm, hyperhidrosis, etc. as well as in cosmetic applications such as wrinkle reduction.
- Protein drugs, including botulinum toxin proteins suffer from many problems during the preparation thereof. The problems, most of which are attributed to protein instability, are particularly pronounced for the protein drugs which are formulated with very low concentrations of active proteins, such as botulinum toxins.
- Albumin is selected in most cases for use as a stabilizer in the formulation of botulinum toxin. In addition to stabilizing the active protein ingredients in pharmaceutical compositions, albumin enjoys the advantage of showing negligible im- munogenicity even when injected into the body. However, serum products such as albumin are not completely free from the possibility of being contaminated with pathogens or microorganisms and thus acting as mediators of disease, particularly viral diseases or Creutzfeldt- Jakob disease.
- gelatin is employed in place of albumin.
- Gelatin is recommended not to be used as a stabilizer for drug formulation because this protein, similarly to albumin, is also obtained from animals and may mediate diseases.
- a stabilizer derived from non-animal sources is provided for the pharmaceutical formulation of botulinum toxin by Korean Patent No. 10-0799400 in whichre- combinant serum albumin (rSA), produced in yeast, is applied for pharmaceutical formulation.
- rSA re- combinant serum albumin
- complete avoidance cannot be provided to the possibility that a neoepitope, a new antigenic structure, may be generated in the course of the production, isolation and recovery of recombinant serum albumin (rSA), eliciting an immune response from the recipient of the drug.
- 10-0665469 discloses a pharmaceuticalcomposition comprising a botulinum toxin, polysaccharides (including hydroxyethyl starch) and an amino acid such as lysine, glycine, histidine or arginine.
- This pharmaceutical composition is provided in a dosage form prepared by lyophylization and must unfortunately be stored at low-temperature in a refrigerator or freezer. The requirement that the lyophilized bolulinum toxin be thawed or diluted just before use may cause an error in the protein.
- lyophilized botulinum toxins are difficult to develop into a pre-filled syringe administration type.
- the composition comprises a non-ionic detergent, preferably polysorbate, and a combination of either glutamine and glutamic acid or asparagine and aspartic acid.
- a dilution of botulinum toxin in the liquid composition was observed to be stable for 8 months when stored at 4 0 C.
- the composition has limited use for the stabilization of protein agents, such as botulinum toxin, in pharmaceuticals to be stored at room temperature. This deficit is, in the opinion of the present inventors, attributed to the presence of the polar amino acids and particularly the acidic amino acids such as glutamic acid or aspartic acid. Disclosure of Invention Technical Problem
- an object of the present invention is to provide apharmaceutical composition which can maintain the activity of botulinum toxin even after being stored for a long period of time at room temperature as well as at a refrigerated temperature and is in a liquid form more convenient for use than a lyophilized form.
- animal-derived protein such as albumin or gelatin
- a liquid pharmaceutical composition comprising botulinum toxin, polysorbate 20, and methionine.
- liquid pharmaceutical composition comprising botulinum toxin, polysorbate 20, methionine and isoleucine.
- the methionine is present in an amount of
- 0.5 to 100 ⁇ mol per 100 units of botulinum toxin and preferably ranges in concentration from 0.5 to 100 mM and more preferably from 25 to 75 mM.
- polysorbate 20 is present in an amount of 0.01 to 50 mg per 100 units of botulinum toxinand preferably ranges in concentration from 0.01 to 50 mg/mL and more preferably form 0.1 to 2.5 mg/mL.
- the botulinum toxin is selected from a group consisting of botulinum toxin serotypes A, B, C, D, E, F, and G and may be in a non-complex form or in a complex form with a protein.
- the botulinum toxin ranges in concentration from 50 to 5,000 units/ mL.
- the liquid pharmaceutical composition according to the present invention preferably ranges in pH from 5.5 to 7.0.
- the liquid pharmaceuticalcomposition according to the present invention eliminates the risk of contaminating the body with serum-derived pathogens or microorganisms and can be administered safely.
- the liquid pharmaceutical composition of the present invention can be convenient for use as a direct injection for patients.
