Classifications

• • 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
• • 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
  • 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)
• • 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
  • A61K47/02—Inorganic compounds
• • 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
• • 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
• • 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
  • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
• • 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
  • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
  • A61K8/27—Zinc; Compounds 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
  • A61K8/40—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
• • 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
  • 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
  • A61K2800/51—Chelating agents
• • 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

Definitions

• the improved light stability of the liquid botulinum toxin formulation of the present invention simplifies the manufacturing process, allows the product to be filled and packaged without extensive light protection, and reduces potential loss of activity due to light-exposed storage at the physician's place prior to use. Overall, the reduced sensitivity of the liquid formulation of the present invention generally improves handleability and ease of use of botulinum toxin during injection treatments.
• liquid formulation generally refers to an aqueous formulation and is typically an aqueous solution.
• liquid formulation may be interchangeably used with “liquid composition”.
• the liquid formulation is a pharmaceutically acceptable liquid formulation.
• pharmaceutically acceptable means that the liquid formulation does not cause unacceptable adverse side effects when administered to a human patient or subject, i.e., it means that the liquid formulation is suitable for human use.
• the term "pure botulinum neurotoxin”, as used herein, means the botulinum neurotoxin free of complexing proteins (sometimes also referred to as the "neurotoxic component"), or more precisely, the botulinum neurotoxin without neurotoxin- associated complexing proteins (NAPs).
• the pure botulinum neurotoxin is the (active) neurotoxic polypeptide that ultimately inhibits acetylcholine release. It is a di-chain protein comprised of a light chain (LC; about 50 kDa) and a heavy chain (HC; about 100 kDa), held together by a disulfide bond.
• the active neurotoxic polypeptide may therefore also be referred to herein as the "150 kDa neurotoxin", “Clostridium botulinum neurotoxin (150 kD)” or "neurotoxic component”.
• the LD50 mouse bioassay is the gold standard among various biological, chemical or immunological detection methods for botulinum toxin and is known to those skilled in the art (see, e.g., Pearce, L. B.; Borodic, G. E.; First, E. R.; MacCallum, R. D. Measurement of botulinum toxin activity: Evaluation of the lethality assay. Toxicol. Appl. Pharmacol. 1994, 128:69-77). A person skilled in the art will be able to determine suitable botulinum toxin concentrations depending on the serotype and the intended use.
• a cell-based assay can be used to determine botulinum toxin activity, as described in WO 2009/114748, WO 2013/049508 or WO201 4/207109.
• a person skilled in the art will be able to correlate botulinum toxin activity results obtained with a cell-based assay with results obtained in the mouse LD50 assay by calibration using a LD50 reference standard.
• the stabilizing protein may be, for example, human serum albumin (HSA), ovalbumin, casein, or a mixture thereof. Particularly preferred for use herein is human serum albumin, ovalbumin, or a mixture thereof, and most preferred is HSA.
• HSA human serum albumin
• human serum albumin or "HSA” is intended to refer to donor HSA (HSA derived from human blood or, more precisely, from human plasma), recombinant HSA and/or HSA from any other source.
• the human serum albumin is recombinant HSA or HSA derived from human blood.
• aminopolycarboxylic acids include NTA (nitrilotriacetate), DOTA (1 ,4,7,10-tetraazacyclododecan-1 ,4,7,10- tetraacetate), TED (ethylenediaminotriacetate), EDTA (ethylenediaminetetraacetic acid), EGTA (ethylene glycol-bis(p-aminoethylether)-A/ ; A/ ; A/(A/'-tetraacetic acid), BAPTA (1 ,2-bis(o-aminophenoxy)ethane-A/,A/,A/',A/'-tetraacetic acid), DTPA (diethylenetriaminepenta-acetic acid), and TTHA (triethylenetetraminehexaacetate).
• NTA nitrilotriacetate
• DOTA 1,4,7,10-tetraazacyclododecan-1 ,4,7,10- tetraacetate
• phosphate may be used in the liquid formulation of the present invention to achieve a reduced light sensitivity of the formulation. In fact, it was unexpectedly found that also the presence of phosphate results in a markedly increased light stability.