- the liquid pharmaceutical composition of the present invention is very useful for storing botulinum toxin under an emergency condition such as an environment without maintaining low temperature, thus being superior to conventional liquid pharmaceutical compositions employing either detergents or amino acids.
- liquid pharmaceutical composition of the present invention can be readily prepared because it employs a detergent and an amino acid(s) without a lyophilization process.
- a liquid pharmaceutical composition with improvement in botulinum stability is provided in accordance with the present invention.
- the liquid pharmaceutical composition comprises a botulinum toxin, polysorbate 20 and methionine and optionally isoleucine.
- the liquid pharmaceutical composition comprising a botulinum toxin, polysorbate 20 and methionine, or alternatively, a botulinum toxin, polysorbate 20, methionine and isoleucine in accordance with the present invention is much improved in botulinum toxin stability.
- the liquid pharmaceutical composition of the present invention excludes the potential risk of infecting the recipient with serum-derived pathogens or microorganisms and is thus safe for ingestion into the body.
- the use of the stabilizers polysorbate 20, methionine and optionally isoleucine in combination guarantees higher stability to botulinum toxin at 25 ⁇ 27°C than does the use of them in a separate manner.
- the botulinum toxin may be one selected from among serotypes A, B, C, D, E, F and G.
- the term botulinum toxin is a generic term embracing the family of toxins produced by the anaerobic bacterium Clostridium botulinum and, to date, seven immunologically distinct neurotoxins serotypes have been identified. These have been given the designationsA, B, C, D, E, F and G, which differ one from theother in their effects on target animals, and paralysis extent and duration. All serotypes of botulinum toxin are known to act as a neurotoxin by inhibiting the neurotransmitter acetylcholine at neuromuscular junctions.
- the botulinum toxin of the liquid pharmaceutical composition according to the present invention may be in a non-complex form or in a complex form with another protein.
- Botulinum toxin serotype A, B, C, D, E, F or G alone, synthesized by Clostridium botulinum, itself has a molecular weight of approximately 150 kDa.
- the botulinum toxin forms various complexes with hemagglutinin proteins and non-hemagglutinin proteins which aid and protect the activity thereof.
- Naturally occurring botulinum type A complexes have a molecular weight of approximately 900 kDa, 500 kDa or 300 kDa.
- Molecular weights are measured to be approximately 500 kDa for botulinum toxin type B complexes and type C complexes, approximately 300 kDa or 500 kDa for type D complexes, and approximately 300 kDa for type E and type F complexes.
- the concentration of the botulinum toxin in the liquid pharmaceutical composition of the present invention preferably ranges from 50 to 5,000 units/mL depending on the general use thereof.
- Methionine is present in an amount from 0.5 to 100 ⁇ mol per 100 units of botulinum toxin,and preferably ranges in concentration from 0.5 to 100 mM and more preferably from 25 to 75 mM in the liquid pharmaceutical composition of the present invention.
- One unit (U) of botulinum toxin is defined as the LD upon intraperitoneal injection into female Swiss Webster mice weighing 18 - 20 grams each.
- 50 toxin in mice corresponds to about 50 picograms.
- methionine properly ranges in concentration from 0.5 to 100 mM when the botulinum toxin has a concentration of 100 units/mL. Its proper concentration is adjusted to 25 ⁇ 75 mM in consideration of the concentration range of polysorbate 20.
- polysorbate 20 is present in an amount of 0.01 to 50 mg per 100 units of botulinum toxin and preferably ranges in concentration from 0.01 to 50 mg/mL and more preferably form 0.1 to 2.5 mg/mL.
- Polysorbates are a class of emulsifiers used in some pharmaceuticals and in food preparation. They are often used in cosmetics to dissolve essential oils into water- based (oil-in-water) products. There are many kinds of polysorbatesthat are classified by a number referring to the total number of oxy ethylene groups, such as polysorbate 20, 40, 60 and 80.
- the liquid pharmaceutical composition of the present invention employs polysorbate 20 (commercially available as brand name Tween 20) as a stabilizer for bolulinum toxin.
- the liquid pharmaceutical composition of the present invention contains polysorbate 20 in an amount less than 0.01 mg per 100 units of botulinum toxin, its long-term stabilization effect on botulinum toxin at room temperature does not reach a desirable level. On the other hand, a polysorbate 20 concentration exceeding 50 mg/ mL does not provide any additional effect in addition to incurring an economic disadvantage. At a concentration of 100 units/mL of botulinum toxin in the liquid pharmaceutical composition of the present invention, polysorbate 20 is properly present in an amount of 0.01-50 mg/mL and preferably in an amount of 0.1-2.5 mg/mL when the methionine concentration is taken into consideration.
- the concentration of polysorbate 20 in the liquid pharmaceutical composition of the present invention is less than 0.1 mg/mL, its long-term stabilization effect on botulinum toxin at room temperature does not reach a desired level, which is obtainable by the target concentration of polysorbate 20.
- a polysorbate 20 concentration exceeding 2.5 mg/mL does not provide any additional effect.
- the liquid pharmaceutical composition has a pH of 5.5 - 7.0.
- the liquid pharmaceutical composition of the present invention adjusted to a pH of 5.5 - 7.0, botulinum toxin is stably maintained at room temperature (particularly 40 0 C) for a long period of time.
- a botulinum toxin was diluted to a final concentration of 100 units/mL in a stabilizing solution.
- liquid botulinum toxin compositions containing Various candidates of botulinum toxin stabilizer were prepared and analyzed for botulinum toxin stability over time during storage at 25 0 C or 37°C. Results of the stability experiments at 25 0 C and 37 0 C are summarized in Tables 1 and 2, respectively.
- HSA stands for human serum albumin
- PEG8000 represents polyethylene glycol 8000.
- the liquid composition comprising L-methione(20mM)+polysorbate 20(2mg/mL)+botulinum toxin(100 units/mL) or HSA(5mg/mL)+polysorbate 20(2mg/mL)+botulinum toxin(100 units/mL) was found to maintain the activity of botulinum toxin for a long period of time as seen in Table 2.
- the activity of botulinum toxin was stably maintained for 56 days at a methionine concentration of 0.5-20 mM and for 70 days at a methionine concentration of 50-100 mM.
- the composition employing both methionine and polysorbate 20 greatly improved the stability of botulinum toxin as compared with the composition employing polysorbate 20 alone.
- the activity of botulinum toxin was stably maintained for 202 days at a polysorbate 20 concentrations of 0.5-2.0 mg/mL, for 167 days at a polysorbate 20 concentration of 0.01 mg/mL and for 120 days at a polysorbate 20 concentration of 10 mg/mL.
- the composition employing both methionine and polysorbate 20 was greatly improved in the stability of botulinum toxin as compared with the composition employing methionine alone.
- Liquid botulinum toxin compositions comprising various concentrations of a combination of methionine and polysorbate 20 as botulinum toxin stabilizers were assayed for their ability to maintain the activity of botulinum toxin under a 37 0 C storage condition.
- the experimental results (mortality rate, %)of the stability of botulinum toxin after storage for 30 and 60 days at various concentrations of methionine and polysorbate 20 (Example 12) are summarized in Tables 5 and 6, respectively.
- botulinum toxin had a concentration of 100 units/mL.
- the liquid pharmaceutical botulinum toxincomposition according to the present invention shows greatly improved botulinum toxin stability. It is useful in the treatment of dystonia, stiff muscle spasm,neurological disorders (migraine, lumbago, cervical spinal disorder, etc.) as well as in the cosmetic application for hyperhidrosis treatment and wrinkle reduction.
- the liquid pharmaceutical botulinum toxin composition of the present invention may be directly used as an injection and guarantees the activity of botulinum toxin for a long period of time even at 25 ⁇ 37 0 C as well as at a refrigerated temperature, which is very advantageous for transportation and sale.