• the phosphate may be present in the liquid formulation at a concentration of at least 0.1 mM or at least 1 mM or at least 5 mM. Preferably, the phosphate is present in the liquid formulation at a concentration of 0.1 -100 mM, preferably 1 -50 mM, more preferably 5-30 mM.
• Exemplary tonicity agents include sucrose, glucose, sodium carbonate, amino acids, polyethyleneglycol (PEG), dextran, cyclodextrin, and colloides (e.g., colloidal polysaccharides).
• concentration of the tonicity agent is in the range of 0-2.0% w/v, in particular 0.01 -2.0% w/v or 0.1 -1.5% w/v, more particularly 0.6- 1 .2% w/v.
• the liquid formulation may optionally further comprise:
• buffering agent means an agent which maintains the pH of the liquid formulation in an acceptable range, i.e., an agent capable of controlling the pH of the formulation.
• Suitable buffers are those that are not chemically reactive with other ingredients and are present in amounts sufficient to provide the desired degree of pH buffering.
• Such buffers include, for example, amino acids, acetate, malic acid, ascorbate, citrate, tartrate, fumarate, succinate, phosphate, bicarbonate, TRIS, Bis-TRIS, ACES, MES, BES, MOPS, HEPES, TES, PIPES, tricine, and imidazole.
• the liquid formulation of the present invention does not contain detergents, particularly does not contain polysorbate, more particularly does not contain polysorbate 20 and/or polysorbate 80.
• the liquid formulation of the present invention does not contain alginate.
• the liquid formulation of the present invention does not contain succinate.
• the liquid formulation of the present invention does not contain one or more (e.g., 2, 3, 4 or 5) amino acids selected from the group consisting of: arginine, glutamic acid, methionine, tryptophane, and serine.
• the liquid formulation of the present invention does not contain a saccharide, such as a mono-, oligo- or polysaccharide or a mixture thereof.
• a preferred liquid formulation of the present invention comprises (i) botulinum toxin, (ii) HSA, (iii) a chelating agent selected from the group consisting of DOTA, TED, EDTA, EGTA, BAPTA, DTPA and TTHA or a chelating agent selected from the group consisting of EDTA, EGTA, BAPTA, DTPA and TTHA, and (iv) a salt of calcium, magnesium or zinc, or a mixture thereof, preferably calcium chloride.
• a preferred liquid formulation of the present invention comprises (i) botulinum toxin, (ii) HSA, (iii) EDTA, and (iv) a salt of calcium, magnesium or zinc, or a mixture thereof, preferably calcium chloride.
• a preferred liquid formulation of the present invention comprises (i) botulinum toxin at a concentration of 10-200 ll/rnl, (ii) HSA in an amount of 0.01 -0.5% w/v, (iii) EDTA at a concentration of 0.05-20 mM, and (iv) a salt of calcium, magnesium or zinc, or a mixture thereof, preferably calcium chloride, at a concentration of 0.05-20 mM.
• a preferred liquid formulation of the present invention comprises (i) botulinum toxin, (ii) HSA, (iii) a chelating agent selected from the group consisting of DOTA, TED, EDTA, EGTA, BAPTA, DTPA and TTHA or a chelating agent selected from the group consisting of EDTA, EGTA, BAPTA, DTPA and TTHA, (iv) a salt of calcium, magnesium or zinc, or a mixture thereof, preferably calcium chloride, and (v) a phosphate buffer and/or histidine.
• the above-described preferred liquid formulations further contain sodium chloride, in particular sodium chloride at a concentration of about 0.9% w/v.
• the pH is preferably in the range of 6.0-7-5.
• the botulinum toxin is preferably of serotype A and is, particularly, the neurotoxic component of serotype A.
• Exemplary preferred liquid formulations of the present invention include the following:
• the present invention relates to a method for stabilizing a liquid botulinum toxin formulation, comprising combining (i) botulinum toxin, (ii) a stabilizing protein, preferably human serum albumin (HSA), (iii) a chelating agent or phosphate, and optionally one or more of components (iv) to (vi), wherein components (i) to (v) are as defined herein.
• a stabilizing protein preferably human serum albumin (HSA)
• HSA human serum albumin
• a chelating agent or phosphate optionally one or more of components (iv) to (vi)
• the present invention relates to a use of phosphate for increasing the light stability of an aqueous botulinum toxin formulation containing (i) botulinum toxin and (ii) a stabilizing protein, preferably human serum albumin, and optionally one or more of components (iv) to (vi), wherein components (i), (ii), and (iv) to (vi) are as defined herein.
• a stabilizing protein preferably human serum albumin
• the liquid formulation of the present invention may be used in the treatment of neuromuscular diseases, pain, sialorrhea, hyperhidrosis, urological disorders, and neurological disorders.