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Abstract
Description
Claims
Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BRPI0813948A BRPI0813948B8 (en) | 2007-07-10 | 2008-05-28 | pharmaceutical liquid botulinum toxin composition with improved stability |
CN2008800230010A CN101687046B (en) | 2007-07-10 | 2008-05-28 | Pharmaceutical liquid composition of botulinum toxin with improved stability |
ES08765945T ES2391798T3 (en) | 2007-07-10 | 2008-05-28 | Botulinum toxin pharmaceutical liquid composition with improved stability |
EP08765945A EP2170400B1 (en) | 2007-07-10 | 2008-05-28 | Pharmaceutical liquid composition of botulinum toxin with improved stability |
JP2010515962A JP5259710B2 (en) | 2007-07-10 | 2008-05-28 | Pharmaceutical liquid composition with improved stability of botulinum toxin |
CA2690773A CA2690773C (en) | 2007-07-10 | 2008-05-28 | Pharmaceutical liquid composition of botulinum toxin with improved stability |
US12/666,592 US8617568B2 (en) | 2007-07-10 | 2008-05-28 | Pharmaceutical liquid composition of botulinum toxin with improved stability |
US14/088,821 US9220780B2 (en) | 2007-07-10 | 2013-11-25 | Pharmaceutical liquid composition of botulinum toxin with improved stability |
US14/980,285 US10293034B2 (en) | 2007-07-10 | 2015-12-28 | Pharmaceutical liquid composition of botulinum toxin with improved stability and method of use |
US16/416,758 US20190298813A1 (en) | 2007-07-10 | 2019-05-20 | Pharmaceutical liquid composition of botulinum toxin with improved stability |
US17/326,797 US20210379165A1 (en) | 2007-07-10 | 2021-05-21 | Pharmaceutical liquid composition of botulinum toxin with improved stability |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR20070069363 | 2007-07-10 | ||
KR10-2007-0069363 | 2007-07-10 |
Related Child Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/666,592 A-371-Of-International US8617568B2 (en) | 2007-07-10 | 2008-05-28 | Pharmaceutical liquid composition of botulinum toxin with improved stability |
US12/666,595 A-371-Of-International US20110021468A1 (en) | 2007-07-03 | 2008-07-03 | Treatment of cardiovascular disease with salicylates |
US66659210A A-371-Of-International | 2007-07-10 | 2010-07-27 | |
US14/088,821 Continuation US9220780B2 (en) | 2007-07-10 | 2013-11-25 | Pharmaceutical liquid composition of botulinum toxin with improved stability |
Publications (1)
Publication Number | Publication Date |
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WO2009008595A1 true WO2009008595A1 (en) | 2009-01-15 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/KR2008/002975 WO2009008595A1 (en) | 2007-07-10 | 2008-05-28 | Pharmaceutical liquid composition of botulinum toxin with improved stability |
Country Status (10)
Country | Link |
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US (5) | US8617568B2 (en) |
EP (1) | EP2170400B1 (en) |
JP (1) | JP5259710B2 (en) |
KR (1) | KR101087017B1 (en) |
CN (1) | CN101687046B (en) |
BR (1) | BRPI0813948B8 (en) |
CA (1) | CA2690773C (en) |
ES (1) | ES2391798T3 (en) |
RU (1) | RU2440825C2 (en) |
WO (1) | WO2009008595A1 (en) |
Cited By (13)
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US8617568B2 (en) | 2013-12-31 |
CA2690773C (en) | 2013-09-17 |
US20160206710A1 (en) | 2016-07-21 |
US20210379165A1 (en) | 2021-12-09 |
US20190298813A1 (en) | 2019-10-03 |
KR101087017B1 (en) | 2011-12-09 |
EP2170400A4 (en) | 2010-09-08 |
RU2440825C2 (en) | 2012-01-27 |
EP2170400B1 (en) | 2012-07-25 |
ES2391798T3 (en) | 2012-11-30 |
US9220780B2 (en) | 2015-12-29 |
US10293034B2 (en) | 2019-05-21 |
BRPI0813948B1 (en) | 2019-08-06 |
KR20090005963A (en) | 2009-01-14 |
JP2010532784A (en) | 2010-10-14 |
CN101687046A (en) | 2010-03-31 |
CA2690773A1 (en) | 2009-01-15 |
US20100291136A1 (en) | 2010-11-18 |
US20140161783A1 (en) | 2014-06-12 |
CN101687046B (en) | 2012-12-26 |
EP2170400A1 (en) | 2010-04-07 |
BRPI0813948A2 (en) | 2016-06-28 |
RU2009148286A (en) | 2011-06-27 |
JP5259710B2 (en) | 2013-08-07 |
BRPI0813948B8 (en) | 2021-05-25 |
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