• neuromuscular diseases include dystonia, cervical dystonia, spasm, post-stroke spasticity, blepharospasm, tremor, hyperkinetic movement disorders, and cerebral palsy.
• the urological disorders include, among others, conditions characterized by detrusor overactivity, overactive bladder, neurogenic bladder and interstitial cystitis, treatment of vulvodynia and chronic pelvic pain, benign prostate hyperplasia (BPH) and detrusor sphincter dyssynergia (DSD).
• Exemplary neurological disorders include chronic migraines, trigeminal pain, peripheral neuropathic pain, diabetic neuropathic pain and depression.
• rhytid preferably refers to a mild form of wrinkles and may describe the specific wrinkle in certain locations.
• a “rhytid”, as used herein, has essentially the same meaning of wrinkle.
• a “rhytid” preferably refers to a skin structure that is formed by irregular aggregation of lines.
• a “furrow” is a deep fold or deep line in the skin.
• the disease or condition may be any one of the diseases and conditions mentioned hereinabove, irrespective of whether it is a therapeutic or cosmetic indication.
• the present invention relates to a (non- therapeutic) method of treating a cosmetic (aesthetic) condition, preferably a skin condition, comprising administering an effective amount of the liquid formulation of the present invention to a person in need thereof.
• the present invention relates to a (non-therapeutic) method of treating a cosmetic (aesthetic) condition, preferably a skin condition, comprising injecting an effective amount of the liquid formulation of the present invention into a person in need thereof.
• the person to be treated is not particularly limited other than by having a disease or condition that can be treated in accordance with the present invention. Those skilled in the art will be able to determine appropriate administration regimens for the treatment of a given therapeutic or cosmetic indication.
• the injection may be intradermal, subdermal (subcutaneous), or intramuscular, depending on the disease or condition to be treated.
• neuronal cells were incubated with the neurotoxin containing sample and a reference standard of known potency. After the incubation period, the cells were lyzed and the amount of cleaved SNAP25 protein was determined by an immunoassay. The biological activity of the sample is then calculated by comparing the cleavage rate of the cells treated with the sample with those treated with the reference standard.
• HSA composition A HSA-containing composition
• comparative composition 1 50 ll/ml BoNT/A, 0.015% polysorbate 20, 0.02% methionine, 0.9% NaCI, 0.078% NaH2PO4; pH 6.5
• comparative composition 2 50 ll/ml BoNT/A, 0.01% polysorbate 80, 0.155% histidine, 0.4% saccharose, 0.9% NaCI; pH 6.5.
• One portion of each composition was stored in the dark at 2-8°C and analyzed in the CBA within 7 days ("TO").
• compositions were stored at elevated temperature (40°C) for 2 weeks prior to determining the biological activity.
• the botulinum toxin used in all compositions was the 150 kDa BoNT/A neurotoxin without complexing proteins. The results are shown in Table 1.
• BoNT/A (150 kDa) compositions comprising buffered 0.9% NaCI (pH 6.0) and different concentrations of human serum albumin (0.03-1.0 mg/ml HSA) were prepared and then exposed to light for 7 hours at 250 W/m 2 .
• identical BoNT/A (150 kDa) compositions with different concentrations of HSA (0.03 mg/mL, 0.1 mg/mL, 0.3 mg/mL, and 1 .0 mg/mL) were stored in the dark for the same period of time (control). Thereafter, the biological activity was measured for the compositions exposed to light and the respective control compositions stored in the dark. The relative BoNT/A activity expressed as percentage of the respective control was then calculated as a measure of light stability. The results are shown in Table 3.
• Composition 3 0.085% HSA, 10 mM histidine, 0.9% NaCI, 3,5 mM EDTA, 3.5 mM MgCI 2 , pH 6.0

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Citations (9)

• 2023
  • 2023-02-14 EP EP23704173.6A patent/EP4479012A1/en active Pending
  • 2023-02-14 WO PCT/EP2023/053634 patent/WO2023156385A1/en not_active Ceased
  • 2023-02-14 US US18/838,546 patent/US20250161186A1/en active Pending
  • 2023-02-14 CA CA3243198A patent/CA3243198A1/en active Pending
  • 2023-02-14 AR ARP230100337A patent/AR128515A1/es unknown
  • 2023-02-14 IL IL314995A patent/IL314995A/en unknown
  • 2023-02-14 JP JP2024547665A patent/JP2025504247A/ja active Pending
  • 2023-02-14 AU AU2023222384A patent/AU2023222384A1/en active Pending
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  • 2023-02-14 KR KR1020247030631A patent/KR20240150786A/ko active Pending
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